Application of chromosome karyotype-CNV-seq-WES stepped detection strategy for fetal lateral ventricle widening in prenatal genetic counseling and clinical prognosis analysis

Abstract

The invention belongs to the technical field of prenatal detection, and discloses application of a fetal side ventricle broadening karyotype-CNV-seq-WES stepped detection strategy in prenatal genetic counseling and clinical prognosis analysis, retrospective queue research design is adopted, 166 cases of FVM diagnosed by prenatal ultrasound are incorporated, and the detection strategy is applied to prenatal genetic counseling and clinical prognosis analysis. The system analyzes the relevance of FVM severity, anatomy types and chromosome abnormalities. The clinical application value of the genetic detection technology is evaluated by comparing genetic detection results and pregnancy outcomes of different subgroups. Through the analysis, more information is provided for the fetal medicine multidisciplinary team, so that the quasi parents are helped to obtain more comprehensive prenatal consultation and decision support.

Description

Technical Field

[0001] The present invention belongs to the field of prenatal detection technology, and specifically relates to the application of a chromosome karyotype-CNV-seq-WES step-by-step detection strategy for fetal ventriculomegaly in prenatal genetic counseling and clinical prognosis analysis. Background Art

[0002] The lateral ventricles, as an important component of the ventricular system, exhibit a specific cavity structure that primarily functions as a reservoir for cerebrospinal fluid (CSF) and circulates it, playing a key role in maintaining intracranial pressure homeostasis. During the second and third trimesters of normal pregnancy (12-40 weeks of gestation), the width of the fetal lateral ventricle body changes dynamically, with ultrasound examination showing a typical width ranging from 5.4 to 7.6 mm. According to international prenatal diagnosis guidelines, ventriculomegaly (VM) is diagnosed when the diameter of the lateral ventricle exceeds 10 mm. Clinical classification is based on the degree of ventriculomegaly, with three levels: mild (10-12 mm), moderate (12-15 mm), and severe (≥15 mm). VM, the most commonly observed neurological soft marker in prenatal ultrasound screening, has a detection rate of 0.78% to 2.2% in newborns. Its development involves multiple factors, including genetic abnormalities, environmental influences, and synergistic effects. Genetics are particularly crucial, and can manifest as chromosomal abnormalities in number or structure, single-gene disorders, and polygenic inheritance. Research data show that systematic genetic testing and evaluation can significantly improve the clinical diagnosis and treatment accuracy of VM and effectively predict pregnancy outcomes.

[0003] Based on the presence or absence of other systemic structural abnormalities, FVM can be divided into isolated ventriculomegaly (IFVM) and non-isolated ventriculomegaly (NIFVM). NIFVM is often associated with other intracranial abnormalities, such as Dandy-Walker syndrome, agenesis of the corpus callosum, and arachnoid cysts, and is often associated with extracranial malformations, such as cardiac, urinary, and skeletal abnormalities. Furthermore, from an anatomical perspective, FVM can be further divided into unilateral and bilateral ventriculomegaly; based on maternal characteristics, it can be divided into advanced age (≥35 years) and non-advanced age groups; and based on the gestational age at diagnosis, it can be divided into mid-gestation (12-27 + 6 weeks) and late-gestation (≥28 weeks) groups. Significant heterogeneity in intrauterine outcomes, perinatal outcomes, and neurodevelopmental prognosis is observed among different FVM classifications.

[0004] With the advancement of genomic technology, prenatal diagnostic methods for FVM are constantly being updated and improved. A variety of testing methods are now routinely used for prenatal genetic assessment of FVM. Summary of the Invention

[0005] The present invention provides an application of a chromosome karyotype-CNV-seq-WES step-by-step detection strategy for fetal ventriculomegaly in prenatal genetic counseling and clinical prognosis analysis.

[0006] Purpose of the present invention:

[0007] To analyze the genetic testing results of fetal ventriculomegaly (VM) and its pregnancy outcomes, and to explore the genetic testing of fetal ventriculomegaly and pregnancy outcomes.

