Variant interpretation acquisition method and apparatus

Abstract

The embodiment of the present application provides a kind of variation interpretation acquisition method and device, suitable for obtaining the variation interpretation of the detected genetic variation to the case of being detected, comprising: obtaining the detected genetic variation of the case of being detected;Based on the detected genetic variation, obtain the variation combination corresponding to the detected genetic variation including the detected genetic variation, the gene corresponding to the detected genetic variation, the disease corresponding to the gene and the genetic mode corresponding to the disease;According to the detected genetic variation in the variation combination, the gene, the disease and the genetic mode, at least two of variation pathogenicity, disease similarity and mendelian inheritance consistency are acquired;According to the variation pathogenicity, the disease similarity and the mendelian inheritance consistency three at least two acquired, the variation interpretation of the variation combination is acquired.This application embodiment provides the variation interpretation acquisition method can improve variation sequencing result accuracy and the efficiency of etiological variation analysis.

Description

TECHNICAL FIELD

[0001] Embodiments of the present application relate to the field of medical information technology, and in particular to a variant interpretation obtaining method and device. BACKGROUND

[0002] High-throughput sequencing is a powerful means for molecular diagnosis of genetic diseases. A large number of variants (for example, about 30,000 to 40,000 in whole exome sequencing) are generated through secondary analysis, and need to be annotated and interpreted in tertiary analysis to identify some variants for inclusion in the test report. The identification criteria for this process, i.e., whether the variant can "explain" the etiology of the case under test.

[0003] Generally, the explanation degree of the variant to the case under test is considered from three dimensions: 1. whether the variant is harmful in biological function (damages normal function and can cause disease); 2. how similar the relevant phenotype of the gene where the variant is located (phenotype or disease caused by abnormality of the gene) is to the clinical manifestation of the case under test; and 3. whether the zygosity of the variant in the individual and the affected status of the individual are consistent with the genetic mode of the disease related to the gene where the variant is located.

[0004] However, each of the above explanation dimensions makes the process of identifying etiological variants dependent on repeated trade-offs by analysts, which is very inefficient and also makes the variant ranking result inaccurate.

[0005] Therefore, how to improve the accuracy of the variant ranking result and the efficiency of etiological variant analysis has become a technical problem to be solved. SUMMARY

[0006] The technical problem solved by embodiments of the present application is how to improve the accuracy of the variant ranking result and the efficiency of etiological variant analysis.

[0007] To solve the above problems, embodiments of the present application provide a variant interpretation obtaining method suitable for obtaining the variant interpretation of a detected genetic variant to a case under test, comprising:

[0008] obtaining a detected genetic variant of the case under test;

[0009] based on the detected genetic variant, obtaining a variant combination corresponding to the detected genetic variant, the variant combination comprising the detected genetic variant, a gene corresponding to the detected genetic variant, a disease corresponding to the gene, and a genetic mode corresponding to the disease;

[0010] at least two of the variant pathogenicity, the disease similarity, and the Mendelian inheritance consistency are obtained according to the detected genetic variant, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the genetic mode corresponding to the disease in the variant combination;

[0011] the variant explanation of the variant combination is obtained according to at least two of the variant pathogenicity, the disease similarity, and the Mendelian inheritance consistency.

[0012] Optionally, the step of obtaining the variant combination corresponding to the detected genetic variant based on the detected genetic variant comprises:

[0013] each gene corresponding to the detected genetic variant is obtained based on the detected genetic variant;

[0014] each disease corresponding to the gene is obtained;

[0015] a corresponding genetic mode is obtained according to each disease;

[0016] the detected genetic variant, the gene, the disease, and the genetic mode corresponding to each other are combined to obtain each variant combination.

[0017] Optionally, the step of obtaining at least two of the variant pathogenicity, the disease similarity, and the Mendelian inheritance consistency according to the detected genetic variant, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the genetic mode corresponding to the disease in the variant combination comprises:

[0018] a current variant combination in each variant combination is determined;

[0019] at least two of the variant pathogenicity, the disease similarity, and the Mendelian inheritance consistency are obtained by performing at least two of the following steps:

[0020] a current variant pathogenicity is obtained according to the detected genetic variant, the gene, the disease, and the genetic mode in the current variant combination;

[0021] a current disease similarity is obtained according to the disease in the current variant combination;

[0022] a current Mendelian inheritance consistency is obtained at least according to the detected genetic variant and the genetic mode in the current variant combination;

[0023] The step of obtaining the variant interpretation of the variant combination based on at least two of the three factors: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency includes:

[0024] The current variant interpretation for the current variant combination is obtained based on at least two of the current variant pathogenicity, the current disease similarity, and the current Mendelian genetic consistency, until the respective variant interpretations corresponding to each variant combination are obtained.

[0025] Optionally, after obtaining the variant interpretation of the variant combination based on at least two of the three factors—the pathogenicity of the variant, the disease similarity, and the Mendelian genetic consistency—the method further includes:

[0026] The maximum value of each of the aforementioned variant interpretations is determined to obtain the variant interpretation corresponding to the detected genetic variant.

[0027] Optionally, the step of obtaining the variant interpretation of the variant combination based on at least two of the three factors—the pathogenicity of the variant, the disease similarity, and the Mendelian genetic consistency—includes:

[0028] The interpretation of the variant is obtained by cross-producting at least two of the three factors: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency.

[0029] Optionally, the step of obtaining the pathogenicity of the detected genetic variant based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease includes:

[0030] Based on the detected genetic variation, the gene, the disease, and the inheritance pattern, obtain evidence of various variations related to the detected genetic variation;

[0031] Determine the mutation intensity corresponding to each of the mutation evidences, and determine the number of mutation evidences corresponding to each mutation intensity, to obtain the number of mutation evidences;

[0032] The pathogenicity of the mutation is determined based on the amount of evidence for the mutation.

[0033] Optionally, the step of obtaining the pathogenicity of the variant based on the amount of variant evidence includes:

[0034] The pathogenicity is determined based on the amount of evidence presented.

[0035] Obtain a pathogenicity correspondence table, which includes the variant pathogenicity corresponding to each pathogenicity intensity;

[0036] The pathogenicity of the variant corresponding to the pathogenicity intensity is determined according to the pathogenicity correspondence table.

[0037] Optionally, the step of obtaining the pathogenicity of the detected genetic variant based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease includes:

[0038] Based on the detected genetic variation, the gene, the disease, and the inheritance pattern, obtain evidence of various variations related to the detected genetic variation;

[0039] Determine the mutation intensity corresponding to each of the mutation evidences, and determine the number of mutation evidences corresponding to each mutation intensity, to obtain the number of mutation evidences;

[0040] The combined pathogenicity chance is obtained by using a pathogenicity chance function based on the amount of mutation evidence.

[0041] The pathogenicity of the variant is obtained by utilizing the combined pathogenicity chance and the prior probability of pathogenicity, wherein the prior probability of pathogenicity is determined based on the variant intensity.

[0042] Optionally, the variation intensity includes very strong variation intensity, and the step of determining the pathogenic prior probability based on the variation intensity includes:

[0043] The mutation intensity was determined to be a very strong mutation intensity;

[0044] The pathogenic prior probability is determined based on the very strong variation intensity.

[0045] Optionally, the step of obtaining the disease similarity to the disease based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease includes:

[0046] Each test case characterization group is obtained based on the various characteristics exhibited by the test cases under the disease.

[0047] Any disease characterization group is obtained from the human phenotype ontology database, wherein the disease characterization group includes all standard disease characterizations of any disease manifestation in human diseases.

[0048] Based on the tested case characterization group and any disease characterization group, obtain the corresponding tested case characterization association set and standard disease characterization association set respectively. The tested case characterization association set includes the tested case characterization and the sub-tested case characterization associated with the tested case characterization. The standard disease characterization association set includes the standard disease characterization and the sub-standard disease characterization associated with the standard disease characterization.

[0049] By using different permutation rules, the association sets of the tested cases and the association sets of the standard diseases are permuted and combined to obtain permutation association pairs corresponding to each permutation rule;

[0050] Determine the corresponding permutation Jaccard similarity coefficient based on each of the permutation association pairs;

[0051] Determine the maximum similarity coefficient among the Jaccard similarity coefficients of each of the given permutations, and obtain the disease similarity based on the maximum similarity coefficient.

[0052] Optionally, the step of determining the corresponding permutation Jaccard similarity coefficient based on each of the permutation association pairs includes:

[0053] Determine the current permutation association pair among all the aforementioned permutation association pairs;

[0054] Based on the combination pairs of the tested case characterization association sets and the standard disease characterization association sets included in the current arrangement association pairs, calculate the Jaccard similarity coefficient of each combination pair;

[0055] The Jaccard similarity coefficients of each of the aforementioned combination pairs are summed to obtain the Jaccard similarity coefficients of the currently arranged associated pairs;

[0056] Other permutation association pairs in each of the aforementioned permutation association pairs are identified as new current permutation association pairs, until all the permutation Jaccard similarity coefficients are obtained.

[0057] Optionally, the step of obtaining the maximum similarity coefficient includes:

[0058] Determine the maximum number of characteristics contained in the characterization group of the examined cases and the maximum number of characteristics contained in any disease characterization group;

[0059] The reciprocal of the maximum value is used to obtain the similarity coefficient of the maximum value.

[0060] Optionally, the step of obtaining the Mendelian genetic consistency corresponding to the genetic pattern based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the genetic pattern corresponding to the disease includes:

[0061] When the genetic pattern is determined to be a dominant genetic pattern, the Mendelian genetic consistency value of the tested case and its family members corresponding to the detected genetic variation is determined according to the Mendelian genetic consistency corresponding to the dominant genetic pattern.

[0062] The Mendelian genetic consistency is obtained by combining the individual Mendelian genetic consistency values.

[0063] Optionally, the step of determining the Mendelian genetic consistency value of the tested case and its family members based on the Mendelian genetic synergy corresponding to the dominant inheritance pattern includes:

[0064] The affected status of each family member in the tested case is determined based on the tested case corresponding to the detected genetic variation;

[0065] The measured genotypes of the examined cases and their family members for the detected genetic variations are determined based on the dominant inheritance pattern corresponding to each of the affected conditions and the diseases.

[0066] The corresponding standard genotype is determined based on the dominant inheritance pattern corresponding to the disease;

[0067] Compare the affected status of each measured genotype with that of the standard genotype one by one. If they match, the Mendelian genetic consistency value corresponding to the measured genotype is counted as 1. If they do not match, the Mendelian genetic consistency value is reduced by one order of magnitude.

[0068] The step of combining the individual Mendelian genetic consistency values ​​to obtain the Mendelian genetic uniformity includes:

[0069] The Mendelian genetic consistency is obtained by multiplying the Mendelian genetic consistency values ​​by comparing all the measured genotypes.

[0070] Optionally, the step of obtaining the Mendelian genetic consistency corresponding to the genetic pattern based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the genetic pattern corresponding to the disease includes:

[0071] When the genetic pattern is determined to be a recessive genetic pattern, the gene corresponding to the recessive genetic pattern is determined, and other detected genetic variations different from the detected genetic variation are determined based on the gene. The detected genetic variation is then combined with each of the other detected genetic variations to obtain a combination variation pair.

[0072] The Mendelian genetic consistency value of the detected genetic variation in the tested case and its family members is determined based on the Mendelian genetic consistency corresponding to the recessive inheritance pattern.

[0073] Based on the Mendelian genetic synergy corresponding to the recessive inheritance pattern, the Mendelian genetic consistency value of the combined variation pairs of the tested cases and their family members corresponding to each of the combined variation pairs is determined;

[0074] The Mendelian genetic consistency values ​​of each of the detected genetic variations are combined to obtain the Mendelian genetic consistency of the detected genetic variations;

[0075] The Mendelian genetic consistency of each of the aforementioned combined variants is obtained by combining the Mendelian genetic consistency of each combined variant.

[0076] The maximum value among the Mendelian genetic consistency of the detected genetic variant and the Mendelian genetic consistency of each of the combined variants is determined as the Mendelian genetic consistency corresponding to the detected genetic variant.

[0077] This invention provides a variation interpretation acquisition device, suitable for acquiring the variation interpretation of detected genetic variations in a tested case, including:

[0078] The genetic variation detection module is adapted to acquire the detected genetic variations of the tested case;

[0079] The variant combination acquisition module is adapted to acquire the variant combination corresponding to the detected genetic variant based on the detected genetic variant, wherein the variant combination includes the detected genetic variant, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease.

[0080] The indicator acquisition module is adapted to acquire at least two of the following three factors based on the detected genetic variation in the variation combination, the gene corresponding to the detected genetic variation, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease: the pathogenicity of the detected genetic variation, the disease similarity to the disease, and the Mendelian genetic consistency corresponding to the inheritance pattern.

[0081] The variant interpretation acquisition module is adapted to acquire the variant interpretation of the variant combination based on at least two of the three factors: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency.

[0082] Optionally, the variant combination acquisition module is adapted to acquire the variant combination corresponding to the detected genetic variant based on the detected genetic variant, including:

[0083] Based on the detected genetic variations, obtain the genes corresponding to the detected genetic variations;

[0084] Obtain the diseases corresponding to each of the aforementioned genes;

[0085] Based on each of the diseases described, the corresponding genetic patterns are obtained;

[0086] The detected genetic variations, the genes, the diseases, and the genetic patterns that correspond to each other are combined to obtain various variation combinations.

[0087] Optionally, the indicator acquisition module is adapted to acquire at least two of the following three factors based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease: pathogenicity of the detected genetic variant, disease similarity to the disease, and Mendelian genetic consistency corresponding to the inheritance pattern.

[0088] Determine the current variant combination among all variant combinations;

[0089] Perform at least two of the following steps to obtain at least two of the three: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency:

[0090] The pathogenicity of the current variant is obtained based on the detected genetic variant, the gene, the disease, and the inheritance pattern in the current variant combination;

[0091] Obtain current disease similarity based on the disease in the current variant combination;

[0092] At least based on the detected genetic variants and the genetic pattern in the current variant combination, current Mendelian genetic consistency is obtained;

[0093] The variant interpretation acquisition module is adapted to acquire the variant interpretation of the variant combination based on at least two of the three factors: the pathogenicity of the variant, the disease similarity, and the Mendelian genetic consistency, including:

[0094] The current variant interpretation for the current variant combination is obtained based on at least two of the current variant pathogenicity, the current disease similarity, and the current Mendelian genetic consistency, until the respective variant interpretations corresponding to each variant combination are obtained.

[0095] Optionally, the variant interpretation acquisition module is adapted to acquire the variant interpretation of the variant combination based on at least two of the three factors: variant pathogenicity, disease similarity, and Mendelian genetic consistency, including:

[0096] The maximum value of each of the aforementioned variant interpretations is determined to obtain the variant interpretation corresponding to the detected genetic variant.

[0097] Optionally, the variant interpretation module is adapted to obtain the variant interpretation of the variant combination based on at least two of the three factors: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency, including:

[0098] The interpretation of the variant is obtained by cross-producting at least two of the three factors: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency.

