Treatment of ophthalmic conditions with angiopoietin-like 7 (angptl7) inhibitors

Abstract

To provide methods of treating patients having an ophthalmic disease, methods of identifying a subject having an increased risk of developing an ophthalmic disease, methods of detecting human angiopoietin like 7 (ANGPTL7) variant nucleic acid molecules and variant polypeptides, and ANGPTL7 variant nucleic acid molecules and variant polypeptides.SOLUTION: A method of treating a patient having increased IOP comprises administering an angiopoietin like 7 (ANGPTL7) inhibitor to the patient.SELECTED DRAWING: Figure 6A

Description

[Technical Field]

[0001] Sequence Listing Reference This application contains a Sequence Listing that has been submitted electronically as a text file named 18923801602SEQ, created on January 18, 2020, and is 111 kilobytes in size. The Sequence Listing is incorporated herein by reference.

[0002] The present disclosure generally relates to the treatment of patients with ocular diseases with angiopoietin-like 7 (ANGPTL7) inhibitors, methods for identifying subjects at increased risk for developing ocular diseases, methods for detecting ANGPTL7 mutant nucleic acid molecules and mutant polypeptides, and mutant ANGPTL7 nucleic acid molecules and mutant ANGPTL7 polypeptides. [Background technology]

[0003] Glaucoma is a group of disorders that damage the optic nerve of the eye, potentially resulting in partial vision loss and blindness. Several types of glaucoma exist. In primary open-angle glaucoma, fluid builds up within the eye, increasing pressure inside the eye (intraocular pressure; IOP) to a level that damages the optic nerve. In low- or normal-pressure glaucoma, optic nerve damage and lateral visual field constriction occur in people with normal intraocular pressure. In angle-closure glaucoma, fluid in the anterior segment of the eye cannot drain properly, which can cause a sudden increase in intraocular pressure. In congenital glaucoma, children are born with an eye defect that delays normal fluid drainage. Glaucoma treatments include medication, laser trabeculoplasty, and conventional surgery. While these treatments may preserve residual vision, they do not improve vision already lost to glaucoma.

[0004] ANGPTL7 is a secreted glycoprotein structurally related to the angiopoietin family of growth factors. ANGPTL7 contains a C-terminal (fibrinogen-like) and an N-terminal (coiled) domain. ANGPTL7 is found primarily in the extracellular matrix of the corneal stroma and trabecular meshwork. Summary of the Invention

[0005] The present disclosure provides methods of treating a patient with increased IOP, the methods comprising administering to the patient an ANGPTL7 inhibitor. The present disclosure also provides a method of treating a patient with glaucoma, the method comprising administering to the patient an ANGPTL7 inhibitor.

[0006] In some embodiments, the method further includes detecting the presence or absence of a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encoding a human ANGPTL7 polypeptide in a biological sample from the patient. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a genomic nucleic acid molecule having a nucleotide sequence comprising a thymine at position 4,291 according to SEQ ID NO: 2, an mRNA molecule having a nucleotide sequence comprising a uracil at position 529 according to SEQ ID NO: 5, or a cDNA molecule generated from an mRNA molecule having a nucleotide sequence comprising a thymine at position 529 according to SEQ ID NO: 8. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a genomic nucleic acid molecule having a nucleotide sequence comprising a thymine at position 4,287 according to SEQ ID NO: 3, an mRNA molecule having a nucleotide sequence comprising a uracil at position 525 according to SEQ ID NO: 6, or a cDNA molecule generated from an mRNA molecule having a nucleotide sequence comprising a thymine at position 525 according to SEQ ID NO: 9. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a genomic nucleic acid molecule having a nucleotide sequence that includes an adenine at position 4,243 according to SEQ ID NO: 132, an mRNA molecule having a nucleotide sequence that includes an adenine at position 481 according to SEQ ID NO: 135, or a cDNA molecule generated from an mRNA molecule having a nucleotide sequence that includes an adenine at position 481 according to SEQ ID NO: 138. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a genomic nucleic acid molecule having a nucleotide sequence that includes an adenine at position 4,325 according to SEQ ID NO: 133, an mRNA molecule having a nucleotide sequence that includes an adenine at position 563 according to SEQ ID NO: 136, or a cDNA molecule generated from an mRNA molecule having a nucleotide sequence that includes an adenine at position 563 according to SEQ ID NO: 139.In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a genomic nucleic acid molecule having a nucleotide sequence that includes a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, an mRNA molecule having a nucleotide sequence that includes a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, or a cDNA molecule generated from an mRNA molecule having a nucleotide sequence that includes a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140.

[0007] In some embodiments, the detecting step comprises sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule in the biological sample, the nucleotide sequence of an ANGPTL7 mRNA molecule in the biological sample, or the nucleotide sequence of an ANGPTL7 cDNA molecule in the biological sample.

[0008] In some embodiments, the detecting step comprises contacting the nucleic acid molecule of the biological sample with a mutation-specific probe comprising a detectable label, and detecting the detectable label.

[0009] The present disclosure also provides a method of treating a patient suffering from an ocular disease with a therapeutic agent that treats or inhibits the ocular disease, the method comprising determining whether the patient has a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encoding a human ANGPTL7 polypeptide by obtaining or having obtained a biological sample from the patient and performing or having performed a genotyping assay on the biological sample to determine whether the patient has a genotype that includes a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7, and if the patient has an ANGPTL7 reference type, then determining whether the patient has the ocular disease. and if the patient is heterozygous for a predicted loss-of-function variant of ANGPTL7, then administering or continuing to administer to the patient a therapeutic agent that treats or inhibits the ocular disease at the same or a lower dose than the standard dose and administering to the patient an ANGPTL7 inhibitor, wherein the presence of a genotype having a predicted loss-of-function variant of ANGPTL7 nucleic acid molecule encoding a human ANGPTL7 polypeptide indicates that the patient has a reduced risk of developing the ocular disease.

[0010] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the U.S. Patent and Trademark Office upon request and payment of the necessary fee. [Brief explanation of the drawings]

[0011] [Figure 1] Manhattan plot showing the association of rare (NAF<0.01), protein-altering variants (including those predicted to affect splicing) with IOP in individuals of European ancestry in a meta-analysis of UKB and GHS studies. Significance thresholds: 1 × 10-5 (blue line) and 5 × 10-8 (red line). [Figure 2A]Figure 2 shows the association of the ANGPTL7 Gln175His (Figures 2A, 2C, and 2E) and Arg177* (Figures 2B, 2D, and 2F) variants with IOP and glaucoma in individuals of European descent. The effect on the association with IOP is measured in standard deviation units. Association p-values ​​were calculated using BOLT-LMM adjusted for age, age-squared, sex, top principal components, and, in the case of UKB, genotyping array and assessment center (Figures 2A and 2B). Boxplots depict Goldmann tonometer-equivalent intraocular pressure (IOPg) between UK Biobank genotypes (Figures 2C and 2D). Heterozygous and homozygous carriers of Gln175His have median IOPg values ​​0.8 mmHg and 4.1 mmHg lower, respectively, compared to non-carriers (Figure 2C). Carriers of the Arg177* heterozygote had a 1.4 mmHg lower IOPg compared with noncarriers (Figure 2D). Association with glaucoma was performed across four series for Gln175His and Arg177*: GHS VCRome: approximately 60,000 individuals from Geisinger captured by VCRome; GHS IDT: approximately 85,000 individuals captured by IDT; UKB: UK Biobank; MSSM: Mt. Sinai Medical School BioMe Biobank; MDCS: Malmo Diet and Cancer Study (Figures 2E and 2F); AAF = alternative allele frequency. [Figure 2B] Same as above. [Figure 2C] Same as above. [Figure 2D] Same as above. [Figure 2E] Same as above. [Figure 2F] Same as above. [Figure 3]ANGPTL7 missense and predicted loss-of-function (pLOF) variants and IOP levels in individuals of European ancestry are shown. The plots represent Goldmann tonometer-equivalent IOP (average of both eyes) levels in carriers of one pLOF variant and six missense variants in ANGPTL7, across approximately 150,000 UK Biobank individuals with available exome sequence data. These variants are predicted to be deleterious by five different algorithms and have at least four carriers with IOP measurements. The median IOP level (15.11 mmHg) across all 34 carriers of pLOF ANGPTL7 variants and predicted deleterious missense ANGPTL7 variants is shown in red, while the median IOP level (15.51 mmHg) in non-carriers is shown in blue. The magenta diamonds represent the median IOP levels in carriers of each variant. Below the plots are the median IOP and interquartile range for each variant, as well as the number of glaucoma case carriers and control subjects. [Figure 4A] We demonstrate ANGPTL7 expression in ocular tissues across species, with RNA sequencing-based expression levels (measured in transcripts per million (TPM)) being highest in the cornea, trabecular meshwork (TM), and sclera in the human eye. [Figure 4B] We demonstrate ANGPTL7 expression in ocular tissues across species, with RNA-sequencing-based expression levels (measured in transcripts per million (TPM)) being highest in the cornea, trabecular meshwork (TM), and sclera in African green monkey eyes. [Figure 4C] We demonstrate ANGPTL7 expression in ocular tissues across species, with RNA sequencing-based expression levels (measured in transcripts per million (TPM)) being highest in the cornea, TM, sclera, optic nerve, and choroid / RPE in C57BL / 6J mice. [Figure 4D] In situ hybridization (RNAScope) shows expression of ANGPTL7 / Angptl7 (red) in the TM, cornea, and sclera of the human eye. Nuclei are counterstained with DAPI staining (blue). RPE: retinal pigment epithelium; SC: Schlemm's canal; CM: ciliary muscle; AC: anterior chamber; TM: trabecular meshwork. [Figure 4E]In situ hybridization (RNAScope) shows expression of ANGPTL7 / Angptl7 (red) in the TM, cornea, and sclera of mouse eyes. Cell nuclei are counterstained with DAPI staining (blue). RPE: retinal pigment epithelium; CB: ciliary body; TM: trabecular meshwork; RGC: retinal ganglion cell; INL: inner nuclear layer; ONL: outer nuclear layer. [Figure 5] Dexamethasone (DEX)-induced gene expression changes in three primary human trabecular meshwork (hTM) cell lines from three independent human eyes were measured by quantitative PCR (qPCR). hTM cells were treated with DEX for 72 hours followed by qPCR analysis. DEX treatment increased ANGPTL7 expression in two of the three hTM cell lines. Ctrl represents untreated cells, and EtOH represents ethanol treatment. Data are shown as the mean ± standard error across two replicate samples. *p=0.01, **p=0.001, ***p=0.0001 using one-way ANOVA. [Figure 6A] Figure 1 shows that increasing mAngptl7 levels in mouse eyes increases IOP. Mouse Angptl7 (mAngptl7) protein was injected intravitreally into mouse eyes, and IOP was measured over time. After the first instillation, IOP was elevated in Angptl7-treated eyes compared to control eyes. Data are shown as mean ± SEM. [Figure 6B] Figure 1 shows that increasing mAngptl7 levels in mouse eyes increases IOP. Mouse Angptl7 (mAngptl7) protein was injected into mouse eyes via the anterior chamber, and IOP was measured over time. After the first instillation, IOP was elevated in Angptl7-treated eyes compared to control eyes. Data are shown as mean ± SEM. [Figure 7A] Figure 1 shows the association between ANGPTL7 Trp188* and IOP in individuals of African descent across two cohorts. [Figure 7B] Figure 1 shows the association of ANGPTL7 Trp188* with glaucoma in individuals of African descent across two cohorts. [Figure 7C]Figure 1 shows a meta-analysis of the pLOF variants in ANGPTL7, European-enriched Arg177* and African-enriched Trp188*, on IOP. The Arg177* variant is represented by the cohort designated "EUR," which includes only individuals of European descent. The Trp188* variant is represented by the cohort designated "AFR," which includes only individuals of African descent. [Figure 7D] (A) Meta-analysis of the European-enriched Arg177* and African-enriched Trp188* pLOF variants in ANGPTL7 for glaucoma. The Arg177* variant is represented by the cohort designated "EUR," which includes only individuals of European descent. The Trp188* variant is represented by the cohort designated "AFR," which includes only individuals of African descent. [Figure 8A] 1 shows the expression of two mutants of ANGPTL7 (Gln175His and Arg177Stop) in HEK293 whole cell lysates. [Figure 8B] 1 shows the expression of two mutants of ANGPTL7 (Gln175His and Arg177Stop) in HEK293 whole cell lysates. [Figure 8C] A dramatic reduction in the Gln175His mutant was observed in cell supernatants compared to wild-type ANGPTL7. [Figure 8D] A dramatic reduction in the Gln175His mutant was observed in cell supernatants compared to wild-type ANGPTL7. [Figure 8E] This shows that the Arg177Stop mutant could not be secreted into the supernatant. [Figure 9A] 1 shows RT-PCR analysis of wild-type and mutant forms of ANGPTL7 at 48 hours after HEK293 transfection. Expression values ​​are calculated relative to the GAPDH housekeeping gene. [Figure 9B] Western blotting showing intracellular protein levels of ANGPTL7 wild-type, ANGPTL7 Gln175His, and ANGPTL7 Arg177* is shown. [Figure 9C]ELISA assay showing intracellular protein levels of ANGPTL7 wild-type, ANGPTL7 Gln175His, and ANGPTL7 Arg177*. For quantification, each cell lysate was diluted 1:1,000. [Figure 9D] Western blotting showing extracellular protein levels of ANGPTL7 wild-type, ANGPTL7 Gln175His, and ANGPTL7 Arg177*. Analyses were repeated in three independent biological replicates. [Figure 9E] ELISA assays showing extracellular protein levels of ANGPTL7 wild-type, ANGPTL7 Gln175His, and ANGPTL7 Arg177* are shown. For quantification, each supernatant was diluted 1:10,000. Western blotting and ELISA analysis were repeated in three independent biological replicates. Technical replicates (n=3) were performed for RT-PCR and ELISA analysis. DETAILED DESCRIPTION OF THE INVENTION

[0012] Various terms relating to aspects of the present disclosure are used throughout the specification and claims. Such terms shall be given their ordinary meaning in the art unless otherwise indicated. Other terms that are specifically defined shall be interpreted in a manner consistent with the definitions set forth herein.

[0013] Unless expressly stated otherwise, it is not intended that any method or aspect described herein be construed as requiring that its steps be performed in a particular order. Thus, if a method claim does not specifically recite in the claim or description that the steps are to be limited to a particular order, no order is intended to be inferred in any respect. This also applies to any possible implicit criteria of interpretation, including logical matters regarding the arrangement of steps or operational flow, general meanings derived from grammatical construction or punctuation, or the number or type of aspects described herein.

[0014] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. As used herein, the terms "subject" and "patient" are used interchangeably. A subject can include any animal, including mammals. Mammals include, but are not limited to, livestock (e.g., horses, cows, pigs, etc.), companion animals (e.g., dogs, cats, etc.), laboratory animals (e.g., mice, rats, rabbits, etc.), and non-human primates. In some embodiments, the subject is a human.

[0015] As used herein, "nucleic acid," "nucleic acid molecule," "nucleic acid sequence," "polynucleotide," or "oligonucleotide" can include polymeric forms of nucleotides of any length, can include DNA and / or RNA, and can be single-stranded, double-stranded, or multi-stranded. A single strand of a nucleic acid also refers to its complementary strand.

[0016] As used herein, the term "comprising" may be replaced with "consisting of" or "consisting essentially of" in certain embodiments, as desired. An "isolated" nucleic acid molecule is a polynucleotide that is in a state other than its natural environment, such as blood or animal tissue. In a preferred form, the isolated nucleic acid molecule is substantially free of other polynucleotides, particularly other polynucleotides of animal origin. It is preferred to provide the nucleic acid molecule in a highly purified form, i.e., greater than 95% pure, more preferably greater than 99% pure. As used in this context, the term "isolated" does not exclude the existence of the same nucleic acid molecule in alternative physical forms, such as dimers, or alternatively in phosphorylated or derivatized forms.

[0017] Certain variants of the ANGPTL7 gene are associated with a reduced risk of developing eye diseases such as increased IOP and glaucoma in human subjects. For example, it has been observed that genetic mutations that change the cytosine nucleotide at position 4,291 of the human ANGPTL7 reference sequence (see SEQ ID NO: 1) to thymine, or change the guanine nucleotide at position 4,287 of the human ANGPTL7 reference sequence (see SEQ ID NO: 1) to thymine, indicate that people with such mutations may have a reduced risk of developing eye diseases such as increased IOP and glaucoma. In summary, the genetic analysis described herein indicates that certain variants of the ANGPTL7 gene are associated with a reduced risk of developing eye diseases such as increased IOP and glaucoma. Therefore, human subjects with an ANGPTL7 reference type who are at an increased risk of developing eye diseases such as increased IOP and glaucoma can be treated to prevent such eye diseases, alleviate their symptoms, and / or suppress the onset of symptoms. Thus, the present disclosure provides isolated ANGPTL7 variant genomic nucleic acid molecules, variant mRNA molecules, and variant cDNA molecules. Furthermore, the disclosure provides methods that utilize the identification of such variants in subjects to identify or stratify the risk of developing eye diseases such as elevated IOP and glaucoma in such subjects, or to diagnose subjects as being at increased risk of developing eye diseases such as elevated IOP and glaucoma, so that at-risk subjects or subjects with active disease can be treated accordingly. Thus, provided herein are ANGPTL7 loss-of-function variant nucleic acid molecules that have been discovered to be associated with a reduced risk of developing eye diseases such as elevated IOP and glaucoma.

[0018] For purposes of this disclosure, any particular human can be classified as having one of three ANGPTL7 genotypes: i) the ANGPTL7 reference type, ii) a heterozygote for a predicted loss-of-function variant of ANGPTL7, and iii) a homozygote for a predicted loss-of-function variant of ANGPTL7. Humans in the ANGPTL7 reference type classification have no copies of the predicted loss-of-function variant nucleic acid molecule of ANGPTL7. Humans in the heterozygote for a predicted loss-of-function variant of ANGPTL7 have a single copy of the predicted loss-of-function variant nucleic acid molecule of ANGPTL7. A predicted loss-of-function variant nucleic acid molecule of ANGPTL7 is any ANGPTL7 nucleic acid molecule (such as a genomic nucleic acid molecule, an mRNA molecule, or a cDNA molecule generated from such an mRNA molecule) that encodes an ANGPTL7 polypeptide having a partial loss of function, a complete loss of function, a predicted partial loss of function, or a predicted complete loss of function. A person who has an ANGPTL7 polypeptide with partial loss of function (or predicted partial loss of function) is ANGPTL7 hypomorphic.The predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is considered to be any nucleic acid molecule encoding Gln175His, Arg177Stop, Lys192Gln, Phe161Ile, Trp188Stop, Arg340His, Arg220His, Asn302Lys, or Arg220Cys of ANGPTL7.In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Gln175His, Arg177Stop, Lys192Gln, Phe161Ile, or Trp188Stop of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Gln175His, Arg177Stop, Trp188Stop, Lys192Gln, or Phe161Ile of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Gln175His, Trp188Stop, or Arg177Stop of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Gln175His of ANGPTL7.In some embodiments, the predicted loss-of-function variant nucleic acid molecule of ANGPTL7 encodes Arg177Stop of ANGPTL7. In some embodiments, the predicted loss-of-function variant nucleic acid molecule of ANGPTL7 encodes Trp188Stop of ANGPTL7. In some embodiments, the predicted loss-of-function variant nucleic acid molecule of ANGPTL7 encodes Lys192Gln of ANGPTL7. In some embodiments, the predicted loss-of-function variant nucleic acid molecule of ANGPTL7 encodes Phe161Ile of ANGPTL7. A human homozygous for a predicted loss-of-function variant of ANGPTL7 has two copies of the predicted loss-of-function variant nucleic acid molecule of ANGPTL7.

[0019] For human subjects or patients who are genotyped or determined to be of the ANGPTL7 reference type, such human subjects or patients are at increased risk for developing ocular disorders such as increased IOP, pre-glaucoma, glaucoma, and reduced corneal plasticity. For human subjects or patients who are genotyped or determined to be either the ANGPTL7 reference type or heterozygous for a predicted loss-of-function variant of ANGPTL7, such human subjects or patients can be treated with an ANGPTL7 inhibitor.

[0020] The present disclosure provides a method for treating a patient with glaucoma, the method comprising administering an ANGPTL7 inhibitor to the patient. In some embodiments, the glaucoma is primary open-angle glaucoma, angle-closure glaucoma, normal-tension glaucoma, congenital glaucoma, neovascular glaucoma, steroid-induced glaucoma, or glaucoma associated with ocular trauma.

[0021] The present disclosure also provides methods of treating a patient with increased IOP, the methods comprising administering to the patient an ANGPTL7 inhibitor. In some embodiments, the increased IOP is corrected IOP unaffected by corneal thickness (IOPcc) or Goldmann tonometer equivalent IOP (IOPg).

[0022] The present disclosure also provides methods of treating a patient with pre-glaucoma, the methods comprising administering to the patient an ANGPTL7 inhibitor. The present disclosure also provides a method of treating a patient with reduced corneal plasticity, the method comprising administering to the patient an ANGPTL7 inhibitor.

[0023] In some embodiments, the ANGPTL7 inhibitor comprises an antisense molecule. Examples of antisense molecules include, but are not limited to, antisense nucleic acid molecules, small interfering RNA (siRNA), and short hairpin RNA (shRNA). Such antisense molecules can be designed to target any region of ANGPTL7 mRNA. In some embodiments, the antisense RNA, siRNA, or shRNA hybridizes to a sequence within an ANGPTL7 genomic nucleic acid molecule or mRNA molecule and reduces the expression of the ANGPTL7 polypeptide in a subject's cells. In some embodiments, the ANGPTL7 inhibitor comprises an antisense RNA that hybridizes to an ANGPTL7 genomic nucleic acid molecule or mRNA molecule and reduces the expression of the ANGPTL7 polypeptide in a subject's cells. In some embodiments, the ANGPTL7 inhibitor comprises an siRNA that hybridizes to an ANGPTL7 genomic nucleic acid molecule or mRNA molecule and reduces the expression of the ANGPTL7 polypeptide in a subject's cells. In some embodiments, the ANGPTL7 inhibitor comprises an shRNA that hybridizes to a genomic nucleic acid molecule or mRNA molecule of ANGPTL7 and reduces expression of an ANGPTL7 polypeptide in cells of a subject.

[0024] In some embodiments, the ANGPTL7 inhibitor comprises a nuclease substance that induces one or more nicks or double-strand breaks in the recognition sequence(s), or a DNA-binding protein that binds to the recognition sequence within the ANGPTL7 genomic nucleic acid molecule. The recognition sequence may be located within the coding region of the ANGPTL7 gene or within a regulatory region that affects gene expression. The recognition sequence of the DNA-binding protein or nuclease substance may be located in an intron, exon, promoter, enhancer, regulatory region, or any non-protein-coding region. The recognition sequence may encompass or be adjacent to the start codon of the ANGPTL7 gene. For example, the recognition sequence may be located approximately 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, or 1,000 nucleotides from the start codon. As another example, two or more nuclease substances can be used, each targeting a nuclease recognition sequence encompassing or adjacent to the start codon. As another example, two nuclease agents can be used, one targeting the nuclease recognition sequence encompassing or adjacent to the start codon and one targeting the nuclease recognition sequence encompassing or adjacent to the stop codon, such that cleavage by the nuclease agents can result in the deletion of the coding region flanked by the two nuclease recognition sequences. Any nuclease agent that induces a nick or double-strand break at the desired recognition sequence can be used in the methods and compositions disclosed herein. Any DNA-binding protein that binds to the desired recognition sequence can be used in the methods and compositions disclosed herein.

[0025] Nuclease agents and DNA-binding proteins suitable for use herein include, but are not limited to, zinc finger proteins or zinc finger nuclease (ZFN) pairs, transcription activator-like effector (TALE) proteins or transcription activator-like effector nucleases (TALENs), or clustered regularly interspaced short palindromic repeats (CRISPR) / CRISPR-associated (Cas) systems. The length of the recognition sequence can vary, for example, about 30-36 bp (i.e., about 15-18 bp for each ZFN) recognition sequences for zinc finger proteins or ZFN pairs, about 36 bp recognition sequences for TALE proteins or TALENs, and about 20 bp recognition sequences for CRISPR / Cas guide RNAs.

[0026] In some embodiments, the CRISPR / Cas system can be used to modify the ANGPTL7 genomic nucleic acid molecule in a cell. The methods and compositions disclosed herein can use the CRISPR-Cas system by utilizing a CRISPR complex (comprising a guide RNA (gRNA) complexed with a Cas protein) for site-specific cleavage of the ANGPTL7 nucleic acid molecule.

[0027] Cas proteins generally contain at least one RNA recognition or binding domain capable of interacting with gRNA. Cas proteins may also contain a nuclease domain (e.g., a DNase domain or an RNase domain), a DNA binding domain, a helicase domain, a protein-protein interaction domain, a dimerization domain, and other domains. Suitable Cas proteins include, for example, wild-type Cas9 protein and wild-type Cpf1 protein (e.g., FnCpf1). Cas proteins may have sufficient cleavage activity to create a double-stranded break in the ANGPTL7 genomic nucleic acid molecule, or may be a nickase that creates a single-stranded break in the ANGPTL7 genomic nucleic acid molecule. Additional examples of Cas proteins include Cas1, Cas1B, Cas2, Cas3, Cas4, Cas5, Cas5e (CasD), Cas6, Cas6e, Cas6f, Cas7, Cas8a1, Cas8a2, Cas8b, Cas8c, Cas9 (Csn1 or Csx12), Cas10, Cas10d, CasF, CasG, CasH, Csy1, Csy2, Csy3, Cse1 (CasA), Cse2 (CasB), Cse3 (CasE), C Examples of Cas proteins include, but are not limited to, se4 (CasC), Csc1, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmr1, Cmr3, Cmr4, Cmr5, Cmr6, Csb1, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1, Csx15, Csf1, Csf2, Csf3, Csf4, and Cu1966, as well as homologs or modified forms thereof. Cas proteins can also be operably linked to heterologous polypeptides as fusion proteins. For example, Cas proteins can be fused to a cleavage domain, an epigenetic modification domain, a transcriptional activation domain, or a transcriptional repression domain. Cas proteins can be provided in any form. For example, the Cas protein can be provided in the form of a protein, such as a Cas protein complexed with a gRNA. Alternatively, the Cas protein can be provided in the form of a nucleic acid molecule, such as RNA or DNA, that encodes the Cas protein.

[0028] In some embodiments, targeted gene modification of an ANGPTL7 genomic nucleic acid molecule can be created by contacting a cell with a Cas protein and one or more gRNAs that hybridize to one or more gRNA recognition sequences within the target genomic locus of the ANGPTL7 genomic nucleic acid molecule. For example, the gRNA recognition sequence can be located in the region of SEQ ID NO: 1. In some embodiments, the gRNA recognition sequence encompasses or is adjacent to a position corresponding to position 4,291 according to SEQ ID NO: 1, position 4,287 according to SEQ ID NO: 1, position 4,243 according to SEQ ID NO: 1, position 4,325 according to SEQ ID NO: 1, or position 4,336 according to SEQ ID NO: 1. For example, the gRNA recognition sequence can be located about 1000, 500, 400, 300, 200, 100, 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5 nucleotides from the position corresponding to position 4,291 according to SEQ ID NO: 1. The gRNA recognition sequence can be located about 1000, 500, 400, 300, 200, 100, 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5 nucleotides from the position corresponding to position 4,287 according to SEQ ID NO: 1. The gRNA recognition sequence can be located approximately 1000 nucleotides, 500 nucleotides, 400 nucleotides, 300 nucleotides, 200 nucleotides, 100 nucleotides, 50 nucleotides, 45 nucleotides, 40 nucleotides, 35 nucleotides, 30 nucleotides, 25 nucleotides, 20 nucleotides, 15 nucleotides, 10 nucleotides, or 5 nucleotides from the position corresponding to position 4,243 according to SEQ ID NO:1.The gRNA recognition sequence can be located about 1000, 500, 400, 300, 200, 100, 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5 nucleotides from a position corresponding to position 4,325 according to SEQ ID NO: 1. The gRNA recognition sequence can be located about 1000, 500, 400, 300, 200, 100, 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5 nucleotides from a position corresponding to position 4,336 according to SEQ ID NO: 1. As yet another example, the gRNA recognition sequence can encompass or be adjacent to the start codon of an ANGPTL7 genomic nucleic acid molecule or the stop codon of an ANGPTL7 genomic nucleic acid molecule. For example, the gRNA recognition sequence can be located about 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, or 1,000 nucleotides from the start or stop codon.

[0029] The gRNA recognition sequence within the target genomic locus of the ANGPTL7 genomic nucleic acid molecule is located near a protospacer adjacent motif (PAM) sequence, a 2-6 base pair DNA sequence immediately following the DNA sequence targeted by the Cas9 nuclease. A standard PAM is the sequence 5'-NGG-3', where "N" is any nucleobase and is followed by two guanine ("G") nucleobases. The gRNA can guide Cas9 to any location in the genome for gene editing, but editing will not occur at any site other than where Cas9 recognizes the PAM. Furthermore, 5'-NGA-3' can be a non-standard, highly efficient PAM for human cells. Generally, the PAM is approximately 2-6 nucleotides downstream of the DNA sequence targeted by the gRNA. The PAM can be adjacent to the gRNA recognition sequence. In some embodiments, the gRNA recognition sequence can be adjacent to the PAM at the 3' end. In some embodiments, the gRNA recognition sequence can be adjacent to the PAM at the 5' end. For example, the cleavage site of the Cas protein can be about 1 to about 10 base pairs, about 2 to about 5 base pairs, or 3 base pairs upstream or downstream of the PAM sequence. In some embodiments (e.g., when using S. pyogenes Cas9 or a closely related Cas9), the PAM sequence of the non-complementary strand can be 5'-NGG-3', where N is any DNA nucleotide, adjacent 3' to the gRNA recognition sequence on the non-complementary strand of the target DNA. Thus, the PAM sequence of the complementary strand will be 5'-CCN-3', where N is any DNA nucleotide, adjacent 5' to the gRNA recognition sequence on the complementary strand of the target DNA.