[0008] The method of the present invention:

[0009] Methods: A total of 166 fetuses with ventriculomegaly who underwent invasive prenatal diagnosis at a single hospital between January 2020 and December 2023 were included. Karyotype, low-depth whole-genome sequencing (CNV-seq), and whole-exome sequencing (WES) data were systematically analyzed, and 146 pregnancy outcomes were followed up. Fetuses were divided into mild (10-12 mm), moderate (12-15 mm), and severe (≥15 mm) groups based on the degree of ventriculomegaly; isolated and nonisolated groups based on the presence or absence of other malformations; unilateral and bilateral groups based on the site of involvement; advanced (≥35 years) and nonadvanced maternal age; and mid-pregnancy (12-28 weeks) and late-pregnancy (≥28 weeks) groups based on gestational age. A stepwise genetic testing strategy (karyotyping-CNV-seq-WES) was used to systematically evaluate the correlation between FVM severity, anatomical typing, and genetic abnormalities. A multivariate regression model was constructed to analyze the factors affecting pregnancy outcomes. Liveborn newborns were dynamically followed up, and developmental status was assessed at 3, 6, and 12 months of age. All statistical analyses were performed using the chi-square test (χ 2 Inspection) completed.

[0010] Results: The chromosomal abnormality rate was significantly higher in the bilateral FVM group (17.5%) than in the unilateral group (2.06%, P = 0.0027). The pathogenic variant detection rate in moderate-to-severe FVM was 1.8 times higher than in the mild group (8.89% vs. 4.95%). Gestational age at initial diagnosis ≤ 28 weeks (OR = 4.31, 95% CI 1.45-7.11) and bilateral FVM (OR = 2.89, 95% CI 1.32-6.33) were independent risk factors for pregnancy termination. Among 15 pregnancy terminations, 9 had pathogenic CNVs or chromosomal aneuploidies. Follow-up revealed developmental delay in 7 infants, 5 of whom had concurrent abnormalities in other systems.

[0011] Conclusion: When prenatal examinations suggest fetal ventriculomegaly, combined karyotype, CNV-seq, and WES testing are necessary to improve the detection rate of genetic abnormalities, especially for bilateral ventriculomegaly and those with other malformations. Early gestational age and bilateral ventriculomegaly are high-risk factors for induced labor, and long-term postnatal follow-up of neurodevelopment is necessary.

[0012] The beneficial effects of the present invention are:

[0013] This study employed a retrospective cohort design and enrolled 166 patients with FVM diagnosed by prenatal ultrasound. We systematically analyzed the correlation between FVM severity, anatomic type, and chromosomal abnormalities. We compared genetic testing results and pregnancy outcomes across subgroups to evaluate the clinical value of genetic testing. These analyses aim to provide more information to the multidisciplinary fetal medicine team, enabling more comprehensive prenatal counseling and decision-making support for expectant parents. DETAILED DESCRIPTION

[0014] The following describes the embodiments of the present invention in detail. Unless otherwise specified, the raw materials and equipment used are commercially available or commonly used in the art. The methods described in the embodiments are conventional methods in the art unless otherwise specified. The embodiments are illustrative and are intended only to explain the present invention and are not to be construed as limiting the present invention.

[0015] As a classic detection method, chromosome karyotype analysis can accurately determine abnormal chromosome numbers and large-segment structural aberrations (such as trisomy 21 syndrome) through G-banding technology, and has always occupied an important position in the diagnosis of chromosomal diseases.

[0016] Low-depth whole-genome sequencing (CNV-seq), relying on a high-throughput sequencing platform, can accurately detect copy number variations (CNVs) across the entire genome, significantly improving the detection efficiency of submicroscopic structural abnormalities such as microdeletion / microduplication syndrome.

[0017] Whole exome sequencing (WES) can systematically screen for pathogenic variants such as single nucleotide variants (SNVs) and small insertions and deletions (indels) by targeting and capturing protein-coding regions, providing a key molecular diagnostic basis for the association study between single-gene genetic diseases and FVM.

[0018] The combined application of these technologies has significantly improved the detection rate of genetic causes of FVM (diagnosis rate increased by 15%-30%), providing important support for the development of individualized intervention plans and genetic counseling in the clinic. Cross-modal diagnostic models that integrate imaging and multi-omics data have become an important direction for optimizing prenatal management strategies.