[0099] Optionally, the indicator acquisition module is adapted to acquire the pathogenicity of the detected genetic variant based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease, including:

[0100] Based on the detected genetic variation, the gene, the disease, and the inheritance pattern, obtain evidence of various variations related to the detected genetic variation;

[0101] Determine the mutation intensity corresponding to each of the mutation evidences, and determine the number of mutation evidences corresponding to each mutation intensity, to obtain the number of mutation evidences;

[0102] The pathogenicity of the mutation is determined based on the amount of evidence for the mutation.

[0103] Optionally, the indicator acquisition module is adapted to obtain the pathogenicity of the variant based on the amount of variant evidence, including:

[0104] The pathogenicity is determined based on the amount of evidence presented.

[0105] Obtain a pathogenicity correspondence table, which includes the variant pathogenicity corresponding to each pathogenicity intensity;

[0106] The pathogenicity of the variant corresponding to the pathogenicity intensity is determined according to the pathogenicity correspondence table.

[0107] Optionally, the indicator acquisition module is adapted to acquire the pathogenicity of the detected genetic variant based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease, including:

[0108] Based on the detected genetic variation, the gene, the disease, and the inheritance pattern, obtain evidence of various variations related to the detected genetic variation;

[0109] Determine the mutation intensity corresponding to each of the mutation evidences, and determine the number of mutation evidences corresponding to each mutation intensity, to obtain the number of mutation evidences;

[0110] The combined pathogenicity chance is obtained by using a pathogenicity chance function based on the amount of mutation evidence.

[0111] The pathogenicity of the variant is obtained by utilizing the combined pathogenicity chance and the prior probability of pathogenicity, wherein the prior probability of pathogenicity is determined based on the variant intensity.

[0112] Optionally, the mutation intensity includes very strong mutation intensity, and the pathogenic prior probability is determined based on the mutation intensity, including:

[0113] The mutation intensity was determined to be a very strong mutation intensity;

[0114] The pathogenic prior probability is determined based on the very strong variation intensity.

[0115] Optionally, the indicator acquisition module is adapted to acquire disease similarity with the disease based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease, including:

[0116] Each test case characterization group is obtained based on the various characteristics exhibited by the test cases under the disease.

[0117] Any disease characterization group is obtained from the human phenotype ontology database, wherein the disease characterization group includes all standard disease characterizations of any disease manifestation in human diseases.

[0118] Based on the tested case characterization group and any disease characterization group, obtain the corresponding tested case characterization association set and standard disease characterization association set respectively. The tested case characterization association set includes the tested case characterization and the sub-tested case characterization associated with the tested case characterization. The standard disease characterization association set includes the standard disease characterization and the sub-standard disease characterization associated with the standard disease characterization.

[0119] By using different permutation rules, the association sets of the tested cases and the association sets of the standard diseases are permuted and combined to obtain permutation association pairs corresponding to each permutation rule;

[0120] Determine the corresponding permutation Jaccard similarity coefficient based on each of the permutation association pairs;

[0121] Determine the maximum similarity coefficient among the Jaccard similarity coefficients of each of the given permutations, and obtain the disease similarity based on the maximum similarity coefficient.

[0122] Optionally, the index acquisition module is adapted to determine the corresponding permutation Jaccard similarity coefficient based on each of the permutation association pairs, including:

[0123] Determine the current permutation association pair among all the aforementioned permutation association pairs;

[0124] Based on the combination pairs of the tested case characterization association sets and the standard disease characterization association sets included in the current arrangement association pairs, calculate the Jaccard similarity coefficient of each combination pair;

[0125] The Jaccard similarity coefficients of each of the aforementioned combination pairs are summed to obtain the Jaccard similarity coefficients of the currently arranged associated pairs;

[0126] Other permutation association pairs in each of the aforementioned permutation association pairs are identified as new current permutation association pairs, until all the permutation Jaccard similarity coefficients are obtained.

[0127] Optionally, the index acquisition module is adapted to determine the maximum similarity coefficient among the Jaccard similarity coefficients of each permutation, including:

[0128] Determine the maximum number of characteristics contained in the characterization group of the examined cases and the maximum number of characteristics contained in any disease characterization group;

[0129] The reciprocal of the maximum value is used to obtain the maximum similarity coefficient.

[0130] Optionally, the indicator acquisition module is adapted to obtain Mendelian genetic consistency with the genetic pattern based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the genetic pattern corresponding to the disease, including:

[0131] When the genetic pattern is determined to be a dominant genetic pattern, the Mendelian genetic consistency value of the tested case and its family members corresponding to the detected genetic variation is determined according to the Mendelian genetic consistency corresponding to the dominant genetic pattern.

[0132] The Mendelian genetic consistency is obtained by combining the individual Mendelian genetic consistency values.

[0133] Optionally, the indicator acquisition module is adapted to determine the Mendelian genetic consistency value of the tested case and its family members based on the Mendelian genetic synergy corresponding to the dominant inheritance pattern, including:

[0134] The affected status of each family member in the tested case is determined based on the tested case corresponding to the detected genetic variation;

[0135] The measured genotypes of the examined cases and their family members for the detected genetic variations are determined based on the dominant inheritance pattern corresponding to each of the affected conditions and the diseases.

[0136] The corresponding standard genotype is determined based on the dominant inheritance pattern corresponding to the disease;

[0137] Compare the affected status of each measured genotype with that of the standard genotype one by one. If they match, the Mendelian genetic consistency value corresponding to the measured genotype is counted as 1. If they do not match, the Mendelian genetic consistency value is reduced by one order of magnitude.

[0138] The indicator acquisition module is adapted to combine the various Mendelian genetic consistency values ​​to obtain the Mendelian genetic consistency, including:

[0139] The Mendelian genetic consistency is obtained by multiplying the Mendelian genetic consistency values ​​by comparing all the measured genotypes.

[0140] Optionally, the indicator acquisition module is adapted to obtain Mendelian genetic consistency with the genetic pattern based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the genetic pattern corresponding to the disease, including:

[0141] When the genetic pattern is determined to be a recessive genetic pattern, the gene corresponding to the recessive genetic pattern is determined, and other detected genetic variations different from the detected genetic variation are determined based on the gene. The detected genetic variation is then combined with each of the other detected genetic variations to obtain a combination variation pair.

[0142] The Mendelian genetic consistency value of the detected genetic variation in the tested case and its family members is determined based on the Mendelian genetic consistency corresponding to the recessive inheritance pattern.

[0143] Based on the Mendelian genetic synergy corresponding to the recessive inheritance pattern, the Mendelian genetic consistency value of the combined variation pairs of the tested cases and their family members corresponding to each of the combined variation pairs is determined;

[0144] The Mendelian genetic consistency values ​​of each of the detected genetic variations are combined to obtain the Mendelian genetic consistency of the detected genetic variations;

[0145] The Mendelian genetic consistency of each of the aforementioned combined variants is obtained by combining the Mendelian genetic consistency of each combined variant.

[0146] The maximum value among the Mendelian genetic consistency of the detected genetic variant and the Mendelian genetic consistency of each of the combined variants is determined as the Mendelian genetic consistency corresponding to the detected genetic variant.

[0147] This invention provides an electronic device, including at least one memory and at least one processor; the memory stores a program, and the processor invokes the program to execute the variation interpretation and acquisition method as described in any of the foregoing embodiments.

[0148] This invention also provides a storage medium storing a program suitable for obtaining variant interpretations to implement the variant interpretation acquisition method as described in any of the foregoing embodiments.

[0149] Compared with the prior art, the technical solution of the embodiments of the present invention has the following advantages:

[0150] This invention provides a method for obtaining variant interpretation, suitable for obtaining the variant interpretation of a detected genetic variant in a tested case. First, the detected genetic variant in the tested case is obtained. Next, based on the detected genetic variant, a variant combination corresponding to the detected genetic variant is obtained. The variant combination includes the detected genetic variant, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease. Then, based on the detected genetic variant, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease in the variant combination, at least two of the following three factors are obtained: pathogenicity of the detected genetic variant, disease similarity to the disease, and Mendelian genetic consistency corresponding to the inheritance pattern. Finally, the variant interpretation of the variant combination is obtained based on at least two of the three factors: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency.

[0151] As can be seen, the variation interpretation acquisition method provided in this application obtains the corresponding gene, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease based on the detected genetic variation that can more powerfully explain the etiology of the tested case, thereby obtaining a comprehensive variation combination. Then, the variation combination is used to quantify the pathogenicity of the variation, disease similarity, and Mendelian genetic consistency used for qualitative evaluation of the etiology of the tested case. At least two of the quantified pathogenicity of the variation, disease similarity, and Mendelian genetic consistency are combined to obtain the variation interpretation. In this way, on the one hand, the variation interpretation obtained based on the detected genetic variation can improve the accuracy of the etiology analysis of the tested case, making the obtained variation interpretation more credible. On the other hand, by quantifying and combining the indicators for targeted analysis of the etiology of the tested case, the detected genetic variation corresponding to the variation interpretation obtained through quantitative combination can be placed in a more prominent position in the arrangement of many etiological variations when analyzing the etiology of the tested case. This can assist analysts in analysis and reasoning, speed up the process of arriving at a diagnostic conclusion, and improve the accuracy of variation ranking results and the efficiency of etiological variation analysis.

[0152] In an optional embodiment of the present invention, a method for obtaining variant interpretation includes the step of obtaining variant combinations corresponding to the detected genetic variant based on the detected genetic variant. This step comprises: obtaining each gene corresponding to the detected genetic variant; obtaining the disease corresponding to each gene; obtaining the corresponding inheritance pattern according to each disease; and combining the corresponding detected genetic variant, the gene, the disease, and the inheritance pattern to obtain various variant combinations. This allows for the acquisition of all genes corresponding to the detected genetic variant, all diseases corresponding to the genes, and the inheritance pattern corresponding to the diseases. This satisfies the requirements for subsequently obtaining pathogenicity of variants, disease similarity, and Mendelian genetic consistency, and ensures the comprehensiveness of the variant interpretation corresponding to each variant combination of the detected genetic variant. This facilitates the final acquisition of variant interpretation and ensures the accuracy of the final variant interpretation corresponding to the detected genetic variant. Attached Figure Description

[0153] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of this application. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0154] Figure 1 This is a flowchart illustrating a method for obtaining variant interpretations provided in an embodiment of this application;

[0155] Figure 2 This is a flowchart illustrating a method for obtaining variant interpretation indicators based on variant combinations in the variant interpretation acquisition method provided in this application embodiment.

[0156] Figure 3 This is a flowchart illustrating a method for obtaining the pathogenicity of a variant in the variant interpretation method provided in this application embodiment;

[0157] Figure 4 A schematic diagram illustrating the evidence of mutation and its contents;

[0158] Figure 5 Table showing the relationship between the amount of evidence for mutations and pathogenicity;

[0159] Figure 6 This is a schematic diagram of the pathogenicity correspondence table;

[0160] Figure 7 Another flowchart illustrating the method for obtaining the pathogenicity of a variant in the variant interpretation method provided in this application embodiment;

[0161] Figure 8This is a schematic diagram illustrating the results of using the pathogenesis chance function;

[0162] Figure 9 This is a schematic diagram illustrating the relationship between very strong variation intensity and prior probability of pathogenicity.

[0163] Figure 10 This is a flowchart illustrating a method for obtaining disease similarity in the variation interpretation method provided in this application embodiment;

[0164] Figure 11 This is a flowchart illustrating the method for obtaining Mendelian genetic consistency in the variation interpretation method provided in this application embodiment;

[0165] Figure 12 This is another flowchart illustrating the method for obtaining Mendelian genetic consistency in the variation interpretation method provided in the embodiments of this application;

[0166] Figure 13 This is an optional block diagram of the variation interpretation and acquisition device provided in the embodiments of this application;

[0167] Figure 14 This is a schematic diagram of the electronic device provided in the embodiments of this application. Detailed Implementation

[0168] As the background technology shows, the process of identifying pathogenic variations relies on repeated weighing by analysts, which is inefficient and leads to inaccurate variation ranking results.

[0169] To improve the accuracy of variant ordination results and the efficiency of etiological variant analysis, embodiments of the present invention provide a method and apparatus for obtaining variant interpretation, wherein the variant interpretation acquisition method is suitable for obtaining the variant interpretation of detected genetic variants in a tested case, including:

[0170] Obtain the detected genetic variations in the tested cases;

[0171] Based on the detected genetic variation, the variation combination corresponding to the detected genetic variation is obtained. The variation combination includes the detected genetic variation, the gene corresponding to the detected genetic variation, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease.

[0172] Based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease, at least two of the following three factors are obtained: pathogenicity of the detected genetic variant, disease similarity to the disease, and Mendelian genetic consistency with the inheritance pattern.

[0173] The interpretation of the variant combination is obtained based on at least two of the three factors: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency.

[0174] As can be seen, the variation interpretation acquisition method provided in this embodiment of the invention obtains the corresponding gene, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease based on the detected genetic variation that can more powerfully explain the etiology of the tested case, thereby obtaining a comprehensive variation combination. Then, the variation combination is used to quantify the pathogenicity of the variation, disease similarity, and Mendelian genetic consistency used for qualitative evaluation of the etiology of the tested case. At least two of the quantified pathogenicity of the variation, disease similarity, and Mendelian genetic consistency are combined to obtain the variation interpretation. In this way, on the one hand, the variation interpretation obtained based on the detected genetic variation can improve the accuracy of the etiology analysis of the tested case, making the obtained variation interpretation more credible. On the other hand, by quantifying and combining the indicators for targeted analysis of the etiology of the tested case, the detected genetic variation corresponding to the variation interpretation obtained through quantitative combination can be placed in a more prominent position in the arrangement of many etiological variations when analyzing the etiology of the tested case. This can assist analysts in their analysis and reasoning, speed up the process of arriving at a diagnostic conclusion, and improve the accuracy of variation ranking results and the efficiency of etiological variation analysis.

[0175] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0176] It should be noted that the orientations or positional relationships indicated in this specification are based on the orientations or positional relationships shown in the accompanying drawings, and are only for the purpose of facilitating and simplifying the description, and are not intended to indicate or imply that the device referred to must have a specific orientation or be constructed in a specific orientation, and therefore should not be construed as a limitation of the present invention.

[0177] To facilitate understanding of this solution, some basic concepts in this field will be explained first:

[0178] High-throughput sequencing refers to a technology that can rapidly analyze nucleic acid sequences and generate massive amounts of data by simultaneously sequencing hundreds of thousands to millions of DNA molecules in parallel. It is a powerful tool for molecular diagnosis of hereditary diseases.

[0179] Molecular diagnostics is a diagnostic method that seeks the molecular causes of a disease in a tested case (such as gene sequences). A tested case refers to the unit that receives patients when a hereditary disease is initially diagnosed. It usually consists of a single human individual (single proband case) or multiple human individuals with blood relations from the same family (family case).

[0180] The gene testing workflow based on high-throughput sequencing (i.e., molecular diagnostics) includes three major steps: primary analysis, secondary analysis, and tertiary analysis. Primary analysis refers to the process from sample processing and library construction to sequencing, ultimately obtaining the sequencing fragments. Secondary analysis, also known as bioinformatics analysis, involves aligning the sequencing fragments to a reference genome to obtain a list of detected genetic variations in the tested cases. Tertiary analysis, also known as clinical annotation, involves functionally annotating the numerous detected genetic variations obtained in the secondary analysis and interpreting these variations to generate final test results and conclusions for clinical diagnosis, and to produce a test report.