[0030] gRNA is an RNA molecule that binds to Cas protein and directs Cas protein to a specific position in the ANGPTL7 genomic nucleic acid molecule. One exemplary gRNA is a gRNA that is effective for directing Cas enzyme to bind to or cleave the ANGPTL7 genomic nucleic acid molecule, and this gRNA comprises a DNA-directing segment that hybridizes to a gRNA recognition sequence in the ANGPTL7 genomic nucleic acid molecule, and this gRNA recognition sequence encompasses or is adjacent to the position corresponding to position 4,291 according to SEQ ID NO: 1, or encompasses or is adjacent to the position corresponding to position 4,287 according to SEQ ID NO: 1, or encompasses or is adjacent to the position corresponding to position 4,243 according to SEQ ID NO: 1, or encompasses or is adjacent to the position corresponding to position 4,325 according to SEQ ID NO: 1, or encompasses or is adjacent to the position corresponding to position 4,336 according to SEQ ID NO: 1. For example, a gRNA can be selected to hybridize to a gRNA recognition sequence located about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 200, 300, 400, 500, or 1,000 nucleotides from a position corresponding to position 4,291 according to SEQ ID NO: 1. A gRNA can also be selected to hybridize to a gRNA recognition sequence located about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 200, 300, 400, 500, or 1,000 nucleotides from a position corresponding to position 4,287 according to SEQ ID NO: 1.A gRNA can also be selected to hybridize to a gRNA recognition sequence located about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 200, 300, 400, 500, or 1,000 nucleotides from a position corresponding to position 4,243 according to SEQ ID NO: 1. A gRNA can also be selected to hybridize to a gRNA recognition sequence located about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 200, 300, 400, 500, or 1,000 nucleotides from a position corresponding to position 4,325 according to SEQ ID NO: 1. The gRNA can also be selected to hybridize to a gRNA recognition sequence located approximately 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 200, 300, 400, 500, or 1,000 nucleotides from the position corresponding to position 4,336 according to SEQ ID NO: 1. Other exemplary gRNAs contain a DNA-directed segment that hybridizes to a gRNA recognition sequence within an ANGPTL7 genomic nucleic acid molecule located in the region of SEQ ID NO: 1. Other exemplary gRNAs contain a DNA-directed segment that hybridizes to a gRNA recognition sequence within an ANGPTL7 genomic nucleic acid molecule that encompasses or is adjacent to the start or stop codon.For example, a gRNA can be selected to hybridize to a gRNA recognition sequence located about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 200, 300, 400, 500, or 1,000 nucleotides from the start codon, or about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 200, 300, 400, 500, or 1,000 nucleotides from the start codon or the stop codon. The design and synthesis of gRNAs are described, for example, in Mali et al., Science, 2013, 339, 823-826, Jinek et al., Science, 2012, 337, 816-821, and Hwang. et al., Nat. Biotechnol., 2013, 31, 227-229, Jiang et al., Nat. Biotechnol., 2013, 31, 233-239, and Cong et al., Science, 2013, 339, 819-823. Suitable gRNAs can comprise about 17 to about 23 nucleotides, about 18 to about 22 nucleotides, or about 19 to about 21 nucleotides. In some embodiments, the gRNA can comprise 20 nucleotides.

[0031] Examples of suitable gRNA recognition sequences for the human ANGPTL7 reference gene are set forth in SEQ ID NOs: 13 to 131 and 144 to 165 (see Tables 1 to 9).

[0032] [Table 1]

[0033] [Table 2]

[0034] Table 3

[0035] Table 4

[0036] Table 5

[0037] Table 6

[0038] Table 7

[0039] Table 8

[0040] Table 9

[0041] The Cas protein and gRNA form a complex, and the Cas protein cuts the target ANGPTL7 genomic nucleic acid molecule. The Cas protein can cut the nucleic acid molecule at a site inside or outside the nucleic acid sequence present in the target ANGPTL7 genomic nucleic acid molecule to which the DNA-directed segment of the gRNA binds. For example, the formation of a CRISPR complex (comprising the gRNA hybridized to the gRNA recognition sequence and complexed with the Cas protein) can result in the cleavage of one or both strands within or near (for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50 or more base pairs therefrom) the nucleic acid sequence present in the ANGPTL7 genomic nucleic acid molecule to which the DNA-directed segment of the gRNA binds.

[0042] Such a method can result in an ANGPTL7 genomic nucleic acid molecule, for example, in which the region of SEQ ID NO: 1 is disrupted, the start codon is disrupted, the stop codon is disrupted, or the coding sequence is deleted.Optionally, the cell can be further contacted with one or more additional gRNAs, which hybridize with additional gRNA recognition sequences in the target genomic locus of the ANGPTL7 genomic nucleic acid molecule.By contacting the cell with one or more additional gRNAs (for example, a second gRNA that hybridizes with a second gRNA recognition sequence), the cleavage by Cas protein can create two or more double-strand breaks or two or more single-strand breaks.

[0043] In some embodiments, the ANGPTL7 inhibitor comprises a small molecule. In some embodiments, the ANGPTL7 inhibitor is 6,11-dihydro[1]benzothiopyrano[4,3-b]indole (PD146176), 2-bromophenol, 2,4-dibromophenol, 2-(1-thienyl)ethyl-3,4-dihydroxybenzylidene cyanoacetate (TEDC), 4,4'-(2,3-dimethyl-1,4-butanediyl)bis-1,2-benzenediol (nordihydroguaiaretic acid), or cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC).

[0044] In some embodiments, the method further comprises detecting the presence or absence of a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encoding a human ANGPTL7 polypeptide in a biological sample from the patient. As used throughout this disclosure, the term "predicted loss-of-function mutant nucleic acid molecule of ANGPTL7" refers to any ANGPTL7 nucleic acid molecule (e.g., a genomic nucleic acid molecule, an mRNA molecule, or a cDNA molecule) that encodes an ANGPTL7 polypeptide with partial loss-of-function, complete loss-of-function, predicted partial loss-of-function, or predicted complete loss-of-function. For example, a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 can be any nucleic acid molecule encoding Gln175His, Arg177Stop, Trp188Stop, Lys192Gln, Phe161Ile, Arg340His, Arg220His, Asn302Lys, or Arg220Cys of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Gln175His, Arg177Stop, Trp188Stop, Lys192Gln, or Phe161Ile of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Gln175His, Trp188Stop, or Arg177Stop of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Gln175His of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Arg177Stop of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Trp188Stop of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Lys192Gln of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Phe161Ile of ANGPTL7.

[0045] In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is i) a genomic nucleic acid molecule having a nucleotide sequence comprising a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, ii) an mRNA molecule having a nucleotide sequence comprising a uracil at a position corresponding to position 529 according to SEQ ID NO:5, or iii) a cDNA molecule generated from an mRNA molecule having a nucleotide sequence comprising a thymine at a position corresponding to position 529 according to SEQ ID NO:8.

[0046] In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is i) a genomic nucleic acid molecule having a nucleotide sequence comprising a thymine at a position corresponding to position 4,287 according to SEQ ID NO:3, ii) an mRNA molecule having a nucleotide sequence comprising a uracil at a position corresponding to position 525 according to SEQ ID NO:6, or iii) a cDNA molecule generated from an mRNA molecule having a nucleotide sequence comprising a thymine at a position corresponding to position 525 according to SEQ ID NO:9.

[0047] In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is i) a genomic nucleic acid molecule having a nucleotide sequence including an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, ii) an mRNA molecule having a nucleotide sequence including an adenine at a position corresponding to position 481 according to SEQ ID NO: 135, or iii) a cDNA molecule generated from an mRNA molecule having a nucleotide sequence including an adenine at a position corresponding to position 481 according to SEQ ID NO: 138.

[0048] In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is i) a genomic nucleic acid molecule having a nucleotide sequence including an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, ii) an mRNA molecule having a nucleotide sequence including an adenine at a position corresponding to position 563 according to SEQ ID NO: 136, or iii) a cDNA molecule generated from an mRNA molecule having a nucleotide sequence including an adenine at a position corresponding to position 563 according to SEQ ID NO: 139.

[0049] In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is i) a genomic nucleic acid molecule having a nucleotide sequence comprising a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, ii) an mRNA molecule having a nucleotide sequence comprising a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, or iii) a cDNA molecule generated from an mRNA molecule having a nucleotide sequence comprising a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140.

[0050] In some embodiments, if the patient is of the ANGPTL7 reference type, the patient is also administered a standard dose of a therapeutic agent that treats or inhibits an ocular disease. In some embodiments, if the patient is heterozygous for a predicted loss-of-function variant of ANGPTL7, the patient is also administered a standard dose of a therapeutic agent that treats or inhibits an ocular disease, at a dose that is the same as or lower than the standard dose.

[0051] The present disclosure also provides a method of treating a patient suffering from an ocular disease with a therapeutic agent that treats or inhibits the ocular disease, the method comprising determining whether the patient has a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encoding a human ANGPTL7 polypeptide by obtaining or having obtained a biological sample from the patient and performing or having performed a genotyping assay on the biological sample to determine whether the patient has a genotype that includes a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7, and if the patient has an ANGPTL7 reference type, then: i) determining whether the patient has the ocular disease; The method includes administering or continuing to administer a therapeutic agent for treating or inhibiting the ocular disease to the patient at a standard dose and administering an ANGPTL7 inhibitor to the patient, and if the patient is heterozygous for a predicted loss-of-function variant of ANGPTL7, then: i) administering or continuing to administer a therapeutic agent for treating or inhibiting the ocular disease to the patient at an amount equal to or lower than the standard dose and administering an ANGPTL7 inhibitor to the patient, wherein the presence of a genotype having a predicted loss-of-function variant of ANGPTL7 nucleic acid molecule encoding a human ANGPTL7 polypeptide indicates that the patient has a reduced risk of developing the ocular disease. In some embodiments, the patient is of the ANGPTL7 reference type. In some embodiments, the patient is heterozygous for a predicted loss-of-function variant of ANGPTL7.

[0052] The present disclosure also provides a method of treating a patient suffering from an ocular disease with a therapeutic agent that treats or inhibits the ocular disease, the method comprising the steps of determining whether the patient has a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encoding a human ANGPTL7 polypeptide, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is i) a genomic nucleic acid molecule having a nucleotide sequence comprising a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, ii) an mRNA molecule having a nucleotide sequence comprising a uracil at a position corresponding to position 529 according to SEQ ID NO:5, or iii) a cDNA molecule generated from an mRNA molecule having a nucleotide sequence comprising a thymine at a position corresponding to position 529 according to SEQ ID NO:8, wherein a biological sample from the patient is obtained or has been obtained, and the patient is and if the patient is a heterozygote for a predicted loss-of-function variant of ANGPTL7, then administering or continuing to administer to the patient a therapeutic agent for treating or inhibiting the ocular disease at a standard dose and administering an ANGPTL7 inhibitor to the patient. If the patient is a heterozygote for a predicted loss-of-function variant of ANGPTL7, then administering or continuing to administer to the patient a therapeutic agent for treating or inhibiting the ocular disease at an amount equal to or lower than the standard dose and administering an ANGPTL7 inhibitor to the patient, wherein the presence of a genotype having a predicted loss-of-function variant of ANGPTL7 nucleic acid molecule encoding a human ANGPTL7 polypeptide indicates that the patient has a reduced risk of developing an ocular disease. In some embodiments, the patient is a genotype having a predicted loss-of-function variant of ANGPTL7. In some embodiments, the patient is a heterozygote for a predicted loss-of-function variant of ANGPTL7.

[0053] The present disclosure also provides a method of treating a patient suffering from an ocular disease with a therapeutic agent that treats or inhibits the ocular disease, the method comprising the steps of determining whether the patient has a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encoding a human ANGPTL7 polypeptide, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is i) a genomic nucleic acid molecule having a nucleotide sequence comprising a thymine at a position corresponding to position 4,287 according to SEQ ID NO: 3, ii) an mRNA molecule having a nucleotide sequence comprising a uracil at a position corresponding to position 525 according to SEQ ID NO: 6, or iii) a cDNA molecule generated from an mRNA molecule having a nucleotide sequence comprising a thymine at a position corresponding to position 525 according to SEQ ID NO: 9, wherein a biological sample from the patient is obtained or has been obtained, and the patient is and if the patient is a heterozygote for a predicted loss-of-function variant of ANGPTL7, then administering or continuing to administer to the patient a therapeutic agent for treating or inhibiting the ocular disease at a standard dose and administering an ANGPTL7 inhibitor to the patient. If the patient is a heterozygote for a predicted loss-of-function variant of ANGPTL7, then administering or continuing to administer to the patient a therapeutic agent for treating or inhibiting the ocular disease at an amount equal to or lower than the standard dose and administering an ANGPTL7 inhibitor to the patient, wherein the presence of a genotype having a predicted loss-of-function variant of ANGPTL7 nucleic acid molecule encoding a human ANGPTL7 polypeptide indicates that the patient has a reduced risk of developing an ocular disease. In some embodiments, the patient is a genotype having a predicted loss-of-function variant of ANGPTL7. In some embodiments, the patient is a heterozygote for a predicted loss-of-function variant of ANGPTL7.

[0054] The present disclosure also provides a method of treating a patient suffering from an ocular disease with a therapeutic agent that treats or inhibits the ocular disease, the method comprising the steps of determining whether the patient has a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encoding a human ANGPTL7 polypeptide, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is i) a genomic nucleic acid molecule having a nucleotide sequence comprising an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, ii) an mRNA molecule having a nucleotide sequence comprising an adenine at a position corresponding to position 481 according to SEQ ID NO: 135, or iii) a cDNA molecule generated from an mRNA molecule having a nucleotide sequence comprising an adenine at a position corresponding to position 481 according to SEQ ID NO: 138, wherein a biological sample from the patient is obtained or has been obtained, and the patient is determined to have a predicted loss-of-function mutant of ANGPTL7. The method includes the steps of: performing or having performed a genotyping assay on a biological sample to determine whether the patient has a genotype comprising the nucleic acid molecule; and if the patient is of the ANGPTL7 reference type, then administering or continuing to administer a therapeutic agent for treating or inhibiting ocular disease at a standard dose to the patient and administering an ANGPTL7 inhibitor to the patient; and if the patient is a heterozygote for a predicted loss-of-function variant of ANGPTL7, then administering or continuing to administer a therapeutic agent for treating or inhibiting ocular disease at a dose equal to or lower than the standard dose to the patient and administering an ANGPTL7 inhibitor to the patient, wherein the presence of a genotype comprising a predicted loss-of-function variant nucleic acid molecule of ANGPTL7 encoding a human ANGPTL7 polypeptide indicates that the patient has a reduced risk of developing ocular disease. In some embodiments, the patient is of the ANGPTL7 reference type. In some embodiments, the patient is a heterozygote for a predicted loss-of-function variant of ANGPTL7.

[0055] The present disclosure also provides a method of treating a patient suffering from an ocular disease with a therapeutic agent that treats or inhibits the ocular disease, the method comprising the steps of determining whether the patient has a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encoding a human ANGPTL7 polypeptide, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is i) a genomic nucleic acid molecule having a nucleotide sequence comprising an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, ii) an mRNA molecule having a nucleotide sequence comprising an adenine at a position corresponding to position 563 according to SEQ ID NO: 136, or iii) a cDNA molecule generated from an mRNA molecule having a nucleotide sequence comprising an adenine at a position corresponding to position 563 according to SEQ ID NO: 139, wherein a biological sample from the patient is obtained or has been obtained, and the patient is The method includes the steps of: performing or having performed a genotyping assay on a biological sample to determine whether the patient has a genotype comprising the nucleic acid molecule; and if the patient is of the ANGPTL7 reference type, then administering or continuing to administer a therapeutic agent for treating or inhibiting ocular disease at a standard dose to the patient and administering an ANGPTL7 inhibitor to the patient; and if the patient is a heterozygote for a predicted loss-of-function variant of ANGPTL7, then administering or continuing to administer a therapeutic agent for treating or inhibiting ocular disease at a dose equal to or lower than the standard dose to the patient and administering an ANGPTL7 inhibitor to the patient, wherein the presence of a genotype comprising a predicted loss-of-function variant nucleic acid molecule of ANGPTL7 encoding a human ANGPTL7 polypeptide indicates that the patient has a reduced risk of developing ocular disease. In some embodiments, the patient is of the ANGPTL7 reference type. In some embodiments, the patient is a heterozygote for a predicted loss-of-function variant of ANGPTL7.

[0056] The present disclosure also provides a method of treating a patient suffering from an ocular disease with a therapeutic agent that treats or inhibits the ocular disease, the method comprising the steps of determining whether the patient has a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encoding a human ANGPTL7 polypeptide, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is i) a genomic nucleic acid molecule having a nucleotide sequence comprising a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, ii) an mRNA molecule having a nucleotide sequence comprising a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, or iii) a cDNA molecule generated from an mRNA molecule having a nucleotide sequence comprising a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140, wherein a biological sample from the patient is obtained or has been obtained, and the patient is The method includes the steps of: performing or having performed a genotyping assay on a biological sample to determine whether the patient has a genotype comprising the nucleic acid molecule; and if the patient is of the ANGPTL7 reference type, then administering or continuing to administer a therapeutic agent for treating or inhibiting ocular disease at a standard dose to the patient and administering an ANGPTL7 inhibitor to the patient; and if the patient is a heterozygote for a predicted loss-of-function variant of ANGPTL7, then administering or continuing to administer a therapeutic agent for treating or inhibiting ocular disease at a dose equal to or lower than the standard dose to the patient and administering an ANGPTL7 inhibitor to the patient, wherein the presence of a genotype comprising a predicted loss-of-function variant nucleic acid molecule of ANGPTL7 encoding a human ANGPTL7 polypeptide indicates that the patient has a reduced risk of developing ocular disease. In some embodiments, the patient is of the ANGPTL7 reference type. In some embodiments, the patient is a heterozygote for a predicted loss-of-function variant of ANGPTL7.

[0057] The predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 can be any ANGPTL7 nucleic acid molecule (e.g., a genomic nucleic acid molecule, an mRNA molecule, or a cDNA molecule) that encodes an ANGPTL7 polypeptide having a partial loss of function, a complete loss of function, a predicted partial loss of function, or a predicted complete loss of function. For example, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 can be any nucleic acid molecule that encodes Gln175His, Arg177Stop, Trp188Stop, Lys192Gln, Phe161Ile, Arg340His, Arg220His, Asn302Lys, or Arg220Cys of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Gln175His, Trp188Stop, or Arg177Stop of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Gln175His of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Arg177Stop of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Trp188Stop of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Lys192Gln of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Phe161Ile of ANGPTL7.

[0058] Detecting the presence or absence of any of the predicted loss-of-function mutant nucleic acid molecules of ANGPTL7 described herein in a biological sample from a patient and / or determining whether a patient has a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 can be performed by any of the methods described herein. In some embodiments, these methods can be performed in vitro. In some embodiments, these methods can be performed in situ. In some embodiments, these methods can be performed in vivo.

[0059] In some embodiments, the determining step, detecting step, or genotyping assay comprises sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule, an ANGPTL7 mRNA molecule, or an ANGPTL7 cDNA molecule in the biological sample, wherein the sequenced portion comprises a mutation(s) that cause or are predicted to cause a loss of function (partial or complete). For example, in some embodiments, the detecting step, detecting step, or genotyping assay comprises: i) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule in the biological sample, wherein the sequenced portion comprises a position corresponding to position 4,291 according to SEQ ID NO:2, or a complement thereof; ii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule in the biological sample, wherein the sequenced portion comprises a position corresponding to position 529 according to SEQ ID NO:5, or a complement thereof; and / or iii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule in the biological sample, wherein the sequenced portion comprises a position corresponding to position 529 according to SEQ ID NO:5, or a complement thereof. The method includes sequencing at least a portion of the nucleotide sequence of the cDNA molecule, wherein the sequenced portion comprises a position corresponding to position 529 according to SEQ ID NO:8, or a complement thereof. If the sequenced portion of the ANGPTL7 genomic nucleic acid molecule of the biological sample comprises a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, the ANGPTL7 genomic nucleic acid molecule of the biological sample is a genomic nucleic acid molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample comprises a uracil at a position corresponding to position 529 according to SEQ ID NO:5, the ANGPTL7 mRNA molecule of the biological sample is an mRNA molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample comprises a thymine at a position corresponding to position 529 according to SEQ ID NO:8, the ANGPTL7 cDNA molecule of the biological sample is a cDNA molecule of a predicted loss-of-function mutant of ANGPTL7.

[0060] In some embodiments, the determining step, detecting step, or genotyping assay includes: a) contacting the biological sample with a primer that hybridizes to: i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,291 according to SEQ ID NO:2; ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule adjacent to a position corresponding to position 529 according to SEQ ID NO:5; and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 529 according to SEQ ID NO:8; b) contacting the primer with at least: i) the position of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule corresponding to position 4,291 according to SEQ ID NO:2; ii) the position of the nucleotide sequence of an ANGPTL7 mRNA molecule corresponding to position 529 according to SEQ ID NO:5; and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 529 according to SEQ ID NO:8. and c) determining whether the extension product of the primer i) contains a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, ii) contains a uracil at a position corresponding to position 529 according to SEQ ID NO:5, and / or iii) contains a thymine at a position corresponding to position 529 according to SEQ ID NO:8.

[0061] In some embodiments, the determining step, detecting step, or genotyping assay includes: a) amplifying at least a portion of a nucleic acid molecule encoding a human ANGPTL7 polypeptide, wherein such portion comprises i) a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, or its complement, ii) a uracil at a position corresponding to position 529 according to SEQ ID NO:5, or its complement, and / or iii) a thymine at a position corresponding to position 529 according to SEQ ID NO:8, or its complement; b) labeling the amplified nucleic acid molecule with a detectable label; c) combining the labeled nucleic acid molecule with a variant nucleic acid molecule; the nucleic acid molecule is amplified, the nucleic acid molecule comprising a nucleotide sequence that hybridizes under stringent conditions to a support comprising a mutation-specific probe, wherein the mutation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to: i) a nucleic acid sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 4,291 according to SEQ ID NO: 2, ii) a nucleic acid sequence of the amplified nucleic acid molecule comprising a uracil or its complement at a position corresponding to position 529 according to SEQ ID NO: 5, and / or iii) a nucleic acid sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 529 according to SEQ ID NO: 8; and d) detecting the detectable label. In some embodiments, the nucleic acid molecule is mRNA, and the determining step further comprises reverse transcribing the mRNA into cDNA prior to the amplifying step.

[0062] In some embodiments, the determining step, detecting step, or genotyping assay comprises contacting a nucleic acid molecule of a biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to a nucleotide sequence of an amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 4,291 according to SEQ ID NO: 2, a nucleotide sequence of an amplified nucleic acid molecule comprising a uracil or its complement at a position corresponding to position 529 according to SEQ ID NO: 5, and / or a thymine or its complement at a position corresponding to position 529 according to SEQ ID NO: 8, and detecting the detectable label.

[0063] In some embodiments, the determining step, detecting step, or genotyping assay comprises: i) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule of the biological sample, wherein the sequenced portion comprises a position corresponding to position 4,287 according to SEQ ID NO: 3, or a complement thereof; ii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule of the biological sample, wherein the sequenced portion comprises a position corresponding to position 525 according to SEQ ID NO: 6, or a complement thereof; and / or iii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule of the biological sample, wherein the sequenced portion comprises a position corresponding to position 525 according to SEQ ID NO: 9, or a complement thereof. If the sequenced portion of the ANGPTL7 genomic nucleic acid molecule of the biological sample comprises a thymine at a position corresponding to position 4,287 according to SEQ ID NO: 3, then the ANGPTL7 genomic nucleic acid molecule of the biological sample is a genomic nucleic acid molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample contains a uracil at the position corresponding to position 525 according to SEQ ID NO: 6, then the ANGPTL7 mRNA molecule of the biological sample is an mRNA molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains a thymine at the position corresponding to position 525 according to SEQ ID NO: 9, then the ANGPTL7 cDNA molecule of the biological sample is a cDNA molecule of a predicted loss-of-function mutant of ANGPTL7.

[0064] In some embodiments, the determining step, detecting step, or genotyping assay includes: a) contacting the biological sample with a primer that hybridizes to i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,287 according to SEQ ID NO:3, ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule adjacent to a position corresponding to position 525 according to SEQ ID NO:6, and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 525 according to SEQ ID NO:9; b) contacting the primer with at least: i) the position of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule corresponding to position 4,287 according to SEQ ID NO:3, ii) the position of the nucleotide sequence of an ANGPTL7 mRNA molecule corresponding to position 525 according to SEQ ID NO:6, and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 525 according to SEQ ID NO:9. and c) determining whether the extension product of the primer i) contains a thymine at a position corresponding to position 4,287 according to SEQ ID NO:3, ii) contains a uracil at a position corresponding to position 525 according to SEQ ID NO:6, and / or iii) contains a thymine at a position corresponding to position 525 according to SEQ ID NO:9.

[0065] In some embodiments, the determining step, detecting step, or genotyping assay includes: a) amplifying at least a portion of a nucleic acid molecule encoding a human ANGPTL7 polypeptide, wherein such portion comprises i) a thymine at a position corresponding to position 4,287 according to SEQ ID NO: 3, or its complement, ii) a uracil at a position corresponding to position 525 according to SEQ ID NO: 6, or its complement, and / or iii) a thymine at a position corresponding to position 525 according to SEQ ID NO: 9, or its complement; b) labeling the amplified nucleic acid molecule with a detectable label; c) combining the labeled nucleic acid molecule with a variant nucleic acid molecule; contacting a support comprising a mutation-specific probe, wherein the mutation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to i) a nucleic acid sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 4,287 according to SEQ ID NO: 3, ii) a nucleic acid sequence of the amplified nucleic acid molecule comprising a uracil or its complement at a position corresponding to position 525 according to SEQ ID NO: 6, and / or iii) a nucleic acid sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 525 according to SEQ ID NO: 9, and d) detecting the detectable label. In some embodiments, the nucleic acid molecule is mRNA, and the determining step further comprises reverse transcribing the mRNA into cDNA prior to the amplifying step.

[0066] In some embodiments, the determining step, detecting step, or genotyping assay comprises contacting a nucleic acid molecule of a biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to a nucleotide sequence of an amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 4,287 according to SEQ ID NO: 3, a nucleotide sequence of an amplified nucleic acid molecule comprising a uracil or its complement at a position corresponding to position 525 according to SEQ ID NO: 6, and / or a thymine or its complement at a position corresponding to position 525 according to SEQ ID NO: 9, and detecting the detectable label.

[0067] In some embodiments, the determining step, detecting step, or genotyping assay comprises: i) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule of the biological sample, wherein the sequenced portion comprises a position corresponding to position 4,243 according to SEQ ID NO: 132, or a complement thereof; ii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule of the biological sample, wherein the sequenced portion comprises a position corresponding to position 481 according to SEQ ID NO: 135, or a complement thereof; and / or iii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule of the biological sample, wherein the sequenced portion comprises a position corresponding to position 481 according to SEQ ID NO: 138, or a complement thereof. If the sequenced portion of the ANGPTL7 genomic nucleic acid molecule of the biological sample contains an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, the ANGPTL7 genomic nucleic acid molecule of the biological sample is a genomic nucleic acid molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample contains an adenine at a position corresponding to position 481 according to SEQ ID NO: 135, the ANGPTL7 mRNA molecule of the biological sample is an mRNA molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains an adenine at a position corresponding to position 481 according to SEQ ID NO: 138, the ANGPTL7 cDNA molecule of the biological sample is a cDNA molecule of a predicted loss-of-function mutant of ANGPTL7.

[0068] In some embodiments, the determining step, detecting step, or genotyping assay comprises: a) contacting the biological sample with a primer that hybridizes to: i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,243 according to SEQ ID NO: 132; ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule adjacent to a position corresponding to position 481 according to SEQ ID NO: 135; and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 481 according to SEQ ID NO: 138; b) contacting the primer with at least: i) the position of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule corresponding to position 4,243 according to SEQ ID NO: 132; ii) the position of the nucleotide sequence of an ANGPTL7 mRNA molecule corresponding to position 481 according to SEQ ID NO: 135; and / or iii) the position of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 481 according to SEQ ID NO: 138. and c) determining whether the extension product of the primer i) contains an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, ii) contains an adenine at a position corresponding to position 481 according to SEQ ID NO: 135, and / or iii) contains an adenine at a position corresponding to position 481 according to SEQ ID NO: 138.

[0069] In some embodiments, the determining step, detecting step, or genotyping assay includes: a) amplifying at least a portion of a nucleic acid molecule encoding a human ANGPTL7 polypeptide, wherein such portion comprises i) an adenine at a position corresponding to 4,243 according to SEQ ID NO: 132, or its complement, ii) an adenine at a position corresponding to 481 according to SEQ ID NO: 135, and / or iii) an adenine at a position corresponding to 481 according to SEQ ID NO: 138, or its complement; b) labeling the amplified nucleic acid molecule with a detectable label; c) combining the labeled nucleic acid molecule with a variation-specific primer; and d) detecting the detectable label. In some embodiments, the nucleic acid molecule is mRNA, and the determining step further comprises reverse transcribing the mRNA into cDNA prior to the amplifying step.

[0070] In some embodiments, the determining step, detecting step, or genotyping assay comprises contacting a nucleic acid molecule of a biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to a nucleotide sequence of an amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 4,243 according to SEQ ID NO: 132, a nucleotide sequence of an amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 481 according to SEQ ID NO: 135, and / or a nucleotide sequence of an amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 481 according to SEQ ID NO: 138, and detecting the detectable label.

[0071] In some embodiments, the determining step, detecting step, or genotyping assay comprises: i) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule of the biological sample, wherein the sequenced portion comprises a position corresponding to position 4,325 according to SEQ ID NO: 133, or a complement thereof; ii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule of the biological sample, wherein the sequenced portion comprises a position corresponding to position 563 according to SEQ ID NO: 136, or a complement thereof; and / or iii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule of the biological sample, wherein the sequenced portion comprises a position corresponding to position 563 according to SEQ ID NO: 139, or a complement thereof. If the sequenced portion of the ANGPTL7 genomic nucleic acid molecule of the biological sample contains an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, the ANGPTL7 genomic nucleic acid molecule of the biological sample is a genomic nucleic acid molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample contains an adenine at a position corresponding to position 563 according to SEQ ID NO: 136, the ANGPTL7 mRNA molecule of the biological sample is an mRNA molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains an adenine at a position corresponding to position 563 according to SEQ ID NO: 139, the ANGPTL7 cDNA molecule of the biological sample is a cDNA molecule of a predicted loss-of-function mutant of ANGPTL7.

[0072] In some embodiments, the determining step, detecting step, or genotyping assay comprises: a) contacting the biological sample with a primer that hybridizes to: i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,325 according to SEQ ID NO: 133; ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule adjacent to a position corresponding to position 563 according to SEQ ID NO: 136; and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 563 according to SEQ ID NO: 139; b) contacting the primer with at least: i) the position of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule corresponding to position 4,325 according to SEQ ID NO: 133; ii) the position of the nucleotide sequence of an ANGPTL7 mRNA molecule corresponding to position 563 according to SEQ ID NO: 136; and / or iii) the position of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 563 according to SEQ ID NO: 139. and c) determining whether the extension product of the primer i) contains an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, ii) contains an adenine at a position corresponding to position 563 according to SEQ ID NO: 136, and / or iii) contains an adenine at a position corresponding to position 563 according to SEQ ID NO: 139.

[0073] In some embodiments, the determining step, detecting step, or genotyping assay includes: a) amplifying at least a portion of a nucleic acid molecule encoding a human ANGPTL7 polypeptide, wherein such portion comprises i) an adenine at a position corresponding to 4,325 according to SEQ ID NO: 133, or its complement, ii) an adenine at a position corresponding to 563 according to SEQ ID NO: 136, or its complement, and / or iii) an adenine at a position corresponding to 563 according to SEQ ID NO: 139, or its complement; b) labeling the amplified nucleic acid molecule with a detectable label; c) combining the labeled nucleic acid molecule with a variant nucleic acid molecule; contacting a support comprising a mutation-specific probe, wherein the mutation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to i) a nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 4,325 according to SEQ ID NO: 133, ii) a nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 563 according to SEQ ID NO: 136, and / or iii) a nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 563 according to SEQ ID NO: 139, and d) detecting the detectable label. In some embodiments, the nucleic acid molecule is mRNA, and the determining step further comprises reverse transcribing the mRNA into cDNA prior to the amplifying step.

[0074] In some embodiments, the determining step, detecting step, or genotyping assay comprises contacting a nucleic acid molecule of a biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to a nucleotide sequence of an amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 4,325 according to SEQ ID NO: 133, a nucleotide sequence of an amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 563 according to SEQ ID NO: 136, and / or a nucleotide sequence of an amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 563 according to SEQ ID NO: 139, and detecting the detectable label.

