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WO2017135768A1 - Procédé et système permettant de prédire le risque de développement d'un trouble génétique dans la progéniture putative - Google Patents

Procédé et système permettant de prédire le risque de développement d'un trouble génétique dans la progéniture putative Download PDF

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WO2017135768A1
WO2017135768A1 PCT/KR2017/001245 KR2017001245W WO2017135768A1 WO 2017135768 A1 WO2017135768 A1 WO 2017135768A1 KR 2017001245 W KR2017001245 W KR 2017001245W WO 2017135768 A1 WO2017135768 A1 WO 2017135768A1
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mutation
genetic disease
subject
disease
information
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기창석
기강현
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Samsung Life Public Welfare Foundation
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Samsung Life Public Welfare Foundation
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B30/00—ICT specially adapted for sequence analysis involving nucleotides or amino acids
    • G16B30/10—Sequence alignment; Homology search
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
    • G16B20/20—Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B30/00—ICT specially adapted for sequence analysis involving nucleotides or amino acids
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B40/00—ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding

Definitions

  • a method and system for predicting the risk of developing genetic diseases of putative progeny between a male subject and a female subject also relates to a computer readable recording medium having recorded thereon a program for realizing the above method.
  • One aspect includes (a) obtaining genomic sequencing data of a male subject and a female subject; (b) the method of obtaining a genomic sequencing of a male subject and a female subject by mapping genomic sequencing data and a standard sequencing of a randomly selected one of the two subjects; Extracting mutations from the genomic sequencing data of each subject through mapping with standard sequences; Determining whether the extracted mutation is associated with an autosomal recessive genetic disease; If the mutation is associated with an autosomal recessive genetic disease, confirming that both subjects have a mutation associated with an autosomal recessive genetic disease in a gene in which the mutation is found; And if both subjects have a mutation associated with an autosomal recessive hereditary disease in the gene, storing mutation information of each subject for that gene; Provides a way to predict risk.
  • the method of predicting the risk of genetic disease development of the estimated progeny of the present invention is to provide information necessary for predicting the onset of genetic disease of a future child between men and women. It can also be expressed as 'presumption of genetic diseases of progeny'.
  • the term "prediction" refers to determining whether a genetic disease is likely to develop in future offspring, or whether a genetic disease is relatively more likely to develop.
  • the method may be used to prevent the occurrence of genetic disease patients or to diagnose a child's genetic disease early, while protecting personal genetic information in a pre-marriage couple or a couple planning a child.
  • subject refers to all animals classified as mammals and may include, for example, humans, non-human primates, cattle, horses, pigs, sheep, goats, dogs, cats, or rodents. In particular, the subject may be a human of any age or race.
  • a method for predicting a risk of developing a genetic disease of a putative progeny between a male subject and a female subject may be performed by one or more processors.
  • the term “processor” is a device for processing a plurality of variation information related to genomic sequencing data of a subject performed by an experimenter, and may classify or delete a plurality of variation information input to a database by an experimenter based on a predetermined criterion. .
  • the processor may be, for example, a computer processor.
  • the method may also be expressed as a 'computer-implemented identification method of predicting the risk of genetic disease development of putative progeny between a male subject and a female subject.' Can be.
  • the genetic disease may be an autosomal recessive genetic disease.
  • the autosomal recessive genetic diseases include, for example, Wilson disease, type 1 glycogen storage disease I, phenylketonuria, Gitelman syndrome, and cystic fibrosis. ), Autosomal Recessive Congenital Hearing Impairment, Primary Congenital Glaucoma, Ataxia Telangiectasia, or Congenital Hypothyrodism.
  • the method includes obtaining genomic sequencing data of male subjects and female subjects.
  • the genomic sequencing data may be exome sequence data, whole genome sequence data, or sequence data of genes known to be associated with a disease.
  • exome refers to any part of the DNA sequence that contains the protein's configuration information, and may refer to any part of the genome except genes and intergenic regions and introns.
  • full length genome also called total genome, refers to the entirety of DNA bases that store a single piece of genetic information.
  • the genomic sequencing data of each subject may be retrieved from a database stored in a processor.
  • the database may store genomic sequencing data of a plurality of subjects.
  • Obtaining genomic sequencing data of each subject can be obtained experimentally.
  • genomic sequencing data of the subject may be obtained by extracting nucleic acids from biological samples derived from each subject and then performing sequencing.
  • biological sample refers to a biological sample of an animal separated in vitro and refers to a blood, plasma, serum, urine, cell, hair or tissue sample.