[0181] Detected genetic variants refer to genetic variations detected in a specific sample (such as a genomic DNA sample) using specific detection methods (such as high-throughput sequencing). The detection of genetic variants suggests that the biological individual providing the sample (such as a patient) carries these variants.

[0182] Sequencing reads are the representation of high-throughput sequencing data, consisting of sequence fragments containing base sequences and quality values. In the context of next-generation sequencing (NGS), a single test can often generate millions or tens of millions of sequencing reads, ranging in length from tens to a couple of hundred bases.

[0183] During the secondary analysis of high-throughput sequencing, a large number of genetic variants are detected (for example, in whole-exome sequencing, the number is about 30,000 to 40,000). These large number of genetic variants need to be annotated and interpreted in the tertiary analysis. From the large number of genetic variants, some of the detected genetic variants (i.e. the most relevant etiological variants that cause the disease in the tested cases) are identified and then included in the test report for the etiological analysis of the tested cases.

[0184] Etiological variation refers to the genetic variation that constitutes the cause of the disease in the examined case. This etiological variation is considered to be the reason for the molecular diagnosis of the examined case (a certain hereditary disease or phenotype).

[0185] The criteria for the three-level analysis process are whether the detected genetic variant can "explain" the examined case. Typically, three qualitative indicators are considered to assess the explanatory power of the variant: (i) whether the variant is biologically harmful (impairing normal function, causing disease); (ii) the degree of similarity between the phenotype of the gene containing the variant (the proven phenotype or disease caused by gene abnormality) and the clinical presentation of the examined case; and (iii) whether the zygosity of the detected genetic variant in the examined case and the patient's condition are consistent with the inheritance pattern of diseases related to the gene containing the detected genetic variant. These three dimensions are the primary indicators for assessing variant explanation, and their application is seen in clinical practice and has been incorporated into numerous guidelines, norms, consensus statements, or standards. For ease of explanation, these three dimensions will be referred to as "variant pathogenicity," "disease similarity," and "Mendelian genetic consistency" in the following text.

[0186] Among them, homozygosity is a collective term for homozygosity, heterozygosity, and hemizygosity.

[0187] Inheritance patterns refer to the regularities exhibited in the intergenerational transmission of hereditary diseases. Inheritance patterns include autosomal dominant inheritance, autosomal recessive inheritance, X-linked dominant inheritance, X-linked recessive inheritance, and Y-linked inheritance.

[0188] The status of involvement indicates whether an individual (the examined case, i.e., their parents or other family members) is affected by the disease. It can be "involved (illness / abnormality)" or "not involved (healthy / normal)".

[0189] Since "variable pathogenicity," "disease similarity," and "Mendelian genetic consistency" are indicators for qualitatively judging the interpretation of variants in the tested cases from different perspectives, analysts need to weigh these factors repeatedly when making qualitative judgments on the interpretation of variants in the tested cases from these three dimensions. This makes the process of identifying pathogenic variants dependent on the analysts, which is inefficient and easily affected by the analysts' subjective preferences, errors, and practices, thus reducing the accuracy of the diagnostic report.

[0190] Therefore, in order to improve the above-mentioned problems, this application provides a method for obtaining variant interpretation, so as to improve the accuracy of variant ranking results and the efficiency of etiological variant analysis.

[0191] For details, please refer to Figure 1 , Figure 1 This is a flowchart illustrating a method for obtaining variation interpretations provided in an embodiment of this application.

[0192] like Figure 1As shown, the process may include the following steps:

[0193] Step S01: Obtain the detected genetic variations of the tested case.

[0194] This application obtains all indicators used to evaluate the tested cases separately at the level of detecting genetic variations. Therefore, the first step is to obtain the detected genetic variations needed for subsequent operations based on the tested cases, which are the pathogenic variations that may cause disease in the tested cases obtained from the aforementioned secondary analysis. It is easy to understand that the number of detected genetic variations obtained from the secondary analysis is very large.

[0195] Specifically, the detected genetic variations of the tested cases can be obtained when performing the variation interpretation acquisition method provided in the embodiments of this application, or they can be obtained and saved in advance, and the detected genetic variations can be directly obtained from the saved data when variation interpretation is required.

[0196] Step S02: Based on the detected genetic variation, obtain the variation combination corresponding to the detected genetic variation. The variation combination includes the detected genetic variation, the gene corresponding to the detected genetic variation, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease.

[0197] Based on the large number of genetic variations detected by the analysis of the tested cases, further, based on any of the detected genetic variations, the gene containing the detected genetic variation, the disease corresponding to the gene, and the genetic pattern corresponding to the disease are obtained. The gene, the disease, and the genetic pattern are then combined to obtain a variation combination.

[0198] Among them, genes can be obtained through the process of detecting genetic variations and annotating them; the diseases corresponding to genes can be obtained through databases such as OMIM or other information sources; and the genetic patterns corresponding to diseases can be obtained through databases such as OMIM or other information sources.

[0199] Each element included in the variant combination is necessary for subsequent determinations of pathogenicity, disease similarity, and Mendelian genetic consistency. Thus, the construction of the variant combination can provide a sufficient and comprehensive data foundation for subsequent steps.

[0200] It is easy to understand that a detected genetic variant may correspond to multiple variant combinations, so there will be multiple variant combinations.

[0201] Specifically, in one implementation, to facilitate the acquisition of various mutation combinations and ensure the comprehensiveness of the acquired mutation combinations, step S02, based on the detected genetic variation, acquiring the mutation combination corresponding to the detected genetic variation may include:

[0202] Based on the detected genetic variations, obtain the genes corresponding to the detected genetic variations;

[0203] Obtain the diseases corresponding to each of the aforementioned genes;

[0204] Based on each of the diseases described, the corresponding genetic patterns are obtained;

[0205] The detected genetic variations, the genes, the diseases, and the genetic patterns that correspond to each other are combined to obtain various variation combinations.

[0206] It should be noted that although there are some genes and diseases with a one-to-one relationship, some genes and diseases with a one-to-many relationship, and some genes and diseases with a many-to-one relationship, the variant combinations described in this application are about the relationship between genes, diseases, and inheritance patterns obtained around a detected genetic variant. Therefore, it is sufficient to ensure that the genes, diseases, and inheritance patterns identified in a variant combination are relative to the same detected genetic variant.

[0207] For ease of explanation, any of the detected genetic variations can be defined as a variant. i The detected genetic variant will be... i Any one of the corresponding genes is defined as a gene. i1 and any of its genes i1 The corresponding disease (i.e., the disease it causes) is defined as disease. i1 and its diseases i1 The corresponding genetic pattern is defined as moi i1 Then, based on any detected genetic variant i any corresponding gene i1 The resulting variant combinations can be represented as:

[0208]

[0209] It can be seen that among the large number of detected genetic variations, there are many genes corresponding to any one detected genetic variation. That is, one detected genetic variation may correspond to multiple genes, and different genes correspond to multiple diseases. Correspondingly, different diseases will also have different inheritance patterns. In this way, based on the detected genetic variations, different combinations of variations associated with any gene, any disease, and any inheritance pattern can be obtained, ensuring the comprehensiveness of the variation combinations. Thus, different variation interpretations can be obtained based on different combinations of variations obtained from different detected genetic variations, which can enrich the information contained in the data and improve the accuracy and reliability of the diagnostic results when analyzing the etiology of the tested cases.

[0210] Of course, in other embodiments, variant combinations can also be obtained in other ways, such as combining only important genes and diseases that occur more commonly.

[0211] Step S03: Based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease, obtain at least two of the following three factors: pathogenicity of the detected genetic variant, disease similarity to the disease, and Mendelian genetic consistency corresponding to the inheritance pattern.

[0212] It should be noted that the combination of "at least two of the three" for obtaining the explanation of the variation can be any combination of at least two of the three: the pathogenicity of the variation, the disease similarity, and the Mendelian genetic consistency. This can include: a combination of the pathogenicity of the variation, the disease similarity, and the Mendelian genetic consistency; a combination of the pathogenicity of the variation and the Mendelian genetic consistency; a combination of the pathogenicity of the variation and the disease similarity; or a combination of the Mendelian genetic consistency and the disease similarity.

[0213] For ease of understanding, the examples of "Cornelia de Lange syndrome 5" and "Inflammatory bowel disease 28" cited in the following description of this application use a combination of the above-mentioned "pathogenicity of the variant, similarity of the disease, and consistency of Mendelian inheritance".

[0214] In other embodiments, for certain genetic diseases with unknown inheritance patterns or low penetrance, the Mendelian genetic consistency cannot be obtained or is not reliable. Therefore, the interpretation of the variant can be obtained by simply combining the pathogenicity of the variant and the similarity to the disease.

[0215] In other embodiments, for certain diseases with high genetic heterogeneity (the same phenotype may be caused by hundreds or thousands of genes), the results of the disease similarity are not very distinguishable. Therefore, the interpretation of the variation can be obtained by simply combining the pathogenicity of the variation with the Mendelian genetic consistency.

[0216] Therefore, at least two of the above-mentioned pathogenicity of the variant, disease similarity, and Mendelian genetic consistency can be freely combined, as long as the obtained interpretation of the variant is accurate and reliable.

[0217] Based on the variant combinations obtained from the aforementioned steps, quantitative pathogenicity, disease similarity, and Mendelian genetic consistency can be obtained respectively, which can be used as the basis for the final interpretation of the variants.

[0218] As can be seen from the foregoing description, the genes corresponding to any detected genetic variation, as well as their diseases and inheritance patterns, are diverse. Therefore, the resulting combination of variations is also diverse. To fully obtain the pathogenicity, disease similarity, and Mendelian genetic consistency of each variation combination, in one implementation, the aforementioned three indicators can be obtained separately. Please refer to [reference needed]. Figure 2 , Figure 2 This is a flowchart illustrating the process of obtaining various variant interpretation indicators based on variant combinations in the variant interpretation acquisition method provided in this application embodiment.

[0219] Specifically, as shown in the figure, the process may include the following steps:

[0220] Step S20: Determine the current variant combination among all variant combinations.

[0221] Since there are many possible combinations of genetic variations that correspond to a single detection, in order to facilitate the acquisition of interpretation indicators for each variation, the current variation combination to be processed is first determined from among the various variation combinations.

[0222] Step S21, perform at least two of the following steps to obtain at least two of the three: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency:

[0223] The pathogenicity of the current variant is obtained based on the detected genetic variant, the gene, the disease, and the inheritance pattern in the current variant combination;

[0224] Obtain current disease similarity based on the disease in the current variant combination;

[0225] At least based on the detected genetic variants and the genetic pattern in the current variant combination, current Mendelian genetic consistency is obtained.

[0226] Since there are many possible variant combinations, in order to obtain each variant combination, it is necessary to first determine the first variant combination to be determined, then locate the determined variant combination as the current variant combination, and then obtain the pathogenicity of the current variant based on the detected genetic variation, the gene, and the disease contained in the current variant combination; obtain the current disease similarity based on the disease in the current variant combination; and obtain the current Mendelian genetic consistency based on the detected genetic variation and the genetic pattern in the current variant combination. Specifically, based on the current variant combination, various indicators used to obtain variant interpretation are obtained, ensuring that there are no omissions or gaps in obtaining variant interpretation indicators based on each variant combination.

[0227] In this way, based on the elements included in the current variant combination determined from a large number of variant combinations, two of the corresponding disease similarity, variant pathogenicity, and Mendelian genetic consistency can be arbitrarily obtained. Appropriate indicator acquisition methods can be selected as needed, thereby ensuring the acquisition of the variant interpretation.

[0228] Furthermore, by obtaining the various combinations of variants, we can obtain the disease similarity, pathogenicity, and Mendelian genetic consistency of each combination of variants corresponding to the detected genetic variants.

[0229] Step S04: Obtain the interpretation of the variant combination based on at least two of the three factors: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency.

[0230] After obtaining the disease similarity, pathogenicity, and Mendelian genetic consistency of each variant combination, we can further obtain the interpretation of the variants in each variant combination.

[0231] Specifically, the interpretation of the variant can be obtained by cross-multiplying at least two of the three factors: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency.

[0232] By using a cross product, at least two of the three factors—pathogenicity of the variant, disease similarity, and Mendelian genetic consistency—can be quantified. This allows for the integration of any two of these three indicators to obtain a new indicator, namely the variant interpretation described in this application. The newly obtained variant interpretation can include biological information represented by multiple indicators, resulting in higher reliability and more accurate analysis results when analyzing the etiology of the examined cases.

[0233] Since any detected genetic variant corresponds to multiple variant combinations, there are also multiple interpretations of the variant. To fully obtain the interpretations for all variant combinations, in one implementation, it is necessary to obtain the pathogenicity, disease similarity, and Mendelian genetic consistency for each variant combination. For the current variant combination, please refer to [reference needed]. Figure 2 .

[0234] like Figure 2 As shown, the process may also include:

[0235] Step S22: Obtain the current variant interpretation of the current variant combination based on at least two of the current variant pathogenicity, the current disease similarity, and the current Mendelian genetic consistency.

[0236] Step S23: Determine whether the current mutation combination is the last mutation combination. If yes, proceed to step S24; otherwise, proceed to step S21.

[0237] When it is determined that the current mutation combination is the last mutation combination, the process of obtaining mutation interpretation is stopped, i.e., step S24.

[0238] Step S24: Stop obtaining variant interpretations.

[0239] When it is determined that the current mutation combination is not the last mutation combination, step S21 is continued until the mutation interpretations corresponding to each mutation combination are obtained.

[0240] In this way, the interpretation of each combination of detected genetic variations can be guaranteed to fully consider all genes, diseases, and inheritance patterns included in the detected genetic variations. This results in different quantitative values ​​for the interpretation of the detected genetic variations. The method of obtaining different combinations of variations based on detected genetic variations can fully consider the impact of the detected genetic variations on the etiology, thereby making the analysis results more reliable when analyzing the etiology of the tested cases.

[0241] By combining any two values ​​from the pathogenicity of the variant, disease similarity, and Mendelian genetic consistency obtained in step S03, a single and quantitative interpretation of the variant can be obtained for the final determination of the detected genetic variant. As can be seen from the previous steps, the number of detected genetic variants is very large. Therefore, each detected genetic variant corresponds to a different interpretation, rather than all variants of the same gene having the same value. This allows for the differentiation of the various interpretations of the detected genetic variants, thereby identifying the most decisive detected genetic variant for the analysis of the etiology.

[0242] As can be seen, the variation interpretation acquisition method provided in this application obtains the corresponding gene, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease based on the detected genetic variation that can more powerfully explain the etiology of the tested case, thereby obtaining a comprehensive variation combination. Then, the variation combination is used to quantify the pathogenicity of the variation, disease similarity, and Mendelian genetic consistency used for qualitative evaluation of the etiology of the tested case. At least two of the quantified pathogenicity of the variation, disease similarity, and Mendelian genetic consistency are combined to obtain the variation interpretation. In this way, on the one hand, the variation interpretation obtained based on the detected genetic variation can improve the accuracy of the etiology analysis of the tested case, making the obtained variation interpretation more credible. On the other hand, by quantifying and combining the indicators for targeted analysis of the etiology of the tested case, the detected genetic variation corresponding to the variation interpretation obtained through quantitative combination can be placed in a more prominent position in the arrangement of many etiological variations when analyzing the etiology of the tested case. This can assist analysts in analysis and reasoning, speed up the process of arriving at a diagnostic conclusion, and improve the accuracy of variation ranking results and the efficiency of etiological variation analysis.