[0075] In some embodiments, the determining step, detecting step, or genotyping assay comprises: i) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule of the biological sample, wherein the sequenced portion comprises a position corresponding to position 4,336 according to SEQ ID NO: 134, or a complement thereof; ii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule of the biological sample, wherein the sequenced portion comprises a position corresponding to position 574 according to SEQ ID NO: 137, or a complement thereof; and / or iii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule of the biological sample, wherein the sequenced portion comprises a position corresponding to position 574 according to SEQ ID NO: 140, or a complement thereof. If the sequenced portion of the ANGPTL7 genomic nucleic acid molecule of the biological sample contains a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, then the ANGPTL7 genomic nucleic acid molecule of the biological sample is a genomic nucleic acid molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample contains a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, then the ANGPTL7 mRNA molecule of the biological sample is an mRNA molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140, then the ANGPTL7 cDNA molecule of the biological sample is a cDNA molecule of a predicted loss-of-function mutant of ANGPTL7.

[0076] In some embodiments, the determining step, detecting step, or genotyping assay comprises: a) contacting the biological sample with a primer that hybridizes to: i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,336 according to SEQ ID NO: 134; ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule adjacent to a position corresponding to position 574 according to SEQ ID NO: 137; and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 574 according to SEQ ID NO: 140; b) contacting the primer with at least: i) the position of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule corresponding to position 4,336 according to SEQ ID NO: 134; ii) the position of the nucleotide sequence of an ANGPTL7 mRNA molecule corresponding to position 574 according to SEQ ID NO: 137; and / or iii) the position of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 574 according to SEQ ID NO: 140. and c) determining whether the extension product of the primer i) contains a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, ii) contains a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, and / or iii) contains a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140.

[0077] In some embodiments, the determining step, detecting step, or genotyping assay includes: a) amplifying at least a portion of a nucleic acid molecule encoding a human ANGPTL7 polypeptide, wherein such portion comprises i) a cytosine at a position corresponding to 4,336 according to SEQ ID NO: 134, or its complement, ii) a cytosine at a position corresponding to 574 according to SEQ ID NO: 137, and / or iii) a cytosine at a position corresponding to 574 according to SEQ ID NO: 140, or its complement; b) labeling the amplified nucleic acid molecule with a detectable label; c) combining the labeled nucleic acid molecule with a variation-specific primer; and d) detecting the detectable label. In some embodiments, the nucleic acid molecule is mRNA, and the determining step further comprises reverse transcribing the mRNA into cDNA prior to the amplifying step.

[0078] In some embodiments, the determining step, detecting step, or genotyping assay comprises contacting a nucleic acid molecule of a biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to a nucleotide sequence of an amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 4,336 according to SEQ ID NO: 134, a nucleotide sequence of an amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 574 according to SEQ ID NO: 139, and / or a nucleotide sequence of an amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 574 according to SEQ ID NO: 140, and detecting the detectable label.

[0079] In any of these embodiments, the nucleic acid molecule can be present in a cell obtained from a human subject. In any of the embodiments described herein, the ocular disease is increased IOP, pre-glaucoma, glaucoma, or decreased corneal plasticity. In some embodiments, the ocular disease is increased IOP. In some embodiments, the increased IOP is IOPcc or IOPg. In some embodiments, the ocular disease is pre-glaucoma. In some embodiments, the ocular disease is glaucoma. In some embodiments, the glaucoma is primary open-angle glaucoma, angle-closure glaucoma, normal-tension glaucoma, congenital glaucoma, neovascular glaucoma, steroid-induced glaucoma, or glaucoma associated with ocular trauma. In some embodiments, the ocular disease is decreased corneal plasticity.

[0080] In the case of a human subject or patient who has been genotyped or determined to be either a heterozygote for the ANGPTL7 reference type or a predicted loss-of-function variant of ANGPTL7, such a human subject or patient can be treated with an ANGPTL7 inhibitor as described herein.

[0081] Examples of therapeutic agents that treat or inhibit ocular diseases include, but are not limited to, prostaglandins, beta-blockers, alpha-adrenergic agonists, carbonic anhydrase inhibitors, rho kinase inhibitors, or miotics or cholinergic agonists.

[0082] In some embodiments, the therapeutic agent for treating or inhibiting an ocular disease is a prostaglandin. In some embodiments, the prostaglandin is Xalatan® (latanoprost), Travatan Z® (travoprost), Zioptan® (tafluprost), Lumigan® (bimatoprost), or Vyzulta® (latanoprost).

[0083] In some embodiments, the therapeutic agent treating or inhibiting an ocular disease is a beta-blocker. In some embodiments, the beta-blocker is Betimol®, Istalol®, or Timoptic® (timolol) or Betoptic® (betaxolol).

[0084] In some embodiments, the therapeutic agent treating or inhibiting an ocular disease is an alpha-adrenergic agonist, hi some embodiments, the alpha-adrenergic agonist is Iopidine® (apraclonidine) or Alphagan® or Qoliana® (brimonidine).

[0085] In some embodiments, the therapeutic agent treating or inhibiting an ocular disease is a carbonic anhydrase inhibitor, hi some embodiments, the carbonic anhydrase inhibitor is Trusopt® (dorzolamide) or Azopt® (brinzolamide).

[0086] In some embodiments, the therapeutic agent treating or inhibiting an ocular disease is a rho kinase inhibitor. In some embodiments, the rho kinase inhibitor is Rhopressa® (netarsudil).

[0087] In some embodiments, the therapeutic agent treating or inhibiting an ocular disease is a miotic or cholinergic agonist, hi some embodiments, the miotic or cholinergic agonist is Isopto® Carpine (pilocarpine).

[0088] In some embodiments, the dose of a therapeutic agent for treating or inhibiting an ocular disease may be reduced (i.e., lower than the standard dose) by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% in a patient or human subject who is heterozygous for a predicted loss-of-function variant of ANGPTL7 compared to a patient or human subject who is an ANGPTL7 reference type (which may receive a standard dose). In some embodiments, the dose of a therapeutic agent for treating or inhibiting an ocular disease may be reduced by about 10%, about 20%, about 30%, about 40%, or about 50%. Furthermore, the dose of a therapeutic agent for treating or inhibiting an ocular disease in a patient or human subject who is heterozygous for a predicted loss-of-function variant of ANGPTL7 may be administered less frequently compared to a patient or human subject who is an ANGPTL7 reference type.

[0089] The administration of the therapeutic agent and / or ANGPTL7 inhibitor for treating or inhibiting an ocular disease can be repeated, for example, after 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, or 3 months. The repeated administration can be the same dose or a different dose. The administration can be repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more times. For example, according to a specific administration regimen, a patient may be treated for a long period of time, for example, 6 months, 1 year, or more.

[0090] Administration of the therapeutic agent and / or ANGPTL7 inhibitor for treating or inhibiting ocular disease can be by any suitable route, including, but not limited to, parenteral, intravenous, oral, subcutaneous, intraarterial, intracranial, intrathecal, intraperitoneal, topical, intranasal, or intramuscular. Pharmaceutical compositions for administration are desirably sterile and substantially isotonic and manufactured under GMP conditions. Pharmaceutical compositions may be provided in unit dosage form (i.e., a single dosage). Pharmaceutical compositions may be formulated using one or more physiologically and pharmaceutically acceptable carriers, diluents, excipients, or adjuvants. Formulations vary depending on the selected route of administration. The term "pharmaceutically acceptable" means that the carrier, diluent, excipient, or adjuvant is compatible with the other ingredients of the formulation and not substantially deleterious to the recipient thereof.

[0091] As used herein, the terms "treat," "treating," and "treatment," as well as "prevent," "preventing," and "prevention," refer to eliciting a desired biological response, such as a therapeutic effect and a prophylactic effect, respectively. In some embodiments, the therapeutic effect comprises one or more of the following after administration of the agent or a composition comprising the agent: reduction / alleviation of ocular disease, reduction / alleviation of the severity of ocular disease (e.g., reduction or inhibition of the onset of ocular disease), reduction / alleviation of symptoms and ocular disease-related effects, delay in the onset of symptoms and ocular disease-related effects, reduction in the severity of symptoms of ocular disease-related effects, reduction in the severity of acute episodes, reduction in the number of symptoms and ocular disease-related effects, reduction in the latency of symptoms and ocular disease-related effects, amelioration of symptoms and ocular disease-related effects, reduction in secondary symptoms, reduction in secondary infections, prevention of recurrence of ocular disease, reduction in the number or frequency of recurrent episodes, increase in the latency to symptomatic episodes, increase in the time to sustained progression, rapid remission, induction of remission, enhanced remission, hastened recovery, or increased effectiveness of or reduced resistance to alternative treatments, and / or increased survival of the affected host animal. A prophylactic effect can include complete or partial avoidance / inhibition or delay (e.g., complete or partial avoidance / inhibition or delay, etc.) of the onset / progression of ocular disease following administration of a treatment protocol, and prolongation of survival of the affected host animal. Treatment of ocular disease includes treatment of patients already diagnosed with any form of ocular disease at any clinical stage or clinical presentation, delaying the onset or progression or worsening or worsening of symptoms or signs of ocular disease, and / or preventing and / or reducing the severity of ocular disease.

[0092] In some embodiments, the detecting step comprises sequencing at least a portion of the polypeptide that includes a position corresponding to any position C-terminal to position 176 according to SEQ ID NO: 11. In some embodiments, the detecting step comprises sequencing the entire polypeptide. In some embodiments, the detecting step comprises an immunoassay to detect the presence of a polypeptide that includes a position corresponding to any position C-terminal to position 176 according to SEQ ID NO: 11.

[0093] In some embodiments, the detecting step comprises sequencing at least a portion of the polypeptide that includes a position corresponding to position 175 according to SEQ ID NO: 10 or SEQ ID NO: 12. In some embodiments, the detecting step comprises sequencing the entire polypeptide. In some embodiments, the detecting step comprises an immunoassay to detect the presence of a polypeptide that includes a position corresponding to position 175 according to SEQ ID NO: 10 or SEQ ID NO: 12.

[0094] In some embodiments, the detecting step comprises sequencing at least a portion of the polypeptide that includes a position corresponding to position 161 according to SEQ ID NO: 141 or SEQ ID NO: 10. In some embodiments, the detecting step comprises sequencing the entire polypeptide. In some embodiments, the detecting step comprises an immunoassay to detect the presence of a polypeptide that includes a position corresponding to position 161 according to SEQ ID NO: 141 or SEQ ID NO: 10.

[0095] In some embodiments, the detecting step comprises sequencing at least a portion of the polypeptide that includes a position corresponding to any position C-terminal to position 187 according to SEQ ID NO: 142. In some embodiments, the detecting step comprises sequencing the entire polypeptide. In some embodiments, the detecting step comprises an immunoassay to detect the presence of a polypeptide that includes a position corresponding to any position C-terminal to position 187 according to SEQ ID NO: 142.

[0096] In some embodiments, the detecting step comprises sequencing at least a portion of the polypeptide that includes a position corresponding to position 192 according to SEQ ID NO: 143 or SEQ ID NO: 10. In some embodiments, the detecting step comprises sequencing the entire polypeptide. In some embodiments, the detecting step comprises an immunoassay to detect the presence of a polypeptide that includes a position corresponding to position 192 according to SEQ ID NO: 143 or SEQ ID NO: 10.

[0097] The present disclosure also provides a method for identifying a human subject at elevated risk for developing an eye disease, the method comprising determining or having determined the presence or absence of a predicted loss-of-function variant of ANGPTL7 nucleic acid molecule (such as a genomic nucleic acid molecule, an mRNA molecule, and / or a cDNA molecule) encoding a human ANGPTL7 polypeptide in a biological sample obtained from the subject, wherein i) if the human subject lacks the predicted loss-of-function variant of ANGPTL7 nucleic acid molecule (i.e., the human subject is classified as having the ANGPTL7 reference genotype), then the human subject is at elevated risk for developing the eye disease, and ii) if the human subject has the predicted loss-of-function variant of ANGPTL7 nucleic acid molecule (i.e., the human subject is classified as being heterozygous for the predicted loss-of-function variant of ANGPTL7 or homozygous for the predicted loss-of-function variant of ANGPTL7), then the human subject is at reduced risk for developing the eye disease. Possession of a single copy of a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 confers protection to a human subject from developing eye disease.

[0098] Without intending to be limited to any particular theory or mechanism of action, it is believed that a single copy of a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 (i.e., a heterozygote for a predicted loss-of-function mutant of ANGPTL7) may confer protection to a human subject from developing eye disease, and that having two copies of a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 (i.e., a homozygote for a predicted loss-of-function mutant of ANGPTL7) may confer additional protection to a human subject from developing eye disease compared to a human subject with a single copy. Thus, in some embodiments, a single copy of a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 may not be completely protective, but may instead result in partial or incomplete protection of a human subject from developing eye disease. Without wishing to be bound by any particular theory, it is believed that additional factors or molecules involved in the development of eye disease may still be present in a human subject with a single copy of a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7, resulting in less than complete protection from developing eye disease.

[0099] The present disclosure also provides a method for identifying a human subject at elevated risk for developing an eye disease, the method comprising detecting the presence or absence of a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encoding a human ANGPTL7 polypeptide in a biological sample from the patient, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is i) a genomic nucleic acid molecule having a nucleotide sequence comprising a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, or a complement thereof, or ii) a nucleotide sequence comprising a uracil at a position corresponding to position 529 according to SEQ ID NO:5. or iii) a cDNA molecule generated from the mRNA molecule and having a nucleotide sequence comprising a thymine at position 529 according to SEQ ID NO:8, or a complement thereof, wherein if the human subject is of the ANGPTL7 reference type, then the human subject is at increased risk of developing an eye disease; and if the human subject is a heterozygote for a predicted loss-of-function variant of ANGPTL7 or a homozygote for a predicted loss-of-function variant of ANGPTL7, then the human subject is at reduced risk of developing an eye disease. In some embodiments, the patient is of the ANGPTL7 reference type. In some embodiments, the patient is a heterozygote for a predicted loss-of-function variant of ANGPTL7.

[0100] The present disclosure also provides a method for identifying a human subject at elevated risk for developing an eye disease, the method comprising detecting the presence or absence of a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encoding a human ANGPTL7 polypeptide in a biological sample from the patient, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is i) a genomic nucleic acid molecule having a nucleotide sequence comprising a thymine at a position corresponding to position 4,287 according to SEQ ID NO: 3, or a complement thereof, or ii) a nucleotide sequence comprising a uracil at a position corresponding to position 525 according to SEQ ID NO: 6. or iii) a cDNA molecule generated from the mRNA molecule and having a nucleotide sequence comprising a thymine at position 525 according to SEQ ID NO:9, or its complement, wherein if the human subject is of the ANGPTL7 reference type, then the human subject is at increased risk of developing an eye disease; and if the human subject is a heterozygote for a predicted loss-of-function variant of ANGPTL7 or a homozygote for a predicted loss-of-function variant of ANGPTL7, then the human subject is at reduced risk of developing an eye disease. In some embodiments, the patient is of the ANGPTL7 reference type. In some embodiments, the patient is a heterozygote for a predicted loss-of-function variant of ANGPTL7.

[0101] The present disclosure also provides a method for identifying a human subject at elevated risk for developing an eye disease, the method comprising detecting the presence or absence of a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encoding a human ANGPTL7 polypeptide in a biological sample from the patient, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is i) a genomic nucleic acid molecule having a nucleotide sequence comprising an adenine at position 4,243 according to SEQ ID NO: 132, or a complement thereof, or ii) a nucleotide sequence comprising an adenine at position 481 according to SEQ ID NO: 135. or iii) a cDNA molecule generated from the mRNA molecule and having a nucleotide sequence comprising an adenine at position 481 according to SEQ ID NO: 138, or a complement thereof, wherein if the human subject is of the ANGPTL7 reference type, then the human subject is at increased risk of developing an eye disease; and if the human subject is a heterozygote for a predicted loss-of-function variant of ANGPTL7 or a homozygote for a predicted loss-of-function variant of ANGPTL7, then the human subject is at reduced risk of developing an eye disease. In some embodiments, the patient is of the ANGPTL7 reference type. In some embodiments, the patient is a heterozygote for a predicted loss-of-function variant of ANGPTL7.

[0102] The present disclosure also provides a method for identifying a human subject at elevated risk for developing an eye disease, the method comprising detecting the presence or absence of a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encoding a human ANGPTL7 polypeptide in a biological sample from the patient, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is i) a genomic nucleic acid molecule having a nucleotide sequence comprising an adenine at position 4,325 according to SEQ ID NO: 133, or a complement thereof, or ii) a nucleotide sequence comprising an adenine at position 563 according to SEQ ID NO: 136. or iii) a cDNA molecule, or its complement, generated from the mRNA molecule and having a nucleotide sequence comprising an adenine at position 563 according to SEQ ID NO: 139, or its complement, wherein if the human subject is of the ANGPTL7 reference type, then the human subject is at increased risk of developing an eye disease; and if the human subject is a heterozygote for a predicted loss-of-function variant of ANGPTL7 or a homozygote for a predicted loss-of-function variant of ANGPTL7, then the human subject is at reduced risk of developing an eye disease. In some embodiments, the patient is of the ANGPTL7 reference type. In some embodiments, the patient is a heterozygote for a predicted loss-of-function variant of ANGPTL7.

[0103] The present disclosure also provides a method for identifying a human subject at elevated risk for developing an eye disease, the method comprising detecting the presence or absence of a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encoding a human ANGPTL7 polypeptide in a biological sample from the patient, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is: i) a genomic nucleic acid molecule having a nucleotide sequence comprising a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, or a complement thereof; or ii) a nucleotide sequence comprising a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137. or iii) a cDNA molecule generated from the mRNA molecule and having a nucleotide sequence comprising a cytosine at position 574 according to SEQ ID NO: 140, or a complement thereof, wherein if the human subject is of the ANGPTL7 reference type, then the human subject is at increased risk of developing an eye disease; and if the human subject is a heterozygote for a predicted loss-of-function variant of ANGPTL7 or a homozygote for a predicted loss-of-function variant of ANGPTL7, then the human subject is at reduced risk of developing an eye disease. In some embodiments, the patient is of the ANGPTL7 reference type. In some embodiments, the patient is a heterozygote for a predicted loss-of-function variant of ANGPTL7.

[0104] The predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 can be any ANGPTL7 nucleic acid molecule (e.g., a genomic nucleic acid molecule, an mRNA molecule, or a cDNA molecule) that encodes an ANGPTL7 polypeptide having a partial loss of function, a complete loss of function, a predicted partial loss of function, or a predicted complete loss of function. For example, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 can be any nucleic acid molecule that encodes Gln175His, Arg177Stop, Trp188Stop, Lys192Gln, Phe161Ile, Arg340His, Arg220His, Asn302Lys, or Arg220Cys of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Gln175His, Arg177Stop, Trp188Stop, Lys192Gln, or Phe161Ile of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Gln175His, Trp188Stop, or Arg177Stop of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Gln175His of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Arg177Stop of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Trp188Stop of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Lys192Gln of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Phe161Ile of ANGPTL7.

[0105] In any of the embodiments described herein, the ocular disease is increased IOP, pre-glaucoma, glaucoma, or decreased corneal plasticity. In some embodiments, the ocular disease is increased IOP. In some embodiments, the increased IOP is IOPcc or IOPg. In some embodiments, the ocular disease is pre-glaucoma. In some embodiments, the ocular disease is glaucoma. In some embodiments, the glaucoma is primary open-angle glaucoma, angle-closure glaucoma, normal-tension glaucoma, congenital glaucoma, neovascular glaucoma, steroid-induced glaucoma, or glaucoma associated with ocular trauma. In some embodiments, the ocular disease is decreased corneal plasticity.

[0106] Determining the presence or absence of a particular nucleic acid molecule in a sample obtained from a subject can be or has been determined by any of the methods described herein. In some embodiments, these methods can be performed in vitro. In some embodiments, these methods can be performed in situ. In some embodiments, these methods can be performed in vivo.

[0107] In some embodiments, the determining step comprises i) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 4,291 according to SEQ ID NO:2, or a complement thereof, ii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 529 according to SEQ ID NO:5, or a complement thereof, and / or iii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 529 according to SEQ ID NO:8, or a complement thereof. If the sequenced portion of the ANGPTL7 genomic nucleic acid molecule from the biological sample comprises a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, then the ANGPTL7 genomic nucleic acid molecule from the biological sample is a genomic nucleic acid molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample contains a uracil at the position corresponding to position 529 according to SEQ ID NO: 5, then the ANGPTL7 mRNA molecule of the biological sample is an mRNA molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains a thymine at the position corresponding to position 529 according to SEQ ID NO: 8, then the ANGPTL7 cDNA molecule of the biological sample is a cDNA molecule of a predicted loss-of-function mutant of ANGPTL7.

[0108] In some embodiments, the determining step includes a) contacting the biological sample with a primer that hybridizes to: i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,291 according to SEQ ID NO:2, ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule adjacent to a position corresponding to position 529 according to SEQ ID NO:5, and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 529 according to SEQ ID NO:8; b) contacting the primer with at least: i) the position of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule corresponding to position 4,291 according to SEQ ID NO:2, ii) the position of the nucleotide sequence of an ANGPTL7 mRNA molecule corresponding to position 529 according to SEQ ID NO:5, and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 529 according to SEQ ID NO:8. and c) determining whether the extension product of the primer i) contains a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, ii) contains a uracil at a position corresponding to position 529 according to SEQ ID NO:5, and / or iii) contains a thymine at a position corresponding to position 529 according to SEQ ID NO:8.

[0109] In some embodiments, the determining step comprises: a) amplifying at least a portion of a nucleic acid molecule encoding a human ANGPTL7 polypeptide, wherein such portion comprises i) a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, or a complement thereof, ii) a uracil at a position corresponding to position 529 according to SEQ ID NO:5, or a complement thereof, or iii) a thymine at a position corresponding to position 529 according to SEQ ID NO:8, or a complement thereof; b) labeling the amplified nucleic acid molecule with a detectable label; and c) detecting a mutation-specific probe comprising the labeled nucleic acid molecule and a mutation-specific probe. and d) detecting the detectable label. In some embodiments, the nucleic acid molecule is mRNA, and the determining step further comprises reverse transcribing the mRNA into cDNA prior to the amplifying step.

[0110] In some embodiments, the determining step comprises contacting the nucleic acid molecule of the biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to i) a nucleotide sequence of the amplified nucleic acid molecule comprising thymine or its complement at a position corresponding to position 4,291 according to SEQ ID NO: 2, ii) a nucleotide sequence of the amplified nucleic acid molecule comprising uracil or its complement at a position corresponding to position 529 according to SEQ ID NO: 5, or iii) a nucleotide sequence of the amplified nucleic acid molecule comprising thymine or its complement at a position corresponding to position 529 according to SEQ ID NO: 8, and detecting the detectable label.

[0111] In some embodiments, the determining step comprises: i) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule of the biological sample, wherein the sequenced portion comprises a position corresponding to position 4,287 according to SEQ ID NO: 3, or a complement thereof; ii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule of the biological sample, wherein the sequenced portion comprises a position corresponding to position 525 according to SEQ ID NO: 6, or a complement thereof; and / or iii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule of the biological sample, wherein the sequenced portion comprises a position corresponding to position 525 according to SEQ ID NO: 9, or a complement thereof. If the sequenced portion of the ANGPTL7 genomic nucleic acid molecule of the biological sample comprises a thymine at a position corresponding to position 4,287 according to SEQ ID NO: 3, then the ANGPTL7 genomic nucleic acid molecule of the biological sample is a genomic nucleic acid molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample contains a uracil at the position corresponding to position 525 according to SEQ ID NO: 6, then the ANGPTL7 mRNA molecule of the biological sample is an mRNA molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains a thymine at the position corresponding to position 525 according to SEQ ID NO: 9, then the ANGPTL7 cDNA molecule of the biological sample is a cDNA molecule of a predicted loss-of-function mutant of ANGPTL7.

[0112] In some embodiments, the determining step includes a) contacting the biological sample with a primer that hybridizes to: i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,287 according to SEQ ID NO:3; ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule adjacent to a position corresponding to position 525 according to SEQ ID NO:6; and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 525 according to SEQ ID NO:9; b) contacting the primer with at least: i) the position of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule corresponding to position 4,287 according to SEQ ID NO:3; ii) the position of the nucleotide sequence of an ANGPTL7 mRNA molecule corresponding to position 525 according to SEQ ID NO:6; and / or iii) the position of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 525 according to SEQ ID NO:9. and c) determining whether the extension product of the primer i) contains a thymine at a position corresponding to position 4,287 according to SEQ ID NO:3, ii) contains a uracil at a position corresponding to position 525 according to SEQ ID NO:6, and / or iii) contains a thymine at a position corresponding to position 525 according to SEQ ID NO:9.

[0113] In some embodiments, the determining step comprises: a) amplifying at least a portion of a nucleic acid molecule encoding a human ANGPTL7 polypeptide, wherein such portion comprises i) a thymine at a position corresponding to position 4,287 according to SEQ ID NO: 3, or a complement thereof, ii) a uracil at a position corresponding to position 525 according to SEQ ID NO: 6, or a complement thereof, or iii) a thymine at a position corresponding to position 525 according to SEQ ID NO: 9, or a complement thereof; b) labeling the amplified nucleic acid molecule with a detectable label; and c) detecting a mutation-specific probe comprising the labeled nucleic acid molecule and a mutation-specific probe. and d) detecting the detectable label. In some embodiments, the nucleic acid molecule is mRNA, and the determining step further comprises reverse transcribing the mRNA into cDNA prior to the amplifying step.

[0114] In some embodiments, the determining step comprises contacting the nucleic acid molecule of the biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to i) a nucleotide sequence of the amplified nucleic acid molecule comprising thymine or its complement at a position corresponding to position 4,287 according to SEQ ID NO: 3, ii) a nucleotide sequence of the amplified nucleic acid molecule comprising uracil or its complement at a position corresponding to position 525 according to SEQ ID NO: 6, or iii) a nucleotide sequence of the amplified nucleic acid molecule comprising thymine or its complement at a position corresponding to position 525 according to SEQ ID NO: 9, and detecting the detectable label.

[0115] In some embodiments, the determining step comprises: i) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 4,243 according to SEQ ID NO: 132, or a complement thereof; ii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 481 according to SEQ ID NO: 135, or a complement thereof; and / or iii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 481 according to SEQ ID NO: 138, or a complement thereof. If the sequenced portion of the ANGPTL7 genomic nucleic acid molecule from the biological sample comprises an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, then the ANGPTL7 genomic nucleic acid molecule from the biological sample is a genomic nucleic acid molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample contains an adenine at the position corresponding to position 481 according to SEQ ID NO: 135, then the ANGPTL7 mRNA molecule of the biological sample is an mRNA molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains an adenine at the position corresponding to position 481 according to SEQ ID NO: 138, then the ANGPTL7 cDNA molecule of the biological sample is a cDNA molecule of a predicted loss-of-function mutant of ANGPTL7.

[0116] In some embodiments, the determining step includes: a) contacting the biological sample with a primer that hybridizes to i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,243 according to SEQ ID NO: 132, ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule adjacent to a position corresponding to position 481 according to SEQ ID NO: 135, and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 481 according to SEQ ID NO: 138; b) extending a primer through at least i) the position in the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule corresponding to position 4,243 according to SEQ ID NO: 132, ii) the position in the nucleotide sequence of an ANGPTL7 mRNA molecule corresponding to position 481 according to SEQ ID NO: 135, and / or iii) the position in the nucleotide sequence of an ANGPTL7 cDNA molecule corresponding to position 481 according to SEQ ID NO: 138, and c) determining whether the extension product of the primer i) contains an adenine at the position corresponding to position 4,243 according to SEQ ID NO: 132, ii) contains an adenine at the position corresponding to position 481 according to SEQ ID NO: 135, and / or iii) contains an adenine at the position corresponding to position 481 according to SEQ ID NO: 138.

[0117] In some embodiments, the determining step comprises: a) amplifying at least a portion of a nucleic acid molecule encoding a human ANGPTL7 polypeptide, wherein such portion comprises i) an adenine at a position corresponding to 4,243 according to SEQ ID NO: 132, or a complement thereof, ii) an adenine at a position corresponding to 481 according to SEQ ID NO: 135, and / or iii) an adenine at a position corresponding to 481 according to SEQ ID NO: 138, or a complement thereof; b) labeling the amplified nucleic acid molecule with a detectable label; c) combining the labeled nucleic acid molecule with a support comprising a mutation-specific probe. contacting, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to i) a nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 4,243 according to SEQ ID NO: 132, ii) a nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 481 according to SEQ ID NO: 135, and / or iii) a nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 481 according to SEQ ID NO: 138, and d) detecting the detectable label. In some embodiments, the nucleic acid molecule is mRNA, and the determining step further comprises reverse transcribing the mRNA into cDNA prior to the amplifying step.

[0118] In some embodiments, the determining step comprises contacting the nucleic acid molecule of the biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to a nucleotide sequence of an amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 4,243 according to SEQ ID NO: 132, a nucleotide sequence of an amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 481 according to SEQ ID NO: 135, and / or a nucleotide sequence of an amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 481 according to SEQ ID NO: 138, and detecting the detectable label.

[0119] In some embodiments, the determining step comprises: i) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 4,325 according to SEQ ID NO: 133, or a complement thereof; ii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 563 according to SEQ ID NO: 136, or a complement thereof; and / or iii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 563 according to SEQ ID NO: 139, or a complement thereof. If the sequenced portion of the ANGPTL7 genomic nucleic acid molecule from the biological sample comprises an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, then the ANGPTL7 genomic nucleic acid molecule from the biological sample is a genomic nucleic acid molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample contains an adenine at the position corresponding to position 563 according to SEQ ID NO: 136, then the ANGPTL7 mRNA molecule of the biological sample is an mRNA molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains an adenine at the position corresponding to position 563 according to SEQ ID NO: 139, then the ANGPTL7 cDNA molecule of the biological sample is a cDNA molecule of a predicted loss-of-function mutant of ANGPTL7.

[0120] In some embodiments, the determining step includes: a) contacting the biological sample with a primer that hybridizes to i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,325 according to SEQ ID NO: 133, ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule adjacent to a position corresponding to position 563 according to SEQ ID NO: 136, and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 563 according to SEQ ID NO: 139; b) extending a primer through at least i) the position in the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule corresponding to position 4,325 according to SEQ ID NO: 133, ii) the position in the nucleotide sequence of an ANGPTL7 mRNA molecule corresponding to position 563 according to SEQ ID NO: 136, and / or iii) the position in the nucleotide sequence of an ANGPTL7 cDNA molecule corresponding to position 563 according to SEQ ID NO: 139; and c) determining whether the extension product of the primer i) contains an adenine at the position corresponding to position 4,325 according to SEQ ID NO: 133, ii) contains an adenine at the position corresponding to position 563 according to SEQ ID NO: 136, and / or iii) contains an adenine at the position corresponding to position 563 according to SEQ ID NO: 139.

[0121] In some embodiments, the determining step comprises: a) amplifying at least a portion of a nucleic acid molecule encoding a human ANGPTL7 polypeptide, wherein such portion comprises i) an adenine at a position corresponding to 4,325 according to SEQ ID NO: 133, or its complement, ii) an adenine at a position corresponding to 563 according to SEQ ID NO: 136, or its complement, and / or iii) an adenine at a position corresponding to 563 according to SEQ ID NO: 139, or its complement; b) labeling the amplified nucleic acid molecule with a detectable label; and c) detecting a mutation-specific probe comprising the labeled nucleic acid molecule and a mutation-specific probe. and d) detecting the detectable label. In some embodiments, the nucleic acid molecule is mRNA, and the determining step further comprises reverse transcribing the mRNA into cDNA prior to the amplifying step.