  • the biological sample may be blood collected from a subject.
  • the sequencing may be specifically by next generation sequencing (NGS).
  • NGS next generation sequencing
  • the method includes extracting mutations from the genomic sequencing data of the two subjects obtained.
  • variant extraction refers to identifying and / or discriminating information regarding the substitution, addition, or deletion of a nucleotide in the sequence of nucleotides constituting the exon of a subject gene. Substitution, addition, or deletion of such nucleotides can occur for a variety of reasons, for example due to structural differences including mutations, truncation, deletions, duplications, inversions and / or translocations of a chromosome.
  • the variant extraction may be performed by mapping genomic sequencing data to standard sequencing.
  • the mapping between the genome sequencing data and the standard nucleotide sequence means an operation of comparing the genome sequencing with the standard nucleotide sequence.
  • reference neucleotide sequence may refer to a genomic sequence that does not include a mutation, to which reference is made for identification of the mutation.
  • a human gene sequence published in a database of the National Institute of Bioscience and Biotechnology Information Institute (NCBI), specifically NCBI37.1 or UCSC hg19 (GRCh37), may be used as the standard sequence.
  • NCBI National Institute of Bioscience and Biotechnology Information Institute
  • UCSC hg19 UCSC hg19
  • the comparison between the nucleotide sequence and the standard sequence of the genomic DNA can be performed using various known sequence comparison analysis programs, for example, Maq, Bowtie, SOAP, GSNAP and the like.
  • the difference between the object and the standard nucleotide sequence is extracted, and then, the reliable mutation information is extracted.
  • the extracted mutation information is compared with the existing database to determine whether it is a new mutation and affects amino acid change or protein structure. Predictive annotations can be performed. In this case, after performing and annotating the variation information extraction for all the reads, the next step may be performed, or after extracting and annotating the variation information for one lead, the process of proceeding to the next step may be repeated.
  • Exome Aggregation Consortium http://exac.broadinstitute.org/
  • Exome Variant Server http://evs.gs.washington.edu/EVS 1000 Genome Project (http://browser.1000genomes.org)
  • dbSNP http://www.ncbi.nlm.nih.gov/snp
  • dbVar http://ncbi.nlm.nih.gov/dbvar
  • the method for predicting the risk of genetic disease development of the putative progeny includes identifying whether the mutation extracted from each subject is associated with an autosomal recessive genetic disease.
  • the variation extracted from each subject may be one or more. Confirming whether the mutation extracted from each subject is related to an autosomal recessive genetic disease, specifically confirming whether the mutation is present in an autosomal recessive genetic disease gene; If the mutation is present in an autosomal recessive genetic disease gene, determining whether the mutation corresponds to a polymorphism that does not cause disease; And if the variation does not correspond to polymorphism, determining whether the variation corresponds to a known mutation or pathogenesis.
  • Checking whether the mutation is present in an autosomal recessive genetic disease gene means determining whether the mutation is found in a gene that causes an autosomal recessive genetic disease. More than 1,139 autosomal recessive genetic diseases are known.
  • the causative gene of autosomal recessive inherited disease which is the basis of the identification, includes all known cause of autosomal recessive inherited disease or genes known to cause severe disease or common recession according to the race or race of the test subject. Only genetic disease related genes (PMID: 21228398, 26354092, 26334176, 22170460).
  • Polymorphism refers to the case in which a population in the entire genome differs for each chromosome in a population, and means an individual-to-individual difference in the sequences present on such genome. Polymorphism can cause differences in human traits regardless of the disease, or can cause the disease. Criteria for determining polymorphism may be a polymorphism database (dbSNP), Exome Aggregation Server (ExAC), and / or Korean Reference Genome Database (KRGDB).
  • dbSNP polymorphism database
  • ExAC Exome Aggregation Server
  • KRGDB Korean Reference Genome Database
  • Identifying whether the mutation corresponds to a known mutation or pathogenic is performed if the mutation does not correspond to polymorphism.
  • Human Gene Mutation Database HGVS
  • ClinVar / or disease-specific, gene-specific mutation databases
  • AMP Association for Molecular Pathology
  • mutation information of each subject not related to autosomal recessive genetic disease is deleted.
  • the term 'delete' means that all information related to a subject having a mutation is discarded and / or removed so that no information is disclosed to anyone, including a subject, an inspector, an analyst, and the like.