[0243] Because the number of detected genetic variations is large, the number of corresponding variant interpretations is also large. Therefore, in one implementation, the various variant interpretations can be ranked, and the maximum value can be determined as the variant interpretation for that detected genetic variation. Please refer to [link to relevant documentation]. Figure 1 .

[0244] like Figure 1 As shown, the variation interpretation acquisition method provided in this application embodiment may further include:

[0245] Step S05: Determine the maximum value of each of the variant interpretations to obtain the variant interpretation corresponding to the detected genetic variant.

[0246] In this way, selecting the highest-ranking and most quantified variant interpretation as the variant interpretation of the detected genetic variant ensures that the detected genetic variant corresponding to this variant interpretation is biologically significant in the analysis of the etiology of the tested case, providing reliable judgment basis for subsequent analysts in clinical diagnosis and accelerating the analysis efficiency of the analysts.

[0247] To facilitate understanding of the process of obtaining pathogenicity, disease similarity, and Mendelian genetic consistency based on the aforementioned combination of variants, the following embodiments are provided in this application for illustration.

[0248] In one implementation, to more easily obtain the pathogenicity of the variant, it can be obtained by querying a database; please refer to the following for details. Figure 3 , Figure 3This is a flowchart illustrating a method for obtaining the pathogenicity of a variant in the variant interpretation method provided in this application embodiment.

[0249] like Figure 3 As shown, the variation interpretation acquisition method provided in this application embodiment may include the following steps:

[0250] Step S30: Obtain evidence of various variations related to the detected genetic variation based on the detected genetic variation, the gene, the disease, and the genetic pattern.

[0251] To determine the pathogenicity of a variant, evidence of the variant should be collected within the framework of the ACMG guidelines and their derivative detailed guidelines. Pathogenicity should then be determined and calculated using different methods according to the user's needs.

[0252] For specific evidence of the mutations and related information, please refer to [link / reference]. Figure 4 As shown, Figure 4 This is a schematic diagram of the evidence of mutation and its contents.

[0253] certainly, Figure 4 The illustration shown is merely a partial representation of the evidence for variation, intended for illustrative purposes. As can be seen, Figure 4 The evidence of genetic variation is first divided into two categories: pathogenic and benign. Each piece of evidence corresponds to a variation intensity, which indicates the strength or probability that the detected genetic variation will cause disease in the examined case. The variation intensity corresponding to each piece of evidence is coded accordingly, such as... Figure 4 When the indicated variation strength is very strong, it is coded as PVS1. This means that the presence of a PVS1 code indicates that the variation strength of the shift evidence is very strong. The corresponding information can be found by searching... Figure 4 The explanation for PVS1 is as follows: the detected genetic variation is nonsense mutation, frameshift mutation, classical splicing site mutation at position 1 / 2 or above, start codon mutation, single or multiple exon deletions, and loss of function is the pathogenic mechanism of the gene containing the variation.

[0254] In this way, the intensity of each variant can be obtained quickly and easily, along with the specific content corresponding to the detected genetic variant.

[0255] Step S31: Determine the mutation intensity corresponding to each of the mutation evidences, and determine the number of mutation evidences corresponding to each mutation intensity, to obtain the number of mutation evidences.

[0256] Based on the mutation evidence determined in the previous step, the corresponding mutation intensity is obtained, and then the number of mutations with the same intensity is statistically analyzed to obtain the number of mutation intensities.

[0257] The number of variant evidences includes each variant evidence of the detected genetic variant and its corresponding variant intensity, which is used for subsequent determination of pathogenicity.

[0258] Step S32: Obtain the pathogenicity of the mutation based on the amount of mutation evidence.

[0259] To determine the pathogenicity of a variant based on the amount of evidence for the variant, one can first determine the pathogenicity intensity based on the amount of evidence for the variant, and then determine the pathogenicity of the variant based on the pathogenicity intensity.

[0260] Specifically, the amount of evidence for each variant and its corresponding pathogenicity can be referenced. Figure 5 As shown, Figure 5 This is a table showing the relationship between the amount of evidence for mutations and the pathogenicity.

[0261] Since there are multiple pieces of evidence of genetic variation obtained from the detection of genetic variations, these pieces of evidence are combined, and then searched... Figure 5 The combination of the number of each variant evidence shown can be used to obtain the pathogenicity.

[0262] For example, if the evidence of genetic variation obtained from the detection of a genetic variation is either very strong (PVS1) or strong (PS1-PS4), with one item corresponding to each, then according to... Figure 5 By looking up the number of pieces of evidence shown, we can determine the pathogenicity of this number of pieces of evidence as: pathogenic.

[0263] In this way, corresponding evidence of variation can be obtained based on the detected genetic variation, thereby obtaining the pathogenicity and ultimately the pathogenicity of the variation. This makes the pathogenicity of the variation more supportive when analyzing the interpretation of the detected genetic variation.

[0264] After obtaining the pathogenicity intensity, it is necessary to further determine the pathogenicity of the variant based on the pathogenicity intensity. To facilitate the determination of the pathogenicity of the variant based on the pathogenicity intensity, in one embodiment, it can be determined based on the correspondence between pathogenicity intensity and pathogenicity of the variant. Specifically, this may include:

[0265] Obtain a pathogenicity correspondence table, which includes the variant pathogenicity corresponding to each pathogenicity intensity;

[0266] The pathogenicity of the variant corresponding to the pathogenicity intensity is determined according to the pathogenicity correspondence table.

[0267] The pathogenicity correspondence table can be referenced here. Figure 6 , Figure 6 This is a schematic diagram of the pathogenicity correspondence table.

[0268] Continuing with the aforementioned case, based on Figure 5By looking up the corresponding pathogenicity level of the number of pieces of evidence shown, we can determine that the pathogenicity level of this variant's evidence is: pathogenic. Further, based on... Figure 6 The pathogenicity correspondence table shown shows that the pathogenicity of the variant corresponding to the pathogenicity is 0.99. Therefore, the pathogenicity of the variant is finally obtained as 0.99 based on the detected genetic variant.

[0269] In this way, by looking up a table, the pathogenicity of the variant can be obtained quickly, and the pathogenicity index of the variant used for qualitative analysis of the etiology of the examined cases can be redesigned into a quantitative pathogenicity of the variant. That is, the pathogenicity of the variant is not a qualitative evaluation of pathogenicity or non-pathogenicity, but a quantitative value representing pathogenicity or non-pathogenicity, providing a quantitative data foundation for obtaining the interpretation of the variant in the future.

[0270] In other specific implementations, the pathogenicity of the variant can also be obtained using Bayesian quantification methods based on ACMG grading. For details, please refer to... Figure 7 , Figure 7 This is another flowchart illustrating the method for obtaining the pathogenicity of a variant in the variant interpretation method provided in the embodiments of this application.

[0271] like Figure 7 As shown, the process may include the following steps:

[0272] Step S40: Obtain evidence of various variations related to the detected genetic variation based on the detected genetic variation, the gene, the disease, and the genetic pattern.

[0273] The specific content of step S40 is basically the same as that of step S30, and will not be repeated here.

[0274] Step S41: Determine the mutation intensity corresponding to each of the mutation evidences, and determine the number of mutation evidences corresponding to each mutation intensity, thereby obtaining the number of mutation evidences.

[0275] The specific content of step S41 is basically the same as that of step S31, and will not be repeated here.

[0276] Step S42: Obtain the combined pathogenicity chance using the pathogenicity chance function based on the amount of mutation evidence.

[0277] The odds of pathogenicity are represented by OP, and their formula can be expressed as:

[0278]

[0279] Among them, O PVStThis indicates that the strengths of each mutation are combined to form a very strong mutation strength (PVSt) (the strengths of each mutation can be transformed into each other by exponential powers, so here each mutation strength is transformed into the strongest mutation strength). PSu indicates that the mutation strength corresponding to the mutation evidence is the supporting mutation strength, PM indicates the moderate mutation strength, PSt indicates the strong mutation strength, PVSt indicates the very strong mutation strength, N indicates the number of mutation evidences corresponding to each mutation strength, and X indicates the exponent used when transforming each mutation evidence, which is determined according to actual needs.

[0280] For details, please refer to Figure 8 As shown, Figure 8 This is a schematic diagram illustrating the results of using the disease-causing opportunity function.

[0281] by Figure 8 Explaining the first row of data, we can see that the "Quantity of Variable Evidence" item includes: 1 piece of very strong evidence (PVS) plus at least 1 piece of strong evidence (PS1-PS4). Therefore, the content of the index in the above formula is:

[0282]

[0283] Here, strong mutation evidence is set to 2, very strong mutation evidence is set to 1, and X is set to 2.

[0284] Step S43: Obtain the pathogenicity of the variant using the combined pathogenicity chance and the prior probability of pathogenicity, wherein the prior probability of pathogenicity is determined based on the variant intensity.

[0285] After obtaining the combined pathogenicity opportunity, the pathogenicity of the variant is obtained by further combining the prior probability of pathogenicity.

[0286] Continue with Figure 8 The first row of data in the example is used for illustration.

[0287] It should be noted that the formula used to obtain the pathogenicity of the variant from the combined chance of pathogenicity and the prior probability of pathogenicity is:

[0288]

[0289] Where Post_P represents the pathogenicity of the variant, OddsPath represents the joint pathogenicity chance (i.e., the index obtained according to the aforementioned pathogenicity chance function OP), and Prio_P represents the prior probability of pathogenicity. Here, the variant strength is set to a very strong variant strength, and the corresponding prior probability of pathogenicity can be determined according to... Figure 9 The diagram shown is used to obtain the information. Figure 9 This is a schematic diagram illustrating the relationship between the intensity of a very strong mutation and the prior probability of pathogenicity.

[0290] Using the above-mentioned pathogenicity chance function and the formula for calculating the pathogenicity of the variant, according to Figure 8 The first row of data is used to calculate the pathogenicity of the variant, specifically as follows:

[0291] First, calculate the chances of combined pathogenicity.

[0292] Here, the value of the very strong mutation strength is set to 350. Figure 8 The process by which the combined pathogenicity chance in the first row is obtained using the pathogenicity chance function OP can be represented as follows:

[0293]

[0294] The calculated combined pathogenicity chance is 6548.

[0295] Then, based on the combined chance of pathogenicity and the prior probability of pathogenicity, the pathogenicity of the variant is calculated using the formula for calculating the pathogenicity of the variant. The prior probability of pathogenicity can be calculated according to... Figure 9 The search revealed that, since the mutation strength was set to 350, the corresponding prior probability of pathogenicity was 0.1, specifically:

[0296]

[0297] The pathogenicity of the variant was calculated to be 0.999.

[0298] In this way, the pathogenicity of variants, which was originally qualitatively rated, can be transformed into quantitative pathogenicity based on detected genetic variations, providing a strong data foundation for the subsequent interpretation of constituent variants.

[0299] In addition to obtaining the pathogenicity of the variant, it is also necessary to obtain disease similarity. The following explains how to obtain disease similarity. In one implementation, the disease similarity can be calculated based on the polarity of the Jaccard similarity coefficient. For details, please refer to [link / reference needed]. Figure 10 , Figure 10 This is a flowchart illustrating the steps for obtaining disease similarity in the variation interpretation method provided in this application embodiment.

[0300] like Figure 10 As shown, the process may include the following steps:

[0301] Step S50: Obtain each test case characterization group based on the various characteristics exhibited by the test cases under the disease.

[0302] The clinical manifestations (characteristics) of the examined cases are used to form a standard phenotype group, which is set as P. Each element in P, that is, the characterization of the examined case, corresponds to an entry number in the Human Phenotype Ontology Database (HPO), providing a data basis for subsequent calculations.

[0303] It should be noted that the characteristics included in the tested case characterization group can be represented using the specific terminology corresponding to the characterization or other labels, as long as the characterization can be clearly indicated.

[0304] This example uses the assumption that P contains {representation 1; representation 2} as an example for further explanation. Of course, this is just an example, and the specific elements included should be determined according to actual needs.

[0305] Step S51: Obtain any disease characterization group from the human phenotype ontology database. The disease characterization group includes all standard disease characterizations of any disease manifestation in human diseases.

[0306] The human phenotype ontology database contains all clinical manifestations corresponding to all diseases in humans. Based on the disease phenotype annotation information provided by the human phenotype ontology database, all representations of each disease (here referring to genetic diseases) can be obtained. The combination of all representations is labeled D, and any disease representation group is represented as D. i It includes all the standard disease characteristics of any disease manifestation.

[0307] Of course, any disease characterization terminology group can also include a characterization represented by the specific terminology corresponding to that characterization, or by other labels, as long as the characterization is clearly indicated.

[0308] Here we assume D i The following explanation will use the example of {Standard Representation 1; Standard Representation 2; Standard Representation 3} as an example. Of course, this is only an example, and the specific elements included should be determined according to actual needs.

[0309] Step S52: Obtain the corresponding test case representation association set and standard disease representation association set according to the test case representation group and any disease representation group respectively. The test case representation association set includes the test case representation and the sub-test case representation associated with the test case representation. The standard disease representation association set includes the standard disease representation and the sub-standard disease representation associated with the standard disease representation.

[0310] Specifically, when obtaining the association set of the tested case characteristics and the association set of the standard disease characteristics, a collection function s = f(t) can be defined, where t represents any characteristic, and an algorithm can be used to automatically obtain the association set of the tested case characteristics and the association set of the standard disease characteristics.

[0311] The set of associations representing the examined cases can be defined as p, assuming that p includes the elements {representation 1; sub-representation 11; sub-representation 12} and {representation 2; sub-representation 21; sub-representation 22}.

[0312] The standard disease characterization association set can be defined as d i d i The included elements are {standard representation 1; sub-standard representation 11}; {standard representation 2; sub-standard representation 21; sub-standard representation 22}; {standard representation 3; sub-standard representation 31}.

[0313] Of course, the examples above are for illustrative purposes only, and the specific usage should be determined based on the actual situation.

[0314] Step S53: Use different permutation rules to permutate and combine the test case characterization association set and the standard disease characterization association set to obtain permutation association pairs corresponding to each permutation rule.

[0315] The arrangement rules can include various methods, such as sequentially and individually arranging each element set in the standard disease characterization association set p according to the corresponding arrangement order, and then arranging them one by one with the standard disease characterization association set d. i Combining the elements in the set, the resulting permutation and associative pairs can be represented as:

[0316] {representation1; subrepresentation11; subrepresentation12} and {standard representation1; substandard representation11}, {representation2; subrepresentation21; subrepresentation22} and {standard representation2; substandard representation21; substandard representation22}.