[0122] In some embodiments, the determining step comprises contacting the nucleic acid molecule of the biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to the nucleotide sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 4,325 according to SEQ ID NO: 133, the nucleotide sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 563 according to SEQ ID NO: 136, and / or the nucleotide sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 563 according to SEQ ID NO: 139, and detecting the detectable label.

[0123] In some embodiments, the determining step comprises i) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 4,336 according to SEQ ID NO: 134, or a complement thereof, ii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 574 according to SEQ ID NO: 137, or a complement thereof, and / or iii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 574 according to SEQ ID NO: 140, or a complement thereof. If the sequenced portion of the ANGPTL7 genomic nucleic acid molecule from the biological sample comprises a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, then the ANGPTL7 genomic nucleic acid molecule from the biological sample is a genomic nucleic acid molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample contains a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, then the ANGPTL7 mRNA molecule of the biological sample is an mRNA molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140, then the ANGPTL7 cDNA molecule of the biological sample is a cDNA molecule of a predicted loss-of-function mutant of ANGPTL7.

[0124] In some embodiments, the determining step includes: a) contacting the biological sample with a primer that hybridizes to i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,336 according to SEQ ID NO: 134, ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule adjacent to a position corresponding to position 574 according to SEQ ID NO: 137, and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 574 according to SEQ ID NO: 140; b) extending a primer through at least i) the position in the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule corresponding to position 4,336 according to SEQ ID NO: 134, ii) the position in the nucleotide sequence of an ANGPTL7 mRNA molecule corresponding to position 574 according to SEQ ID NO: 137, and / or iii) the position in the nucleotide sequence of an ANGPTL7 cDNA molecule corresponding to position 574 according to SEQ ID NO: 140; and c) determining whether the extension product of the primer i) contains a cytosine at the position corresponding to position 4,336 according to SEQ ID NO: 134, ii) contains a cytosine at the position corresponding to position 574 according to SEQ ID NO: 137, and / or iii) contains a cytosine at the position corresponding to position 574 according to SEQ ID NO: 140.

[0125] In some embodiments, the determining step includes: a) amplifying at least a portion of a nucleic acid molecule encoding a human ANGPTL7 polypeptide, wherein such portion comprises i) a cytosine at a position corresponding to 4,336 according to SEQ ID NO: 134, or a complement thereof, ii) a cytosine at a position corresponding to 574 according to SEQ ID NO: 137, and / or iii) a cytosine at a position corresponding to 574 according to SEQ ID NO: 140, or a complement thereof; b) labeling the amplified nucleic acid molecule with a detectable label; c) combining the labeled nucleic acid molecule with a support comprising a variation-specific probe. contacting, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to i) a nucleic acid sequence of the amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 4,336 according to SEQ ID NO: 134, ii) a nucleic acid sequence of the amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 574 according to SEQ ID NO: 137, and / or iii) a nucleic acid sequence of the amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 574 according to SEQ ID NO: 140, and d) detecting the detectable label. In some embodiments, the nucleic acid molecule is mRNA, and the determining step further comprises reverse transcribing the mRNA into cDNA prior to the amplifying step.

[0126] In some embodiments, the determining step comprises contacting the nucleic acid molecule of the biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to a nucleotide sequence of an amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 4,336 according to SEQ ID NO: 134, a nucleotide sequence of an amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 574 according to SEQ ID NO: 137, and / or a nucleotide sequence of an amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 574 according to SEQ ID NO: 140, and detecting the detectable label.

[0127] In any of these embodiments, the nucleic acid molecule can be present in a cell obtained from a human subject. In some embodiments, the human subject is further treated with a therapeutic agent that treats or inhibits an ocular disease and / or an ANGPTL7 inhibitor, as described herein. For example, if a human subject is of the ANGPTL7 reference type and is therefore at increased risk of developing an ocular disease, the human subject is administered an ANGPTL7 inhibitor. In some embodiments, such a patient is also administered a therapeutic agent that treats or inhibits an ocular disease. In some embodiments, if the patient is heterozygous for a predicted loss-of-function variant of ANGPTL7, the patient is administered a therapeutic agent that treats or inhibits an ocular disease at a dose that is the same as or lower than the standard dose, and is also administered an ANGPTL7 inhibitor. In some embodiments, the patient is of the ANGPTL7 reference type. In some embodiments, the patient is heterozygous for a predicted loss-of-function variant of ANGPTL7.

[0128] The present disclosure also provides methods for detecting the presence of predicted loss-of-function mutant ANGPTL7 genomic nucleic acid molecules, predicted loss-of-function mutant mRNA molecules, and / or predicted loss-of-function mutant cDNA molecules of ANGPTL7 in a biological sample from a human subject. It is understood that gene sequences and mRNA molecules encoded by such genes within a population may vary due to polymorphisms, such as single nucleotide polymorphisms. The sequences of ANGPTL7 mutant genomic nucleic acid molecules, ANGPTL7 mutant mRNA molecules, and ANGPTL7 mutant cDNA molecules provided herein are merely exemplary sequences. Other sequences of ANGPTL7 mutant genomic nucleic acid molecules, mutant mRNA molecules, and mutant cDNA molecules are also possible.

[0129] A biological sample can be derived from any cell, tissue, or biological fluid from a subject. The sample can include any clinically relevant tissue, such as a bone marrow sample, tumor biopsy, fine needle aspirate, or a bodily fluid sample, such as blood, gingival crevicular fluid, plasma, serum, lymph, ascites, cyst fluid, or urine. In some cases, the sample includes a buccal swab. The samples used in the methods disclosed herein vary based on the assay format, the nature of the detection method, and the tissue, cell, or extract used as the sample. The biological sample can be processed differently depending on the assay used. For example, when detecting any ANGPTL7 mutant nucleic acid molecule, a preliminary treatment designed to isolate or enrich the sample for genomic DNA can be used. A wide variety of known techniques can be used for this purpose. When detecting any ANGPTL7 mutant mRNA level, different techniques can be used to enrich the biological sample for mRNA. A variety of methods can be used to detect the presence or level of mRNA or the presence of a specific mutant genomic DNA locus.

[0130] In some embodiments, a method for detecting a predicted loss-of-function mutant nucleic acid molecule of human ANGPTL7 in a human subject comprises assaying a biological sample obtained from the human subject to determine whether the ANGPTL7 genomic nucleic acid molecule, ANGPTL7 mRNA molecule, or ANGPTL7 cDNA molecule in the biological sample contains one or more mutations that cause or are predicted to cause loss-of-function (partial or complete). For example, in some embodiments, a method for detecting a predicted loss-of-function mutant nucleic acid molecule of human ANGPTL7 in a human subject comprises assaying a biological sample obtained from the subject to determine whether the ANGPTL7 nucleic acid molecule in the biological sample contains a nucleotide sequence comprising: i) a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, or its complement; ii) a uracil at a position corresponding to position 529 according to SEQ ID NO:5, or its complement; or iii) a thymine at a position corresponding to position 529 according to SEQ ID NO:8, or its complement. In some embodiments, the method is an in vitro method.

[0131] In some embodiments, a method for detecting the presence or absence of a predicted loss-of-function mutant nucleic acid molecule (e.g., a genomic nucleic acid molecule, an mRNA molecule, and / or a cDNA molecule, etc.) of ANGPTL7 in a human subject comprises performing an assay on a biological sample obtained from the human subject, wherein the assay determines whether a nucleic acid molecule of the biological sample comprises a nucleotide sequence encoding i) a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2 (the genomic nucleic acid molecule), ii) a uracil at a position corresponding to position 529 according to SEQ ID NO:5 (the mRNA molecule), or iii) a thymine at a position corresponding to position 529 according to SEQ ID NO:8 (the cDNA molecule). In some embodiments, the biological sample comprises a cell or a cell lysate. Such methods can further include, for example, obtaining a biological sample from a subject containing an ANGPTL7 genomic nucleic acid molecule or mRNA molecule, optionally reverse transcribing the mRNA into cDNA in the case of mRNA, and performing an assay on the biological sample to determine that the position of the ANGPTL7 genomic nucleic acid molecule, mRNA, or cDNA encodes a thymine at position corresponding to position 4,291 according to SEQ ID NO: 2, a uracil at position corresponding to position 529 according to SEQ ID NO: 5, or a thymine at position corresponding to position 529 according to SEQ ID NO: 8, respectively. Such an assay can include, for example, determining the uniqueness of these positions in a particular ANGPTL7 nucleic acid molecule. In some embodiments, the method is an in vitro method.

[0132] In some embodiments, the assay comprises sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule, an ANGPTL7 mRNA molecule, or an ANGPTL7 cDNA molecule in a biological sample, wherein the sequenced portion comprises one or more mutations that cause partial or complete loss of function. For example, in some embodiments, the assay comprises: i) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule in a biological sample, wherein the sequenced portion comprises a position corresponding to position 4,291 according to SEQ ID NO: 2, or a complement thereof; ii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule in a biological sample, wherein the sequenced portion comprises a position corresponding to position 529 according to SEQ ID NO: 5, or a complement thereof; or iii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule in a biological sample, wherein the sequenced portion comprises a position corresponding to position 529 according to SEQ ID NO: 8, or a complement thereof. If a sequenced portion of an ANGPTL7 genomic nucleic acid molecule from a biological sample contains a thymine at a position corresponding to position 4,291 according to SEQ ID NO: 2, then the ANGPTL7 genomic nucleic acid molecule from that biological sample is a genomic nucleic acid molecule of a predicted loss-of-function mutant of ANGPTL7. If a sequenced portion of an ANGPTL7 mRNA molecule from a biological sample contains a uracil at a position corresponding to position 529 according to SEQ ID NO: 5, then the ANGPTL7 mRNA molecule from that biological sample is an mRNA molecule of a predicted loss-of-function mutant of ANGPTL7. If a sequenced portion of an ANGPTL7 cDNA molecule from a biological sample contains a thymine at a position corresponding to position 529 according to SEQ ID NO: 8, then the ANGPTL7 cDNA molecule from that biological sample is a cDNA molecule of a predicted loss-of-function mutant of ANGPTL7.

[0133] In some embodiments, the assay comprises: a) contacting a biological sample with a primer that hybridizes to: i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,291 according to SEQ ID NO:2; ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule adjacent to a position corresponding to position 529 according to SEQ ID NO:5; or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 529 according to SEQ ID NO:8; b) contacting the primer with at least: i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule corresponding to position 4,291 according to SEQ ID NO:2; ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule corresponding to position 529 according to SEQ ID NO:5; or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 529 according to SEQ ID NO:8. and c) determining whether the extension product of the primer i) contains a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, ii) contains a uracil at a position corresponding to position 529 according to SEQ ID NO:5, or iii) contains a thymine at a position corresponding to position 529 according to SEQ ID NO:8. In some embodiments, the assay comprises sequencing the entire nucleic acid molecule. In some embodiments, only the ANGPTL7 genomic nucleic acid molecule is analyzed. In some embodiments, only the ANGPTL7 mRNA is analyzed. In some embodiments, the ANGPTL7 mRNA obtained from the ANGPTL7 genomic nucleic acid molecule is analyzed. Only the cDNA is analyzed.

[0134] In some embodiments, the assay comprises: a) amplifying at least a portion of a nucleic acid molecule encoding a human ANGPTL7 polypeptide, wherein such portion comprises i) a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, or its complement; ii) a uracil at a position corresponding to position 529 according to SEQ ID NO:5, or its complement; or iii) a thymine at a position corresponding to position 529 according to SEQ ID NO:8, or its complement; b) labeling the amplified nucleic acid molecule with a detectable label; and c) comprising a labeled nucleic acid molecule and a mutation-specific probe. and d) detecting the detectable label. In some embodiments, the nucleic acid molecule is mRNA, and the determining step further comprises reverse transcribing the mRNA into cDNA prior to the amplifying step.

[0135] In some embodiments, the assay includes contacting a nucleic acid molecule of a biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to a nucleotide sequence of an amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 4,291 according to SEQ ID NO:2, a uracil or its complement at a position corresponding to position 529 according to SEQ ID NO:5, or a thymine or its complement at a position corresponding to position 529 according to SEQ ID NO:8, and detecting the detectable label. Variation-specific polymerase chain reaction techniques can be used to detect mutations, such as SNPs, in nucleic acid sequences. Variation-specific primers can be used because DNA polymerase will not extend if a mismatch with the template is present.

[0136] In some embodiments, a method for detecting a predicted loss-of-function mutant nucleic acid molecule of human ANGPTL7 in a human subject comprises assaying a biological sample obtained from the subject to determine whether an ANGPTL7 nucleic acid molecule in the biological sample comprises a nucleotide sequence comprising: i) a thymine at a position corresponding to position 4,287 according to SEQ ID NO: 3, or a complement thereof, ii) a uracil at a position corresponding to position 525 according to SEQ ID NO: 6, or a complement thereof, or iii) a thymine at a position corresponding to position 525 according to SEQ ID NO: 9, or a complement thereof. In some embodiments, the method is an in vitro method.

[0137] In some embodiments, a method for detecting the presence or absence of a predicted loss-of-function mutant nucleic acid molecule (e.g., a genomic nucleic acid molecule, an mRNA molecule, and / or a cDNA molecule, etc.) of ANGPTL7 in a human subject comprises performing an assay on a biological sample obtained from the human subject, wherein the assay determines whether a nucleic acid molecule of the biological sample comprises a nucleotide sequence encoding i) a thymine at a position corresponding to position 4,287 according to SEQ ID NO:3 (the genomic nucleic acid molecule), ii) a uracil at a position corresponding to position 525 according to SEQ ID NO:6 (the mRNA molecule), or iii) a thymine at a position corresponding to position 525 according to SEQ ID NO:9 (the cDNA molecule). In some embodiments, the biological sample comprises a cell or a cell lysate. Such a method can further include, for example, obtaining a biological sample from a subject containing an ANGPTL7 genomic nucleic acid molecule or mRNA molecule, optionally reverse transcribing the mRNA into cDNA in the case of mRNA, and performing an assay on the biological sample to determine that the position of the ANGPTL7 genomic nucleic acid molecule, mRNA, or cDNA encodes a thymine at position corresponding to position 4,287 according to SEQ ID NO: 3, a uracil at position corresponding to position 525 according to SEQ ID NO: 6, or a thymine at position corresponding to position 525 according to SEQ ID NO: 9, respectively. Such an assay can include, for example, determining the uniqueness of these positions in a particular ANGPTL7 nucleic acid molecule. In some embodiments, the method is an in vitro method.

[0138] In some embodiments, the assay comprises sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule, an ANGPTL7 mRNA molecule, or an ANGPTL7 cDNA molecule in a biological sample, wherein the sequenced portion comprises one or more mutations that cause partial or complete loss of function.For example, in some embodiments, the assay comprises: i) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule in a biological sample, wherein the sequenced portion comprises a position corresponding to position 4,287 according to SEQ ID NO:3, or a complement thereof; ii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule in a biological sample, wherein the sequenced portion comprises a position corresponding to position 525 according to SEQ ID NO:6, or a complement thereof; or iii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule in a biological sample, wherein the sequenced portion comprises a position corresponding to position 525 according to SEQ ID NO:9, or a complement thereof. If the sequenced portion of the ANGPTL7 genomic nucleic acid molecule of the biological sample contains a thymine at a position corresponding to position 4,287 according to SEQ ID NO: 3, the ANGPTL7 genomic nucleic acid molecule of the biological sample is a genomic nucleic acid molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample contains a uracil at a position corresponding to position 525 according to SEQ ID NO: 6, the ANGPTL7 mRNA molecule of the biological sample is an mRNA molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains a thymine at a position corresponding to position 525 according to SEQ ID NO: 9, the ANGPTL7 cDNA molecule of the biological sample is a cDNA molecule of a predicted loss-of-function mutant of ANGPTL7.

[0139] In some embodiments, the assay comprises: a) contacting a biological sample with a primer that hybridizes to i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,287 according to SEQ ID NO:3, ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule adjacent to a position corresponding to position 525 according to SEQ ID NO:6, or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 525 according to SEQ ID NO:9; and b) contacting the primer with at least: i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule corresponding to position 4,287 according to SEQ ID NO:3, ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule corresponding to position 525 according to SEQ ID NO:6, or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 525 according to SEQ ID NO:9. and c) determining whether the extension product of the primer i) contains a thymine at a position corresponding to position 4,287 according to SEQ ID NO:3, ii) contains a uracil at a position corresponding to position 525 according to SEQ ID NO:6, or iii) contains a thymine at a position corresponding to position 525 according to SEQ ID NO:9. In some embodiments, the assay comprises sequencing the entire nucleic acid molecule. In some embodiments, only the ANGPTL7 genomic nucleic acid molecule is analyzed. In some embodiments, only the ANGPTL7 mRNA is analyzed. In some embodiments, the ANGPTL7 mRNA obtained from the ANGPTL7 genomic nucleic acid molecule is analyzed. Only the cDNA is analyzed.

[0140] In some embodiments, the assay comprises: a) amplifying at least a portion of a nucleic acid molecule encoding a human ANGPTL7 polypeptide, wherein such portion comprises i) a thymine at a position corresponding to position 4,287 according to SEQ ID NO: 3, or its complement; ii) a uracil at a position corresponding to position 525 according to SEQ ID NO: 6, or its complement; or iii) a thymine at a position corresponding to position 525 according to SEQ ID NO: 9, or its complement; b) labeling the amplified nucleic acid molecule with a detectable label; and c) comprising a labeled nucleic acid molecule and a mutation-specific probe. and d) detecting the detectable label. In some embodiments, the nucleic acid molecule is mRNA, and the determining step further comprises reverse transcribing the mRNA into cDNA prior to the amplifying step.

[0141] In some embodiments, the assay includes contacting a nucleic acid molecule of a biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to a nucleotide sequence of an amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 4,287 according to SEQ ID NO: 3, a uracil or its complement at a position corresponding to position 525 according to SEQ ID NO: 6, or a thymine or its complement at a position corresponding to position 525 according to SEQ ID NO: 9, and detecting the detectable label. Variation-specific polymerase chain reaction techniques can be used to detect mutations, such as SNPs, in nucleic acid sequences. Variation-specific primers can be used because DNA polymerase will not extend if a mismatch with the template is present.

[0142] In some embodiments, a method for detecting a predicted loss-of-function mutant nucleic acid molecule of human ANGPTL7 in a human subject comprises assaying a biological sample obtained from the subject to determine whether an ANGPTL7 nucleic acid molecule in the biological sample comprises a nucleotide sequence including: i) an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, or a complement thereof, ii) an adenine at a position corresponding to position 481 according to SEQ ID NO: 135, or a complement thereof, or iii) an adenine at a position corresponding to position 481 according to SEQ ID NO: 138, or a complement thereof. In some embodiments, the method is an in vitro method.

[0143] In some embodiments, a method for detecting the presence or absence of a predicted loss-of-function mutant nucleic acid molecule (e.g., a genomic nucleic acid molecule, an mRNA molecule, and / or a cDNA molecule, etc.) of ANGPTL7 in a human subject comprises performing an assay on a biological sample obtained from the human subject, wherein the assay determines whether a nucleic acid molecule of the biological sample comprises a nucleotide sequence encoding i) an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, or its complement, ii) an adenine at a position corresponding to position 481 according to SEQ ID NO: 135, and / or iii) an adenine at a position corresponding to position 481 according to SEQ ID NO: 138. In some embodiments, the biological sample comprises a cell or a cell lysate. Such methods can further include, for example, obtaining a biological sample from a subject containing an ANGPTL7 genomic nucleic acid molecule or mRNA molecule, optionally reverse transcribing the mRNA into cDNA in the case of mRNA, and performing an assay on the biological sample to determine that the positions of the ANGPTL7 genomic nucleic acid molecule, mRNA, or cDNA encode an adenine at position 4,243 according to SEQ ID NO: 132, an adenine at position 481 according to SEQ ID NO: 135, or an adenine at position 481 according to SEQ ID NO: 138, respectively. Such an assay can include, for example, determining the uniqueness of these positions in a particular ANGPTL7 nucleic acid molecule. In some embodiments, the method is an in vitro method.

[0144] In some embodiments, the assay comprises: i) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 4,243 according to SEQ ID NO: 132, or a complement thereof; ii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 481 according to SEQ ID NO: 135, or a complement thereof; and / or iii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 481 according to SEQ ID NO: 138, or a complement thereof. If the sequenced portion of the ANGPTL7 genomic nucleic acid molecule from the biological sample comprises an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, then the ANGPTL7 genomic nucleic acid molecule from the biological sample is a genomic nucleic acid molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample contains an adenine at the position corresponding to position 481 according to SEQ ID NO: 135, then the ANGPTL7 mRNA molecule of the biological sample is an mRNA molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains an adenine at the position corresponding to position 481 according to SEQ ID NO: 138, then the ANGPTL7 cDNA molecule of the biological sample is a cDNA molecule of a predicted loss-of-function mutant of ANGPTL7.

[0145] In some embodiments, the assay comprises: a) contacting a biological sample with a primer that hybridizes to: i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,243 according to SEQ ID NO: 132; ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule adjacent to a position corresponding to position 481 according to SEQ ID NO: 135; and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 481 according to SEQ ID NO: 138; b) contacting the primer with at least: i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule corresponding to position 4,243 according to SEQ ID NO: 132; ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule corresponding to position 481 according to SEQ ID NO: 135; and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 481 according to SEQ ID NO: 138. and c) determining whether the extension product of the primer i) contains an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, ii) contains an adenine at a position corresponding to position 481 according to SEQ ID NO: 135, and / or iii) contains an adenine at a position corresponding to position 481 according to SEQ ID NO: 138.

[0146] In some embodiments, the assay comprises: a) amplifying at least a portion of a nucleic acid molecule encoding a human ANGPTL7 polypeptide, wherein such portion comprises i) an adenine at a position corresponding to 4,243 according to SEQ ID NO: 132, or its complement, ii) an adenine at a position corresponding to 481 according to SEQ ID NO: 135, and / or iii) an adenine at a position corresponding to 481 according to SEQ ID NO: 138, or its complement; b) labeling the amplified nucleic acid molecule with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising a mutation-specific probe. and d) detecting the detectable label. In some embodiments, the nucleic acid molecule is mRNA, and the determining step further comprises reverse transcribing the mRNA into cDNA prior to the amplifying step.

[0147] In some embodiments, the assay comprises contacting a nucleic acid molecule of a biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to a nucleotide sequence of an amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 4,243 according to SEQ ID NO: 132, a nucleotide sequence of an amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 481 according to SEQ ID NO: 135, and / or a nucleotide sequence of an amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 481 according to SEQ ID NO: 138, and detecting the detectable label.

[0148] In some embodiments, a method for detecting a predicted loss-of-function mutant nucleic acid molecule of human ANGPTL7 in a human subject comprises assaying a biological sample obtained from the subject to determine whether an ANGPTL7 nucleic acid molecule in the biological sample comprises a nucleotide sequence including: i) an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, or a complement thereof, ii) an adenine at a position corresponding to position 563 according to SEQ ID NO: 136, or a complement thereof, or iii) an adenine at a position corresponding to position 563 according to SEQ ID NO: 139, or a complement thereof. In some embodiments, the method is an in vitro method.

[0149] In some embodiments, a method for detecting the presence or absence of a predicted loss-of-function mutant nucleic acid molecule (e.g., a genomic nucleic acid molecule, an mRNA molecule, and / or a cDNA molecule, etc.) of ANGPTL7 in a human subject comprises performing an assay on a biological sample obtained from the human subject, wherein the assay determines whether a nucleic acid molecule of the biological sample comprises a nucleotide sequence encoding i) an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, ii) an adenine at a position corresponding to position 563 according to SEQ ID NO: 136, and / or iii) an adenine at a position corresponding to position 563 according to SEQ ID NO: 139. In some embodiments, the biological sample comprises a cell or a cell lysate. Such a method can further include, for example, obtaining a biological sample from a subject containing an ANGPTL7 genomic nucleic acid molecule or mRNA molecule, optionally reverse transcribing the mRNA into cDNA in the case of mRNA, and performing an assay on the biological sample to determine that the positions of the ANGPTL7 genomic nucleic acid molecule, mRNA, or cDNA encode an adenine at position 4,325 according to SEQ ID NO: 133, an adenine at position 563 according to SEQ ID NO: 136, or an adenine at position 563 according to SEQ ID NO: 139, respectively. Such an assay can include, for example, determining the uniqueness of these positions in a particular ANGPTL7 nucleic acid molecule. In some embodiments, the method is an in vitro method.

[0150] In some embodiments, the assay comprises: i) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 4,325 according to SEQ ID NO: 133, or a complement thereof; ii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 563 according to SEQ ID NO: 136, or a complement thereof; and / or iii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 563 according to SEQ ID NO: 139, or a complement thereof. If the sequenced portion of the ANGPTL7 genomic nucleic acid molecule from the biological sample comprises an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, then the ANGPTL7 genomic nucleic acid molecule from the biological sample is a genomic nucleic acid molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample contains an adenine at the position corresponding to position 563 according to SEQ ID NO: 136, then the ANGPTL7 mRNA molecule of the biological sample is an mRNA molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains an adenine at the position corresponding to position 563 according to SEQ ID NO: 139, then the ANGPTL7 cDNA molecule of the biological sample is a cDNA molecule of a predicted loss-of-function mutant of ANGPTL7.

[0151] In some embodiments, the assay comprises: a) contacting a biological sample with a primer that hybridizes to: i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,325 according to SEQ ID NO: 133; ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule adjacent to a position corresponding to position 563 according to SEQ ID NO: 136; and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 563 according to SEQ ID NO: 139; b) contacting the primer with at least: i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule corresponding to position 4,325 according to SEQ ID NO: 133; ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule corresponding to position 563 according to SEQ ID NO: 136; and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 563 according to SEQ ID NO: 139. and c) determining whether the extension product of the primer i) contains an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, ii) contains an adenine at a position corresponding to position 563 according to SEQ ID NO: 136, and / or iii) contains an adenine at a position corresponding to position 563 according to SEQ ID NO: 139.

[0152] In some embodiments, the assay comprises: a) amplifying at least a portion of a nucleic acid molecule encoding a human ANGPTL7 polypeptide, wherein such portion comprises i) an adenine at a position corresponding to 4,325 according to SEQ ID NO: 133, or its complement, ii) an adenine at a position corresponding to 563 according to SEQ ID NO: 136, or its complement, and / or iii) an adenine at a position corresponding to 563 according to SEQ ID NO: 139, or its complement; b) labeling the amplified nucleic acid molecule with a detectable label; c) amplifying the amplified nucleic acid molecule using a support comprising the labeled nucleic acid molecule and a mutation-specific probe. and d) detecting the detectable label. In some embodiments, the nucleic acid molecule is mRNA, and the determining step further comprises reverse transcribing the mRNA into cDNA prior to the amplifying step.

[0153] In some embodiments, the assay comprises contacting a nucleic acid molecule of a biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to a nucleotide sequence of an amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 4,325 according to SEQ ID NO: 133, a nucleotide sequence of an amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 563 according to SEQ ID NO: 136, and / or a nucleotide sequence of an amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 563 according to SEQ ID NO: 139, and detecting the detectable label.

[0154] In some embodiments, a method for detecting a predicted loss-of-function mutant nucleic acid molecule of human ANGPTL7 in a human subject comprises assaying a biological sample obtained from the subject to determine whether an ANGPTL7 nucleic acid molecule in the biological sample comprises a nucleotide sequence including: i) a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, or a complement thereof, ii) a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, or a complement thereof, or iii) a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140, or a complement thereof. In some embodiments, the method is an in vitro method.

[0155] In some embodiments, a method for detecting the presence or absence of a predicted loss-of-function mutant nucleic acid molecule (e.g., a genomic nucleic acid molecule, an mRNA molecule, and / or a cDNA molecule, etc.) of ANGPTL7 in a human subject comprises performing an assay on a biological sample obtained from the human subject, wherein the assay determines whether a nucleic acid molecule of the biological sample comprises a nucleotide sequence encoding i) a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, ii) a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, and / or iii) a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140. In some embodiments, the biological sample comprises a cell or a cell lysate. Such methods can further include, for example, obtaining a biological sample from a subject containing an ANGPTL7 genomic nucleic acid molecule or mRNA molecule, optionally reverse transcribing the mRNA into cDNA in the case of mRNA, and performing an assay on the biological sample to determine that the positions of the ANGPTL7 genomic nucleic acid molecule, mRNA, or cDNA encode a cytosine at position 4,336 according to SEQ ID NO: 134, a cytosine at position 574 according to SEQ ID NO: 137, or a cytosine at position 574 according to SEQ ID NO: 140, respectively. Such an assay can include, for example, determining the uniqueness of these positions in a particular ANGPTL7 nucleic acid molecule. In some embodiments, the method is an in vitro method.

[0156] In some embodiments, the assay comprises: i) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 4,336 according to SEQ ID NO: 134, or a complement thereof; ii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 574 according to SEQ ID NO: 137, or a complement thereof; and / or iii) sequencing at least a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule from the biological sample, wherein the sequenced portion comprises a position corresponding to position 574 according to SEQ ID NO: 140, or a complement thereof. If the sequenced portion of the ANGPTL7 genomic nucleic acid molecule from the biological sample comprises a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, then the ANGPTL7 genomic nucleic acid molecule from the biological sample is a genomic nucleic acid molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample contains a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, then the ANGPTL7 mRNA molecule of the biological sample is an mRNA molecule of a predicted loss-of-function mutant of ANGPTL7. If the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140, then the ANGPTL7 cDNA molecule of the biological sample is a cDNA molecule of a predicted loss-of-function mutant of ANGPTL7.

[0157] In some embodiments, the assay comprises: a) contacting a biological sample with a primer that hybridizes to: i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,336 according to SEQ ID NO: 134; ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule adjacent to a position corresponding to position 574 according to SEQ ID NO: 137; and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 574 according to SEQ ID NO: 140; b) contacting the primer with at least: i) a portion of the nucleotide sequence of an ANGPTL7 genomic nucleic acid molecule corresponding to position 4,336 according to SEQ ID NO: 134; ii) a portion of the nucleotide sequence of an ANGPTL7 mRNA molecule corresponding to position 574 according to SEQ ID NO: 137; and / or iii) a portion of the nucleotide sequence of an ANGPTL7 cDNA molecule adjacent to a position corresponding to position 574 according to SEQ ID NO: 140. and c) determining whether the extension product of the primer i) contains a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, ii) contains a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, and / or iii) contains a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140.

[0158] In some embodiments, the assay comprises: a) amplifying at least a portion of a nucleic acid molecule encoding a human ANGPTL7 polypeptide, wherein such portion comprises i) a cytosine at a position corresponding to 4,336 according to SEQ ID NO: 134, or its complement, ii) a cytosine at a position corresponding to 574 according to SEQ ID NO: 137, and / or iii) a cytosine at a position corresponding to 574 according to SEQ ID NO: 140, or its complement; b) labeling the amplified nucleic acid molecule with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising a mutation-specific probe. and d) detecting the detectable label. In some embodiments, the nucleic acid molecule is mRNA, and the determining step further comprises reverse transcribing the mRNA into cDNA prior to the amplifying step.

[0159] In some embodiments, the assay comprises contacting a nucleic acid molecule of a biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to a nucleotide sequence of an amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 4,336 according to SEQ ID NO: 134, a nucleotide sequence of an amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 574 according to SEQ ID NO: 137, and / or a nucleotide sequence of an amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 574 according to SEQ ID NO: 140, and detecting the detectable label.

[0160] In some embodiments, the nucleic acid molecule of the sample is mRNA, and the mRNA is reverse transcribed into cDNA prior to the amplification step. In some embodiments, the nucleic acid molecule is present in a cell obtained from a human subject.