  • the mutation of each subject does not exist in an autosomal recessive genetic disease gene, corresponds to a polymorphism that does not develop a disease, or does not correspond to a known mutation and pathogenesis, information about the mutation is deleted. Since mutation information not related to the autosomal recessive genetic disease is deleted, the mutation information is not disclosed to anyone, thereby protecting the privacy of each subject.
  • the method confirms the association of autosomal recessive genetic disease to the mutation of each subject, and when the mutation of each subject is associated with autosomal recessive genetic disease, both subjects autosomal to the gene in which the mutation was found.
  • the autosomal recessive genetic disease-related mutations of both subjects may be the same or different from each other.
  • the identification step may be performed by comparing genes of each subject in which mutations that are not deleted because they are related to autosomal recessive genetic disease are determined to be identical to each other.
  • the method stores information about a mutation associated with an autosomal recessive inherited disease of each subject found in the gene when both male and female subjects have a mutation associated with an autosomal recessive genetic disease in the gene in which the mutation is found. It includes a step. For example, when the same genes are found by comparing the genes of the respective subjects where the mutations associated with autosomal recessive genetic diseases are located, the mutation information of the two subjects existing in the same gene may be stored.
  • the mutation information may include, for example, the type of mutation, the location of the mutation, genetic information in which the mutation exists, or information on a genetic disease causing the mutation.
  • the method deletes information about the mutation if both subjects do not have a mutation associated with an autosomal recessive genetic disease in the gene in which the mutation is found. That is, corresponding mutation information of an autosomal recessive inherited disease related mutation gene present in only one subject may be deleted.
  • the method may further comprise validating the stored variation information.
  • the verification step may be performed after it is determined that both the subjects have a mutation associated with an autosomal recessive genetic disease in the gene in which the mutation is found.
  • the verifying step may be performed before or after storing the information on the variation of each object.
  • the verification step is performed before storing the variation information of each object, only the variation information determined to be valid in the verification step is stored, and the invalid variation information is deleted.
  • the verification step is performed after storing the variation information of each object, the variation information determined as invalid in the verification step is deleted.
  • the verification may be for verification of sequencing results of genes in which mutation information is stored.
  • Verification of the sequencing results of the gene in which the mutation information is stored may be to confirm whether the found mutations are found to be identical by, for example, polymerase chain reaction, microarray analysis, or Sanger sequencing method.
  • the verification may be to perform a bioinformatics analysis to determine the etiology, may be performed by re-checking the mutation / polymorphism database and the like. As a result of the verification, if the stored variation information is invalid, the stored variation information is deleted.
  • the method may perform the step of validating the variation information before the storing the variation information. That is, when both the male subject and the female subject have a mutation associated with an autosomal recessive genetic disease in the gene in which the mutation is found, verification of the sequencing result of the gene is performed for each variation of the corresponding gene of the male subject and the female subject. Can be. Verification is as described above. As a result of the verification, when all the sequencing results of the variation of each subject are valid, the information about the variation is stored, and when the validation is invalid, the information about the variation is deleted.
  • the method may further include calculating a risk of developing a genetic disease associated with stored variation information of the estimated offspring based on the total stored variation information. For example, if it was found that two couples each had one known mutation or pathogenic mutation in the same gene, their putative progeny could have a 25% chance of having an autosomal recessive genetic disease related to that mutation.
  • the probability may be represented as a risk level.
  • the risk may be scored by reflecting the probability by reflecting a predetermined criterion and various factors. For example, the risk may be scored by reflecting factors such as the probability of occurrence of a disease in a genetic disorder, race, sex, eating habits, and / or lifestyle.
  • the method may further comprise displaying total stored variation information.
  • the displaying may include displaying stored variation information when stored mutation information exists, and, for example, when there is no stored mutation information, for example, 'no risk of developing an autosomal recessive genetic disease' or ' not detected '.
  • the displaying of the stored mutation information may specifically indicate the presence or absence of a genetic disease associated with the total stored mutation and its risk of development. When expressed as a risk, for example, a 'positive' indication for a disease associated with a stored variation and a risk score calculated at the risk calculation step may be displayed.
  • the method may further comprise providing the subject with a report comprising the total stored variation information.
  • the report may include the calculated risk of developing genetic diseases of putative progeny.
  • the report may include information about the variation (eg, location of the variation, characteristics of the specific variation, and name of the variation and found gene, etc.) and risk of developing the genetic disease, depending on the subject's selection.
  • the report can be printed, stored on a computer, viewed online, or viewed in an app.