[0317] The permutation rule is defined as follows: each element in the standard disease characterization association set p is associated with the standard disease characterization association set d. i The permutation association pair obtained by combining the elements at the next adjacent positions of the elements at corresponding positions in the permutation can be represented as:

[0318] {representation 1; sub-representation 11; sub-representation 12} and {standard representation 2; sub-standard representation 21; sub-standard representation 22}, {representation 2; sub-representation 21; sub-representation 22} and {standard representation 3; sub-standard representation 31}.

[0319] This allows for the generation of different permutation association pairs based on different permutation rules. The more permutation rules there are, the more permutation association pairs are generated, resulting in more sufficient data for calculating the Jaccard similarity coefficient and more accurate calculation results.

[0320] Step S54: Determine the corresponding permutation Jaccard similarity coefficient based on each of the permutation association pairs.

[0321] The permutation relationships obtained from the two permutation rules mentioned above will be explained.

[0322] It can be seen that different permutation rules result in different permutation association pairs, so it is necessary to calculate the permutation association pairs obtained under each permutation rule.

[0323] In one implementation, the step of determining the corresponding permutation Jaccard similarity coefficient based on each of the permutation association pairs includes:

[0324] Determine the current permutation association pair among all the aforementioned permutation association pairs;

[0325] Based on the combination pairs of the tested case characterization association sets and the standard disease characterization association sets included in the current arrangement association pairs, calculate the Jaccard similarity coefficient of each combination pair;

[0326] The Jaccard similarity coefficients of each of the aforementioned combination pairs are summed to obtain the Jaccard similarity coefficients of the currently arranged associated pairs;

[0327] Other permutation association pairs in each of the aforementioned permutation association pairs are identified as new current permutation association pairs, until all the permutation Jaccard similarity coefficients are obtained.

[0328] For ease of understanding, firstly, using the first permutation rule mentioned above: combining each element in the standard disease representation association set p sequentially and individually with the elements in the standard disease representation association set di, the resulting permutation association pair can be represented as:

[0329] Take {representation 1; sub-representation 11; sub-representation 12} and {standard representation 1; sub-standard representation 11}, and {representation 2; sub-representation 21; sub-representation 22} and {standard representation 2; sub-standard representation 21; sub-standard representation 22} as examples.

[0330] That is, to determine the current arrangement of related pairs.

[0331] Then, based on the combinations of the tested case representation association sets and the standard disease representation association sets included in the current arrangement association pairs, namely: {representation 1; sub-representation 11; sub-representation 12} and {standard representation 1; sub-standard representation 11}, {representation 2; sub-representation 21; sub-representation 22} and {standard representation 2; sub-standard representation 21; sub-standard representation 22}, the Jaccard similarity coefficient of each combination pair is calculated respectively;

[0332] It should be noted that the Jaccard similarity coefficient is an index used to measure the degree of similarity between elements in sets. Let set A and set B have an intersection with the number of elements |A∩B| and a union with the number of elements |A∪B|, then JSC = (|A∩B|) / (|A∪B|).

[0333] Set A can be considered as {representation 1; sub-representation 11; sub-representation 12} in the first combination pair mentioned above, and set B can be considered as {standard representation 1; sub-standard representation 11} in the first combination pair mentioned above. Then the Jaccard similarity coefficient for the corresponding combination pair is calculated as follows:

[0334] JSC1 = (|{representation 1; subrepresentation 11; subrepresentation 12} ∩ {standard representation 1; substandard representation 11}|) / (|{representation 1; subrepresentation 11; subrepresentation 12} ∪ {standard representation 1; substandard representation 11}|).

[0335] Similarly, the Jaccard similarity coefficient for the next combination pair can be calculated:

[0336] JSC2 = (|{representation2; subrepresentation21; subrepresentation22}∩{standard representation2; substandard representation21; substandard representation22}|) / (|{representation2; subrepresentation21; subrepresentation22}∪{standard representation2; substandard representation21; substandard representation22}|).

[0337] Next, the two Jaccard similarity coefficients are summed to obtain the Jaccard similarity coefficient corresponding to the permutation rule.

[0338] Finally, other permutation association pairs in each of the aforementioned permutation association pairs are identified as new current permutation association pairs, until all the permutation Jaccard similarity coefficients are obtained.

[0339] Step S55: Determine the maximum similarity coefficient among the Jaccard similarity coefficients of each of the permutations, and obtain the disease similarity based on the maximum similarity coefficient.

[0340] In this way, the disease similarity obtained based on the maximum similarity coefficient can be more accurate and reliable.

[0341] Based on the above introduction, it can be seen that the Jaccard similarity coefficients of the permutations have different values ​​depending on the permutation rules. Therefore, in order to ensure the accuracy of the final Jaccard similarity coefficients used, it is necessary to sort the various permutation Jaccard similarity coefficients. Specifically, this step may include:

[0342] Determine the maximum number of characteristics contained in the characterization group of the examined cases and the maximum number of characteristics contained in any disease characterization group;

[0343] The reciprocal of the maximum value is used to obtain the similarity coefficient of the maximum value.

[0344] Taking the aforementioned standard disease characterization association set p and standard disease characterization association set di as examples, the maximum value is: max(count(P), count(D)). i ))=max(2,3)=3.

[0345] The maximum similarity coefficient is 1 / 3.

[0346] This ensures that the maximum similarity coefficient ultimately used to obtain disease similarity is most useful for analyzing the etiology of the examined cases.

[0347] Finally, to facilitate obtaining Mendelian genetic consistency, the following explanation of Mendelian genetic consistency is provided.

[0348] Please refer to Figure 11 , Figure 11 This is a flowchart illustrating the method for obtaining Mendelian genetic consistency in the variation interpretation method provided in this application embodiment.

[0349] As shown in the figure, the process may include the following steps:

[0350] Step S60: Obtain the genetic pattern.

[0351] Step S61: Determine whether the inheritance pattern is a dominant inheritance pattern. If yes, proceed to step S62; otherwise, proceed to step S64.

[0352] Since the gene corresponding to the dominant inheritance pattern is a dominant gene, the phenotype of the corresponding inheritance pattern will definitely appear as long as the dominant gene is present, i.e., step S62. We can directly consider the Mendelian genetic consistency of the variant combination corresponding to the detected genetic variant, and we will not miss the judgment and acquisition of the Mendelian genetic consistency of the gene in the dominant inheritance pattern. However, in the recessive inheritance pattern, the corresponding gene is a recessive gene, and there are cases where two different variants of the gene cause disease in a compound heterozygous form. This will cause the acquisition of the Mendelian genetic consistency of the recessive gene to be incomplete, which will affect the judgment of the Mendelian genetic consistency of the recessive gene in the recessive inheritance pattern. Therefore, it is necessary to consider the Mendelian genetic consistency of the recessive gene corresponding to the detected genetic variant among other detected genetic variants belonging to the same gene, i.e., step S64.

[0353] Step S62: Determine the Mendelian genetic consistency value of the tested case and its family members corresponding to the detected genetic variation based on the Mendelian genetic consistency corresponding to the dominant inheritance pattern.

[0354] Step S63: Combine the Mendelian genetic consistency values ​​to obtain the Mendelian genetic consistency.

[0355] In this way, when the inheritance pattern is determined to be a dominant inheritance pattern, Mendelian genetic consistency can be determined simply by considering the detected genetic variation itself, making the results of Mendelian genetic consistency more reliable and providing a reliable data basis for subsequent interpretation of variations.

[0356] In one implementation, to facilitate the calculation of Mendelian genetic consistency, step S62 may include the following steps, please refer to [reference needed]. Figure 12 , Figure 12 This is another flowchart illustrating the method for obtaining Mendelian genetic consistency in the variation interpretation method provided in the embodiments of this application.

[0357] like Figure 12 As shown, the process may include the following steps:

[0358] Step S620: Determine the affected status of each family member of the tested case based on the tested case corresponding to the detected genetic variation.

[0359] Based on the aforementioned explanation of the affected status, it can be understood that it is used to indicate the disease status of the examined case and its family members, that is, whether the family members of the examined case have the same disease symptoms as the examined case.

[0360] Here it is assumed that the father and mother of the examined case are both normal, but the examined case is said to be diseased.

[0361] Step S621: Determine the measured genotype of the detected genetic variation for the examined case and each of the family members based on the dominant inheritance pattern corresponding to each of the affected conditions and the disease.

[0362] The tested genotypes are those obtained based on the actual disease status of the tested cases and their family members. The genotype is determined by the gene expression under this inheritance pattern. The disease is defined as Cornelia de Langesyndrome 5. Continuing with the example of the tested case where both the father and mother are normal, and the tested case is affected, the tested genotypes are: XaXa, XaY, and XAXa (assuming the tested case is a girl). Of course, the gene expression is only for illustrative purposes, and the actual situation should be taken into account.

[0363] Step S622: Determine the corresponding standard genotype based on the dominant inheritance pattern corresponding to the disease.

[0364] For example, based on the aforementioned disease being Cornelia de Lange syndrome, which corresponds to an X-linked inheritance pattern, the corresponding standard genotypes can be determined. That is, the standard genotypes of patients under the X-linked inheritance pattern are: XAXA or XAXa for girls and XAY for boys. The standard genotypes of those who are not affected (i.e., normal) are: XaXa for girls and XaY for boys.

[0365] Step S623: Compare the affected status of each tested genotype with that of the standard genotype. If they match, the Mendelian genetic consistency value corresponding to the tested genotype is counted as 1. If they do not match, the Mendelian genetic consistency value is reduced by one order of magnitude.

[0366] This step involves comparing the previously mentioned tested genotypes (mother's tested genotype: XaXa, father's tested genotype: XaY, diseased tested genotype: XAXa) with the standard genotypes (patient's standard genotype: XAXA or XAXa for girls, XAY for boys, and standard genotypes for those without disease: XaXa for girls and XaY for boys) to see if the parents' and the tested case's genotypes match the standard genotypes.

[0367] As can be seen, the tested genotypes of the examined case and the father and mother conform to the standard genotypes of the corresponding inheritance pattern of this disease. Therefore, the corresponding individual Mendelian genetic consistency is 1.

[0368] Step S63 may include:

[0369] Step S624, until all the measured genotypes have been compared, multiply each Mendelian genetic consistency value to obtain the Mendelian genetic consistency.

[0370] Continuing with the aforementioned case, the Mendelian genetic consistency of the tested case and its parents is 1. Therefore, the Mendelian genetic heterogeneity of the tested case is: 1×1×1=1.

[0371] Thus, the quantitative Mendelian genetic consistency obtained by comprehensively considering the cases examined and the disease status of their parents can be more biologically significant.

[0372] When the genetic pattern is determined to be a recessive genetic pattern, it is necessary to consider not only the Mendelian genetic consistency of the detected genetic variant itself, but also the Mendelian genetic consistency of other detected genetic variants belonging to the same gene with respect to the detected genetic variant. In this way, the Mendelian genetic consistency included in the recessive gene can be comprehensively considered, thereby enhancing the reliability and accuracy of the Mendelian genetic consistency corresponding to the detected genetic variant in the recessive genetic pattern.

[0373] Specifically, when the inheritance pattern is determined to be non-dominant, please continue to refer to... Figure 11 ,like Figure 11 As shown, the process may also include:

[0374] Step S64: Determine the gene corresponding to the recessive inheritance pattern, determine other detected genetic variations different from the detected genetic variation based on the gene, and combine the detected genetic variation with each of the other detected genetic variations to obtain combined variation pairs.

[0375] For ease of explanation, the gene corresponding to this recessive inheritance pattern is designated as a, and the allele of the same gene, namely gene a, is designated as A.

[0376] To fully obtain the Mendelian genetic consistency of gene a, it is necessary to consider all other detected genetic variations corresponding to allele A of gene a, thereby obtaining the Mendelian genetic consistency of the combination variation pairs obtained by combining the detected genetic variation with other detected genetic variations.

[0377] Step S65: Determine the Mendelian genetic consistency value of the detected genetic variation in the tested case and its family members based on the Mendelian genetic consistency corresponding to the recessive inheritance pattern.

[0378] This step can obtain the Mendelian genetic consistency value of each detected genetic variant based on the content of the aforementioned step S62.

[0379] Step S66: Determine the Mendelian genetic consistency value of the combined variation pairs of the tested cases and their family members corresponding to each of the recessive inheritance patterns based on the Mendelian genetic synergy.

[0380] The Mendelian genetic conformity value of the combined variant pair is determined by combining the genotypes of the detected genetic variants and the genotypes of other detected genetic variants included in each combined variant pair to determine whether the tested case and its family members conform to Mendelian genetic conformity. If they conform, the Mendelian genetic conformity value of the combined variant pair is determined to be 1. If they do not conform, the Mendelian genetic conformity value of the combined variant pair is reduced by one order of magnitude.

[0381] Step S67: Combine the Mendelian genetic consistency values ​​of each detected genetic variant to obtain the Mendelian genetic consistency of the detected genetic variant.

[0382] In this step, the Mendelian genetic consistency of the detected genetic variant can be obtained by referring to the content of step S62, assuming that the Mendelian genetic consistency of the detected genetic variant is 1.

[0383] Step S68: Combine the Mendelian genetic consistency values ​​of each of the combined variant pairs to obtain the Mendelian genetic consistency of each combined variant pair.

[0384] For each of the aforementioned mutation combinations, the consistency of the mutation combinations with Mendelian inheritance can be obtained as follows:

[0385] Assuming the gene a corresponds to the detected genetic variation, and other detected genetic variations corresponding to A belonging to the same gene are: detected genetic variation 1 and detected genetic variation 2, then the Mendelian genetic consistency of each other detected genetic variation and the variation combination pairs obtained by combining the detected genetic variation is obtained respectively.

[0386] First, calculate the consistency of Mendelian inheritance with respect to the combined variations under detected genetic variation 1:

[0387] Combination variant pair 1: {Detected genetic variant, Detected genetic variant 1}, that is, the Mendelian genetic consistency value of each combination variant pair of the tested case and its family members under the combination variant pair consisting of the genotype corresponding to the detected genetic variant and the genotype corresponding to the detected genetic variant 1. It is assumed that the Mendelian genetic consistency of the combination variant pair {Detected genetic variant, Detected genetic variant 1} is 0.01.

[0388] Similarly, calculate the consistency of Mendelian inheritance for the combined variations under detected genetic variation 2:

[0389] Combination variant pair 2: {Detected genetic variant, Detected genetic variant 2}, similarly, calculate the Mendelian genetic consistency values ​​of each combination variant pair of the tested case and its family members under the combination variant pair consisting of the genotype corresponding to the detected genetic variant and the genotype corresponding to the detected genetic variant 2. Assume that the Mendelian genetic consistency of the combination variant pair {Detected genetic variant, Detected genetic variant 2} is 0.1.

[0390] For ease of understanding, continuing with gene a as an example, when the genotype of the tested case corresponding to the detected genetic variation is Aa (i.e., heterozygous), the inheritance pattern of the tested case and the detected genetic variation does not conform to Mendelian inheritance laws. Therefore, considering the genotypes corresponding to the detected genetic variation under other detected genetic variations of this gene, i.e., the genotypes of combination variation pair 1: {detected genetic variation, detected genetic variation 1}, in one specific implementation:

[0391] When the tested case is a compound heterozygote for the combined variation pair 1: {detected genetic variation, detected genetic variation 1}, its corresponding genotype is the allele a1 corresponding to a. Therefore, the compound heterozygous genotype at this time is aa1. The affected status of the tested case is in accordance with Mendelian inheritance (recessive inheritance), and the Mendelian inheritance conformity value of the combined variation pair for this tested case is 1.