[0161] The predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 can be any ANGPTL7 nucleic acid molecule (e.g., a genomic nucleic acid molecule, an mRNA molecule, or a cDNA molecule) that encodes an ANGPTL7 polypeptide having a partial loss of function, a complete loss of function, a predicted partial loss of function, or a predicted complete loss of function. For example, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 can be any nucleic acid molecule that encodes Gln175His, Arg177Stop, Trp188Stop, Lys192Gln, Phe161Ile, Arg340His, Arg220His, Asn302Lys, or Arg220Cys of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Gln175His, Arg177Stop, Trp188Stop, Lys192Gln, or Phe161Ile of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Gln175His, Trp188Stop, or Arg177Stop of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Gln175His of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Arg177Stop of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Trp188Stop of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Lys192Gln of ANGPTL7. In some embodiments, the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encodes Phe161Ile of ANGPTL7.

[0162] In some embodiments, the assay involves contacting the biological sample with a primer or probe, such as a mutation-specific primer or a mutation-specific probe, that specifically hybridizes to the ANGPTL7 variant genomic sequence, variant mRNA sequence, or variant cDNA sequence under stringent conditions and does not hybridize to the corresponding ANGPTL7 reference sequence, and determining whether hybridization occurs.

[0163] In some embodiments, the assay comprises RNA sequencing (RNA-Seq). In some embodiments, the assay also comprises reverse transcribing mRNA into cDNA, such as by reverse transcription polymerase chain reaction (RT-PCR).

[0164] In some embodiments, the methods utilize probes and primers of sufficient nucleotide length to bind to target nucleotide sequences and specifically detect and / or identify polynucleotides comprising mutant ANGPTL7 genomic nucleic acid molecules, mutant mRNA molecules, or mutant cDNA molecules. Hybridization or reaction conditions can be determined by the operator to achieve this result. The nucleotide length can be any length sufficient for use in the detection method of choice, including any of the assays described or exemplified herein. Such probes and primers can specifically hybridize to the target nucleotide sequence under high stringency hybridization conditions. While the probes and primers can have complete nucleotide sequence identity for consecutive nucleotides within the target nucleotide sequence, probes can be conventionally designed to differ from the target nucleotide sequence while retaining the ability to specifically detect and / or identify the target nucleotide sequence. Thus, the probe and primer can share about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% sequence identity or complementarity to the nucleotide sequence of the target nucleic acid molecule.

[0165] In some embodiments, to determine whether an ANGPTL7 nucleic acid molecule (genomic nucleic acid molecule, mRNA molecule, or cDNA molecule) or its complement in a biological sample contains a nucleotide sequence including a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2 (genomic nucleic acid molecule), or a uracil at a position corresponding to position 529 according to SEQ ID NO:5 (mRNA molecule), or a thymine at a position corresponding to position 529 according to SEQ ID NO:8 (cDNA molecule), the biological sample can be subjected to an amplification method, wherein the thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, or a uracil at a position corresponding to position 529 according to SEQ ID NO:5, or a thymine at a position corresponding to position 529 according to SEQ ID NO:8, is detected. and a second primer derived from the 3'-flanking sequence adjacent to a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, or a uracil at a position corresponding to position 529 according to SEQ ID NO:5, or a thymine at a position corresponding to position 529 according to SEQ ID NO:8, to generate an amplicon indicative of the presence of a SNP at a position containing a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, a uracil at a position corresponding to position 529 according to SEQ ID NO:5, or a thymine at a position corresponding to position 529 according to SEQ ID NO:8. In some embodiments, the length of the amplicon can range from the combined length of the primer pair plus one nucleotide base pair to any length of an amplicon that can be produced by a DNA amplification protocol. This distance can range from one nucleotide base pair to the limit of the amplification reaction or up to about 20,000 nucleotide base pairs.Optionally, the primer pair flanks a region that includes a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, or a uracil at a position corresponding to position 529 according to SEQ ID NO:5, or a thymine at a position corresponding to position 529 according to SEQ ID NO:8, and at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more nucleotides on each side of the position that includes a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, or a uracil at a position corresponding to position 529 according to SEQ ID NO:5, or a thymine at a position corresponding to position 529 according to SEQ ID NO:8.

[0166] In some embodiments, to determine whether an ANGPTL7 nucleic acid molecule (genomic nucleic acid molecule, mRNA molecule, or cDNA molecule) or its complement in a biological sample contains a nucleotide sequence including a thymine at a position corresponding to position 4,287 according to SEQ ID NO:3 (genomic nucleic acid molecule), or a uracil at a position corresponding to position 525 according to SEQ ID NO:6 (mRNA molecule), or a thymine at a position corresponding to position 525 according to SEQ ID NO:9 (cDNA molecule), the biological sample can be subjected to an amplification method, wherein the thymine at a position corresponding to position 4,287 according to SEQ ID NO:3, or a uracil at a position corresponding to position 525 according to SEQ ID NO:6, or a thymine at a position corresponding to position 525 according to SEQ ID NO:9, is detected. and a second primer derived from the 3'-flanking sequence adjacent to a thymine at a position corresponding to position 4,287 according to SEQ ID NO:3, or a uracil at a position corresponding to position 525 according to SEQ ID NO:6, or a thymine at a position corresponding to position 525 according to SEQ ID NO:9, to generate an amplicon indicative of the presence of a SNP at a position containing a thymine at a position corresponding to position 4,287 according to SEQ ID NO:3, a uracil at a position corresponding to position 525 according to SEQ ID NO:6, or a thymine at a position corresponding to position 525 according to SEQ ID NO:9. In some embodiments, the length of the amplicon can range from the combined length of the primer pair plus one nucleotide base pair to any length of an amplicon that can be produced by a DNA amplification protocol. This distance can range from one nucleotide base pair to the limit of the amplification reaction or up to about 20,000 nucleotide base pairs.Optionally, the primer pair flanks a region that includes a thymine at a position corresponding to position 4,287 according to SEQ ID NO:3, or a uracil at a position corresponding to position 525 according to SEQ ID NO:6, or a thymine at a position corresponding to position 525 according to SEQ ID NO:9, and at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more nucleotides on each side of the position that includes a thymine at a position corresponding to position 4,287 according to SEQ ID NO:3, or a uracil at a position corresponding to position 525 according to SEQ ID NO:6, or a thymine at a position corresponding to position 525 according to SEQ ID NO:9.

[0167] In some embodiments, to determine whether an ANGPTL7 nucleic acid molecule (genomic nucleic acid molecule, mRNA molecule, or cDNA molecule) or its complement in a biological sample contains a nucleotide sequence including an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132 (genomic nucleic acid molecule), or an adenine at a position corresponding to position 481 according to SEQ ID NO: 135 (mRNA molecule), or an adenine at a position corresponding to position 481 according to SEQ ID NO: 138 (cDNA molecule), the biological sample can be subjected to an amplification method, wherein the adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, or an adenine at a position corresponding to position 481 according to SEQ ID NO: 135, or an adenine at a position corresponding to position 481 according to SEQ ID NO: 138, is detected. and a second primer derived from the 3'-flanking sequence adjacent to the adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, or adenine at a position corresponding to position 481 according to SEQ ID NO: 135, or adenine at a position corresponding to position 481 according to SEQ ID NO: 138, to generate an amplicon indicative of the presence of a SNP at a position encoding an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, or adenine at a position corresponding to position 481 according to SEQ ID NO: 135, or adenine at a position corresponding to position 481 according to SEQ ID NO: 138. In some embodiments, the length of the amplicon can range from the combined length of the primer pair plus one nucleotide base pair to any length of an amplicon that can be produced by a DNA amplification protocol. This distance can range from one nucleotide base pair to the limit of the amplification reaction, or up to about 20,000 nucleotide base pairs.Optionally, the primer pair flanks a region that includes an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, or an adenine at a position corresponding to position 481 according to SEQ ID NO: 135, or an adenine at a position corresponding to position 481 according to SEQ ID NO: 138, and at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more nucleotides on each side of the position that includes an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, or an adenine at a position corresponding to position 481 according to SEQ ID NO: 135, or an adenine at a position corresponding to position 481 according to SEQ ID NO: 138.

[0168] In some embodiments, to determine whether an ANGPTL7 nucleic acid molecule (genomic nucleic acid molecule, mRNA molecule, or cDNA molecule) or its complement in a biological sample contains a nucleotide sequence including an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133 (genomic nucleic acid molecule), or an adenine at a position corresponding to position 563 according to SEQ ID NO: 136 (mRNA molecule), or an adenine at a position corresponding to position 563 according to SEQ ID NO: 139 (cDNA molecule), the biological sample can be subjected to an amplification method, wherein the adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, or an adenine at a position corresponding to position 563 according to SEQ ID NO: 136, or an adenine at a position corresponding to position 563 according to SEQ ID NO: 139, is detected. and a second primer derived from the 3'-flanking sequence adjacent to the adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, or adenine at a position corresponding to position 563 according to SEQ ID NO: 136, or adenine at a position corresponding to position 563 according to SEQ ID NO: 139, to generate an amplicon indicative of the presence of a SNP at a position encoding an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, or adenine at a position corresponding to position 563 according to SEQ ID NO: 136, or adenine at a position corresponding to position 563 according to SEQ ID NO: 139. In some embodiments, the length of the amplicon can range from the combined length of the primer pair plus one nucleotide base pair to any length of an amplicon that can be produced by a DNA amplification protocol. This distance can range from one nucleotide base pair to the limit of the amplification reaction or up to about 20,000 nucleotide base pairs.Optionally, the primer pair flanks a region that includes an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, or an adenine at a position corresponding to position 563 according to SEQ ID NO: 136, or an adenine at a position corresponding to position 563 according to SEQ ID NO: 139, and at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more nucleotides on each side of the position that includes an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, or an adenine at a position corresponding to position 563 according to SEQ ID NO: 136, or an adenine at a position corresponding to position 563 according to SEQ ID NO: 139.

[0169] In some embodiments, to determine whether an ANGPTL7 nucleic acid molecule (genomic nucleic acid molecule, mRNA molecule, or cDNA molecule) or its complement in a biological sample contains a nucleotide sequence including a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134 (genomic nucleic acid molecule), or a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137 (mRNA molecule), or a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140 (cDNA molecule), the biological sample can be subjected to an amplification method, wherein the cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, or a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, or a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140, is detected. and a second primer derived from the 3' flanking sequence adjacent to the cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, or a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, or a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140, to generate an amplicon indicative of the presence of a SNP at a position encoding the cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, or a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, or a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140. In some embodiments, the length of the amplicon can range from the combined length of the primer pair plus one nucleotide base pair to any length of an amplicon that can be produced by a DNA amplification protocol. This distance can range from one nucleotide base pair to the limit of the amplification reaction or up to about 20,000 nucleotide base pairs.Optionally, the primer pair flanks a region that includes a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, or a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, or a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140, and at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more nucleotides on each side of the position that includes a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, or a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, or a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140.

[0170] PCR primer pairs can be derived from known sequences using computer programs designed for that purpose, such as the PCR primer analysis tool in Vector NTI version 10 (Informax Inc., Bethesda, Md.), PrimerSelect (DNASTAR Inc., Madison, Wis.), and Primer3 (version 0.4.0 © 1991, Whitehead Institute for Biomedical Research, Cambridge, Mass.). Additionally, sequences can be visually scanned to manually identify primers using known guidelines.

[0171] A wide variety of techniques are available in the art, including, for example, nucleic acid sequencing, nucleic acid hybridization, and nucleic acid amplification. Exemplary nucleic acid sequencing techniques include, but are not limited to, chain terminator (Sanger) sequencing and dye-terminator sequencing.

[0172] Other methods involve nucleic acid hybridization methods other than sequencing, including using labeled primers or probes directed against purified DNA, amplified DNA, and fixed cell preparations (fluorescence in situ hybridization (FISH)). In some methods, the target nucleic acid molecule can be amplified prior to or simultaneously with detection. Exemplary nucleic acid amplification techniques include, but are not limited to, polymerase chain reaction (PCR), ligase chain reaction (LCR), strand displacement amplification (SDA), and nucleic acid sequence-based amplification (NASBA). Other methods include, but are not limited to, ligase chain reaction, strand displacement amplification, and thermophilic SDA (tSDA).

[0173] Hybridization techniques can use stringent conditions to ensure that probes or primers specifically hybridize to their targets. In some embodiments, a polynucleotide primer or probe under stringent conditions hybridizes to its target sequence detectably more than to other non-target sequences, for example, at least 2-fold, at least 3-fold, at least 4-fold, or more, including more than 10-fold over background. In some embodiments, a polynucleotide primer or probe under stringent conditions hybridizes to its target nucleotide sequence detectably more than two-fold more than to other nucleotide sequences. In some embodiments, a polynucleotide primer or probe under stringent conditions hybridizes to its target nucleotide sequence detectably more than three-fold more than to other nucleotide sequences. In some embodiments, a polynucleotide primer or probe under stringent conditions hybridizes to its target nucleotide sequence detectably more than four-fold more than to other nucleotide sequences. In some embodiments, a polynucleotide primer or probe under stringent conditions hybridizes to its target nucleotide sequence to a detectable degree greater than 10-fold over background than to other nucleotide sequences. Stringent conditions are sequence-dependent and will be different in different circumstances.

[0174] Suitable stringency conditions that promote DNA hybridization, such as 6× sodium chloride / sodium citrate (SSC) at about 45° C., followed by a 2× SSC wash at 50° C., are known and can be found in *Current Protocols in Molecular Biology*, John Wiley & Sons, NY (1989), 6.3.1-6.3.6. Typically, stringent conditions for hybridization and detection include conditions in which the salt concentration is about 1.5 M NaCl at pH 7.0-8.3. + Less than 0.01 to 1.0 M Na + The ionic concentration (or other salts) and temperature are at least about 30°C for short probes (e.g., 10 to 50 nucleotides) and at least about 60°C for long probes (e.g., more than 50 nucleotides). Stringent conditions can also be achieved by adding a destabilizing agent such as formamide. Optionally, the wash buffer may contain about 0.1% to about 1% SDS. The duration of hybridization is generally less than about 24 hours, usually about 4 to about 12 hours. The duration of the wash period is at least long enough to reach equilibrium.

[0175] The present disclosure also provides methods for detecting the presence of predicted loss-of-function mutant polypeptides of human ANGPTL7, comprising performing an assay on a sample obtained from a human subject to determine whether the ANGPTL7 polypeptide in the subject contains one or more mutations that cause the polypeptide to have a loss of function (partial or complete). For example, in some embodiments, the method detects the presence of predicted loss-of-function mutant polypeptides of human ANGPTL7, such as the ANGPTL7 Arg177Stop mutant polypeptide, and comprises performing an assay on a sample obtained from the human subject to determine whether the ANGPTL7 polypeptide in the sample terminates at a position corresponding to position 176 according to SEQ ID NO: 11. In some embodiments, the detecting step comprises sequencing at least a portion of the polypeptide, including a position corresponding to any position C-terminal to position 176 according to SEQ ID NO: 11 (such polypeptides are references, and the absence of such positions indicates that the polypeptide terminates at least at position 176 and is a predicted loss-of-function mutant ANGPTL7 polypeptide). In some embodiments, the detecting step comprises sequencing the entire polypeptide. In some embodiments, the detecting step comprises an immunoassay to detect the presence of a polypeptide that terminates at a position corresponding to position 176 according to SEQ ID NO:11.

[0176] The present disclosure also provides isolated nucleic acid molecules that hybridize to a variant ANGPTL7 genomic nucleic acid molecule (such as SEQ ID NO: 2), a variant ANGPTL7 mRNA molecule (such as SEQ ID NO: 5), and / or a variant ANGPTL7 cDNA molecule (such as SEQ ID NO: 8). In some embodiments, the isolated nucleic acid molecule hybridizes to a portion of the ANGPTL7 nucleic acid molecule that includes a position corresponding to position 4,291 according to SEQ ID NO: 2, or that includes a position corresponding to position 529 according to SEQ ID NO: 5 or SEQ ID NO: 8.

[0177] In some embodiments, the method comprises performing an assay on a sample obtained from a human subject to detect the presence of a predicted loss-of-function mutant polypeptide of human ANGPTL7, such as, for example, the ANGPTL7 Gln175His mutant polypeptide, to determine whether the ANGPTL7 polypeptide in the sample comprises a histidine at a position corresponding to position 175 according to SEQ ID NO: 12. In some embodiments, the detecting step comprises sequencing at least a portion of the polypeptide comprising a position corresponding to position 175 according to SEQ ID NO: 10 or SEQ ID NO: 12. In some embodiments, the detecting step comprises sequencing the entire polypeptide. In some embodiments, the detecting step comprises an immunoassay to detect the presence of a polypeptide comprising a position corresponding to position 175 according to SEQ ID NO: 10 or SEQ ID NO: 12.

[0178] The present disclosure also provides isolated nucleic acid molecules that hybridize to a variant ANGPTL7 genomic nucleic acid molecule (such as SEQ ID NO: 3), a variant ANGPTL7 mRNA molecule (such as SEQ ID NO: 6), and / or a variant ANGPTL7 cDNA molecule (such as SEQ ID NO: 9). In some embodiments, the isolated nucleic acid molecule hybridizes to a portion of the ANGPTL7 nucleic acid molecule that includes a position corresponding to position 4,287 according to SEQ ID NO: 3, or that includes a position corresponding to position 525 according to SEQ ID NO: 6 or SEQ ID NO: 9.

[0179] In some embodiments, the method comprises performing an assay on a sample obtained from the human subject to detect the presence of a predicted loss-of-function mutant polypeptide of human ANGPTL7, such as, for example, the ANGPTL7 Phe161Ile mutant polypeptide, to determine whether the ANGPTL7 polypeptide in the sample comprises an isoleucine at a position corresponding to position 161 according to SEQ ID NO: 141. In some embodiments, the detecting step comprises sequencing at least a portion of the polypeptide comprising a position corresponding to position 161 according to SEQ ID NO: 10 or SEQ ID NO: 141. In some embodiments, the detecting step comprises sequencing the entire polypeptide. In some embodiments, the detecting step comprises an immunoassay to detect the presence of a polypeptide comprising a position corresponding to position 161 according to SEQ ID NO: 10 or SEQ ID NO: 141.

[0180] The present disclosure also provides isolated nucleic acid molecules that hybridize to a variant ANGPTL7 genomic nucleic acid molecule (such as SEQ ID NO: 132), a variant ANGPTL7 mRNA molecule (such as SEQ ID NO: 135), and / or a variant ANGPTL7 cDNA molecule (such as SEQ ID NO: 138). In some embodiments, the isolated nucleic acid molecule hybridizes to a portion of the ANGPTL7 nucleic acid molecule that includes a position corresponding to 4,243 according to SEQ ID NO: 132, or that includes a position corresponding to 481 according to SEQ ID NO: 135 or SEQ ID NO: 138.

[0181] In some embodiments, the method comprises performing an assay on a sample obtained from a human subject to detect the presence of a predicted loss-of-function mutant polypeptide of human ANGPTL7, e.g., an ANGPTL7 Trp188Stop mutant polypeptide, and to determine whether an ANGPTL7 polypeptide in the sample terminates at a position corresponding to position 187 according to SEQ ID NO: 142. In some embodiments, the detecting step comprises sequencing at least a portion of the polypeptide including a position corresponding to any position C-terminal to position 187 according to SEQ ID NO: 142 (such polypeptide is a reference; the absence of such a position indicates that the polypeptide terminates at least at position 187 and is a predicted loss-of-function mutant ANGPTL7 polypeptide). In some embodiments, the detecting step comprises sequencing the entire polypeptide. In some embodiments, the detecting step comprises an immunoassay to detect the presence of a polypeptide terminating at a position corresponding to position 187 according to SEQ ID NO: 142.

[0182] The present disclosure also provides isolated nucleic acid molecules that hybridize to a variant ANGPTL7 genomic nucleic acid molecule (such as SEQ ID NO: 133), a variant ANGPTL7 mRNA molecule (such as SEQ ID NO: 136), and / or a variant ANGPTL7 cDNA molecule (such as SEQ ID NO: 139). In some embodiments, the isolated nucleic acid molecule hybridizes to a portion of the ANGPTL7 nucleic acid molecule that includes a position corresponding to 4,325 according to SEQ ID NO: 133, or that includes a position corresponding to 563 according to SEQ ID NO: 136 or SEQ ID NO: 139.

[0183] In some embodiments, the method comprises performing an assay on a sample obtained from the human subject to detect the presence of a predicted loss-of-function mutant polypeptide of human ANGPTL7, e.g., the ANGPTL7 Lys192Gln mutant polypeptide, to determine whether the ANGPTL7 polypeptide in the sample comprises a glutamine at a position corresponding to position 192 according to SEQ ID NO: 143. In some embodiments, the detecting step comprises sequencing at least a portion of the polypeptide comprising a position corresponding to position 192 according to SEQ ID NO: 10 or SEQ ID NO: 143. In some embodiments, the detecting step comprises sequencing the entire polypeptide. In some embodiments, the detecting step comprises an immunoassay to detect the presence of a polypeptide comprising a position corresponding to position 192 according to SEQ ID NO: 10 or SEQ ID NO: 143.

[0184] The present disclosure also provides isolated nucleic acid molecules that hybridize to a variant ANGPTL7 genomic nucleic acid molecule (such as SEQ ID NO: 134), a variant ANGPTL7 mRNA molecule (such as SEQ ID NO: 137), and / or a variant ANGPTL7 cDNA molecule (such as SEQ ID NO: 140). In some embodiments, the isolated nucleic acid molecule hybridizes to a portion of an ANGPTL7 nucleic acid molecule that includes a position corresponding to position 4,336 according to SEQ ID NO: 134, or that includes a position corresponding to position 574 according to SEQ ID NO: 137 or SEQ ID NO: 140.

[0185] In some embodiments, such isolated nucleic acid molecules have a nucleotide sequence of at least about 5, at least about 8, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 55 , at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 85, at least about 90, at least about 95, at least about 100, at least about 200, at least about 300, at least about 400, at least about 500, at least about 600, at least about 700, at least about 800, at least about 900, at least about 1000, at least about 2000, at least about 3000, at least about 4000, or at least about 5000 nucleotides. In some embodiments, such isolated nucleic acid molecules comprise or consist of at least about 5, at least about 8, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, or at least about 25 nucleotides. In preferred embodiments, the isolated nucleic acid molecule comprises or consists of at least about 18 nucleotides. In some embodiments, the isolated nucleic acid molecule comprises or consists of at least about 15 nucleotides. In some embodiments, the isolated nucleic acid molecule comprises or consists of about 10 to about 35, about 10 to about 30, about 10 to about 25, about 12 to about 30, about 12 to about 28, about 12 to about 24, about 15 to about 30, about 15 to about 25, about 18 to about 30, about 18 to about 25, about 18 to about 24, or about 18 to about 22 nucleotides. In preferred embodiments, the isolated nucleic acid molecule comprises or consists of about 18 to about 30 nucleotides.In some embodiments, the isolated nucleic acid molecule comprises or consists of at least about 15 nucleotides to at least about 35 nucleotides.

[0186] In some embodiments, such isolated nucleic acid molecules hybridize under stringent conditions to a mutant ANGPTL7 genomic nucleic acid molecule (such as SEQ ID NO: 2), a mutant ANGPTL7 mRNA molecule (such as SEQ ID NO: 5), and / or a mutant ANGPTL7 cDNA molecule (such as SEQ ID NO: 8). Such nucleic acid molecules can be used, for example, as probes, primers, mutation-specific probes, or mutation-specific primers as described or exemplified herein, including, but not limited to, primers, probes, antisense RNAs, shRNAs, and siRNAs, each of which is described in detail elsewhere herein, and can be used in any of the methods described herein.

[0187] In some embodiments, the isolated nucleic acid molecule hybridizes to at least about 15 contiguous nucleotides of a nucleic acid molecule that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to a variant ANGPTL7 genomic nucleic acid molecule (e.g., SEQ ID NO: 2), a variant ANGPTL7 mRNA molecule (e.g., SEQ ID NO: 5), and / or a variant ANGPTL7 cDNA molecule (e.g., SEQ ID NO: 8). In some embodiments, the isolated nucleic acid molecule comprises or consists of about 15 to about 100 nucleotides, or about 15 to about 35 nucleotides. In some embodiments, the isolated nucleic acid molecule comprises or consists of about 15 to about 100 nucleotides. In some embodiments, the isolated nucleic acid molecule comprises or consists of about 15 to about 35 nucleotides.

[0188] In some embodiments, the isolated variation-specific probe or variation-specific primer comprises at least about 15 nucleotides, and the variation-specific probe or variation-specific primer comprises a nucleotide sequence complementary to a portion of a nucleotide sequence encoding a human ANGPTL7 polypeptide, the portion comprising a position corresponding to position 4,291 or its complement according to SEQ ID NO:2, or corresponding to position 529 or its complement according to SEQ ID NO:5, or corresponding to position 529 or its complement according to SEQ ID NO:8. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence complementary to a portion of a nucleotide sequence comprising a position corresponding to position 4,291 according to SEQ ID NO:2, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence complementary to a portion of a nucleotide sequence comprising a position corresponding to positions 4,289 to 4,291 according to SEQ ID NO:2, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence complementary to a portion of a nucleotide sequence comprising a position corresponding to position 529 according to SEQ ID NO:5, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of a nucleotide sequence that includes a position corresponding to positions 529-531 according to SEQ ID NO: 5, or a complement thereof. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of a nucleotide sequence that includes a position corresponding to position 529 according to SEQ ID NO: 8, or a complement thereof. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of a nucleotide sequence that includes a position corresponding to positions 529-531 according to SEQ ID NO: 8, or a complement thereof.

[0189] In some embodiments, such isolated nucleic acid molecules hybridize under stringent conditions to a mutant ANGPTL7 genomic nucleic acid molecule (such as SEQ ID NO: 3), a mutant ANGPTL7 mRNA molecule (such as SEQ ID NO: 6), and / or a mutant ANGPTL7 cDNA molecule (such as SEQ ID NO: 9). Such nucleic acid molecules can be used, for example, as probes, primers, mutation-specific probes, or mutation-specific primers as described or exemplified herein, including, but not limited to, primers, probes, antisense RNAs, shRNAs, and siRNAs, each of which is described in detail elsewhere herein, and can be used in any of the methods described herein.

[0190] In some embodiments, the isolated nucleic acid molecule hybridizes to at least about 15 contiguous nucleotides of a nucleic acid molecule that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to a variant ANGPTL7 genomic nucleic acid molecule (e.g., SEQ ID NO: 3), a variant ANGPTL7 mRNA molecule (e.g., SEQ ID NO: 6), and / or a variant ANGPTL7 cDNA molecule (e.g., SEQ ID NO: 9). In some embodiments, the isolated nucleic acid molecule comprises or consists of about 15 to about 100 nucleotides, or about 15 to about 35 nucleotides. In some embodiments, the isolated nucleic acid molecule comprises or consists of about 15 to about 100 nucleotides. In some embodiments, the isolated nucleic acid molecule comprises or consists of about 15 to about 35 nucleotides.

[0191] In some embodiments, the isolated variation-specific probe or variation-specific primer comprises at least about 15 nucleotides, and the variation-specific probe or variation-specific primer comprises a nucleotide sequence complementary to a portion of a nucleotide sequence encoding a human ANGPTL7 polypeptide, the portion comprising a position corresponding to position 4,287 or its complement according to SEQ ID NO:3, or corresponding to position 525 or its complement according to SEQ ID NO:6, or corresponding to position 525 or its complement according to SEQ ID NO:9. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence complementary to a portion of a nucleotide sequence comprising a position corresponding to position 4,287 according to SEQ ID NO:3, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence complementary to a portion of a nucleotide sequence comprising a position corresponding to positions 4,285-4,287 according to SEQ ID NO:3, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence complementary to a portion of a nucleotide sequence comprising a position corresponding to position 525 according to SEQ ID NO:6, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of a nucleotide sequence that includes a position corresponding to positions 523-525 according to SEQ ID NO: 6, or a complement thereof. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of a nucleotide sequence that includes a position corresponding to position 525 according to SEQ ID NO: 9, or a complement thereof. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of a nucleotide sequence that includes a position corresponding to positions 523-525 according to SEQ ID NO: 9, or a complement thereof.

[0192] In some embodiments, such isolated nucleic acid molecules hybridize under stringent conditions to a mutant ANGPTL7 genomic nucleic acid molecule (such as SEQ ID NO: 132), a mutant ANGPTL7 mRNA molecule (such as SEQ ID NO: 135), and / or a mutant ANGPTL7 cDNA molecule (such as SEQ ID NO: 138). Such nucleic acid molecules can be used, for example, as probes, primers, mutation-specific probes, or mutation-specific primers as described or exemplified herein, including, but not limited to, primers, probes, antisense RNAs, shRNAs, and siRNAs, each of which is described in detail elsewhere herein, and which can be used in any of the methods described herein.

[0193] In some embodiments, the isolated nucleic acid molecule hybridizes to at least about 15 contiguous nucleotides of a nucleic acid molecule that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to a variant ANGPTL7 genomic nucleic acid molecule (e.g., SEQ ID NO: 132), a variant ANGPTL7 mRNA molecule (e.g., SEQ ID NO: 135), and / or a variant ANGPTL7 cDNA molecule (e.g., SEQ ID NO: 138). In some embodiments, the isolated nucleic acid molecule comprises or consists of about 15 to about 100 nucleotides, or about 15 to about 35 nucleotides. In some embodiments, the isolated nucleic acid molecule comprises or consists of about 15 to about 100 nucleotides. In some embodiments, the isolated nucleic acid molecule comprises or consists of about 15 to about 35 nucleotides.

[0194] In some embodiments, the isolated variation-specific probe or variation-specific primer comprises at least about 15 nucleotides, and such variation-specific probe or variation-specific primer comprises a nucleotide sequence complementary to a portion of a nucleotide sequence encoding a human ANGPTL7 polypeptide, such portion comprising a position corresponding to position 4,243 or its complement according to SEQ ID NO: 132, or corresponding to position 481 or its complement according to SEQ ID NO: 135, or corresponding to position 481 or its complement according to SEQ ID NO: 138. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence complementary to a portion of a nucleotide sequence comprising a position corresponding to position 4,243 according to SEQ ID NO: 132, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence complementary to a portion of a nucleotide sequence comprising positions corresponding to positions 4,243 to 4,245 according to SEQ ID NO: 132, or their complements. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of the nucleotide sequence including a position corresponding to position 481 according to SEQ ID NO: 135, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of the nucleotide sequence including a position corresponding to positions 481-483 according to SEQ ID NO: 135, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of the nucleotide sequence including a position corresponding to position 481 according to SEQ ID NO: 138, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of the nucleotide sequence including a position corresponding to positions 481-483 according to SEQ ID NO: 138, or its complement.

[0195] In some embodiments, such isolated nucleic acid molecules hybridize under stringent conditions to a mutant ANGPTL7 genomic nucleic acid molecule (such as SEQ ID NO: 133), a mutant ANGPTL7 mRNA molecule (such as SEQ ID NO: 136), and / or a mutant ANGPTL7 cDNA molecule (such as SEQ ID NO: 139). Such nucleic acid molecules can be used, for example, as probes, primers, mutation-specific probes, or mutation-specific primers as described or exemplified herein, including, but not limited to, primers, probes, antisense RNAs, shRNAs, and siRNAs, each of which is described in detail elsewhere herein, and can be used in any of the methods described herein.