[0019] 1 Materials and Methods

[0020] 1.1 General Information

[0021] This study, based at a hospital's prenatal diagnosis center, enrolled 166 pregnant women who presented between January 2020 and December 2023 and whose fetuses had prenatal ultrasound findings of lateral ventriculomegaly. After a rigorous screening process, 146 eligible cases were identified and underwent interventional prenatal diagnosis using CNV-seq or WES analysis to further investigate the potential genetic factors underlying fetal lateral ventriculomegaly. All subjects included in the study were singleton pregnancies to ensure the accuracy and reliability of the findings and avoid the potential confounding factors of multiple pregnancies.

[0022] Inclusion criteria:

[0023] (1) Fetuses diagnosed with mild, moderate, or severe VM by prenatal ultrasound; (2) Fetuses without intracranial or extracranial structural malformations; (3) Fetal copy number variations detected by amniocentesis or umbilical cord puncture using low-depth whole-genome sequencing (CNV-seq) technology, and single-gene abnormalities detected by whole-exome (WES) sequencing, and their results were compared. (4) At least one prenatal imaging examination (including prenatal ultrasound and fetal cranial magnetic resonance imaging) was performed; (5) Fetal growth and development and prognosis were followed up; (6) Pregnant women did not have complications such as diabetes and gestational hypertension.

[0024] Exclusion criteria:

[0025] (1) Cases with VM < 10 mm at initial diagnosis; (2) Ultrasound or MRI detected fetal concomitant intracranial and extracranial structural malformations; (3) Fetuses not tested for CNV-seq or WES; (4) No effective follow-up results of fetal and neonatal growth and development; (5) Pregnant women with complications such as diabetes and gestational hypertension.

[0026] 1.2 Instruments and Equipment

[0027] In this study, fetal ultrasound scans were performed using the Mindray Resona R9S ultrasound diagnostic system, either transabdominally or transvaginally. If abnormalities in intracranial structures, such as fetal FVM, were detected during the scan, a more in-depth neurosonographic examination was performed.

[0028] 1.3 Research Methods

[0029] (1) Imaging prenatal diagnosis

[0030] ① Ultrasound examination: (1) The pregnant woman lies in the supine position, and an experienced ultrasound physician uses a color Doppler ultrasound diagnostic device to perform systematic prenatal screening. The examination covers the assessment of the fetal anatomy, including the development of the heart, chest, limbs, liver, kidneys, digestive system, and nervous system. At the same time, parameters such as head circumference (HC), abdominal circumference (AC), biparietal diameter (BPD), and femur length (FL) are obtained and compared with the gestational age reference value. Amniotic fluid index (AFI) and placental position grade are used as auxiliary indicators for simultaneous assessment. For potential abnormal structures, a multi-section combined scanning strategy is adopted: the sagittal plane observes the development of the nasal bones and the continuity of the chest and abdominal walls, and the transverse plane checks for abnormalities in the four-chamber heart structure, gastric bubble morphology, and liver position; the central nervous system screening focuses on analyzing the midline position of the skull, the morphology of the lateral ventricles, and the integrity of the spine through coronal, sagittal, and axial planes to identify malformations such as ventriculomegaly or spina bifida. All abnormal signs must be reviewed by two physicians of associate senior level or above and integrated with the results of clinical genetic testing to provide a basis for subsequent diagnosis and intervention.

[0031] ② Magnetic resonance imaging (MRI): Fetal MRI can be used to detect abnormalities in the development of the fetal central nervous system. Its high soft tissue resolution allows for a clear visualization of brain anatomy, precise measurement of ventricular enlargement, and detection of subtle lesions difficult to discern by ultrasound, such as white matter hypoplasia and vascular malformations. Regarding prognostic assessment, the severity of the condition can be determined based on the extent of brain parenchyma involvement, predicting neurodevelopmental outcomes. For example, parenchymal atrophy indicates a poor prognosis, while mild enlargement without parenchymal abnormalities is a better outcome. Pregnancy recommendations can be made based on the results. Pregnant women with a good prognosis and a treatable etiology can continue the pregnancy; otherwise, termination should be considered to protect the health of both mother and child and the interests of the family, providing critical support for the diagnosis and management of ventricular enlargement.

[0032] (2) Sample collection

[0033] Extract fetal cells and genomic DNA.