[0392] Step S69: Determine the maximum value among the Mendelian genetic consistency of the detected genetic variant and the Mendelian genetic consistency of each of the combined variants as the Mendelian genetic consistency corresponding to the detected genetic variant.

[0393] Continuing with the above example, the Mendelian genetic consistency of the detected genetic variants is 1, the Mendelian genetic consistency of the combined variant pair corresponding to combination variant pair 1 is 0.01, and the Mendelian genetic consistency of the combined variant pair corresponding to combination variant pair 2 is 0.1.

[0394] The detection of the genetic variant indicates the highest Mendelian genetic consistency, meaning that the Mendelian genetic consistency under this recessive inheritance pattern is determined to be 1.

[0395] This makes the final data on Mendelian genetic consistency under this genetic pattern more comprehensive and accurate.

[0396] To address the aforementioned problems, embodiments of this application also provide a variant interpretation acquisition apparatus. This apparatus can be considered as a functional module required to implement the variant interpretation acquisition method provided in embodiments of this application. The apparatus described below can be referred to in correspondence with the method described above.

[0397] As an optional implementation, Figure 13 An optional block diagram of the variation interpretation acquisition apparatus provided in an embodiment of this application is shown. For example... Figure 13 As shown, the device is adapted to obtain the interpretation of detected genetic variations in a tested case, and may include:

[0398] The genetic variation detection module 80 is adapted to acquire the detected genetic variations of the tested case.

[0399] The variant combination acquisition module 81 is adapted to acquire the variant combination corresponding to the detected genetic variant based on the detected genetic variant. The variant combination includes the detected genetic variant, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease.

[0400] In one embodiment, the variant combination acquisition module 81 is adapted to:

[0401] Based on the detected genetic variations, obtain the genes corresponding to the detected genetic variations;

[0402] Obtain the diseases corresponding to each of the aforementioned genes;

[0403] Based on each of the diseases described, the corresponding genetic patterns are obtained;

[0404] The detected genetic variations, the genes, the diseases, and the genetic patterns that correspond to each other are combined to obtain various variation combinations.

[0405] The indicator acquisition module 82 is adapted to acquire at least two of the following three factors based on the detected genetic variation in the variation combination, the gene corresponding to the detected genetic variation, the disease corresponding to the gene, and the genetic pattern corresponding to the disease: the pathogenicity of the detected genetic variation, the disease similarity to the disease, and the Mendelian genetic consistency corresponding to the genetic pattern.

[0406] In one specific embodiment, the indicator acquisition module 82 is adapted to acquire at least two of the following three factors based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease: pathogenicity of the detected genetic variant, disease similarity to the disease, and Mendelian genetic consistency corresponding to the inheritance pattern.

[0407] Determine the current variant combination among all variant combinations;

[0408] Perform at least two of the following steps to obtain at least two of the three: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency:

[0409] The pathogenicity of the current variant is obtained based on the detected genetic variant, the gene, the disease, and the inheritance pattern in the current variant combination;

[0410] Obtain current disease similarity based on the disease in the current variant combination;

[0411] At least based on the detected genetic variants and the genetic pattern in the current variant combination, current Mendelian genetic consistency is obtained.

[0412] The variant interpretation acquisition module 83 is adapted to acquire the variant interpretation of the variant combination based on at least two of the three factors: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency.

[0413] In one specific embodiment, the mutation interpretation acquisition module 83 is further adapted to:

[0414] The maximum value of each of the aforementioned variant interpretations is determined to obtain the variant interpretation corresponding to the detected genetic variant.

[0415] When the indicator acquisition module 82 acquires the variant interpretation of the current variant combination, the variant interpretation acquisition module 83 is adapted to acquire the variant interpretation of the variant combination based on at least two of the three factors: variant pathogenicity, disease similarity, and Mendelian genetic consistency, including:

[0416] The current variant interpretation for the current variant combination is obtained based on at least two of the current variant pathogenicity, the current disease similarity, and the current Mendelian genetic consistency, until the respective variant interpretations corresponding to each variant combination are obtained.

[0417] In one specific embodiment, the variant interpretation acquisition module 83 is adapted to acquire the variant interpretation of the variant combination based on at least two of the three factors: variant pathogenicity, disease similarity, and Mendelian genetic consistency, including:

[0418] The interpretation of the variant is obtained by cross-producting at least two of the three factors: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency.

[0419] When obtaining the pathogenicity of the variant, the indicator acquisition module 82 is adapted to obtain the pathogenicity of the detected genetic variant based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease, including:

[0420] Based on the detected genetic variation, the gene, the disease, and the inheritance pattern, obtain evidence of various variations related to the detected genetic variation;

[0421] The pathogenicity of each variant is determined based on the specific variant evidence, and the pathogenicity of the variant is obtained based on the pathogenicity.

[0422] In one embodiment, the indicator acquisition module 82 is adapted to obtain the pathogenicity of the variant based on the amount of variant evidence, including:

[0423] The pathogenicity is determined based on the amount of evidence presented.

[0424] Obtain a pathogenicity correspondence table, which includes the variant pathogenicity corresponding to each pathogenicity intensity;

[0425] The pathogenicity of the variant corresponding to the pathogenicity intensity is determined according to the pathogenicity correspondence table.

[0426] In other embodiments, to obtain the pathogenicity of a variant, the indicator acquisition module 82 is adapted to obtain the pathogenicity of the detected genetic variant based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease, including:

[0427] Based on the detected genetic variation, the gene, the disease, and the inheritance pattern, obtain evidence of various variations related to the detected genetic variation;

[0428] The pathogenicity is determined based on each of the aforementioned variant evidences, and the number of variant evidences corresponding to each pathogenicity is determined based on each of the aforementioned pathogenicities.

[0429] The combined pathogenicity chance is obtained using a pathogenicity chance function based on the amount of mutation evidence.

[0430] The pathogenicity of the variant is obtained by utilizing the combined pathogenicity chance and the prior probability of pathogenicity, wherein the prior probability of pathogenicity is determined based on the variant intensity.

[0431] In some embodiments, the mutation intensity includes very strong mutation intensity, and the pathogenic prior probability is determined based on the mutation intensity, including:

[0432] The mutation intensity was determined to be a very strong mutation intensity;

[0433] The pathogenic prior probability is determined based on the very strong variation intensity.

[0434] To obtain disease similarity, in one specific embodiment, the indicator acquisition module 82 is adapted to obtain disease similarity with the disease based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease, including:

[0435] Each test case characterization group is obtained based on the various characteristics exhibited by the test cases under the disease.

[0436] Any disease characterization group is obtained from the human phenotype ontology database, wherein the disease characterization group includes all standard disease characterizations of any disease manifestation in human diseases.

[0437] Based on the tested case characterization group and any disease characterization group, obtain the corresponding tested case characterization association set and standard disease characterization association set respectively. The tested case characterization association set includes the tested case characterization and the sub-tested case characterization associated with the tested case characterization. The standard disease characterization association set includes the standard disease characterization and the sub-standard disease characterization associated with the standard disease characterization.

[0438] By using different permutation rules, the association sets of the tested cases and the association sets of the standard diseases are permuted and combined to obtain permutation association pairs corresponding to each permutation rule;

[0439] Determine the corresponding permutation Jaccard similarity coefficient based on each of the permutation association pairs;

[0440] Determine the maximum similarity coefficient among the Jaccard similarity coefficients of each of the given permutations, and obtain the disease similarity based on the maximum similarity coefficient.

[0441] In one specific embodiment, the index acquisition module 82 is adapted to determine the corresponding permutation Jaccard similarity coefficient based on each of the permutation association pairs, including:

[0442] Determine the current permutation association pair among all the aforementioned permutation association pairs;

[0443] Based on the combination pairs of the tested case characterization association sets and the standard disease characterization association sets included in the current arrangement association pairs, calculate the Jaccard similarity coefficient of each combination pair;

[0444] The Jaccard similarity coefficients of each of the aforementioned combination pairs are summed to obtain the Jaccard similarity coefficients of the currently arranged associated pairs;

[0445] Other permutation association pairs in each of the aforementioned permutation association pairs are identified as new current permutation association pairs, until all the permutation Jaccard similarity coefficients are obtained.

[0446] In one implementation, the step of determining module 82 to obtain the maximum similarity coefficient includes:

[0447] Determine the maximum number of characteristics contained in the characterization group of the examined cases and the maximum number of characteristics contained in any disease characterization group;

[0448] The maximum similarity coefficient is obtained by taking the reciprocal of the maximum value.

[0449] To obtain Mendelian genetic consistency, in one embodiment, the indicator acquisition module 82 is adapted to obtain Mendelian genetic consistency corresponding to the genetic pattern based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the genetic pattern corresponding to the disease, including:

[0450] When the genetic pattern is determined to be a dominant genetic pattern, the Mendelian genetic consistency value of the tested case and its family members corresponding to the detected genetic variation is determined according to the Mendelian genetic consistency corresponding to the dominant genetic pattern.

[0451] The Mendelian genetic consistency is obtained by combining the individual Mendelian genetic consistency values.

[0452] To facilitate obtaining the Mendelian genetic consistency, in one embodiment, the indicator acquisition module is adapted to determine the Mendelian genetic consistency value of the tested case and its family members based on the Mendelian genetic synergy corresponding to the dominant inheritance pattern, including:

[0453] The affected status of each family member in the tested case is determined based on the tested case corresponding to the detected genetic variation;

[0454] The measured genotypes of the examined cases and their family members for the detected genetic variations are determined based on the dominant inheritance pattern corresponding to each of the affected conditions and the diseases.

[0455] The corresponding standard genotype is determined based on the dominant inheritance pattern corresponding to the disease;

[0456] Compare the affected status of each measured genotype with that of the standard genotype one by one. If they match, the Mendelian genetic consistency value corresponding to the measured genotype is counted as 1. If they do not match, the Mendelian genetic consistency value is reduced by one order of magnitude.

[0457] The indicator acquisition module is adapted to combine the various Mendelian genetic consistency values ​​to obtain the Mendelian genetic consistency, including:

[0458] The Mendelian genetic consistency is obtained by multiplying the Mendelian genetic consistency values ​​by comparing all the measured genotypes.

[0459] In another implementation, the acquisition of Mendelian genetic consistency can also be:

[0460] The indicator acquisition module is adapted to obtain Mendelian genetic consistency with the genetic pattern based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the genetic pattern corresponding to the disease, including:

[0461] When the genetic pattern is determined to be a recessive genetic pattern, the gene corresponding to the recessive genetic pattern is determined, and other detected genetic variations different from the detected genetic variation are determined based on the gene. The detected genetic variation is then combined with each of the other detected genetic variations to obtain a combination variation pair.

[0462] The Mendelian genetic consistency value of the detected genetic variation in the tested case and its family members is determined based on the Mendelian genetic consistency corresponding to the recessive inheritance pattern.

[0463] Based on the Mendelian genetic synergy corresponding to the recessive inheritance pattern, the Mendelian genetic consistency value of the combined variation pairs of the tested cases and their family members corresponding to each of the combined variation pairs is determined;

[0464] The Mendelian genetic consistency values ​​of each of the detected genetic variations are combined to obtain the Mendelian genetic consistency of the detected genetic variations;

[0465] The Mendelian genetic consistency of each of the aforementioned combined variants is obtained by combining the Mendelian genetic consistency of each combined variant.

[0466] The maximum value among the Mendelian genetic consistency of the detected genetic variant and the Mendelian genetic consistency of each of the combined variants is determined as the Mendelian genetic consistency corresponding to the detected genetic variant.

[0467] As can be seen, the variation interpretation acquisition device provided in this application obtains the corresponding gene, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease based on the detected genetic variation that can more powerfully explain the etiology of the tested case, thereby obtaining a comprehensive variation combination. Then, the variation combination is used to quantify the pathogenicity of the variation, disease similarity, and Mendelian genetic consistency used for qualitative evaluation of the etiology of the tested case. At least two of the quantified pathogenicity of the variation, disease similarity, and Mendelian genetic consistency are combined to obtain the variation interpretation. In this way, on the one hand, the variation interpretation obtained based on the detected genetic variation can improve the accuracy of the etiology analysis of the tested case, making the obtained variation interpretation more credible. On the other hand, by quantifying and combining the indicators for targeted analysis of the etiology of the tested case, the detected genetic variation corresponding to the variation interpretation obtained through quantitative combination can be placed in a more prominent position in the arrangement of many etiological variations when analyzing the etiology of the tested case. This can assist analysts in analysis and reasoning, speed up the process of arriving at a diagnostic conclusion, and improve the accuracy of variation ranking results and the efficiency of etiological variation analysis.

[0468] This application also provides an electronic device, including at least one memory 91 and at least one processor 92; the memory 91 stores a program, and the processor 92 calls the program to execute the variation interpretation acquisition method as described in any of the foregoing embodiments.

[0469] like Figure 14 As shown, Figure 14 This is a schematic diagram of the electronic device provided in the embodiments of this application.

[0470] It is understood that the device may also include at least one communication interface 93 and at least one communication bus 94; the processor 92 and the memory 91 may be located in the same electronic device, for example, the processor 92 and the memory 91 may be located in a server unit device or a terminal device; the processor 92 and the memory 91 may also be located in different electronic devices.

[0471] In the embodiments provided in this application, the number of processor 92, communication interface 93, memory 91, and communication bus 94 is at least one, and the processor 92, communication interface 93, and memory 91 communicate with each other through communication bus 94; obviously, Figure 13 The communication connection diagram of processor 92, communication interface 93, memory 91 and communication bus 94 shown is only one optional method.

[0472] Optionally, the communication interface 93 can be an interface of a communication module, such as the interface of a GSM module; the processor 92 may be a central processing unit (CPU), a specific integrated circuit (ASIC), or one or more integrated circuits configured to implement the embodiments of this application; the memory 91 may include high-speed RAM or non-volatile memory, such as at least one disk storage.

[0473] It should be noted that the above-described device may also include other devices (not shown) that may not be essential to understanding the content disclosed in the embodiments of the present invention; given that these other devices may not be essential for understanding the content disclosed in the embodiments of the present invention, the embodiments of the present invention will not describe them one by one.

[0474] This application also provides a storage medium storing a program suitable for obtaining variant interpretations to implement the variant interpretation acquisition method as described in any of the foregoing embodiments.

[0475] To further understand the variation interpretation and acquisition method provided by this invention, this application provides two specific embodiments (one for a dominant inheritance pattern and the other for a recessive inheritance pattern) as reference.