  • the report may be accessible through a computer, Internet website, telephone, or information source, an online portal that is easily accessible to the individual using other means of similar access to the information.
  • the online portal may be a secure online portal or website.
  • Another aspect includes a) obtaining genomic sequencing data of a male subject and a female subject; b) extracting mutations from the genomic sequencing data of each subject through mapping with standard sequences; c) identifying whether one of the extracted mutations is associated with an autosomal recessive genetic disease for the mutation found in one subject; d) if the mutation found in one subject is associated with an autosomal recessive genetic disease, confirming that the other subject has a mutation in the gene of interest associated with the autosomal recessive genetic disease; e) if the other subject has a mutation in the gene, determining whether the mutation in the other subject is related to an autosomal recessive genetic disease; And f) if the mutation of the other subject is associated with an autosomal recessive genetic disease, storing mutation information of each subject for that gene, the genetic disease of the putative progeny between the male subject and the female subject. Provides a way to predict risk of development
  • the genetic disease of the putative progeny may be an autosomal recessive genetic disease.
  • the autosomal recessive genetic disease is as described above.
  • the method includes extracting mutations from genomic sequencing data of each subject and then identifying whether the mutation found in any one of two subjects is associated with an autosomal recessive genetic disease.
  • the variation found in the one subject may be one or more.
  • the randomly selected subject may be a male subject or a female subject, specifically, a female subject.
  • Identification of the mutation found in the subject related to an autosomal recessive genetic disease may include determining whether the mutation is present in an autosomal recessive genetic disease gene; If the mutation is present in an autosomal recessive genetic disease gene, determining whether the mutation corresponds to a polymorphism that does not cause disease; And if the variation does not correspond to polymorphism, determining whether the variation corresponds to a known mutation or pathogenesis. Each step is as described above.
  • the mutation found in the subject in the identifying step is not related to autosomal recessive genetic disease
  • information about the mutation is deleted. That is, information about mutations found in a subject not related to autosomal recessive genetic disease is deleted.
  • the mutation found in the subject is not present in an autosomal recessive genetic disease gene, corresponds to a polymorphism that does not develop a disease, or is not a known mutation and does not correspond to pathogenicity, the mutation information is deleted.
  • the method comprises the steps of identifying if a mutation found in the subject is associated with an autosomal recessive genetic disease and if the other subject has a mutation in the gene of interest associated with the autosomal recessive genetic disease found in the subject. Can be done.
  • the variation that the other subject has may be the same variation as the variation found in one subject or another variation.
  • the identification of whether the other subject has a mutation in the gene may include, for example, whether the gene in which the mutation of another subject extracted in the mutation extraction step is the same as the gene of the mutation associated with an autosomal recessive genetic disease in the subject. Can be carried out through the judgment of.
  • genomic sequence reads from the genomic sequencing data of another subject to standard nucleotide sequences and then reading and / or annotating variant information for the reads mapped to the gene in which the mutation associated with an autosomal recessive genetic disease was found in the subject This can be done through running. If another subject does not have a mutation in the gene of interest associated with an autosomal recessive inherited disease found in one subject, information about the mutation associated with an autosomal recessive inherited disease found in the subject is deleted.
  • the method may be performed when the other subject has a mutation in a corresponding gene of a mutation related to an autosomal recessive genetic disease found in one subject, and the method checks whether the mutation in the other subject is related to an autosomal recessive genetic disease. do.
  • Determining whether the mutation of another subject is related to an autosomal recessive genetic disease comprises: determining whether the mutation corresponds to a polymorphism that does not cause disease; And when the mutation does not correspond to a polymorphism that does not cause the disease, determining whether the variation corresponds to a known mutation or pathogenesis.
  • the method deletes the mutation information if the mutation of the other subject corresponds to a polymorphism that does not cause autosomal recessive genetic disease, or if it is not a known mutation and does not correspond to pathogenicity.
  • the variation information may be mutation information related to an autosomal recessive genetic disease of one subject and / or mutation information of another subject.
  • the mutation of the other subject corresponds to a known mutation or pathogenic mutation, storing the information on the variation of each subject present in the gene.
  • the method is performed for each variation extracted from one subject, and each stage of steps c) to f) is completed after the completion of each stage, or by selecting any variation from the variation extracted from one subject for each variation.
  • the steps c) to f) may be sequentially performed.
  • the steps c) to f) are selected sequentially by selecting the random variation, and the steps c) to f) are completed for any selected variation, and then c) to f for the next selected variation.