[0034] (3) Cell culture and G-banding karyotype analysis: After sterile collection, the amniotic fluid samples of pregnant women were centrifuged to remove the supernatant. The precipitates were inoculated into two independent culture bottles for primary (I line) and passage (II line) double-line culture. The culture system was maintained in a standard cell culture incubator at a constant temperature of 37°C and a CO2 concentration of 5%. After 12 days of culture, the double-line cell suspension was collected synchronously using 0.025% trypsin digestion. Chromosome fixation, hypotonic treatment and G-banding staining were completed strictly in accordance with the department's standardized operating procedures (SOP). After chromosome preparation, 80 high-resolution images were obtained using a fully automatic chromosome scanning system, and 50 cell karyotype counts and 20 division phase structure analyses were preliminarily completed. In order to eliminate technical errors and enhance the reliability of the results in view of the karyotype abnormalities in the double-line culture results, the karyotype count was expanded to 100 cells for secondary verification.

[0035] (4) CNV-seq detection: CNV-seq detection strictly follows the standardized operating procedures, including the entire process from DNA extraction to bioinformatics analysis, specifically involving genomic DNA isolation, restriction enzyme digestion reaction, fragment purification, library preparation, library quality assessment, high-throughput sequencing and subsequent data analysis. The test results are annotated based on the human genome reference version hg19, and clinical interpretation is completed by comprehensively comparing DGV (Database of Genomic Variants), DECIPHER (Database of Genomic Variants and Phenotypes), OMIM (Online Mendelian Inheritance Database), UCSC (Genome Browser) and PubMed literature data. According to the International Common Classification of Clinical Genetics, the clinical significance of CNV is divided into five levels: benign variation, possibly benign variation, variation of unknown clinical significance (VOUS), suspected pathogenic variation and pathogenic variation. On this basis, for pathogenic or suspected pathogenic submicroscopic structural variations found in fetal testing, clinical guidelines recommend performing CNV-seq traceability analysis on both parents. The value of this testing solution is twofold: first, it can trace the genetic origin of the variant (de novo or inherited), and second, it helps to assess its clinical relevance in combination with family phenotypic data.

[0036] (5) WES testing: Complete the preparation of fetal amniotic fluid and parental peripheral blood DNA samples. The DNA concentration of all samples meets the detection standards (concentration>50ng / μL, total amount>1.5μg, A260 / A280 value stable in the range of 1.8-2.0). After ultrasonic fragmentation, library construction, hybridization capture and quality control are completed in sequence, and then high-throughput sequencing is carried out. The raw sequencing data is analyzed by genome alignment using BWA0.6.2-r126 software to generate SAM format files. After removing repeated sequences using the SAMtools tool, it is converted into BAM format files. GATK software is further used to complete local realignment and base quality correction, and finally single nucleotide variation (SNV) and short fragment insertion / deletion (In / Del) data are obtained. A localized analysis process is used to implement mutation annotation and hazard prediction. At the same time, authoritative database resources such as OMIM, HGMD and NCBI are integrated to systematically analyze the potential association between variant sites and genetic diseases and their pathogenic mechanisms.

[0037] (6) Sanger sequencing verification: Based on the WES test results, specific primers targeting the mutant gene are designed and PCR amplification is performed on fetal amniotic fluid DNA and parental peripheral blood DNA. The amplified DNA fragments are detected by Sanger sequencing, and the specific gene mutation sites of the fetus and parents are confirmed through family analysis.

[0038] 1.4 Statistical methods

[0039] All experimental parameters in this study were verified by three independent replicates, and the experimental data were averaged for subsequent statistical analysis. When SPSS 25.0 statistical analysis system was used for data processing, the distribution characteristics of the data set were first verified for normality using the Kolmogorov-Smirnov (KS) method. For quantitative data that conformed to the normal distribution and met the requirements for homogeneity of variance, the mean ± standard deviation (X ± s) was used for statistical description. The independent sample t-test method was used for inter-group difference analysis, and the paired t-test strategy was applied for intra-group longitudinal data comparison. The Pearson product-moment correlation coefficient method was used to test the association between variables. All statistical inferences used a two-sided test probability P < 0.05 as the threshold for statistical significance.