[0196] In some embodiments, the isolated nucleic acid molecule hybridizes to at least about 15 contiguous nucleotides of a nucleic acid molecule that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to a variant ANGPTL7 genomic nucleic acid molecule (e.g., SEQ ID NO: 133), a variant ANGPTL7 mRNA molecule (e.g., SEQ ID NO: 136), and / or a variant ANGPTL7 cDNA molecule (e.g., SEQ ID NO: 139). In some embodiments, the isolated nucleic acid molecule comprises or consists of about 15 to about 100 nucleotides, or about 15 to about 35 nucleotides. In some embodiments, the isolated nucleic acid molecule comprises or consists of about 15 to about 100 nucleotides. In some embodiments, the isolated nucleic acid molecule comprises or consists of about 15 to about 35 nucleotides.

[0197] In some embodiments, the isolated variation-specific probe or variation-specific primer comprises at least about 15 nucleotides, and the variation-specific probe or variation-specific primer comprises a nucleotide sequence complementary to a portion of a nucleotide sequence encoding a human ANGPTL7 polypeptide, the portion comprising a position corresponding to position 4,325 or its complement according to SEQ ID NO: 133, or corresponding to position 563 or its complement according to SEQ ID NO: 136, or corresponding to position 563 or its complement according to SEQ ID NO: 139. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence complementary to a portion of a nucleotide sequence comprising a position corresponding to position 4,325 according to SEQ ID NO: 133, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence complementary to a portion of a nucleotide sequence comprising a position corresponding to positions 4,324 to 4,326 according to SEQ ID NO: 133, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of the nucleotide sequence including a position corresponding to position 563 according to SEQ ID NO: 136, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of the nucleotide sequence including a position corresponding to positions 562-564 according to SEQ ID NO: 136, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of the nucleotide sequence including a position corresponding to position 563 according to SEQ ID NO: 139, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of the nucleotide sequence including a position corresponding to positions 562-564 according to SEQ ID NO: 139, or its complement.

[0198] In some embodiments, such isolated nucleic acid molecules hybridize under stringent conditions to a mutant ANGPTL7 genomic nucleic acid molecule (such as SEQ ID NO: 134), a mutant ANGPTL7 mRNA molecule (such as SEQ ID NO: 137), and / or a mutant ANGPTL7 cDNA molecule (such as SEQ ID NO: 140). Such nucleic acid molecules can be used, for example, as probes, primers, mutation-specific probes, or mutation-specific primers as described or exemplified herein, including, but not limited to, primers, probes, antisense RNAs, shRNAs, and siRNAs, each of which is described in detail elsewhere herein, and which can be used in any of the methods described herein.

[0199] In some embodiments, the isolated nucleic acid molecule hybridizes to at least about 15 contiguous nucleotides of a nucleic acid molecule that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to a variant ANGPTL7 genomic nucleic acid molecule (e.g., SEQ ID NO: 134), a variant ANGPTL7 mRNA molecule (e.g., SEQ ID NO: 137), and / or a variant ANGPTL7 cDNA molecule (e.g., SEQ ID NO: 140). In some embodiments, the isolated nucleic acid molecule comprises or consists of about 15 to about 100 nucleotides, or about 15 to about 35 nucleotides. In some embodiments, the isolated nucleic acid molecule comprises or consists of about 15 to about 100 nucleotides. In some embodiments, the isolated nucleic acid molecule comprises or consists of about 15 to about 35 nucleotides.

[0200] In some embodiments, the isolated variation-specific probe or variation-specific primer comprises at least about 15 nucleotides, and such variation-specific probe or variation-specific primer comprises a nucleotide sequence complementary to a portion of a nucleotide sequence encoding a human ANGPTL7 polypeptide, such portion comprising a position corresponding to position 4,336 or its complement according to SEQ ID NO: 134, or corresponding to position 574 or its complement according to SEQ ID NO: 137, or corresponding to position 574 or its complement according to SEQ ID NO: 140. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of a nucleotide sequence comprising a position corresponding to position 4,336 according to SEQ ID NO: 134, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of a nucleotide sequence comprising a position corresponding to positions 4,336 to 4,338 according to SEQ ID NO: 134, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of the nucleotide sequence comprising a position corresponding to position 574 according to SEQ ID NO: 137, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of the nucleotide sequence comprising a position corresponding to positions 574-576 according to SEQ ID NO: 137, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of the nucleotide sequence comprising a position corresponding to position 574 according to SEQ ID NO: 140, or its complement. In some embodiments, the variation-specific probe or variation-specific primer comprises a nucleotide sequence that is complementary to a portion of the nucleotide sequence comprising a position corresponding to positions 574-576 according to SEQ ID NO: 140, or its complement.

[0201] In some embodiments, the variation-specific probe and variation-specific primer comprise DNA. In some embodiments, the variation-specific probe and variation-specific primer comprise RNA.

[0202] In some embodiments, the probes and primers described herein (including variation-specific probes and variation-specific primers) have nucleotide sequences that specifically hybridize to any of the nucleic acid molecules disclosed herein, or their complements. In some embodiments, the probes and primers specifically hybridize to any of the nucleic acid molecules disclosed herein under stringent conditions.

[0203] In some embodiments, primers, including variation-specific primers, can be used in second-generation sequencing or high-throughput sequencing. In some cases, primers, including variation-specific primers, can be modified. In particular, primers can contain various modifications used in different steps of, for example, massive parallel signature sequencing (MPSS), polony sequencing, and 454 pyrosequencing. Modified primers can be used in several steps of the process, including biotinylated primers in the cloning step and fluorescently labeled primers used in the bead loading and detection steps. Polony sequencing is generally performed using paired-end tag libraries, where each molecule of DNA template is approximately 135 bp in length. Biotinylated primers are used in the bead loading step and emulsion PCR. Fluorescently labeled degenerate nonamer oligonucleotides are used in the detection step. Adapters can contain 5'-biotin tags for immobilization of DNA libraries on streptavidin-coated beads.

[0204] The probes and primers described herein can be used to detect a C4,291T mutation in a mutant ANGPTL7 genomic nucleic acid molecule (e.g., according to SEQ ID NO: 2), a C529U mutation in a mutant ANGPTL7 mRNA molecule (e.g., according to SEQ ID NO: 5), or a C529T mutation in a mutant ANGPTL7 cDNA molecule (e.g., according to SEQ ID NO: 8). For example, primers can be used to amplify a mutant ANGPTL7 genomic nucleic acid molecule or a fragment thereof containing a C4,291T mutation. Primers can also be used to amplify a mutant ANGPTL7 mRNA or a fragment thereof containing a C529U mutation. Primers can also be used to amplify a mutant ANGPTL7 cDNA or a fragment thereof containing a C529T mutation.

[0205] The probes and primers described herein can be used to detect a G4,287T mutation in a mutant ANGPTL7 genomic nucleic acid molecule (e.g., according to SEQ ID NO: 3), a G525U mutation in a mutant ANGPTL7 mRNA molecule (e.g., according to SEQ ID NO: 6), or a G525T mutation in a mutant ANGPTL7 cDNA molecule (e.g., according to SEQ ID NO: 9). For example, primers can be used to amplify a mutant ANGPTL7 genomic nucleic acid molecule or a fragment thereof containing a G4,287T mutation. Primers can also be used to amplify a mutant ANGPTL7 mRNA or a fragment thereof containing a G525U mutation. Primers can also be used to amplify a mutant ANGPTL7 cDNA or a fragment thereof containing a G525T mutation.

[0206] The probes and primers described herein can be used to detect a T4,243A mutation in a mutant ANGPTL7 genomic nucleic acid molecule (e.g., according to SEQ ID NO: 132), a U481A mutation in a mutant ANGPTL7 mRNA molecule (e.g., according to SEQ ID NO: 135), or a T481A mutation in a mutant ANGPTL7 cDNA molecule (e.g., according to SEQ ID NO: 138). For example, primers can be used to amplify a mutant ANGPTL7 genomic nucleic acid molecule or a fragment thereof containing a T4,243A mutation. Primers can also be used to amplify a mutant ANGPTL7 mRNA or a fragment thereof containing a U481A mutation. Primers can also be used to amplify a mutant ANGPTL7 cDNA or a fragment thereof containing a T481A mutation.

[0207] The probes and primers described herein can be used to detect a G4,325A mutation in a mutant ANGPTL7 genomic nucleic acid molecule (e.g., according to SEQ ID NO: 133), a G563A mutation in a mutant ANGPTL7 mRNA molecule (e.g., according to SEQ ID NO: 136), or a G563A mutation in a mutant ANGPTL7 cDNA molecule (e.g., according to SEQ ID NO: 139). For example, primers can be used to amplify a mutant ANGPTL7 genomic nucleic acid molecule or a fragment thereof containing a G4,325A mutation. Primers can also be used to amplify a mutant ANGPTL7 mRNA or a fragment thereof containing a G563A mutation. Primers can also be used to amplify a mutant ANGPTL7 cDNA or a fragment thereof containing a G563A mutation.

[0208] The probes and primers described herein can be used to detect an A4,336C mutation in a mutant ANGPTL7 genomic nucleic acid molecule (e.g., according to SEQ ID NO: 134), an A574C mutation in a mutant ANGPTL7 mRNA molecule (e.g., according to SEQ ID NO: 137), or an A574C mutation in a mutant ANGPTL7 cDNA molecule (e.g., according to SEQ ID NO: 140). For example, primers can be used to amplify a mutant ANGPTL7 genomic nucleic acid molecule or a fragment thereof containing the A4,336C mutation. Primers can also be used to amplify a mutant ANGPTL7 mRNA or a fragment thereof containing the A574C mutation. Primers can also be used to amplify a mutant ANGPTL7 cDNA or a fragment thereof containing the A574C mutation.

[0209] The present disclosure also provides a primer pair comprising any of the above primers. If one of the 3' ends of the primers hybridizes to cytosine (rather than thymine) at a position corresponding to position 4,291 in a specific ANGPTL7 genomic nucleic acid molecule (compared to SEQ ID NO:1 and SEQ ID NO:2), the presence of an amplified fragment is considered to indicate the presence of a reference genomic nucleic acid molecule of ANGPTL7. Conversely, if one of the 3' ends of the primers hybridizes to thymine (rather than cytosine) at a position corresponding to position 4,291 in a specific ANGPTL7 genomic nucleic acid molecule (compared to SEQ ID NO:1 and SEQ ID NO:2), the presence of an amplified fragment is considered to indicate the presence of a variant genomic nucleic acid molecule of ANGPTL7. In some embodiments, the nucleotide of the primer complementary to the thymine at the position corresponding to position 4,291 in SEQ ID NO:2 may be at the 3' end of the primer. Furthermore, if one of the 3' ends of the primers hybridizes to cytosine (rather than uracil) at a position corresponding to position 529 in a particular ANGPTL7 mRNA molecule (compared to SEQ ID NO:4 and SEQ ID NO:5), the presence of an amplified fragment would indicate the presence of a reference mRNA molecule of ANGPTL7. Conversely, if one of the 3' ends of the primers hybridizes to uracil (rather than cytosine) at a position corresponding to position 529 in a particular ANGPTL7 mRNA molecule (compared to SEQ ID NO:4 and SEQ ID NO:5), the presence of an amplified fragment would indicate the presence of a mutant mRNA molecule of ANGPTL7. In some embodiments, the nucleotide of the primer complementary to uracil at the position corresponding to position 529 of SEQ ID NO:5 may be at the 3' end of the primer. Furthermore, if one of the 3' ends of the primers hybridizes to cytosine (rather than thymine) at a position corresponding to position 529 in a particular ANGPTL7 cDNA molecule (compared to SEQ ID NO:7 and SEQ ID NO:8), the presence of an amplified fragment is considered to indicate the presence of the reference cDNA molecule of ANGPTL7.Conversely, if one of the 3' ends of the primers hybridizes to thymine (rather than cytosine) at a position corresponding to position 529 in a particular ANGPTL7 cDNA molecule (compared to SEQ ID NO:7 and SEQ ID NO:8), the presence of an amplified fragment is considered to indicate the presence of a mutant cDNA molecule of ANGPTL7. In some embodiments, the nucleotide of the primer complementary to the thymine at the position corresponding to position 529 of SEQ ID NO:8 may be at the 3' end of the primer.

[0210] In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to a portion of an ANGPTL7 genomic nucleic acid molecule comprising a thymine at a position corresponding to position 4,291 according to SEQ ID NO: 2, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to an ANGPTL7 genomic nucleic acid molecule comprising SEQ ID NO: 2, or to the complement of this nucleic acid molecule, at a portion comprising a thymine at a position corresponding to position 4,291 according to SEQ ID NO: 2. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to a portion of an ANGPTL7 mRNA molecule comprising a uracil at a position corresponding to position 529 according to SEQ ID NO: 5, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to an ANGPTL7 mRNA molecule comprising SEQ ID NO: 5, or to the complement of this nucleic acid molecule, at a portion comprising a uracil at a position corresponding to position 529 according to SEQ ID NO: 5. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to a portion of an ANGPTL7 cDNA molecule comprising a thymine at a position corresponding to position 529 according to SEQ ID NO: 8, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to an ANGPTL7 cDNA molecule comprising SEQ ID NO: 8, at a portion comprising a thymine at a position corresponding to position 529 according to SEQ ID NO: 8, or to the complement of this nucleic acid molecule.

[0211] If one of the 3' ends of the primers hybridizes to guanine (rather than thymine) at a position corresponding to position 4,287 in a particular ANGPTL7 genomic nucleic acid molecule (compared to SEQ ID NO:1 and SEQ ID NO:3), the presence of an amplified fragment is considered to indicate the presence of a reference genomic nucleic acid molecule of ANGPTL7. Conversely, if one of the 3' ends of the primers hybridizes to thymine (rather than guanine) at a position corresponding to position 4,287 in a particular ANGPTL7 genomic nucleic acid molecule (compared to SEQ ID NO:1 and SEQ ID NO:3), the presence of an amplified fragment is considered to indicate the presence of a variant genomic nucleic acid molecule of ANGPTL7. In some embodiments, the nucleotide of the primer complementary to the thymine at the position corresponding to position 4,287 of SEQ ID NO:3 may be at the 3' end of the primer. Furthermore, if one of the 3' ends of the primers hybridizes to guanine (rather than uracil) at a position corresponding to position 525 in a particular ANGPTL7 mRNA molecule (compared to SEQ ID NO:4 and SEQ ID NO:6), the presence of an amplified fragment is considered to indicate the presence of a reference ANGPTL7 mRNA molecule. Conversely, if one of the 3' ends of the primers hybridizes to uracil (rather than guanine) at a position corresponding to position 525 in a particular ANGPTL7 mRNA molecule (compared to SEQ ID NO:4 and SEQ ID NO:6), the presence of an amplified fragment is considered to indicate the presence of a mutant ANGPTL7 mRNA molecule. In some embodiments, the nucleotide of the primer complementary to uracil at the position corresponding to position 525 in SEQ ID NO:6 may be the 3' end of the primer. Furthermore, if one of the 3' ends of the primers hybridizes to guanine (rather than thymine) at a position corresponding to position 525 in a particular ANGPTL7 cDNA molecule (compared to SEQ ID NO:7 and SEQ ID NO:9), the presence of an amplified fragment is considered to indicate the presence of a reference ANGPTL7 cDNA molecule. Conversely, if one of the 3' ends of the primers hybridizes to thymine (rather than guanine) at a position corresponding to position 525 in a particular ANGPTL7 cDNA molecule (compared to SEQ ID NO:7 and SEQ ID NO:9), the presence of an amplified fragment is considered to indicate the presence of a mutant cDNA molecule of ANGPTL7.In some embodiments, the nucleotide of the primer complementary to the thymine at the position corresponding to position 525 of SEQ ID NO: 9 may be at the 3' end of the primer.

[0212] In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to a portion of an ANGPTL7 genomic nucleic acid molecule comprising a thymine at a position corresponding to position 4,287 according to SEQ ID NO: 3, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to an ANGPTL7 genomic nucleic acid molecule comprising SEQ ID NO: 3, at a portion comprising a thymine at a position corresponding to position 4,287 according to SEQ ID NO: 3, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to a portion of an ANGPTL7 mRNA molecule comprising a uracil at a position corresponding to position 525 according to SEQ ID NO: 6, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to an ANGPTL7 mRNA molecule comprising SEQ ID NO: 6, at a portion comprising a uracil at a position corresponding to position 525 according to SEQ ID NO: 6, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to a portion of an ANGPTL7 cDNA molecule comprising a thymine at a position corresponding to position 525 according to SEQ ID NO: 9, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to an ANGPTL7 cDNA molecule comprising SEQ ID NO: 9, at a portion comprising a thymine at a position corresponding to position 525 according to SEQ ID NO: 9, or to the complement of this nucleic acid molecule.

[0213] If one of the 3' ends of the primer hybridizes to thymine (rather than adenine) at a position corresponding to position 4,243 in a specific ANGPTL7 genomic nucleic acid molecule (compared to SEQ ID NO: 1 and SEQ ID NO: 132), the presence of an amplified fragment is considered to indicate the presence of a reference genomic nucleic acid molecule of ANGPTL7. Conversely, if one of the 3' ends of the primer hybridizes to adenine (rather than thymine) at a position corresponding to position 4,243 in a specific ANGPTL7 genomic nucleic acid molecule (compared to SEQ ID NO: 1 and SEQ ID NO: 132), the presence of an amplified fragment is considered to indicate the presence of a variant genomic nucleic acid molecule of ANGPTL7. In some embodiments, the nucleotide of the primer complementary to the adenine at the position corresponding to position 4,243 according to SEQ ID NO: 132 may be at the 3' end of the primer. Furthermore, if one of the 3' ends of the primer hybridizes to a specific ANGPTL7 genomic nucleic acid molecule (compared to SEQ ID NO: 1 and SEQ ID NO: 132), the presence of an amplified fragment is considered to indicate the presence of a variant genomic nucleic acid molecule of ANGPTL7. If one of the 3' ends of the primers hybridizes to uracil (rather than adenine) at a position corresponding to position 481 in an mRNA molecule (compared to SEQ ID NO: 4 and SEQ ID NO: 135), the presence of the amplified fragment is considered to indicate the presence of a reference mRNA molecule of ANGPTL7. Conversely, if one of the 3' ends of the primers hybridizes to adenine (rather than uracil) at a position corresponding to position 481 in a particular ANGPTL7 mRNA molecule (compared to SEQ ID NO: 4 and SEQ ID NO: 135), the presence of the amplified fragment is considered to indicate the presence of a mutant mRNA molecule of ANGPTL7. In some embodiments, the nucleotide of the primer complementary to the adenine at the position corresponding to position 481 according to SEQ ID NO: 135 may be at the 3' end of the primer. Furthermore, if one of the 3' ends of the primers hybridizes to thymine (rather than adenine) at a position corresponding to position 481 in a particular ANGPTL7 cDNA molecule (compared to SEQ ID NO: 7 and SEQ ID NO: 138), the presence of the amplified fragment is considered to indicate the presence of a reference cDNA molecule of ANGPTL7. Conversely, if one of the 3' ends of the primers hybridizes to adenine (rather than thymine) at a position corresponding to position 481 in a particular ANGPTL7 cDNA molecule (compared to SEQ ID NO: 4 and SEQ ID NO: 138), the presence of an amplified fragment is considered to indicate the presence of a mutant cDNA molecule of ANGPTL7. In some embodiments, the nucleotide of the primer complementary to the adenine at a position corresponding to position 481 according to SEQ ID NO: 138 may be at the 3' end of the primer.

[0214] In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to a portion of an ANGPTL7 genomic nucleic acid molecule comprising an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to an ANGPTL7 genomic nucleic acid molecule comprising SEQ ID NO: 132, at a portion comprising an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to a portion of an ANGPTL7 mRNA molecule comprising an adenine at a position corresponding to position 481 according to SEQ ID NO: 135, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to an ANGPTL7 mRNA molecule comprising SEQ ID NO: 135 at a portion comprising an adenine at a position corresponding to position 481 according to SEQ ID NO: 135, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to a portion of an ANGPTL7 cDNA molecule comprising an adenine at a position corresponding to position 481 according to SEQ ID NO: 138, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to an ANGPTL7 cDNA molecule comprising SEQ ID NO: 138 at a portion comprising an adenine at a position corresponding to position 481 according to SEQ ID NO: 138, or to the complement of this nucleic acid molecule.

[0215] If one of the 3' ends of the primers hybridizes to guanine (rather than adenine) at a position corresponding to position 4,325 in a particular ANGPTL7 genomic nucleic acid molecule (compared to SEQ ID NO: 1 and SEQ ID NO: 133), the presence of an amplified fragment is considered to indicate the presence of a reference genomic nucleic acid molecule of ANGPTL7. Conversely, if one of the 3' ends of the primers hybridizes to adenine (rather than guanine) at a position corresponding to position 4,325 in a particular ANGPTL7 genomic nucleic acid molecule (compared to SEQ ID NO: 1 and SEQ ID NO: 133), the presence of an amplified fragment is considered to indicate the presence of a variant genomic nucleic acid molecule of ANGPTL7. In some embodiments, the nucleotide of the primer complementary to the adenine at the position corresponding to position 4,325 according to SEQ ID NO: 133 may be at the 3' end of the primer. Furthermore, if one of the 3' ends of the primers hybridizes to guanine (rather than adenine) at a position corresponding to position 563 in a particular ANGPTL7 mRNA molecule (compared to SEQ ID NO: 4 and SEQ ID NO: 136), the presence of an amplified fragment is considered to indicate the presence of a reference mRNA molecule of ANGPTL7. Conversely, if one of the 3' ends of the primers hybridizes to adenine (rather than guanine) at a position corresponding to position 563 in a particular ANGPTL7 mRNA molecule (compared to SEQ ID NO: 4 and SEQ ID NO: 136), the presence of an amplified fragment is considered to indicate the presence of a mutant mRNA molecule of ANGPTL7. In some embodiments, the nucleotide of the primer complementary to the adenine at the position corresponding to position 563 according to SEQ ID NO: 136 may be at the 3' end of the primer. Furthermore, if one of the 3' ends of the primers hybridizes to guanine (rather than adenine) at a position corresponding to position 563 in a particular ANGPTL7 cDNA molecule (compared to SEQ ID NO: 7 and SEQ ID NO: 139), the presence of an amplified fragment is considered to indicate the presence of the reference cDNA molecule of ANGPTL7.Conversely, if one of the 3' ends of the primers hybridizes to adenine (rather than guanine) at a position corresponding to position 563 in a particular ANGPTL7 cDNA molecule (compared to SEQ ID NO: 7 and SEQ ID NO: 139), the presence of an amplified fragment is considered to indicate the presence of a mutant cDNA molecule of ANGPTL7. In some embodiments, the nucleotide of the primer complementary to the adenine at the position corresponding to position 563 according to SEQ ID NO: 139 may be at the 3' end of the primer.

[0216] In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to a portion of an ANGPTL7 genomic nucleic acid molecule comprising an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to an ANGPTL7 genomic nucleic acid molecule comprising SEQ ID NO: 133, at a portion comprising an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to a portion of an ANGPTL7 mRNA molecule comprising an adenine at a position corresponding to position 563 according to SEQ ID NO: 136, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to an ANGPTL7 mRNA molecule comprising SEQ ID NO: 136 at a portion comprising an adenine at a position corresponding to position 563 according to SEQ ID NO: 136, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to a portion of an ANGPTL7 cDNA molecule comprising an adenine at a position corresponding to position 563 according to SEQ ID NO: 139, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to an ANGPTL7 cDNA molecule comprising SEQ ID NO: 139 at a portion comprising an adenine at a position corresponding to position 563 according to SEQ ID NO: 139, or to the complement of this nucleic acid molecule.

[0217] If one of the 3' ends of the primers hybridizes to adenine (rather than cytosine) at a position corresponding to position 4,336 in a particular ANGPTL7 genomic nucleic acid molecule (compared to SEQ ID NO:1 and SEQ ID NO:134), the presence of an amplified fragment is considered to indicate the presence of a reference genomic nucleic acid molecule of ANGPTL7. Conversely, if one of the 3' ends of the primers hybridizes to cytosine (rather than adenine) at a position corresponding to position 4,336 in a particular ANGPTL7 nucleic acid molecule (compared to SEQ ID NO:1 and SEQ ID NO:134), the presence of an amplified fragment is considered to indicate the presence of a variant genomic nucleic acid molecule of ANGPTL7. In some embodiments, the nucleotide of the primer complementary to the cytosine at the position corresponding to position 4,336 according to SEQ ID NO:134 may be at the 3' end of the primer. Furthermore, if one of the 3' ends of the primers hybridizes to adenine (rather than cytosine) at a position corresponding to position 574 in a particular ANGPTL7 mRNA molecule (compared to SEQ ID NO: 4 and SEQ ID NO: 137), the presence of an amplified fragment is considered to indicate the presence of a reference mRNA molecule of ANGPTL7. Conversely, if one of the 3' ends of the primers hybridizes to cytosine (rather than adenine) at a position corresponding to position 574 in a particular ANGPTL7 mRNA molecule (compared to SEQ ID NO: 4 and SEQ ID NO: 137), the presence of an amplified fragment is considered to indicate the presence of a mutant mRNA molecule of ANGPTL7. In some embodiments, the nucleotide of the primer complementary to the cytosine at the position corresponding to position 574 according to SEQ ID NO: 137 may be at the 3' end of the primer. Furthermore, if one of the 3' ends of the primers hybridizes to adenine (rather than cytosine) at a position corresponding to position 574 in a particular ANGPTL7 cDNA molecule (compared to SEQ ID NO: 7 and SEQ ID NO: 140), the presence of an amplified fragment is considered to indicate the presence of the reference cDNA molecule of ANGPTL7.Conversely, if one of the 3' ends of the primers hybridizes to cytosine (rather than adenine) at a position corresponding to position 574 in a particular ANGPTL7 cDNA molecule (compared to SEQ ID NO:7 and SEQ ID NO:140), the presence of an amplified fragment is considered to indicate the presence of a mutant cDNA molecule of ANGPTL7. In some embodiments, the nucleotide of the primer complementary to the cytosine at the position corresponding to position 574 according to SEQ ID NO:140 may be at the 3' end of the primer.

[0218] In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to a portion of an ANGPTL7 genomic nucleic acid molecule comprising a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to an ANGPTL7 genomic nucleic acid molecule comprising SEQ ID NO: 134, at a portion comprising a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to a portion of an ANGPTL7 mRNA molecule comprising a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to an ANGPTL7 mRNA molecule comprising SEQ ID NO: 137 at a portion comprising a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to a portion of an ANGPTL7 cDNA molecule comprising a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140, or to the complement of this nucleic acid molecule. In some embodiments, the probe or primer comprises a nucleotide sequence that hybridizes to an ANGPTL7 cDNA molecule comprising SEQ ID NO: 140 at a portion comprising a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140, or to the complement of this nucleic acid molecule.

[0219] In the context of this disclosure, "specifically hybridizes" means that the probe or primer (e.g., a mutation-specific probe or mutation-specific primer, etc.) does not hybridize to a nucleic acid sequence encoding a reference genomic nucleic acid molecule of ANGPTL7, a reference mRNA molecule of ANGPTL7, and / or a reference cDNA molecule of ANGPTL7.

[0220] In some embodiments, the probe (e.g., the mutation-specific probe, etc.) comprises a label. In some embodiments, the label is a fluorescent label, a radiolabel, or biotin. The present disclosure also provides a support comprising a substrate to which any one or more of the probes disclosed herein are attached. The solid support may be a solid-state substrate or a support to which a molecule, such as any of the probes disclosed herein, can be associated. The form of the solid support is an array. Another form of solid support is an array detector. An array detector is a solid support to which multiple different probes are attached in an array, grid, or other organized pattern. The form of the solid-state substrate is a microtiter dish, such as a standard 96-well format. In some embodiments, a multiwell glass slide can be used, typically containing one array per well.

[0221] The present disclosure also provides a molecular complex comprising or consisting of any of the ANGPTL7 nucleic acid molecules (genomic nucleic acid molecules, mRNA molecules, or cDNA molecules) or their complements described herein and any of the mutation-specific primers or mutation-specific probes described herein. In some embodiments, the ANGPTL7 nucleic acid molecule (genomic nucleic acid molecule, mRNA molecule, or cDNA molecule) or its complement in the molecular complex is single-stranded. In some embodiments, the ANGPTL7 nucleic acid molecule is any of the genomic nucleic acid molecules described herein. In some embodiments, the ANGPTL7 nucleic acid molecule is any of the mRNA molecules described herein. In some embodiments, the ANGPTL7 nucleic acid molecule is any of the cDNA molecules described herein. In some embodiments, the molecular complex comprises or consists of any of the ANGPTL7 nucleic acid molecules (genomic nucleic acid molecules, mRNA molecules, or cDNA molecules) or their complements described herein and any of the mutation-specific primers described herein. In some embodiments, the molecular complex comprises or consists of any of the ANGPTL7 nucleic acid molecules (genomic nucleic acid molecules, mRNA molecules, or cDNA molecules) or their complements described herein and any of the variation-specific probes described herein. In some embodiments, the molecular complex comprises a variation-specific probe or variation-specific primer that includes a label. In some embodiments, the label is a fluorescent label, a radiolabel, or biotin. In some embodiments, the molecular complex further comprises a non-human polymerase.

[0222] The present disclosure also provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the polypeptide terminates at a position corresponding to position 176 according to SEQ ID NO: 11, or its complement. In some embodiments, the isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 11, and terminates at a position corresponding to position 176 according to SEQ ID NO: 11. In some embodiments, the isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that is at least about 90% sequence identity to SEQ ID NO: 11, and terminates at a position corresponding to position 176 according to SEQ ID NO: 11. In some embodiments, the isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that is at least about 92% sequence identity to SEQ ID NO: 11, and terminates at a position corresponding to position 176 according to SEQ ID NO: 11. In some embodiments, the isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that is at least about 94% sequence identity to SEQ ID NO: 11, and terminates at a position corresponding to position 176 according to SEQ ID NO: 11. In some embodiments, the isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that is at least about 96% sequence identity to SEQ ID NO: 11, and terminates at a position corresponding to position 176 according to SEQ ID NO: 11. In some embodiments, the isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that is at least about 98% sequence identity to SEQ ID NO: 11, and terminates at a position corresponding to position 176 according to SEQ ID NO: 11.

[0223] In some embodiments, the nucleic acid molecule encodes an ANGPTL7 polypeptide comprising SEQ ID NO: 11. In some embodiments, the nucleic acid molecule encodes an ANGPTL7 polypeptide consisting of SEQ ID NO:11.

[0224] The present disclosure also provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the polypeptide comprises a histidine or its complement at a position corresponding to position 175 according to SEQ ID NO: 12. In some embodiments, the isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 12 and comprises a histidine at a position corresponding to position 175 according to SEQ ID NO: 12. In some embodiments, the isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that has at least about 90% sequence identity to SEQ ID NO: 12 and comprises a histidine at a position corresponding to position 175 according to SEQ ID NO: 12. In some embodiments, an isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that has at least about 92% sequence identity to SEQ ID NO: 12 and includes a histidine at a position corresponding to position 175 according to SEQ ID NO: 12. In some embodiments, an isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that has at least about 94% sequence identity to SEQ ID NO: 12 and includes a histidine at a position corresponding to position 175 according to SEQ ID NO: 12. In some embodiments, an isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that has at least about 96% sequence identity to SEQ ID NO: 12 and includes a histidine at a position corresponding to position 175 according to SEQ ID NO: 12. In some embodiments, an isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that has at least about 98% sequence identity to SEQ ID NO: 12 and includes a histidine at a position corresponding to position 175 according to SEQ ID NO: 12.

[0225] In some embodiments, the nucleic acid molecule encodes an ANGPTL7 polypeptide comprising SEQ ID NO: 12. In some embodiments, the nucleic acid molecule encodes an ANGPTL7 polypeptide consisting of SEQ ID NO:12.