[0476] One example of calculating Explanation of Variation (EPS) (Case from the 2021 Interlaboratory Quality Assessment of High-Throughput Sequencing Detection for Genetic Diseases by the National Health Commission Clinical Laboratory Center)

[0477] Clinical information of the examined case: "Female, 7 years old, presented to the outpatient clinic due to 'developmental delay for 3 years'. Present illness: The child was found to have growth and developmental delay 3 years ago, with unknown annual height increase. She had no headaches, vomiting, polydipsia, or polyuria, but presented with intellectual disability, occasional fecal incontinence, and normal urination. Bone age was estimated at 5.2 years, with a bone age delay >2 SD, and a suspected diagnosis of 'short stature'. The child was born at gestational age (G2P1), via full-term cesarean section, with a birth length of 52 cm and a birth weight of 3100 g, and no history of asphyxia requiring resuscitation. Father's height: 172 cm." Mother's height: 158cm. Prenatal checkups during pregnancy indicated hydrocephalus, but no specific treatment was given. Feeding history: Breastfed after birth. Introduced complementary foods at 10 months, with a normal diet. Growth and development history: Lifts head at 7 months, can sit at 12 months, can stand at 16 months, walks with support at 18 months, speaks at 18 months, academic performance is average. Not a close relative. Denies any family history of hereditary or congenital diseases. This case, after high-throughput sequencing and upstream data analysis and filtering, yielded 792 candidate variants. One of these variants is used as an example to demonstrate the EPS calculation process.

[0478]

[0479] As noted in the annotations, this mutation is located in gene HDAC8, resulting in a cDNA-level variation: c.295+3A>C. A search of the OMIM database (https: / / www.omim.org / ) reveals that HDAC8 can cause the disease "Cornelia de Langesyndrome 5," which is inherited in an X-linked dominant (XLD) pattern.

[0480] Variation Gene Disease Inheritance pattern chrX-71788601-T-G HDAC8 Cornelia de Lange syndrome 5 XLD

[0481] (1) Calculation of Pathogenicity of the Variant (VPS). According to the results of the Gene-Disease Association Working Group of GlinGen, the HDAC8 gene has a high association with the disease, and no adjustment of the judgment level is required. This variant affects the standard splice site, causing exon skipping and frame of reference changes, and predicts that it will cause nonsense mutation-mediated mRNA degradation, which is consistent with PVS1 evidence. This variant is a de novo variant, but the phenotype has high genetic heterogeneity, which is consistent with PS2_supporting evidence. The allele frequency of this mutation is missing in the population frequency of public databases such as gnomAD and local databases, which is consistent with PM2_supporting evidence. Therefore, this variant is judged as a "pathogenic variant", according to Figure 6 The information is: VPS=0.99.

[0482] (2) Calculation of Disease Similarity (DSS). The standard phenotypes of the proband extracted from the clinical information of this case are: HP:0001249 Intellectual disability; HP:0001263 Global developmental delay; HP:0001270 Motor delay; HP:0002607 Bowel incontinence; HP:0003799 Marked delay in bone age; HP:0004322 Short stature. A search of the HPO database reveals that the corresponding standard phenotypes for Cornelia de Lange syndrome 5 are: HP:0008897 Postnatal growth retardation; HP:0001956 Truncalobesity; HP:0004322 Short stature; HP:0000175 Cleft palate; HP:0002714 Downturned corners of mouth; HP:0000687 Widely spaced teeth; etc. According to the method for obtaining disease similarity described above in this application, DSS = 0.06.

[0483] (3) Calculation of Mendelian Genetic Consistency (MCS). Clinical information from the examined cases indicates that the proband, the proband's mother, and the proband's father were "affected," "normal," and "normal," respectively. Test results show that the zygosity of this variant in the proband, the proband's mother, and the proband's father was "heterozygous," "wild-type," and "wild-type," respectively. Since the inheritance pattern of the disease corresponding to this detected genetic variant is XLD, it can be concluded that the conditions of the proband, the proband's mother, and the proband's father all conform to Mendelian inheritance laws. Using the Mendelian genetic consistency method exemplified in the aforementioned embodiments of this application, MCS = 1 × 1 × 1 = 1.

[0484] Therefore, DEPS = VPS × DSS × MCS = 0.99 × 0.06 × 1 = 0.0594.

[0485] Therefore, EPS = max(DEPS) = 0.0594.

[0486] Thus, the variation interpretation (EPS) described in this application is obtained.

[0487] Example 2 of EPS calculation (Case from the 2020 Interlaboratory Quality Assessment of High-Throughput Sequencing Detection for Genetic Diseases by the National Health Commission Clinical Laboratory Center)

[0488] Clinical information of the examined case: "Male, 2 months old, admitted to the hospital due to diarrhea and intermittent fever for more than 10 days. The child had more than 10 yellow, watery stools per day, occasionally with blood streaks, but no mucus. Blood routine showed high white blood cell count, gastroscopy showed esophagitis and superficial gastritis, and colonoscopy showed perianal ulcers and colitis. Pathological examination showed eosinophilia, suggesting allergic colitis. Physical examination: weight 4.56kg, subcutaneous fat <0.8cm, weight below the third percentile of children of the same age and sex. Current diagnosis: 1. Colitis (allergic colitis), 2. Esophagitis, 3. Malnutrition, 4. Pneumonia. Family history: The child's parents are healthy and not consanguineous. The child has an older brother who died 2 months after birth due to recurrent fever and diarrhea.

[0489] This case study, through high-throughput sequencing and upstream data analysis and filtering, yielded 699 candidate variants. One of these variants is used as an example to demonstrate the EPS calculation process.

[0490]

[0491] As noted in the annotations, this mutation is located in the IL10RA gene, resulting in a cDNA-level variation c.301C>T and an amino acid sequence variation p.R101W. A search of the OMIM database (https: / / www.omim.org / ) reveals that IL10RA can cause "Inflammatory Bowel Disease 28," which is inherited in an autosomal recessive (AR) pattern.

[0492] Variation Gene Disease Inheritance pattern chr11-117860269-C-T IL10RA Inflammatory bowel disease 28 AR

[0493] (1) Calculation of pathogenicity of the variant (VPS). The allele frequency of the mutation at this site is missing in both public databases such as gnomAD and local databases, consistent with PM2_supporting evidence. Therefore, this variant was classified as a "variable of undetermined significance," based on... Figure 6 The information is as follows: VPS=0.5.

[0494] (2) Calculation of disease similarity (DSS). The standard phenotypes of the proband extracted from the clinical information of this case are: HP:0002014 Diarrhea; HP:0001945 Fever; HP:0002583 Colitis; HP:0100633 Esophagitis; HP:0410151 Eosinophilic infiltration of the esophagus; HP:0001510 Growth delay. A search of the HPO database revealed that the standard phenotypes corresponding to Inflammatory bowel disease 28 are: HP:0002573 Hematochezia; HP:0000155 Oral ulcer; HP:0004387 Enterocolitis; HP:0100280 Crohn's disease; HP:0002583 Colitis; HP:0000999 Pyoderma; HP:0009789 Perianal abscess; HP:0025084 Folliculitis; HP:0001510 Growth delay. Based on the aforementioned method for obtaining disease similarity in this application, the DSS = 0.25.

[0495] (3) Calculation of Mendelian Genetic Consistency (MCS). Clinical information from the examined cases indicates that the proband, the proband's mother, and the proband's father were "affected," "normal," and "normal," respectively. Test results show that the zygosity of this variant in the proband, the proband's mother, and the proband's father was "heterozygous," "wild-type," and "heterozygous," respectively. We first examine the possibility of this variant acting as a single cause. Since the inheritance pattern of the disease corresponding to this detected genetic variant is AR, the proband's condition does not conform to Mendelian inheritance laws, while the proband's mother and father's conditions do. Using the Mendelian genetic consistency method exemplified in the aforementioned embodiments of this application, MCS = 0.1 × 1 × 1 = 0.1. Since the genetic pattern of the disease corresponding to this detected genetic variant is AR, we also need to consider the possibility that this detected genetic variant, together with other detected variants on the same corresponding gene (IL10RA), forms a variant pair (i.e., the aforementioned {detected genetic variant, detected genetic variant 1} or {detected genetic variant, detected genetic variant 2} in this application) as a compound heterozygous form as the cause. Through searching for candidate variants, we found another variant detected on IL10RA, as shown in the table below.

[0496]

[0497] Therefore, the variant chr11-117860269-CT can generate one variant pair, consisting of itself and the above chr11-117864125-GA, i.e., (chr11-117860269-CT, chr11-117864125-GA). The genotypes of this variant pair in the tested cases are shown in the table below.

[0498]

[0499] Since the inheritance pattern is AR and the affected statuses of the proband, the proband's mother, and the proband's father are "affected," "normal," and "normal," respectively, it can be concluded that for the variant pair (chr11-117860269-CT, chr11-117864125-GA) (i.e., the combination pair of genotypes consists of a heterozygous genotype with two mutant alleles at the same locus on two homologous chromosomes, and the heterozygous gene on the complex heterozygote together with the wild-type allele forms a complex allele series), the statuses of the proband, the proband's mother, and the proband's father all conform to Mendelian inheritance laws. Using the Mendelian inheritance consistency method exemplified in the aforementioned embodiments of this application, then MCS = 1 × 1 × 1 = 1.

[0500] Take the maximum MCS of the two cases above as the MCS of the variant chr11-117860269-CT, i.e. max(0.1,1)=1.

[0501] Therefore, DEPS = VPS × DSS × MCS = 0.5 × 0.25 × 1 = 0.125.

[0502] Therefore, EPS = max(DEPS) = 0.125.

[0503] Thus, the variation interpretation (EPS) described in this application is obtained.

[0504] While the embodiments of the present invention have been disclosed above, the present invention is not limited thereto. Any person skilled in the art can make various modifications and alterations without departing from the spirit and scope of the present invention; therefore, the scope of protection of the present invention should be determined by the scope defined in the claims.

Claims

1. A method for obtaining variant interpretation, characterized in that, Suitable for obtaining the interpretation of detected genetic variations in the tested cases, including: Obtain the detected genetic variations in the tested cases; Based on the detected genetic variation, the variation combination corresponding to the detected genetic variation is obtained. The variation combination includes the detected genetic variation, the gene corresponding to the detected genetic variation, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease. Based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease, at least two of the following three factors are obtained: pathogenicity of the detected genetic variant, disease similarity to the disease, and Mendelian genetic consistency with the inheritance pattern. The interpretation of the variant combination is obtained based on at least two of the three factors: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency. The step of obtaining the variant interpretation of the variant combination based on at least two of the three factors—the pathogenicity of the variant, the disease similarity, and the Mendelian genetic consistency—includes the following: The interpretation of the variant is obtained by cross-producting at least two of the three factors: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency.

2. The variation interpretation and acquisition method as described in claim 1, characterized in that, The step of obtaining the variant combination corresponding to the detected genetic variant based on the detected genetic variant includes: Based on the detected genetic variations, obtain the genes corresponding to the detected genetic variations; Obtain the diseases corresponding to each of the aforementioned genes; Based on each of the diseases described, the corresponding genetic patterns are obtained; The detected genetic variations, the genes, the diseases, and the genetic patterns that correspond to each other are combined to obtain various variation combinations.

3. The method for obtaining variant interpretation as described in claim 1, characterized in that, The step of obtaining at least two of the following three factors based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease: pathogenicity of the detected genetic variant, disease similarity to the disease, and Mendelian genetic consistency corresponding to the inheritance pattern: Determine the current variant combination among all variant combinations; Perform at least two of the following steps to obtain at least two of the three: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency: The pathogenicity of the current variant is obtained based on the detected genetic variant, the gene, the disease, and the inheritance pattern in the current variant combination; Obtain current disease similarity based on the disease in the current variant combination; At least based on the detected genetic variants and the genetic pattern in the current variant combination, current Mendelian genetic consistency is obtained; The step of obtaining the variant interpretation of the variant combination based on at least two of the three factors: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency includes: The current variant interpretation for the current variant combination is obtained based on at least two of the current variant pathogenicity, the current disease similarity, and the current Mendelian genetic consistency, until the respective variant interpretations corresponding to each variant combination are obtained.

4. The method for obtaining variant interpretation as described in claim 3, characterized in that, The step of obtaining the variant interpretation of the variant combination based on at least two of the three factors—the pathogenicity of the variant, the disease similarity, and the Mendelian genetic consistency—followed by: The maximum value of each of the aforementioned variant interpretations is determined to obtain the variant interpretation corresponding to the detected genetic variant.

5. The method for obtaining variant interpretation as described in claim 1, characterized in that, The step of obtaining the pathogenicity of the detected genetic variant based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease includes: Based on the detected genetic variation, the gene, the disease, and the inheritance pattern, obtain evidence of various variations related to the detected genetic variation; Determine the mutation intensity corresponding to each of the mutation evidences, and determine the number of mutation evidences corresponding to each mutation intensity, to obtain the number of mutation evidences; The pathogenicity of the mutation is determined based on the amount of evidence for the mutation.

6. The method for obtaining variation interpretation as described in claim 5, characterized in that, The step of determining the pathogenicity of the variant based on the amount of variant evidence includes: The pathogenicity is determined based on the amount of evidence presented. Obtain a pathogenicity correspondence table, which includes the variant pathogenicity corresponding to each pathogenicity intensity; The pathogenicity of the variant corresponding to the pathogenicity intensity is determined according to the pathogenicity correspondence table.

7. The method for obtaining variant interpretation as described in claim 1, characterized in that, The step of obtaining the pathogenicity of the detected genetic variant based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease includes: Based on the detected genetic variation, the gene, the disease, and the inheritance pattern, obtain evidence of various variations related to the detected genetic variation; Determine the mutation intensity corresponding to each of the mutation evidences, and determine the number of mutation evidences corresponding to each mutation intensity, to obtain the number of mutation evidences; The combined pathogenicity chance is obtained by using a pathogenicity chance function based on the amount of mutation evidence. The pathogenicity of the variant is obtained by utilizing the combined pathogenicity chance and the prior probability of pathogenicity, wherein the prior probability of pathogenicity is determined based on the variant intensity; The pathogenicity chance function is represented by OP, and its formula is as follows: ; Among them, O PVSt This indicates that the combined mutation strengths are transformed into a very strong mutation strength. PSu indicates that the mutation strength corresponding to the mutation evidence is the supporting mutation strength. PM indicates a moderate mutation strength. PSt indicates a strong mutation strength. PVSt indicates a very strong mutation strength. N indicates the number of mutation evidences corresponding to each mutation strength. X indicates the exponent used when transforming each mutation evidence. The formula used to obtain the pathogenicity of the variant from the combined pathogenicity chance and the prior pathogenicity probability is: ; Where Post_P represents the pathogenicity of the variant, OddsPath represents the joint pathogenicity chance, and Prio_P represents the prior probability of pathogenicity; the joint pathogenicity chance is an index obtained from the pathogenicity chance function.

8. The method for obtaining variant interpretation as described in claim 7, characterized in that, The mutation intensity includes very strong mutation intensity, and the step of determining the pathogenic prior probability based on the mutation intensity includes: The mutation intensity was determined to be a very strong mutation intensity; The pathogenic prior probability is determined based on the very strong variation intensity.