[0040] 2 Results

[0041] 2.1 Clinical characteristics of different degrees of fetal ventricular dilatation

[0042] This study included 166 pregnant women with fetal lateral ventriculomegaly, and 146 valid cases were found after screening. The age distribution of the study subjects ranged from 20 to 40 years old, including 15 cases (10.3%) of advanced maternal age (≥35 years old). The average gestational age at which ultrasound screening first revealed fetal lateral ventriculomegaly was 26.5±3.9 weeks. The data showed that there were 101 cases in the mild widening group and 45 cases in the moderate to severe widening group; from the perspective of anatomical distribution characteristics, there were 99 cases of unilateral lesions and 47 cases of bilateral lesions. The study showed that there was a significant correlation between the degree of widening and the anatomical distribution (P < 0.05). Specific data are shown in Table 1.

[0043] Table 1 Clinical characteristics of different degrees of fetal ventriculomegaly [n (%)] 2020-2023

[0044]

[0045] 2.2 Prenatal diagnosis of ventriculomegaly

[0046] This study uniformly performed invasive prenatal diagnosis on 146 pregnant women who underwent prenatal genetic counseling. Testing methods included karyotyping, CNV-seq, and whole-exome sequencing. The data showed that the chromosomal abnormality rate in the unilateral ventriculomegaly group was 2.06%, significantly lower than the 17.5% in the bilateral group (P = 0.0027). However, there was no statistically significant difference in abnormality rates between the mild ventriculomegaly group (4.95%) and the moderate to severe ventriculomegaly group (8.89%) (P = 0.5863). Furthermore, the chromosomal abnormality rate between the isolated ventriculomegaly group (6.25%) and the non-isolated ventriculomegaly group (6.45%) also did not differ significantly (P = 0.7642). Specific data are shown in Table 2.

[0047] Table 2 Relationship between lateral ventriculomegaly and chromosomal abnormalities [n(%)] 2020-2023

[0048]

[0049] The results of chromosome testing showed that karyotype analysis detected abnormalities in 6 of the 146 samples, including 2 cases of trisomy 21, 1 case of trisomy 18, and 3 cases of chromosomal structural abnormalities (including 1 case of superandrogenic syndrome, 1 case of balanced translocation (46,XY,t(1;2)(q32;q35)) and 1 case of derivative chromosome (46,XN,der(20)t(7;20)(p15;p13)). In addition, 9 copy number variations were detected using CNV-seq technology, of which 8 were clearly pathogenic and 1 was possibly pathogenic. Combined diagnosis of karyotype analysis and CNV-seq detection revealed 5 cases with dual abnormalities. The corresponding pregnancy outcomes showed that 4 cases underwent termination of pregnancy and 1 case completed full-term cesarean section delivery. Specific data are shown in Tables 3, 4, and 5.

[0050] Table 3 Results of karyotype abnormalities in prenatal diagnosis of ventriculomegaly 2020-2023

[0051]

[0052] Table 4 Prenatal diagnosis of CNV abnormalities in ventriculomegaly 2020-2023

[0053]

[0054]

[0055] Table 5 Karyotype and CNV-seq are abnormal

[0056]

[0057]

[0058] 2.3 Pregnancy outcomes in patients with ventriculomegaly

[0059] This study included 166 fetal cases of ventriculomegaly, of whom 131 (78.9%) underwent normal delivery, 15 (9%) underwent induced labor, and 20 were lost to follow-up. Among the cases of induced labor, 5 cases had no significant abnormalities at prenatal diagnosis but were associated with neurological or multisystem structural malformations, 5 cases had CNV variants of uncertain clinical significance (all with associated structural abnormalities), 4 cases had both karyotype and CNV abnormalities, and 5 cases had isolated CNV abnormalities. Statistical analysis showed that factors such as gestational age at initial diagnosis (P < 0.05) and the distribution of ventriculomegaly (unilateral / bilateral, P < 0.05) were significantly associated with delivery outcomes. However, maternal age (P = 0.3861), the degree of ventriculomegaly (P = 0.9417), and the presence of multisystem structural malformations (P = 0.5017) were not statistically significant. Detailed data are shown in Table 6.