[0226] The present disclosure also provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the polypeptide comprises an isoleucine or its complement at a position corresponding to position 161 according to SEQ ID NO: 141. In some embodiments, the isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 141 and comprises an isoleucine at a position corresponding to position 161 according to SEQ ID NO: 141. In some embodiments, the isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that has at least about 90% sequence identity to SEQ ID NO: 141 and comprises an isoleucine at a position corresponding to position 161 according to SEQ ID NO: 141. In some embodiments, an isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that has at least about 92% sequence identity to SEQ ID NO: 141 and includes an isoleucine at a position corresponding to position 161 according to SEQ ID NO: 141. In some embodiments, an isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that has at least about 94% sequence identity to SEQ ID NO: 141 and includes an isoleucine at a position corresponding to position 161 according to SEQ ID NO: 141. In some embodiments, an isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that has at least about 96% sequence identity to SEQ ID NO: 141 and includes an isoleucine at a position corresponding to position 161 according to SEQ ID NO: 141. In some embodiments, an isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that has at least about 98% sequence identity to SEQ ID NO: 141 and includes an isoleucine at a position corresponding to position 161 according to SEQ ID NO: 141.

[0227] In some embodiments, the nucleic acid molecule encodes an ANGPTL7 polypeptide comprising SEQ ID NO: 141. In some embodiments, the nucleic acid molecule encodes an ANGPTL7 polypeptide consisting of SEQ ID NO:141.

[0228] The present disclosure also provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the polypeptide terminates at a position corresponding to position 187 according to SEQ ID NO: 142, or its complement. In some embodiments, the isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 142, and terminates at a position corresponding to position 187 according to SEQ ID NO: 142. In some embodiments, the isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that is at least about 90% sequence identity to SEQ ID NO: 142, and terminates at a position corresponding to position 187 according to SEQ ID NO: 142. In some embodiments, the isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that is at least about 92% sequence identity to SEQ ID NO: 142, and terminates at a position corresponding to position 187 according to SEQ ID NO: 142. In some embodiments, the isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that is at least about 94% sequence identity to SEQ ID NO: 142, and terminates at a position corresponding to position 187 according to SEQ ID NO: 142. In some embodiments, the isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that is at least about 96% sequence identity to SEQ ID NO: 142, and terminates at a position corresponding to position 187 according to SEQ ID NO: 142. In some embodiments, the isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that is at least about 98% sequence identity to SEQ ID NO: 142, and terminates at a position corresponding to position 187 according to SEQ ID NO: 142.

[0229] In some embodiments, the nucleic acid molecule encodes an ANGPTL7 polypeptide comprising SEQ ID NO: 142. In some embodiments, the nucleic acid molecule encodes an ANGPTL7 polypeptide consisting of SEQ ID NO:142.

[0230] The present disclosure also provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the polypeptide comprises a glutamine or its complement at a position corresponding to position 192 according to SEQ ID NO: 143. In some embodiments, the isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 143 and that comprises a glutamine at a position corresponding to position 192 according to SEQ ID NO: 143. In some embodiments, the isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that has at least about 90% sequence identity to SEQ ID NO: 143 and that comprises a glutamine at a position corresponding to position 192 according to SEQ ID NO: 143. In some embodiments, an isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that has at least about 92% sequence identity to SEQ ID NO: 143 and includes a glutamine at a position corresponding to position 192 according to SEQ ID NO: 143. In some embodiments, an isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that has at least about 94% sequence identity to SEQ ID NO: 143 and includes a glutamine at a position corresponding to position 192 according to SEQ ID NO: 143. In some embodiments, an isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that has at least about 96% sequence identity to SEQ ID NO: 143 and includes a glutamine at a position corresponding to position 192 according to SEQ ID NO: 143. In some embodiments, an isolated nucleic acid molecule encodes an ANGPTL7 polypeptide having an amino acid sequence that has at least about 98% sequence identity to SEQ ID NO: 143 and includes a glutamine at a position corresponding to position 192 according to SEQ ID NO: 143.

[0231] In some embodiments, the nucleic acid molecule encodes an ANGPTL7 polypeptide comprising SEQ ID NO: 143. In some embodiments, the nucleic acid molecule encodes an ANGPTL7 polypeptide consisting of SEQ ID NO:143.

[0232] The nucleotide sequence of the reference genomic nucleic acid molecule of ANGPTL7 is set forth in SEQ ID NO: 1. With respect to SEQ ID NO: 1, position 4,291 of the reference genomic nucleic acid molecule of ANGPTL7 is a cytosine. With respect to SEQ ID NO: 1, position 4,287 of the reference genomic nucleic acid molecule of ANGPTL7 is a guanine. With respect to SEQ ID NO: 1, position 4,243 of the reference genomic nucleic acid molecule of ANGPTL7 is a thymine. With respect to SEQ ID NO: 1, position 4,325 of the reference genomic nucleic acid molecule of ANGPTL7 is a guanine. With respect to SEQ ID NO: 1, position 4,336 of the reference genomic nucleic acid molecule of ANGPTL7 is an adenine.

[0233] A variant genomic nucleic acid molecule of ANGPTL7 exists in which a cytosine at position 4,291 (with respect to the reference genomic sequence set forth in SEQ ID NO: 1) is replaced with a thymine. The nucleotide sequence of this variant genomic nucleic acid molecule of ANGPTL7 is set forth in SEQ ID NO: 2.

[0234] Another variant genomic nucleic acid molecule of ANGPTL7 exists in which the guanine at position 4,287 (with respect to the reference genomic sequence set forth in SEQ ID NO: 1) is replaced with a thymine. The nucleotide sequence of this variant genomic nucleic acid molecule of ANGPTL7 is set forth in SEQ ID NO: 3.

[0235] Another variant genomic nucleic acid molecule of ANGPTL7 exists in which the thymine at position 4,243 (with respect to the reference genomic sequence set forth in SEQ ID NO: 1) is replaced with an adenine. The nucleotide sequence of this variant genomic nucleic acid molecule of ANGPTL7 is set forth in SEQ ID NO: 132.

[0236] Another variant genomic nucleic acid molecule of ANGPTL7 exists in which the guanine at position 4,325 (with respect to the reference genomic sequence set forth in SEQ ID NO: 1) is replaced with an adenine. The nucleotide sequence of this variant genomic nucleic acid molecule of ANGPTL7 is set forth in SEQ ID NO: 133.

[0237] Another variant genomic nucleic acid molecule of ANGPTL7 exists in which the adenine at position 4,336 (with respect to the reference genomic sequence set forth in SEQ ID NO: 1) is replaced with a cytosine. The nucleotide sequence of this variant genomic nucleic acid molecule of ANGPTL7 is set forth in SEQ ID NO: 134.

[0238] The present disclosure provides an isolated genomic nucleic acid molecule comprising or consisting of a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises a thymine (C4,291T) at a position corresponding to position 4,291 according to SEQ ID NO:2, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises a thymine (C4,291T) at a position corresponding to position 4,291 according to SEQ ID NO:2, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule consists of a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises a thymine (C4,291T) at a position corresponding to position 4,291 according to SEQ ID NO:2, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises a TGA codon at a position corresponding to positions 4,289 to 4,291 according to SEQ ID NO:2.

[0239] In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:2, and comprises a thymine, or a complement thereof, at a position corresponding to position 4,291 according to SEQ ID NO:2. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90% sequence identity to SEQ ID NO:2, and comprises a thymine, or a complement thereof, at a position corresponding to position 4,291 according to SEQ ID NO:2. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 92% sequence identity to SEQ ID NO:2, and comprises a thymine, or a complement thereof, at a position corresponding to position 4,291 according to SEQ ID NO:2. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 94% sequence identity to SEQ ID NO:2 and comprises a thymine, or its complement, at a position corresponding to position 4,291 according to SEQ ID NO:2. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 96% sequence identity to SEQ ID NO:2 and comprises a thymine, or its complement, at a position corresponding to position 4,291 according to SEQ ID NO:2. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 98% sequence identity to SEQ ID NO:2 and comprises a thymine, or its complement, at a position corresponding to position 4,291 according to SEQ ID NO:2. As used herein, when referring to percent sequence identity, higher sequence identities are preferred than lower percentages.

[0240] In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:2, and comprises a TGA codon at a position corresponding to positions 4,289 to 4,291 according to SEQ ID NO:2, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90% sequence identity to SEQ ID NO:2, and comprises a TGA codon at a position corresponding to positions 4,289 to 4,291 according to SEQ ID NO:2, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 92% sequence identity to SEQ ID NO:2, and comprises a TGA codon at a position corresponding to positions 4,289 to 4,291 according to SEQ ID NO:2, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 94% sequence identity to SEQ ID NO:2, and comprises a TGA codon at a position corresponding to positions 4,289-4,291 according to SEQ ID NO:2, or its complement. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 96% sequence identity to SEQ ID NO:2, and comprises a TGA codon at a position corresponding to positions 4,289-4,291 according to SEQ ID NO:2, or its complement. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 98% sequence identity to SEQ ID NO:2, and comprises a TGA codon at a position corresponding to positions 4,289-4,291 according to SEQ ID NO:2, or its complement. As used herein, when referring to percent sequence identity, higher sequence identity is preferred over lower percentages.

[0241] In some embodiments, the isolated genomic nucleic acid molecule comprises SEQ ID NO: 2. In some embodiments, the isolated genomic nucleic acid molecule consists of SEQ ID NO: 2. The present disclosure also provides an isolated genomic nucleic acid molecule comprising or consisting of a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises a thymine (G4,287T) at a position corresponding to position 4,287 according to SEQ ID NO:3, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises a thymine (G4,287T) at a position corresponding to position 4,287 according to SEQ ID NO:3, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule consists of a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises a thymine (G4,287T) at a position corresponding to position 4,287 according to SEQ ID NO:3, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises a CAT codon at a position corresponding to positions 4,285 to 4,287 according to SEQ ID NO:3.

[0242] In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:3, and comprises a thymine, or a complement thereof, at a position corresponding to position 4,287 according to SEQ ID NO:3. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90% sequence identity to SEQ ID NO:3, and comprises a thymine, or a complement thereof, at a position corresponding to position 4,287 according to SEQ ID NO:3. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 92% sequence identity to SEQ ID NO:3, and comprises a thymine, or a complement thereof, at a position corresponding to position 4,287 according to SEQ ID NO:3. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 94% sequence identity to SEQ ID NO:3 and comprises a thymine, or its complement, at a position corresponding to position 4,287 according to SEQ ID NO:3. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 96% sequence identity to SEQ ID NO:3 and comprises a thymine, or its complement, at a position corresponding to position 4,287 according to SEQ ID NO:3. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 98% sequence identity to SEQ ID NO:3 and comprises a thymine, or its complement, at a position corresponding to position 4,287 according to SEQ ID NO:3. As used herein, when referring to percent sequence identity, higher sequence identities are preferred than lower percentages.

[0243] In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:3, and comprises a CAT codon at a position corresponding to positions 4,285-4,287 according to SEQ ID NO:3, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90% sequence identity to SEQ ID NO:3, and comprises a CAT codon at a position corresponding to positions 4,285-4,287 according to SEQ ID NO:3, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 92% sequence identity to SEQ ID NO:3, and comprises a CAT codon at a position corresponding to positions 4,285-4,287 according to SEQ ID NO:3, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 94% sequence identity to SEQ ID NO:3 and comprises a CAT codon at a position corresponding to positions 4,285-4,287 according to SEQ ID NO:3, or its complement. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 96% sequence identity to SEQ ID NO:3 and comprises a CAT codon at a position corresponding to positions 4,285-4,287 according to SEQ ID NO:3, or its complement. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 98% sequence identity to SEQ ID NO:3 and comprises a CAT codon at a position corresponding to positions 4,285-4,287 according to SEQ ID NO:3, or its complement. As used herein, when referring to percent sequence identity, higher sequence identity is preferred over lower percentages.

[0244] In some embodiments, the isolated genomic nucleic acid molecule comprises SEQ ID NO: 3. In some embodiments, the isolated genomic nucleic acid molecule consists of SEQ ID NO: 3. The present disclosure also provides an isolated genomic nucleic acid molecule comprising or consisting of a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises an adenine (T4,243A) at a position corresponding to position 4,243 according to SEQ ID NO: 132, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises an adenine (T4,243A) at a position corresponding to position 4,243 according to SEQ ID NO: 132, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule consists of a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises an adenine (T4,243A) at a position corresponding to position 4,243 according to SEQ ID NO: 132, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises an ATC codon at positions corresponding to positions 4,243 to 4,245 according to SEQ ID NO: 132.

[0245] In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 132, and comprises an adenine, or a complement thereof, at a position corresponding to position 4,243 according to SEQ ID NO: 132. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90% sequence identity to SEQ ID NO: 132, and comprises an adenine, or a complement thereof, at a position corresponding to position 4,243 according to SEQ ID NO: 132. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 92% sequence identity to SEQ ID NO: 132, and comprises an adenine, or a complement thereof, at a position corresponding to position 4,243 according to SEQ ID NO: 132. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 94% sequence identity to SEQ ID NO: 132 and comprises an adenine, or its complement, at a position corresponding to position 4,243 according to SEQ ID NO: 132. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 96% sequence identity to SEQ ID NO: 132 and comprises an adenine, or its complement, at a position corresponding to position 4,243 according to SEQ ID NO: 132. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 98% sequence identity to SEQ ID NO: 132 and comprises an adenine, or its complement, at a position corresponding to position 4,243 according to SEQ ID NO: 132. As used herein, when referring to percent sequence identity, higher sequence identity is preferred over lower percentages.

[0246] In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 132, and comprises an ATC codon, or a complement thereof, at a position corresponding to positions 4,243-4,245 according to SEQ ID NO: 132. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90% sequence identity to SEQ ID NO: 132, and comprises an ATC codon, or a complement thereof, at a position corresponding to positions 4,243-4,245 according to SEQ ID NO: 132. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 92% sequence identity to SEQ ID NO: 132, and comprises an ATC codon at a position corresponding to positions 4,243-4,245 according to SEQ ID NO: 132, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 94% sequence identity to SEQ ID NO: 132, and comprises an ATC codon at a position corresponding to positions 4,243-4,245 according to SEQ ID NO: 132, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 96% sequence identity to SEQ ID NO: 132, and comprises an ATC codon at a position corresponding to positions 4,243-4,245 according to SEQ ID NO: 132, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 98% sequence identity to SEQ ID NO: 132, and comprises an ATC codon at a position corresponding to positions 4,243-4,245 according to SEQ ID NO: 132, or its complement. As used herein, when referring to percent sequence identity, higher sequence identities are preferred over lower percentages.

[0247] In some embodiments, the isolated genomic nucleic acid molecule comprises SEQ ID NO: 132. In some embodiments, the isolated genomic nucleic acid molecule consists of SEQ ID NO: 132. The present disclosure also provides an isolated genomic nucleic acid molecule comprising or consisting of a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises an adenine (G4,325A) at a position corresponding to position 4,325 according to SEQ ID NO: 133, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises an adenine (G4,325A) at a position corresponding to position 4,325 according to SEQ ID NO: 133, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule consists of a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises an adenine (G4,325A) at a position corresponding to position 4,325 according to SEQ ID NO: 133, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises a TAG codon at positions corresponding to positions 4,324-4,326 according to SEQ ID NO: 133.

[0248] In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 133, and comprises an adenine, or a complement thereof, at a position corresponding to position 4,325 according to SEQ ID NO: 133. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90% sequence identity to SEQ ID NO: 133, and comprises an adenine, or a complement thereof, at a position corresponding to position 4,325 according to SEQ ID NO: 133. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 92% sequence identity to SEQ ID NO: 133, and comprises an adenine, or a complement thereof, at a position corresponding to position 4,325 according to SEQ ID NO: 133. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 94% sequence identity to SEQ ID NO: 133 and comprises an adenine, or its complement, at a position corresponding to position 4,325 according to SEQ ID NO: 133. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 96% sequence identity to SEQ ID NO: 133 and comprises an adenine, or its complement, at a position corresponding to position 4,325 according to SEQ ID NO: 133. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 98% sequence identity to SEQ ID NO: 133 and comprises an adenine, or its complement, at a position corresponding to position 4,325 according to SEQ ID NO: 133. As used herein, when referring to percent sequence identity, higher sequence identity is preferred than lower percentages.

[0249] In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 133, and comprises a TAG codon at a position corresponding to positions 4,324-4,326, or a complement thereof, according to SEQ ID NO: 133. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90% sequence identity to SEQ ID NO: 133, and comprises a TAG codon at a position corresponding to positions 4,324-4,326, or a complement thereof, according to SEQ ID NO: 133. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 92% sequence identity to SEQ ID NO: 133, and comprises a TAG codon at a position corresponding to positions 4,324-4,326 according to SEQ ID NO: 133, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 94% sequence identity to SEQ ID NO: 133, and comprises a TAG codon at a position corresponding to positions 4,324-4,326 according to SEQ ID NO: 133, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 96% sequence identity to SEQ ID NO: 133, and comprises a TAG codon at a position corresponding to positions 4,324-4,326 according to SEQ ID NO: 133, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 98% sequence identity to SEQ ID NO: 133, and includes a TAG codon at a position corresponding to positions 4,324-4,326 according to SEQ ID NO: 133, or its complement. As used herein, when referring to percent sequence identity, higher sequence identities are preferred over lower percentages.

[0250] In some embodiments, the isolated genomic nucleic acid molecule comprises SEQ ID NO: 133. In some embodiments, the isolated genomic nucleic acid molecule consists of SEQ ID NO: 133. The present disclosure also provides an isolated genomic nucleic acid molecule comprising or consisting of a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises a cytosine (A4,336C) at a position corresponding to position 4,336 according to SEQ ID NO: 134, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises a cytosine (A4,336C) at a position corresponding to position 4,336 according to SEQ ID NO: 134, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule consists of a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises a cytosine (A4,336C) at a position corresponding to position 4,336 according to SEQ ID NO: 134, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises a nucleotide sequence encoding a human ANGPTL7 polypeptide, wherein the nucleotide sequence comprises a CAG codon at a position corresponding to positions 4,336-4,338 according to SEQ ID NO: 134.

[0251] In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 134, and comprises a cytosine, or a complement thereof, at a position corresponding to position 4,336 according to SEQ ID NO: 134. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90% sequence identity to SEQ ID NO: 134, and comprises a cytosine, or a complement thereof, at a position corresponding to position 4,336 according to SEQ ID NO: 134. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 92% sequence identity to SEQ ID NO: 134, and comprises a cytosine, or a complement thereof, at a position corresponding to position 4,336 according to SEQ ID NO: 134. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 94% sequence identity to SEQ ID NO: 134, and comprises a cytosine, or its complement, at a position corresponding to position 4,336 according to SEQ ID NO: 134. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 96% sequence identity to SEQ ID NO: 134, and comprises a cytosine, or its complement, at a position corresponding to position 4,336 according to SEQ ID NO: 134. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 98% sequence identity to SEQ ID NO: 134, and comprises a cytosine, or its complement, at a position corresponding to position 4,336 according to SEQ ID NO: 134. As used herein, when referring to percent sequence identity, higher sequence identity is preferred than lower percentages.

[0252] In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 134, and comprises a CAG codon at a position corresponding to positions 4,336-4,338 according to SEQ ID NO: 134, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 90% sequence identity to SEQ ID NO: 134, and comprises a CAG codon at a position corresponding to positions 4,336-4,338 according to SEQ ID NO: 134, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 92% sequence identity to SEQ ID NO: 134, and comprises a CAG codon at a position corresponding to positions 4,336-4,338 according to SEQ ID NO: 134, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 94% sequence identity to SEQ ID NO: 134, and comprises a CAG codon at a position corresponding to positions 4,336-4,338 according to SEQ ID NO: 134, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 96% sequence identity to SEQ ID NO: 134, and comprises a CAG codon at a position corresponding to positions 4,336-4,338 according to SEQ ID NO: 134, or a complement thereof. In some embodiments, the isolated genomic nucleic acid molecule comprises or consists of a nucleotide sequence that has at least about 98% sequence identity to SEQ ID NO: 134, and includ...

Claims

1. 1. A method of treating a patient suffering from increased IOP, comprising administering to said patient an angiopoietin-like 7 (ANGPTL7) inhibitor.

2. 1. A method of treating a patient with glaucoma, comprising administering to the patient an ANGPTL7 inhibitor.

3. 3. The method of claim 1 or claim 2, wherein the ANGPTL7 inhibitor comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA) that hybridizes to ANGPTL7 mRNA.

4. The method of claim 1 or claim 2, wherein the ANGPTL7 inhibitor comprises a Cas protein and a guide RNA (gRNA) that hybridizes to a gRNA recognition sequence in an ANGPTL7 genomic nucleic acid molecule.

5. 5. The method of claim 4, wherein the Cas protein is Cas9 or Cpf1.

6. 6. The method of claim 4 or claim 5, wherein the gRNA recognition sequence encompasses or is adjacent to a position corresponding to position 4,291 according to SEQ ID NO:1, position 4,287 according to SEQ ID NO:1, position 4,243 according to SEQ ID NO:1, position 4,325 according to SEQ ID NO:1, or position 4,336 according to SEQ ID NO:

1.

7. 7. The method of any one of claims 4 to 6, wherein the gRNA recognition sequence is located about 1000, 500, 400, 300, 200, 100, 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5 nucleotides from a position corresponding to position 4,291 according to SEQ ID NO:1, position 4,287 according to SEQ ID NO:1, position 4,243 according to SEQ ID NO:1, position 4,325 according to SEQ ID NO:1, or position 4,336 according to SEQ ID NO:

1.

8. 8. The method of any one of claims 4 to 7, wherein a protospacer adjacent motif (PAM) sequence is about 2 to 6 nucleotides downstream of the gRNA recognition sequence.

9. 9. The method of any one of claims 4 to 8, wherein the gRNA comprises from about 17 to about 23 nucleotides.

10. The method according to any one of claims 4 to 8, wherein the gRNA recognition sequence comprises a nucleotide sequence set forth in any one of SEQ ID NOs: 13 to 131 and 144 to 165.

11. The method of any one of claims 1 to 10, further comprising detecting the presence or absence of a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encoding a human ANGPTL7 polypeptide in a biological sample from the patient.

12. 12. The method of claim 11, wherein if the patient is ANGPTL7 reference type, the patient is also administered a standard dosage of a therapeutic agent that treats or inhibits the ocular disease.

13. The method of claim 11, wherein if the patient is heterozygous for a predicted loss-of-function variant of ANGPTL7, the patient is also administered a therapeutic agent that treats or inhibits an ocular disease at a dose that is the same as or lower than the standard dose.

14. The method of any one of claims 11 to 13, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a nucleic acid molecule encoding Gln175His, Arg177Stop, Trp188Stop, Lys192Gln, Phe161Ile, Arg340His, Arg220His, Asn302Lys, or Arg220Cys of ANGPTL7.

15. The method according to any one of claims 11 to 13, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a nucleic acid molecule encoding Gln175His, Trp188Stop, Lys192Gln, Phe161Ile, or Arg177Stop of ANGPTL7.

16. The method of claim 15, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a genomic nucleic acid molecule having a nucleotide sequence comprising a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, an mRNA molecule having a nucleotide sequence comprising a uracil at a position corresponding to position 529 according to SEQ ID NO:5, or a cDNA molecule generated from an mRNA molecule having a nucleotide sequence comprising a thymine at a position corresponding to position 529 according to SEQ ID NO:

8.

17. The method of claim 15, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a genomic nucleic acid molecule having a nucleotide sequence comprising a thymine at a position corresponding to position 4,287 according to SEQ ID NO:3, an mRNA molecule having a nucleotide sequence comprising a uracil at a position corresponding to position 525 according to SEQ ID NO:6, or a cDNA molecule generated from an mRNA molecule having a nucleotide sequence comprising a thymine at a position corresponding to position 525 according to SEQ ID NO:

9.

18. The method of claim 15, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a genomic nucleic acid molecule having a nucleotide sequence that includes an adenine at position corresponding to position 4,243 according to SEQ ID NO: 132, an mRNA molecule having a nucleotide sequence that includes an adenine at position corresponding to position 481 according to SEQ ID NO: 135, or a cDNA molecule generated from an mRNA molecule having a nucleotide sequence that includes an adenine at position corresponding to position 481 according to SEQ ID NO:

138.

19. The method of claim 15, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a genomic nucleic acid molecule having a nucleotide sequence that includes an adenine at position corresponding to position 4,325 according to SEQ ID NO: 133, an mRNA molecule having a nucleotide sequence that includes an adenine at position corresponding to position 563 according to SEQ ID NO: 136, or a cDNA molecule generated from an mRNA molecule having a nucleotide sequence that includes an adenine at position corresponding to position 563 according to SEQ ID NO:

139.

20. The method of claim 15, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a genomic nucleic acid molecule having a nucleotide sequence that includes a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, an mRNA molecule having a nucleotide sequence that includes a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, or a cDNA molecule generated from an mRNA molecule having a nucleotide sequence that includes a cytosine at a position corresponding to position 574 according to SEQ ID NO:

140.

21. The method of any one of claims 11 to 20, wherein the detecting step is performed in vitro.

22. The detection step includes: sequencing at least a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 4,291 according to SEQ ID NO:2, or a complement thereof; Sequencing at least a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 529 according to SEQ ID NO:5, or a complement thereof; and / or Sequencing at least a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 529 according to SEQ ID NO:8, or a complement thereof; where if the sequenced portion of the ANGPTL7 genomic nucleic acid molecule of the biological sample comprises a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, then the ANGPTL7 genomic nucleic acid molecule of the biological sample is a predicted loss-of-function mutant genomic nucleic acid molecule of ANGPTL7; if the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample comprises a uracil at a position corresponding to position 529 according to SEQ ID NO:5, then the ANGPTL7 mRNA molecule of the biological sample is a predicted loss-of-function mutant mRNA molecule of ANGPTL7; 22. The method of any one of claims 11-16 and 21, wherein if the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains a thymine at a position corresponding to position 529 according to SEQ ID NO:8, then the ANGPTL7 cDNA molecule of the biological sample is a predicted loss-of-function mutant cDNA molecule of ANGPTL7.

23. The detection step includes: sequencing at least a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 4,287 according to SEQ ID NO:3, or a complement thereof; Sequencing at least a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 525 according to SEQ ID NO:6, or a complement thereof; and / or Sequencing at least a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 525 according to SEQ ID NO:9, or a complement thereof; where if the sequenced portion of the ANGPTL7 genomic nucleic acid molecule of the biological sample comprises a thymine at a position corresponding to position 4,287 according to SEQ ID NO:3, then the ANGPTL7 genomic nucleic acid molecule of the biological sample is a predicted loss-of-function mutant genomic nucleic acid molecule of ANGPTL7; if the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample comprises a uracil at a position corresponding to position 525 according to SEQ ID NO:6, then the ANGPTL7 mRNA molecule of the biological sample is a predicted loss-of-function mutant mRNA molecule of ANGPTL7; 22. The method of any one of claims 11-15, 17, and 21, wherein if the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains a thymine at a position corresponding to position 525 according to SEQ ID NO:9, then the ANGPTL7 cDNA molecule of the biological sample is a predicted loss-of-function mutant cDNA molecule of ANGPTL7.

24. The detection step includes: sequencing at least a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 4,243 according to SEQ ID NO:132; Sequencing at least a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule of the biological sample, wherein the sequenced portion comprises a position corresponding to position 481 according to SEQ ID NO: 135; and / or Sequencing at least a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 481 according to SEQ ID NO: 138; where if the sequenced portion of the ANGPTL7 genomic nucleic acid molecule of the biological sample comprises an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, then the ANGPTL7 genomic nucleic acid molecule of the biological sample is a predicted loss-of-function mutant genomic nucleic acid molecule of ANGPTL7; if the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample comprises an adenine at a position corresponding to position 481 according to SEQ ID NO: 135, then the ANGPTL7 mRNA molecule of the biological sample is a predicted loss-of-function mutant mRNA molecule of ANGPTL7; 22. The method of any one of claims 11-15, 18, and 21, wherein if the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains an adenine at a position corresponding to position 481 according to SEQ ID NO: 138, then the ANGPTL7 cDNA molecule of the biological sample is a predicted loss-of-function mutant cDNA molecule of ANGPTL7.

25. The detection step includes: sequencing at least a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 4,325 according to SEQ ID NO: 133, or a complement thereof; Sequencing at least a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 563 according to SEQ ID NO: 136, or a complement thereof; and / or Sequencing at least a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 563 according to SEQ ID NO: 139, or a complement thereof; where if the sequenced portion of the ANGPTL7 genomic nucleic acid molecule of the biological sample comprises an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, then the ANGPTL7 genomic nucleic acid molecule of the biological sample is a predicted loss-of-function mutant genomic nucleic acid molecule of ANGPTL7; if the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample comprises an adenine at a position corresponding to position 563 according to SEQ ID NO: 136, then the ANGPTL7 mRNA molecule of the biological sample is a predicted loss-of-function mutant mRNA molecule of ANGPTL7; 22. The method of any one of claims 11-15, 19, and 21, wherein if the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample comprises an adenine at a position corresponding to position 563 according to SEQ ID NO: 139, then the ANGPTL7 cDNA molecule of the biological sample is a predicted loss-of-function mutant cDNA molecule of ANGPTL7.

26. The detection step includes: sequencing at least a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 4,336 according to SEQ ID NO:134; Sequencing at least a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 574 according to SEQ ID NO: 137; and / or Sequencing at least a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 574 according to SEQ ID NO: 140; where if the sequenced portion of the ANGPTL7 genomic nucleic acid molecule of the biological sample comprises a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, then the ANGPTL7 genomic nucleic acid molecule of the biological sample is a predicted loss-of-function mutant genomic nucleic acid molecule of ANGPTL7; if the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample comprises a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, then the ANGPTL7 mRNA molecule of the biological sample is a predicted loss-of-function mutant mRNA molecule of ANGPTL7; 22. The method of any one of claims 11-15, 20, and 21, wherein if the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140, then the ANGPTL7 cDNA molecule of the biological sample is a predicted loss-of-function mutant cDNA molecule of ANGPTL7.