9. The method for obtaining variant interpretation as described in claim 1, characterized in that, The step of obtaining the disease similarity to the disease based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease includes: Each test case characterization group is obtained based on the various characteristics exhibited by the test cases under the disease. Any disease characterization group is obtained from the human phenotype ontology database, wherein the disease characterization group includes all standard disease characterizations of any disease manifestation in human diseases. Based on the tested case characterization group and any of the disease characterization groups, corresponding tested case characterization association sets and standard disease characterization association sets are obtained respectively. The tested case characterization association set includes the tested case characterization and sub-tested case characterizations associated with the tested case characterization. The standard disease characterization association set includes the standard disease characterization and sub-standard disease characterizations associated with the standard disease characterization. By using different permutation rules, the association sets of the tested cases and the association sets of the standard diseases are permuted and combined to obtain permutation association pairs corresponding to each permutation rule; Determine the corresponding permutation Jaccard similarity coefficient based on each of the permutation association pairs; Determine the maximum similarity coefficient among the Jaccard similarity coefficients of each of the given permutations, and obtain the disease similarity based on the maximum similarity coefficient.

10. The method for obtaining variation interpretation as described in claim 9, characterized in that, The step of determining the corresponding permutation Jaccard similarity coefficient based on each of the permutation association pairs includes: Determine the current permutation association pair among all the aforementioned permutation association pairs; Based on the combination pairs of the tested case characterization association sets and the standard disease characterization association sets included in the current arrangement association pairs, calculate the Jaccard similarity coefficient for each combination pair. The Jaccard similarity coefficients of each of the aforementioned combination pairs are summed to obtain the Jaccard similarity coefficients of the currently arranged associated pairs; Other permutation association pairs in each of the aforementioned permutation association pairs are identified as new current permutation association pairs, until all the permutation Jaccard similarity coefficients are obtained.

11. The method for obtaining variant interpretation as described in claim 1, characterized in that, The step of obtaining the Mendelian genetic consistency with the genetic pattern based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the genetic pattern corresponding to the disease includes: When the genetic pattern is determined to be a dominant genetic pattern, the Mendelian genetic consistency value of the tested case and its family members corresponding to the detected genetic variation is determined according to the Mendelian genetic consistency corresponding to the dominant genetic pattern. The Mendelian genetic consistency is obtained by combining the individual Mendelian genetic consistency values.

12. The method for obtaining variation interpretation as described in claim 11, characterized in that, The step of determining the Mendelian genetic consistency value of the tested case and its family members based on the Mendelian genetic synergy corresponding to the dominant inheritance pattern includes: The affected status of each family member in the tested case is determined based on the tested case corresponding to the detected genetic variation; The measured genotypes of the examined cases and their family members for the detected genetic variations are determined based on the dominant inheritance pattern corresponding to each of the affected conditions and the diseases. The corresponding standard genotype is determined based on the dominant inheritance pattern corresponding to the disease; Compare the affected status of each measured genotype with that of the standard genotype. If they match, the Mendelian genetic consistency value corresponding to the measured genotype is counted as 1. If they do not match, the Mendelian genetic consistency value is reduced by one order of magnitude. The step of combining the individual Mendelian genetic consistency values ​​to obtain the Mendelian genetic uniformity includes: The Mendelian genetic consistency is obtained by multiplying the Mendelian genetic consistency values ​​by comparing all the measured genotypes.

13. The method for obtaining variant interpretation as described in claim 1, characterized in that, The step of obtaining the Mendelian genetic consistency with the genetic pattern based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the genetic pattern corresponding to the disease includes: When the genetic pattern is determined to be a recessive genetic pattern, the gene corresponding to the recessive genetic pattern is determined, and other detected genetic variations different from the detected genetic variation are determined based on the gene. The detected genetic variation is then combined with each of the other detected genetic variations to obtain a combination variation pair. The Mendelian genetic consistency value of the detected genetic variation in the tested case and its family members is determined based on the Mendelian genetic consistency corresponding to the recessive inheritance pattern. Based on the Mendelian genetic synergy corresponding to the recessive inheritance pattern, the Mendelian genetic consistency value of the combined variation pairs of the tested cases and their family members corresponding to each of the combined variation pairs is determined; The Mendelian genetic consistency values ​​of each of the detected genetic variations are combined to obtain the Mendelian genetic consistency of the detected genetic variations; The Mendelian genetic consistency of each of the aforementioned combined variants is obtained by combining the Mendelian genetic consistency of each combined variant. The maximum value among the Mendelian genetic consistency of the detected genetic variant and the Mendelian genetic consistency of each of the combined variants is determined as the Mendelian genetic consistency corresponding to the detected genetic variant.

14. A variation interpretation and acquisition device, characterized in that, Suitable for obtaining the interpretation of detected genetic variations in the tested cases, including: The genetic variation detection module is adapted to acquire the detected genetic variations of the tested case; The variant combination acquisition module is adapted to acquire the variant combination corresponding to the detected genetic variant based on the detected genetic variant, wherein the variant combination includes the detected genetic variant, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease. The indicator acquisition module is adapted to acquire at least two of the following three factors based on the detected genetic variation in the variation combination, the gene corresponding to the detected genetic variation, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease: the pathogenicity of the detected genetic variation, the disease similarity to the disease, and the Mendelian genetic consistency corresponding to the inheritance pattern. The variant interpretation acquisition module is adapted to acquire the variant interpretation of the variant combination based on at least two of the three factors: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency. The variant interpretation acquisition module is adapted to acquire the variant interpretation of the variant combination based on at least two of the three factors: variant pathogenicity, disease similarity, and Mendelian genetic consistency, including: The interpretation of the variant is obtained by cross-producting at least two of the three factors: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency.

15. The variation interpretation and acquisition apparatus as described in claim 14, characterized in that, The variant combination acquisition module is adapted to acquire, based on the detected genetic variant, the variant combination corresponding to the detected genetic variant, including: Based on the detected genetic variations, obtain the genes corresponding to the detected genetic variations; Obtain the diseases corresponding to each of the aforementioned genes; Based on each of the diseases described, the corresponding genetic patterns are obtained; The detected genetic variations, the genes, the diseases, and the genetic patterns that correspond to each other are combined to obtain various variation combinations.

16. The variation interpretation and acquisition apparatus as described in claim 14, characterized in that, The indicator acquisition module is adapted to acquire at least two of the following three factors based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease: pathogenicity of the detected genetic variant, disease similarity to the disease, and Mendelian genetic consistency corresponding to the inheritance pattern. Determine the current variant combination among all variant combinations; Perform at least two of the following steps to obtain at least two of the three: pathogenicity of the variant, disease similarity, and Mendelian genetic consistency: The pathogenicity of the current variant is obtained based on the detected genetic variant, the gene, the disease, and the inheritance pattern in the current variant combination; Obtain current disease similarity based on the disease in the current variant combination; At least based on the detected genetic variants and the genetic pattern in the current variant combination, current Mendelian genetic consistency is obtained; The variant interpretation acquisition module is adapted to acquire the variant interpretation of the variant combination based on at least two of the three factors: the pathogenicity of the variant, the disease similarity, and the Mendelian genetic consistency, including: The current variant interpretation for the current variant combination is obtained based on at least two of the current variant pathogenicity, the current disease similarity, and the current Mendelian genetic consistency, until the respective variant interpretations corresponding to each variant combination are obtained.

17. The variation interpretation and acquisition apparatus as described in claim 16, characterized in that, The variant interpretation acquisition module is adapted to acquire the variant interpretation of the variant combination based on at least two of the three factors: the pathogenicity of the variant, the disease similarity, and the Mendelian genetic consistency, including: The maximum value of each of the aforementioned variant interpretations is determined to obtain the variant interpretation corresponding to the detected genetic variant.

18. The variation interpretation and acquisition apparatus as described in claim 14, characterized in that, The indicator acquisition module is adapted to acquire the pathogenicity of the detected genetic variant based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease, including: Based on the detected genetic variation, the gene, the disease, and the inheritance pattern, obtain evidence of various variations related to the detected genetic variation; Determine the mutation intensity corresponding to each of the mutation evidences, and determine the number of mutation evidences corresponding to each mutation intensity, to obtain the number of mutation evidences; The pathogenicity of the mutation is determined based on the amount of evidence for the mutation.

19. The variation interpretation and acquisition apparatus as described in claim 18, characterized in that, The indicator acquisition module is adapted to obtain the pathogenicity of the mutation based on the amount of mutation evidence, including: The pathogenicity is determined based on the amount of evidence presented. Obtain a pathogenicity correspondence table, which includes the variant pathogenicity corresponding to each pathogenicity intensity; The pathogenicity of the variant corresponding to the pathogenicity intensity is determined according to the pathogenicity correspondence table.

20. The variation interpretation and acquisition apparatus as described in claim 14, characterized in that, The indicator acquisition module is adapted to acquire the pathogenicity of the detected genetic variant based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease, including: Based on the detected genetic variation, the gene, the disease, and the inheritance pattern, obtain evidence of various variations related to the detected genetic variation; Determine the mutation intensity corresponding to each of the mutation evidences, and determine the number of mutation evidences corresponding to each mutation intensity, to obtain the number of mutation evidences; The combined pathogenicity chance is obtained by using a pathogenicity chance function based on the amount of mutation evidence. The pathogenicity of the variant is obtained by utilizing the combined pathogenicity chance and the prior probability of pathogenicity, wherein the prior probability of pathogenicity is determined based on the variant intensity; The pathogenicity chance function is represented by OP, and its formula is as follows: ; Among them, O PVSt This indicates that the combined mutation strengths are transformed into a very strong mutation strength. PSu indicates that the mutation strength corresponding to the mutation evidence is the supporting mutation strength. PM indicates a moderate mutation strength. PSt indicates a strong mutation strength. PVSt indicates a very strong mutation strength. N indicates the number of mutation evidences corresponding to each mutation strength. X indicates the exponent used when transforming each mutation evidence. The formula used to obtain the pathogenicity of the variant from the combined pathogenicity chance and the prior pathogenicity probability is: ; Where Post_P represents the pathogenicity of the variant, OddsPath represents the joint pathogenicity chance, and Prio_P represents the prior probability of pathogenicity; the joint pathogenicity chance is an index obtained from the pathogenicity chance function.

21. The variation interpretation and acquisition apparatus as described in claim 20, characterized in that, The mutation intensity includes very strong mutation intensity, and the pathogenic prior probability is determined based on the mutation intensity, including: The mutation intensity was determined to be a very strong mutation intensity; The pathogenic prior probability is determined based on the very strong variation intensity.

22. The variation interpretation and acquisition apparatus as described in claim 14, characterized in that, The indicator acquisition module is adapted to acquire disease similarity with the disease based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the inheritance pattern corresponding to the disease, including: Each test case characterization group is obtained based on the various characteristics exhibited by the test cases under the disease. Any disease characterization group is obtained from the human phenotype ontology database, wherein the disease characterization group includes all standard disease characterizations of any disease manifestation in human diseases. Based on the tested case characterization group and any of the disease characterization groups, corresponding tested case characterization association sets and standard disease characterization association sets are obtained respectively. The tested case characterization association set includes the tested case characterization and sub-tested case characterizations associated with the tested case characterization. The standard disease characterization association set includes the standard disease characterization and sub-standard disease characterizations associated with the standard disease characterization. By using different permutation rules, the association sets of the tested cases and the association sets of the standard diseases are permuted and combined to obtain permutation association pairs corresponding to each permutation rule; Determine the corresponding permutation Jaccard similarity coefficient based on each of the permutation association pairs; Determine the maximum similarity coefficient among the Jaccard similarity coefficients of each of the given permutations, and obtain the disease similarity based on the maximum similarity coefficient.

23. The variation interpretation and acquisition apparatus as described in claim 22, characterized in that, The index acquisition module is adapted to determine the corresponding permutation Jaccard similarity coefficient based on each of the permutation association pairs, including: Determine the current permutation association pair among all the aforementioned permutation association pairs; Based on the combination pairs of the tested case characterization association sets and the standard disease characterization association sets included in the current arrangement association pairs, calculate the Jaccard similarity coefficient for each combination pair. The Jaccard similarity coefficients of each of the aforementioned combination pairs are summed to obtain the Jaccard similarity coefficients of the currently arranged associated pairs; Other permutation association pairs in each of the aforementioned permutation association pairs are identified as new current permutation association pairs, until all the permutation Jaccard similarity coefficients are obtained.

24. The variation interpretation and acquisition apparatus as described in claim 14, characterized in that, The indicator acquisition module is adapted to obtain Mendelian genetic consistency with the genetic pattern based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the genetic pattern corresponding to the disease, including: When the genetic pattern is determined to be a dominant genetic pattern, the Mendelian genetic consistency value of the tested case and its family members corresponding to the detected genetic variation is determined according to the Mendelian genetic consistency corresponding to the dominant genetic pattern. The Mendelian genetic consistency is obtained by combining the individual Mendelian genetic consistency values.

25. The variation interpretation and acquisition apparatus as described in claim 24, characterized in that, The indicator acquisition module is adapted to determine the Mendelian genetic conformity value of the tested case and its family members based on the Mendelian genetic conformity corresponding to the dominant inheritance pattern, including: The affected status of each family member in the tested case is determined based on the tested case corresponding to the detected genetic variation; The measured genotypes of the examined cases and their family members for the detected genetic variations are determined based on the dominant inheritance pattern corresponding to each of the affected conditions and the diseases. The corresponding standard genotype is determined based on the dominant inheritance pattern corresponding to the disease; Compare the affected status of each measured genotype with that of the standard genotype. If they match, the Mendelian genetic consistency value corresponding to the measured genotype is counted as 1. If they do not match, the Mendelian genetic consistency value is reduced by one order of magnitude. The indicator acquisition module is adapted to combine the various Mendelian genetic consistency values ​​to obtain the Mendelian genetic consistency, including: The Mendelian genetic consistency is obtained by multiplying the Mendelian genetic consistency values ​​by comparing all the measured genotypes.

26. The variation interpretation and acquisition apparatus as described in claim 14, characterized in that, The indicator acquisition module is adapted to obtain Mendelian genetic consistency with the genetic pattern based on the detected genetic variant in the variant combination, the gene corresponding to the detected genetic variant, the disease corresponding to the gene, and the genetic pattern corresponding to the disease, including: When the genetic pattern is determined to be a recessive genetic pattern, the gene corresponding to the recessive genetic pattern is determined, and other detected genetic variations different from the detected genetic variation are determined based on the gene. The detected genetic variation is then combined with each of the other detected genetic variations to obtain a combination variation pair. The Mendelian genetic consistency value of the detected genetic variation in the tested case and its family members is determined based on the Mendelian genetic consistency corresponding to the recessive inheritance pattern. Based on the Mendelian genetic synergy corresponding to the recessive inheritance pattern, the Mendelian genetic consistency value of the combined variation pairs of the tested cases and their family members corresponding to each of the combined variation pairs is determined; The Mendelian genetic consistency values ​​of each of the detected genetic variations are combined to obtain the Mendelian genetic consistency of the detected genetic variations; The Mendelian genetic consistency of each of the aforementioned combined variants is obtained by combining the Mendelian genetic consistency of each combined variant. The maximum value among the Mendelian genetic consistency of the detected genetic variant and the Mendelian genetic consistency of each of the combined variants is determined as the Mendelian genetic consistency corresponding to the detected genetic variant.

27. An electronic device comprising at least one memory and at least one processor; the memory storing a program, the processor invoking the program to perform the variation interpretation acquisition method as described in any one of claims 1-13.

28. A storage medium, characterized in that, The storage medium stores a program suitable for obtaining variant interpretations to implement the variant interpretation acquisition method as described in any one of claims 1-13.

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