[0060] Table 6 Logistic regression analysis of factors affecting pregnancy outcomes in patients with ventriculomegaly 2020-2023

[0061]

[0062]

[0063] 2.4 Postnatal follow-up of ventricular dilatation

[0064] Telephone follow-up with parents of 146 infants and young children revealed eight cases with abnormal clinical manifestations. One case (0.7%) was diagnosed with a single-gene disorder (intracranial tuberous sclerosis complex) and died within one week of birth. The remaining seven cases presented with developmental delay. Genetic testing revealed one potentially pathogenic copy number variant and four variants of unknown significance in the developmental delay case. Detailed data are shown in Tables 7-1 and 7-2.

[0065] Table 7-1 Postnatal follow-up of fetuses with ventricular enlargement 2020-2023

[0066]

[0067] Table 7-2 Postnatal follow-up of fetuses with lateral ventriculomegaly 2020-2023

[0068]

[0069]

[0070] 3 Discussions

[0071] 3.1. Analysis of genetic testing results for fetal ventriculomegaly

[0072] This study retrospectively analyzed 169 fetal ventriculomegaly samples that underwent interventional prenatal diagnosis in a hospital between January 2020 and December 2023. After screening, 146 valid samples were finally included, and these samples were analyzed for genetic test results such as chromosome karyotype, low-depth high-throughput sequencing (CNV-seq), and whole exome sequencing (WES). The test results showed that the combined analysis of karyotype and CNV-seq detected a total of 9 genetic abnormalities (8 pathogenic variants and 1 suspected pathogenic variant), of which 5 chose to terminate pregnancy, and 4 live births (3 full-term and 1 premature) were not found to have developmental abnormalities. It is worth noting that in 2 cases with negative CNV-seq but WES suggesting possible pathogenic variants, one had developmental delay. By setting up follow-up nodes at birth and 3, 6, and 12 months after birth, a total of 21 adverse pregnancy outcomes were recorded (14 induced labors, 1 stillbirth, and 6 developmental delays).

[0073] Genetic analysis showed that the detection rate of chromosomal abnormalities in bilateral FVM was 17.5%, which was significantly higher than that in the unilateral group (2.06%) (χ 2 =9.21, P = 0.0027), consistent with previously reported findings of a 3.2-fold increased risk of chromosomal abnormalities in bilateral FVMs, suggesting that a wider anatomic range may reflect a more severe genomic imbalance. Further analysis revealed two cases with negative CNV-seq results but with suspected pathogenic variants on WES. One of these cases had ultrasound findings of bilateral ventriculomegaly, suggesting that other occult genetic abnormalities may exist in cases of fetal bilateral ventriculomegaly. Therefore, when ultrasound diagnoses fetal ventriculomegaly, particularly bilateral ventriculomegaly, early karyotyping and CNV-seq are recommended to identify potential chromosomal abnormalities and genomic copy number variations (CNVs). If necessary, whole-exome sequencing (WES) can be performed to exclude single-gene disorders and complex genetic mutations. These tests can provide more accurate genetic information for clinical decision-making and further assess fetal health risks and prognosis.

[0074] Although bilateral ventriculomegaly is often associated with more serious genetic diseases, in actual clinical practice, different types of lateral ventriculomegaly cases still need to be comprehensively evaluated based on their specific circumstances, and combined with genetic testing results to make more accurate diagnosis and management.

[0075] Further analysis revealed that the detection rate of genetic abnormalities in the moderate-to-severe widening group (8.89%) was 1.8 times higher than that in the mild group (4.95%). The abnormality rates in the isolated and nonisolated widening groups were 6.25% and 6.45%, respectively. Two suspected pathogenic cases by WES both presented with moderate widening and multisystem abnormalities. Although the difference between the two groups did not reach statistical significance, the positive detection rate increased in both groups, particularly in the two cases in which WES suggested a suspected pathogenic variant. This further suggests that comprehensive genetic testing is particularly important in fetal ventriculomegaly, especially when combined with other structural abnormalities. Furthermore, previous studies have further confirmed that the degree of widening (P = 0.04) and the presence of other abnormalities (P = 0.002) significantly influence the risk of genetic abnormalities. These findings suggest that for cases of ventriculomegaly with other structural abnormalities, a stepwise testing strategy combining karyotype, CNV-seq, and WES is recommended for accurate genetic diagnosis and risk assessment. By integrating imaging and multi-omics detection technologies, it can provide important basis for fetal prognosis assessment and clinical intervention.