27. The detection step includes: a) contacting the biological sample with a primer that hybridizes to a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,291 according to SEQ ID NO:2; a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule adjacent to a position corresponding to position 529 according to SEQ ID NO:5; and / or a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule adjacent to a position corresponding to position 529 according to SEQ ID NO:8; b) extending said primer through at least the position of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule corresponding to position 4,291 according to SEQ ID NO:2, the position of the nucleotide sequence of the ANGPTL7 mRNA molecule corresponding to position 529 according to SEQ ID NO:5, and / or the position of the nucleotide sequence of the ANGPTL7 cDNA molecule corresponding to position 529 according to SEQ ID NO:8; and c) determining whether the extension product of the primer comprises a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, a uracil at a position corresponding to position 529 according to SEQ ID NO:5, and / or a thymine at a position corresponding to position 529 according to SEQ ID NO:8; The method according to any one of claims 11 to 16, 21 and 22, comprising:

28. The detection step includes: a) contacting the biological sample with a primer that hybridizes to a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,287 according to SEQ ID NO:3; a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule adjacent to a position corresponding to position 525 according to SEQ ID NO:6; and / or a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule adjacent to a position corresponding to position 525 according to SEQ ID NO:9; b) extending said primer through at least the position of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule corresponding to position 4,287 according to SEQ ID NO:3, the position of the nucleotide sequence of the ANGPTL7 mRNA molecule corresponding to position 525 according to SEQ ID NO:6, and / or the position of the nucleotide sequence of the ANGPTL7 cDNA molecule corresponding to position 525 according to SEQ ID NO:9; and c) determining whether the extension product of the primer comprises a thymine at a position corresponding to position 4,287 according to SEQ ID NO:3, a uracil at a position corresponding to position 525 according to SEQ ID NO:6, and / or a thymine at a position corresponding to position 525 according to SEQ ID NO:9; The method of any one of claims 11 to 15, 17, 21 and 23, comprising:

29. The detection step includes: a) contacting the biological sample with a primer that hybridizes to a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,243 according to SEQ ID NO: 132; a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule adjacent to a position corresponding to position 481 according to SEQ ID NO: 135; and / or a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule adjacent to a position corresponding to position 481 according to SEQ ID NO: 138; b) extending said primer through at least the position of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,243 according to SEQ ID NO: 132, the position of the nucleotide sequence of the ANGPTL7 mRNA molecule adjacent to a position corresponding to position 481 according to SEQ ID NO: 135, and / or the position of the nucleotide sequence of the ANGPTL7 cDNA molecule adjacent to a position corresponding to position 481 according to SEQ ID NO: 138; c) determining whether the extension product of the primer contains an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, whether it contains an adenine at a position corresponding to position 481 according to SEQ ID NO: 135, and / or whether it contains an adenine at a position corresponding to position 481 according to SEQ ID NO: 138; The method of any one of claims 11 to 15, 18, 21 and 24, comprising:

30. The detection step includes: a) contacting the biological sample with a primer that hybridizes to a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,325 according to SEQ ID NO: 133; a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule adjacent to a position corresponding to position 563 according to SEQ ID NO: 136; and / or a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule adjacent to a position corresponding to position 563 according to SEQ ID NO: 139; b) extending said primer through at least the position of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,325 according to SEQ ID NO: 133, the position of the nucleotide sequence of the ANGPTL7 mRNA molecule adjacent to a position corresponding to position 563 according to SEQ ID NO: 136, and / or the position of the nucleotide sequence of the ANGPTL7 cDNA molecule adjacent to a position corresponding to position 563 according to SEQ ID NO: 139; c) determining whether the extension product of the primer comprises an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, an adenine at a position corresponding to position 563 according to SEQ ID NO: 136, and / or an adenine at a position corresponding to position 563 according to SEQ ID NO: 139; The method of any one of claims 11 to 15, 19, 21 and 25, comprising:

31. The detection step includes: a) contacting the biological sample with a primer that hybridizes to a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,336 according to SEQ ID NO: 134; a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule adjacent to a position corresponding to position 574 according to SEQ ID NO: 137; and / or a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule adjacent to a position corresponding to position 574 according to SEQ ID NO: 140; b) extending said primer through at least the position of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,336 according to SEQ ID NO: 134, the position of the nucleotide sequence of the ANGPTL7 mRNA molecule adjacent to a position corresponding to position 574 according to SEQ ID NO: 137, and / or the position of the nucleotide sequence of the ANGPTL7 cDNA molecule adjacent to a position corresponding to position 574 according to SEQ ID NO: 140; c) determining whether the extension product of the primer contains a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, and / or a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140; The method of any one of claims 11 to 15, 20, 21 and 26, comprising:

32. The method of any one of claims 22 to 31, wherein the detecting step comprises sequencing the entire nucleic acid molecule.

33. The detection step includes: a) amplifying at least a portion of the nucleic acid molecule encoding the human ANGPTL7 polypeptide, wherein the portion comprises a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, or a complement thereof; a uracil at a position corresponding to position 529 according to SEQ ID NO:5, or a complement thereof; or a thymine at a position corresponding to position 529 according to SEQ ID NO:8, or a complement thereof; b) labeling the amplified nucleic acid molecules with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising a variation-specific probe, the variation-specific probe comprising a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 4,291 according to SEQ ID NO:2; the nucleic acid sequence of the amplified nucleic acid molecule comprising a uracil or its complement at a position corresponding to position 529 according to SEQ ID NO:5; or the nucleic acid sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 529 according to SEQ ID NO:8; and d) detecting said detectable label; The method of any one of claims 11 to 16, 21, 22, 27, and 32, comprising:

34. The detection step includes: a) amplifying at least a portion of the nucleic acid molecule encoding the human ANGPTL7 polypeptide, wherein the portion comprises a thymine at a position corresponding to position 4,287 according to SEQ ID NO:3, or a complement thereof; a uracil at a position corresponding to position 525 according to SEQ ID NO:6, or a complement thereof; or a thymine at a position corresponding to position 525 according to SEQ ID NO:9, or a complement thereof; b) labeling the amplified nucleic acid molecules with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising a variation-specific probe, the variation-specific probe comprising a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 4,287 according to SEQ ID NO:3; the nucleic acid sequence of the amplified nucleic acid molecule comprising a uracil or its complement at a position corresponding to position 525 according to SEQ ID NO:6; or the nucleic acid sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 525 according to SEQ ID NO:9; and d) detecting said detectable label; The method of any one of claims 11 to 15, 17, 21, 23, 28, and 32, comprising:

35. The detection step includes: a) amplifying at least a portion of the nucleic acid molecule encoding the human ANGPTL7 polypeptide, wherein the portion comprises an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, an adenine at a position corresponding to position 481 according to SEQ ID NO: 135, or an adenine at a position corresponding to position 481 according to SEQ ID NO: 138; b) labeling the amplified nucleic acid molecules with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising a variation-specific probe, the variation-specific probe comprising a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132; the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 481 according to SEQ ID NO: 135; or the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine at a position corresponding to position 481 according to SEQ ID NO: 138; and d) detecting said detectable label; The method of any one of claims 11 to 15, 18, 21, 24, 29, and 32, comprising:

36. The detection step includes: a) amplifying at least a portion of the nucleic acid molecule encoding the human ANGPTL7 polypeptide, wherein the portion comprises an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, an adenine at a position corresponding to position 563 according to SEQ ID NO: 136, or an adenine at a position corresponding to position 563 according to SEQ ID NO: 139; b) labeling the amplified nucleic acid molecules with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising a variation-specific probe, the variation-specific probe comprising a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133; the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 563 according to SEQ ID NO: 136; or the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine at a position corresponding to position 563 according to SEQ ID NO: 139; and d) detecting said detectable label; The method of any one of claims 11 to 15, 19, 21, 25, 30, and 32, comprising:

37. The detection step includes: a) amplifying at least a portion of the nucleic acid molecule encoding the human ANGPTL7 polypeptide, wherein the portion comprises a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, or a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140; b) labeling the amplified nucleic acid molecules with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising a variation-specific probe, the variation-specific probe comprising a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134; the nucleic acid sequence of the amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 574 according to SEQ ID NO: 137; or the nucleic acid sequence of the amplified nucleic acid molecule comprising a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140; and d) detecting said detectable label; The method of any one of claims 11 to 15, 20, 21, 26, 31 and 32, comprising:

38. The method according to any one of claims 33 to 37, wherein the nucleic acid molecules of the sample are mRNA, and the mRNA is reverse transcribed into cDNA prior to the amplification step.

39. The detection step includes: contacting the nucleic acid molecule of the biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to the nucleotide sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 4,291 according to SEQ ID NO:2; the nucleotide sequence of the amplified nucleic acid molecule comprising a uracil or its complement at a position corresponding to position 529 according to SEQ ID NO:5; or the nucleotide sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 529 according to SEQ ID NO:8; and detecting the detectable label; The method according to any one of claims 11 to 16 and 21, comprising:

40. The detection step includes: contacting the nucleic acid molecule of the biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to the nucleotide sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 4,287 according to SEQ ID NO:3; the nucleotide sequence of the amplified nucleic acid molecule comprising a uracil or its complement at a position corresponding to position 525 according to SEQ ID NO:6; or the nucleotide sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 525 according to SEQ ID NO:9; and detecting the detectable label; The method of any one of claims 11 to 15, 17 and 21, comprising:

41. The detection step includes: contacting the nucleic acid molecule of the biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132; the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 481 according to SEQ ID NO: 135; or the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine at a position corresponding to position 481 according to SEQ ID NO: 138; and detecting the detectable label; The method of any one of claims 11 to 15, 18 and 21, comprising:

42. The detection step includes: contacting the nucleic acid molecule of the biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133; the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 563 according to SEQ ID NO: 136; or the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine at a position corresponding to position 563 according to SEQ ID NO: 139; and detecting the detectable label; The method of any one of claims 11 to 15, 19 and 21, comprising:

43. The detection step includes: contacting the nucleic acid molecule of the biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134; the nucleic acid sequence of the amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 574 according to SEQ ID NO: 137; or the nucleic acid sequence of the amplified nucleic acid molecule comprising a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140; and detecting the detectable label; The method of any one of claims 11 to 15, 20 and 21, comprising:

44. 1. A method of treating a patient suffering from an ocular disease with a therapeutic agent that treats or inhibits the ocular disease, comprising: determining whether the patient has a predicted loss-of-function mutant angiopoietin-like 7 (ANGPTL7) nucleic acid molecule encoding a human ANGPTL7 polypeptide; obtaining or having obtained a biological sample from the patient; A determining step by performing or having performed a genotyping assay on the biological sample to determine whether the patient has a genotype that includes the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7; and if the patient is ANGPTL7 reference type, then administering or continuing to administer to the patient a standard dose of the therapeutic agent that treats or inhibits the ocular disease and administering to the patient an ANGPTL7 inhibitor; and if the patient is heterozygous for a predicted loss-of-function variant of ANGPTL7, then administering or continuing administration of the therapeutic agent that treats or inhibits the ocular disease to the patient at a standard dose or at a lower dose, and administering an ANGPTL7 inhibitor to the patient; wherein the presence of a genotype having a predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 encoding the human ANGPTL7 polypeptide indicates that the patient is at reduced risk of developing the eye disease.

45. 45. The method of claim 44, wherein the patient is ANGPTL7 reference type, and the patient is administered or continues to be administered a standard dose of the therapeutic agent that treats or inhibits the ocular disease and is administered an ANGPTL7 inhibitor.

46. 45. The method of claim 44, wherein the patient is heterozygous for a predicted loss-of-function variant of ANGPTL7, and the patient is administered or continues to be administered the therapeutic agent that treats or inhibits the ocular disease at a standard dose or at a lower dose, and is administered an ANGPTL7 inhibitor.

47. The method of any one of claims 44 to 46, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a nucleic acid molecule encoding Gln175His, Arg177Stop, Trp188Stop, Lys192Gln, Phe161Ile, Arg340His, Arg220His, Asn302Lys, or Arg220Cys of ANGPTL7.

48. The method according to any one of claims 44 to 46, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a nucleic acid molecule encoding Gln175His, Arg177Stop, Trp188Stop, Lys192Gln, and Phe161Ile of ANGPTL7.

49. The method of any one of claims 44 to 48, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a genomic nucleic acid molecule having a nucleotide sequence that includes a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, an mRNA molecule having a nucleotide sequence that includes a uracil at a position corresponding to position 529 according to SEQ ID NO:5, or a cDNA molecule generated from an mRNA molecule having a nucleotide sequence that includes a thymine at a position corresponding to position 529 according to SEQ ID NO:

8.

50. The method of any one of claims 44 to 48, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a genomic nucleic acid molecule having a nucleotide sequence that includes a thymine at a position corresponding to position 4,287 according to SEQ ID NO:3, an mRNA molecule having a nucleotide sequence that includes a uracil at a position corresponding to position 525 according to SEQ ID NO:6, or a cDNA molecule generated from an mRNA molecule having a nucleotide sequence that includes a thymine at a position corresponding to position 525 according to SEQ ID NO:

9.

51. The method of any one of claims 44 to 48, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a genomic nucleic acid molecule having a nucleotide sequence that includes an adenine at position corresponding to position 4,243 according to SEQ ID NO: 132, an mRNA molecule having a nucleotide sequence that includes an adenine at position corresponding to position 481 according to SEQ ID NO: 135, or a cDNA molecule generated from an mRNA molecule having a nucleotide sequence that includes an adenine at position corresponding to position 481 according to SEQ ID NO:

138.

52. 49. The method of any one of claims 44 to 48, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a genomic nucleic acid molecule having a nucleotide sequence that includes an adenine at position corresponding to position 4,325 according to SEQ ID NO: 133, an mRNA molecule having a nucleotide sequence that includes an adenine at position corresponding to position 563 according to SEQ ID NO: 136, or a cDNA molecule generated from an mRNA molecule having a nucleotide sequence that includes an adenine at position corresponding to position 563 according to SEQ ID NO:

139.

53. The method of any one of claims 44 to 48, wherein the predicted loss-of-function mutant nucleic acid molecule of ANGPTL7 is a genomic nucleic acid molecule having a nucleotide sequence that includes a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, an mRNA molecule having a nucleotide sequence that includes a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, or a cDNA molecule generated from an mRNA molecule having a nucleotide sequence that includes a cytosine at a position corresponding to position 574 according to SEQ ID NO:

140.

54. The genotyping assay comprises: sequencing at least a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 4,291 according to SEQ ID NO:2, or a complement thereof; Sequencing at least a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 529 according to SEQ ID NO:5, or a complement thereof; or sequencing at least a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule generated from an mRNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 529 according to SEQ ID NO:8, or a complement thereof; where if the sequenced portion of the ANGPTL7 genomic nucleic acid molecule of the biological sample comprises a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, then the ANGPTL7 genomic nucleic acid molecule of the biological sample is a predicted loss-of-function mutant genomic nucleic acid molecule of ANGPTL7; if the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample comprises a uracil at a position corresponding to position 529 according to SEQ ID NO:5, then the ANGPTL7 mRNA molecule of the biological sample is a predicted loss-of-function mutant mRNA molecule of ANGPTL7; 50. The method of any one of claims 44-49, wherein if the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains a thymine at a position corresponding to position 529 according to SEQ ID NO:8, then the ANGPTL7 cDNA molecule of the biological sample is a predicted loss-of-function mutant cDNA molecule of ANGPTL7.

55. The genotyping assay comprises: sequencing at least a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 4,287 according to SEQ ID NO:3, or a complement thereof; Sequencing at least a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 525 according to SEQ ID NO:6, or a complement thereof; or sequencing at least a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule generated from an mRNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 525 according to SEQ ID NO:9, or a complement thereof; where if the sequenced portion of the ANGPTL7 genomic nucleic acid molecule of the biological sample comprises a thymine at a position corresponding to position 4,287 according to SEQ ID NO:3, then the ANGPTL7 genomic nucleic acid molecule of the biological sample is a predicted loss-of-function mutant genomic nucleic acid molecule of ANGPTL7; if the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample comprises a uracil at a position corresponding to position 525 according to SEQ ID NO:6, then the ANGPTL7 mRNA molecule of the biological sample is a predicted loss-of-function mutant mRNA molecule of ANGPTL7; 51. The method of any one of claims 44-48 and 50, wherein if the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains a thymine at a position corresponding to position 525 according to SEQ ID NO:9, then the ANGPTL7 cDNA molecule of the biological sample is a predicted loss-of-function mutant cDNA molecule of ANGPTL7.

56. The genotyping assay comprises: sequencing at least a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 4,243 according to SEQ ID NO:132; Sequencing at least a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 481 according to SEQ ID NO: 135; or Sequencing at least a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule generated from an mRNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 481 according to SEQ ID NO: 138; where if the sequenced portion of the ANGPTL7 genomic nucleic acid molecule of the biological sample comprises an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, then the ANGPTL7 genomic nucleic acid molecule of the biological sample is a predicted loss-of-function mutant genomic nucleic acid molecule of ANGPTL7; if the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample comprises an adenine at a position corresponding to position 481 according to SEQ ID NO: 135, then the ANGPTL7 mRNA molecule of the biological sample is a predicted loss-of-function mutant mRNA molecule of ANGPTL7; 52. The method of any one of claims 44-48 and 51, wherein if the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample comprises an adenine at a position corresponding to position 481 according to SEQ ID NO: 138, then the ANGPTL7 cDNA molecule of the biological sample is a predicted loss-of-function mutant cDNA molecule of ANGPTL7.

57. The genotyping assay comprises: sequencing at least a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 4,325 according to SEQ ID NO: 133, or a complement thereof; Sequencing at least a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 563 according to SEQ ID NO: 136, or a complement thereof; or sequencing at least a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule generated from an mRNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 563 according to SEQ ID NO: 139, or a complement thereof; where if the sequenced portion of the ANGPTL7 genomic nucleic acid molecule of the biological sample comprises an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, then the ANGPTL7 genomic nucleic acid molecule of the biological sample is a predicted loss-of-function mutant genomic nucleic acid molecule of ANGPTL7; if the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample comprises an adenine at a position corresponding to position 563 according to SEQ ID NO: 136, then the ANGPTL7 mRNA molecule of the biological sample is a predicted loss-of-function mutant mRNA molecule of ANGPTL7; 53. The method of any one of claims 44-48 and 52, wherein if the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample comprises an adenine at a position corresponding to position 563 according to SEQ ID NO: 139, then the ANGPTL7 cDNA molecule of the biological sample is a predicted loss-of-function mutant cDNA molecule of ANGPTL7.

58. The genotyping assay comprises: sequencing at least a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 4,336 according to SEQ ID NO:134; Sequencing at least a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 574 according to SEQ ID NO: 137; or Sequencing at least a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule of the biological sample, wherein the sequenced portion includes a position corresponding to position 574 according to SEQ ID NO: 140; where if the sequenced portion of the ANGPTL7 genomic nucleic acid molecule of the biological sample comprises a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, then the ANGPTL7 genomic nucleic acid molecule of the biological sample is a predicted loss-of-function mutant genomic nucleic acid molecule of ANGPTL7; if the sequenced portion of the ANGPTL7 mRNA molecule of the biological sample comprises a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, then the ANGPTL7 mRNA molecule of the biological sample is a predicted loss-of-function mutant mRNA molecule of ANGPTL7; 54. The method of any one of claims 44-48 and 53, wherein if the sequenced portion of the ANGPTL7 cDNA molecule of the biological sample contains a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140, then the ANGPTL7 cDNA molecule of the biological sample is a predicted loss-of-function mutant cDNA molecule of ANGPTL7.

59. The genotyping assay comprises: a) contacting the biological sample with a primer that hybridizes to a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,291 according to SEQ ID NO:2; a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule adjacent to a position corresponding to position 529 according to SEQ ID NO:5; or a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule adjacent to a position corresponding to position 529 according to SEQ ID NO:8; b) extending said primer through at least the position of said nucleotide sequence of said ANGPTL7 genomic nucleic acid molecule corresponding to position 4,291 according to SEQ ID NO:2; the position of said nucleotide sequence of said ANGPTL7 mRNA molecule corresponding to position 529 according to SEQ ID NO:5; or the position of said nucleotide sequence of said ANGPTL7 cDNA molecule corresponding to position 529 according to SEQ ID NO:8; and c) determining whether the extension product of the primer comprises a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, a uracil at a position corresponding to position 529 according to SEQ ID NO:5, or a thymine at a position corresponding to position 529 according to SEQ ID NO:8; The method of any one of claims 44 to 49 and 54, comprising:

60. The genotyping assay comprises: a) contacting the biological sample with a primer that hybridizes to a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,287 according to SEQ ID NO:3; a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule adjacent to a position corresponding to position 525 according to SEQ ID NO:6; or a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule adjacent to a position corresponding to position 525 according to SEQ ID NO:9; b) extending said primer through at least the position of said nucleotide sequence of said ANGPTL7 genomic nucleic acid molecule corresponding to position 4,287 according to SEQ ID NO:3; the position of said nucleotide sequence of said ANGPTL7 mRNA molecule corresponding to position 525 according to SEQ ID NO:6; or the position of said nucleotide sequence of said ANGPTL7 cDNA molecule corresponding to position 525 according to SEQ ID NO:9; and c) determining whether the extension product of the primer comprises a thymine at a position corresponding to position 4,287 according to SEQ ID NO:3, a uracil at a position corresponding to position 525 according to SEQ ID NO:6, or a thymine at a position corresponding to position 525 according to SEQ ID NO:9; The method of any one of claims 44 to 48, 50 and 55, comprising:

61. The genotyping assay comprises: a) contacting the biological sample with a primer that hybridizes to a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,243 according to SEQ ID NO: 132; a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule adjacent to a position corresponding to position 481 according to SEQ ID NO: 135; or a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule adjacent to a position corresponding to position 481 according to SEQ ID NO: 138; b) extending said primer through at least the position of said nucleotide sequence of said ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,243 according to SEQ ID NO: 132; the position of said nucleotide sequence of said ANGPTL7 mRNA molecule adjacent to a position corresponding to position 481 according to SEQ ID NO: 135; or the position of said nucleotide sequence of said ANGPTL7 cDNA molecule adjacent to a position corresponding to position 481 according to SEQ ID NO: 138; c) determining whether the extension product of the primer contains an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, whether it contains an adenine at a position corresponding to position 481 according to SEQ ID NO: 135, or whether it contains an adenine at a position corresponding to position 481 according to SEQ ID NO: 138; The method of any one of claims 44 to 48, 51 and 56, comprising:

62. The genotyping assay comprises: a) contacting the biological sample with a primer that hybridizes to a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,325 according to SEQ ID NO: 133; a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule adjacent to a position corresponding to position 563 according to SEQ ID NO: 136; or a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule adjacent to a position corresponding to position 563 according to SEQ ID NO: 139; b) extending said primer through at least the position of said nucleotide sequence of said ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,325 according to SEQ ID NO: 133; the position of said nucleotide sequence of said ANGPTL7 mRNA molecule adjacent to a position corresponding to position 563 according to SEQ ID NO: 136; or the position of said nucleotide sequence of said ANGPTL7 cDNA molecule adjacent to a position corresponding to position 563 according to SEQ ID NO: 139; c) determining whether the extension product of the primer contains an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, whether it contains an adenine at a position corresponding to position 563 according to SEQ ID NO: 136, or whether it contains an adenine at a position corresponding to position 563 according to SEQ ID NO: 139; The method of any one of claims 44 to 48, 52 and 57, comprising:

63. The genotyping assay comprises: a) contacting the biological sample with a primer that hybridizes to a portion of the nucleotide sequence of the ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,336 according to SEQ ID NO: 134; a portion of the nucleotide sequence of the ANGPTL7 mRNA molecule adjacent to a position corresponding to position 574 according to SEQ ID NO: 137; or a portion of the nucleotide sequence of the ANGPTL7 cDNA molecule adjacent to a position corresponding to position 574 according to SEQ ID NO: 140; b) extending said primer through at least the position of said nucleotide sequence of said ANGPTL7 genomic nucleic acid molecule adjacent to a position corresponding to position 4,336 according to SEQ ID NO: 134; the position of said nucleotide sequence of said ANGPTL7 mRNA molecule adjacent to a position corresponding to position 574 according to SEQ ID NO: 137; or the position of said nucleotide sequence of said ANGPTL7 cDNA molecule adjacent to a position corresponding to position 574 according to SEQ ID NO: 140; c) determining whether the extension product of the primer contains a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, or a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140; The method of any one of claims 44 to 48, 53 and 58, comprising:

64. 64. The method of any one of claims 59 to 63, wherein the detecting step comprises sequencing the entire nucleic acid molecule.

65. The genotyping assay comprises: a) amplifying at least a portion of the nucleic acid molecule encoding the human ANGPTL7 polypeptide, wherein the portion comprises a thymine at a position corresponding to position 4,291 according to SEQ ID NO:2, or a complement thereof; a uracil at a position corresponding to position 529 according to SEQ ID NO:5, or a complement thereof; or a thymine at a position corresponding to position 529 according to SEQ ID NO:8, or a complement thereof; b) labeling the amplified nucleic acid molecules with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising a variation-specific probe, the variation-specific probe comprising a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 4,291 according to SEQ ID NO:2; the nucleic acid sequence of the amplified nucleic acid molecule comprising a uracil or its complement at a position corresponding to position 529 according to SEQ ID NO:5; or the nucleic acid sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 529 according to SEQ ID NO:8; and d) detecting said detectable label; The method of any one of claims 44 to 49, 54, 59 and 64, comprising:

66. The genotyping assay comprises: a) amplifying at least a portion of the nucleic acid molecule encoding the human ANGPTL7 polypeptide, wherein the portion comprises a thymine at a position corresponding to position 4,287 according to SEQ ID NO:3, or a complement thereof; a uracil at a position corresponding to position 525 according to SEQ ID NO:6, or a complement thereof; or a thymine at a position corresponding to position 525 according to SEQ ID NO:9, or a complement thereof; b) labeling the amplified nucleic acid molecules with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising a variation-specific probe, the variation-specific probe comprising a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 4,287 according to SEQ ID NO:3; the nucleic acid sequence of the amplified nucleic acid molecule comprising a uracil or its complement at a position corresponding to position 525 according to SEQ ID NO:6; or the nucleic acid sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 525 according to SEQ ID NO:9; and d) detecting said detectable label; The method of any one of claims 44 to 48, 50, 55, 60 and 64, comprising:

67. The genotyping assay comprises: a) amplifying at least a portion of the nucleic acid molecule encoding the human ANGPTL7 polypeptide, wherein the portion comprises an adenine at a position corresponding to position 4,243 according to SEQ ID NO: 132, or a complement thereof; an adenine at a position corresponding to position 481 according to SEQ ID NO: 135, or a complement thereof; or an adenine at a position corresponding to position 481 according to SEQ ID NO: 138, or a complement thereof; b) labeling the amplified nucleic acid molecules with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising a variation-specific probe, the variation-specific probe comprising a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 4,243 according to SEQ ID NO: 132; the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 481 according to SEQ ID NO: 135; or the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 481 according to SEQ ID NO: 138; and d) detecting said detectable label; The method of any one of claims 44 to 48, 51, 56, 61 and 64, comprising:

68. The genotyping assay comprises: a) amplifying at least a portion of the nucleic acid molecule encoding the human ANGPTL7 polypeptide, wherein the portion comprises an adenine at a position corresponding to position 4,325 according to SEQ ID NO: 133, or a complement thereof; an adenine at a position corresponding to position 563 according to SEQ ID NO: 136, or a complement thereof; or an adenine at a position corresponding to position 563 according to SEQ ID NO: 139, or a complement thereof; b) labeling the amplified nucleic acid molecules with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising a variation-specific probe, the variation-specific probe comprising a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 4,325 according to SEQ ID NO: 133; the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 563 according to SEQ ID NO: 136; or the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 563 according to SEQ ID NO: 139; and d) detecting said detectable label; The method of any one of claims 44 to 48, 52, 57, 62 and 64, comprising:

69. The genotyping assay comprises: a) amplifying at least a portion of the nucleic acid molecule encoding the human ANGPTL7 polypeptide, wherein the portion comprises a cytosine at a position corresponding to position 4,336 according to SEQ ID NO: 134, or a complement thereof; a cytosine at a position corresponding to position 574 according to SEQ ID NO: 137, or a complement thereof; or a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140, or a complement thereof; b) labeling the amplified nucleic acid molecules with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising a variation-specific probe, the variation-specific probe comprising a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 4,336 according to SEQ ID NO: 134; the nucleic acid sequence of the amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 574 according to SEQ ID NO: 137; or the nucleic acid sequence of the amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 574 according to SEQ ID NO: 140; and d) detecting said detectable label; The method of any one of claims 44 to 48, 53, 58, 63 and 64, comprising:

70. 70. The method of any one of claims 65 to 69, wherein the nucleic acid molecules of the sample are mRNA, and the mRNA is reverse transcribed into cDNA prior to the amplification step.

71. The genotyping assay comprises: contacting the nucleic acid molecule of the biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to the nucleotide sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 4,291 according to SEQ ID NO:2; the nucleotide sequence of the amplified nucleic acid molecule comprising a uracil or its complement at a position corresponding to position 529 according to SEQ ID NO:5; or the nucleotide sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 529 according to SEQ ID NO:8; and detecting the detectable label; 50. The method of any one of claims 44 to 49, comprising:

72. The genotyping assay comprises: contacting the nucleic acid molecule of the biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to the nucleotide sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 4,287 according to SEQ ID NO:3; the nucleotide sequence of the amplified nucleic acid molecule comprising a uracil or its complement at a position corresponding to position 525 according to SEQ ID NO:6; or the nucleotide sequence of the amplified nucleic acid molecule comprising a thymine or its complement at a position corresponding to position 525 according to SEQ ID NO:9; and detecting the detectable label; The method of any one of claims 44 to 48 and 50, comprising:

73. The genotyping assay comprises the nucleic acid sequence of the amplified nucleic acid molecule, comprising an adenine at a position corresponding to position 4,243 according to SEQ ID NO:132, or a complement thereof, an adenine at a position corresponding to position 481 according to SEQ ID NO:135, or a complement thereof, or an adenine at a position corresponding to position 481 according to SEQ ID NO:138, and detecting the detectable label; The method of any one of claims 44 to 48 and 51, comprising:

74. The genotyping assay comprises: contacting the nucleic acid molecule of the biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 4,325 according to SEQ ID NO: 133; the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine or its complement at a position corresponding to position 563 according to SEQ ID NO: 136; or the nucleic acid sequence of the amplified nucleic acid molecule comprising an adenine at a position corresponding to position 563 according to SEQ ID NO: 139; and detecting the detectable label; The method of any one of claims 44 to 48 and 52, comprising:

75. The genotyping assay comprises: contacting the nucleic acid molecule of the biological sample with a variation-specific probe comprising a detectable label, wherein the variation-specific probe comprises a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 4,336 according to SEQ ID NO: 134; the nucleic acid sequence of the amplified nucleic acid molecule comprising a cytosine or its complement at a position corresponding to position 574 according to SEQ ID NO: 137; or the nucleic acid sequence of the amplified nucleic acid molecule comprising a cytosine at a position corresponding to position 574 according to SEQ ID NO: 140; and detecting the detectable label; The method of any one of claims 44 to 48 and 53, comprising:

76. 76. The method of any one of claims 44 to 75, wherein the nucleic acid molecule is present in a cell obtained from the human subject.

77. 77. The method of any one of claims 44 to 76, wherein the ANGPTL7 inhibitor comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA) that hybridizes to ANGPTL7 mRNA.

78. The method of any one of claims 44 to 76, wherein the ANGPTL7 inhibitor comprises a Cas protein and a guide RNA (gRNA) that hybridizes to a gRNA recognition sequence in an ANGPTL7 genomic nucleic acid molecule.

79. 79. The method of claim 78, wherein the Cas protein is Cas9 or Cpf1.

80. 80. The method of claim 78 or claim 79, wherein the gRNA recognition sequence encompasses or is adjacent to a position corresponding to position 4,291 according to SEQ ID NO:1, position 4,287 according to SEQ ID NO:1, position 4,243 according to SEQ ID NO:1, position 4,325 according to SEQ ID NO:1, or position 4,336 according to SEQ ID NO:

1.

81. 81. The method of any one of claims 78 to 80, wherein the gRNA recognition sequence is located about 1000, 500, 400, 300, 200, 100, 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5 nucleotides from a position corresponding to position 4,291 according to SEQ ID NO:1, position 4,287 according to SEQ ID NO:1, position 4,243 according to SEQ ID NO:1, position 4,325 according to SEQ ID NO:1, or position 4,336 according to SEQ ID NO:

1.

82. 82. The method of any one of claims 78-81, wherein a protospacer adjacent motif (PAM) sequence is about 2-6 nucleotides downstream of the gRNA recognition sequence.

83. 83. The method of any one of claims 78-82, wherein the gRNA comprises from about 17 to about 23 nucleotides.

84. The method of any one of claims 78 to 83, wherein the gRNA recognition sequence comprises a nucleotide sequence set forth in any one of SEQ ID NOs: 13 to 131 and 144 to 165.

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