[0076] 3.2. Pregnancy Outcome and Clinical Prognosis Analysis of Fetal Ventriculomegaly

[0077] 3.2.1. Pregnancy Outcomes In terms of pregnancy outcomes, this study found that the induced labor rates in the unilateral and bilateral ventriculomegaly groups were 6.5% and 22.5%, respectively; the induced labor rates in the mid-pregnancy group and the late-pregnancy group were 21.6% and 5%, respectively. Through logistic regression analysis, the study found that factors such as gestational age and the distribution range of lateral ventriculomegaly had a significant impact on delivery outcomes (P < 0.05). Specifically, the probability of induced labor increased significantly with decreasing gestational age and increasing range of lateral ventriculomegaly. This means that the fetus may face a higher risk in early pregnancy or when the range of lateral ventriculomegaly is extensive. Therefore, gestational age and the type and range of lateral ventriculomegaly become one of the key factors in evaluating pregnancy outcomes.

[0078] 3.2.2. Prognostic Analysis: Clinical observational data show that fetuses with varying degrees of ventriculomegaly exhibit significantly different neurodevelopmental outcomes. A domestic study demonstrated that favorable neurodevelopmental rates were 88%, 57%, and 36% in the mild, moderate, and severe ventriculomegaly groups, respectively. In this cohort study, seven cases of developmental delay were identified (four with mild severity and three with moderate severity). Notably, four of these cases had concurrent neurological or other structural abnormalities. Special cases included a perinatal death in a neonate with intracranial tuberous sclerosis complex and an infant with isolated language delay but normal motor function. Systematic evaluation of the remaining four cases revealed no significant abnormalities during follow-up with ultrasound and MRI imaging, suggesting that their neurodevelopmental trajectories may gradually return to normal. It is noteworthy that although the prognostic differences between the severity groups in this study did not reach statistical significance (P>0.05), this finding may be related to sample size limitations and selection bias for pregnancy terminations. Clinical practice suggests that this conclusion may be subject to certain biases. With increasing gestational age, fetal ventriculomegaly may gradually worsen, and some women may opt for induced labor, resulting in a relatively small number of deliveries of fetuses with severe ventriculomegaly. Therefore, the lack of significant differences in prognosis may be due to insufficient sample size and the influence of induced labor decisions. This selection bias suggests that a dynamic assessment system should be established for prenatal diagnosis case management, with particular emphasis on the evolution of ventriculomegaly and the differential diagnosis of associated abnormalities. When a fetus has multiple structural or functional abnormalities, implementing a multidisciplinary early intervention program will help establish a personalized monitoring strategy, thereby more accurately predicting and improving perinatal outcomes.

[0079] Although the embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations may be made to the above embodiments without departing from the principles and purpose of the present invention, and that the scope of the present invention is defined by the claims and their equivalents.

Claims

1. Application of the chromosome karyotype-CNV-seq-WES stepwise detection strategy for fetal ventriculomegaly in prenatal genetic counseling and clinical prognosis analysis, characterized by: When ultrasound diagnoses fetal ventriculomegaly, chromosome karyotype analysis and low-depth high-throughput sequencing (CNV-seq) are performed to detect possible chromosomal abnormalities and genomic copy number variations (CNVs) early; whole exome sequencing (WES) is performed to rule out single-gene genetic diseases and complex gene mutations.

2. Application of the chromosome karyotype-CNV-seq-WES stepwise detection strategy for fetal lateral ventriculomegaly according to claim 1 in prenatal genetic counseling and clinical prognosis analysis, characterized in that: For cases of ventriculomegaly combined with other structural abnormalities, a step-by-step detection strategy of karyotype-CNV-seq-WES is used to achieve accurate genetic diagnosis and risk assessment.

3. Application of the chromosome karyotype-CNV-seq-WES stepwise detection strategy for fetal lateral ventriculomegaly according to claim 1 in prenatal genetic counseling and clinical prognosis analysis, characterized in that: When the fetus has lateral ventriculomegaly or a wide range of lateral ventriculomegaly in early pregnancy, the fetus faces a higher risk. Gestational age and the type and extent of lateral ventriculomegaly are key factors in assessing pregnancy outcomes.

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