  • Step f) is performed, and steps c) to f) must be performed for all the mutations extracted from one subject to be finished.
  • the other subject is the autosomal recessive. If no mutation exists in the gene of interest associated with the genetic disease, or if the mutation of the other subject is not related to an autosomal recessive genetic disease, delete the mutation information and immediately c for the randomly selected mutation. ) To f) may be performed.
  • the method of selecting any of the variants and sequentially performing steps c) to f) for each variant comprises the steps of: (a) obtaining genomic sequencing data of the male subject and the female subject; (b) extracting mutations from the genomic sequencing data of the two subjects by mapping the genomic sequencing data of the two subjects and the standard sequencing; (c) selecting any of the variations of one subject; (d) identifying whether any of the variations (first variation) is associated with an autosomal recessive genetic disease; (e) if the first variation is associated with an autosomal recessive genetic disease, identifying from the genomic sequencing data of the other subject whether the other subject has a first variation or a first 'variation in the gene in which the first variation is found Making; (f) if the other subject has a first 'mutation in a gene in which the first mutation is found, confirming that the first' mutation corresponds to a known mutation or pathogenesis; (g) if the first 'mutation corresponds to a known mutation or pathogenesis, storing
  • the method may include selecting any variation of the variation of one subject.
  • the first mutation may mean a mutation selected first among the extracted mutations.
  • the first mutation when the first mutation is related to a recessive genetic disease, from the genomic sequencing data of another subject, whether the other subject has the first mutation or the first 'mutation in the gene in which the first mutation is found. It includes a step.
  • the first 'variation means a variation other than the first variation found in the gene in which the first variation is found.
  • step (e) of the embodiment If the other subject has the first mutation as a result of the checking in the step (e) of the embodiment, the step of storing the first variation information of each object immediately (g) 'instead of the steps (f) and (g) can do. Subsequently, step (h) is performed in the same way.
  • the second variation of the variation information extracted from the genomic sequencing data of the subject may be compared to the first variation.
  • Each corresponding step can be performed identically.
  • the second variation may be a randomly selected variation among the extracted variations except for the first variation.
  • the respective steps may be performed identically to a randomly selected third variation among the remaining mutations, and finally, all extracted from the genomic sequencing data of the subject You can perform each corresponding step in sequence for the variation.
  • the method according to another aspect may further include verifying that the stored variation information is valid.
  • the verification step may be performed after it is determined that the mutations of the other subject correspond to known mutations or variable mutations.
  • the verifying step may be performed before or after storing the information on the variation of each object.
  • the verification step is performed before storing the variation information of each object, only the variation information determined to be valid in the verification step is stored, and the invalid variation information is deleted.
  • the verification step is performed after storing the variation information of each object, the variation information determined as invalid in the verification step is deleted.
  • the method may further include calculating a risk of developing a genetic disease associated with stored variation information of the estimated offspring based on the total stored variation information.
  • the method may further comprise displaying total stored variation information.
  • the method may further comprise providing the subject with a report comprising the total stored variation information.
  • the verifying step, calculating the risk of developing the genetic disease, displaying the step, and providing a report to the individual are as described above.
  • Another aspect includes obtaining genomic sequencing data of a female subject; Extracting mutations from the genomic sequencing data of the obtained female subject through mapping with standard sequences; Determining whether the extracted mutation is related to a sex chromosomal recessive genetic disease; And if the mutation is related to a sex chromosomal recessive genetic disease, storing the variation information, and if the variation is not related to a sex chromosomal recessive genetic disease, deleting the corresponding variation information. Provides a way to predict risk.
  • the genetic disease may be a sex chromosomal recessive genetic disease.
  • sex chromosomal recessive genetic diseases include, for example, Duchenne Muscular Dystrophy, Hunter Syndrome, Hemophilia, Adrenoleukodystrophy, Menkes Disease, and the like. .
  • the method extracts genomic sequencing data variation information of female subjects in order to predict the risk of developing sex chromosomal recessive genetic diseases of the putative progeny. Obtaining sequencing data in the method, extracting the variation information is as described above.
  • the method comprises determining whether the extracted mutation is related to sex chromosomal recessive genetic disease.
  • the identification may include determining whether the mutation is present in a sex chromosomal recessive genetic disease gene; If the mutation is present in a recessive genetic disease gene, determining whether the mutation corresponds to a polymorphism that does not cause disease; And when the mutation does not correspond to a polymorphism that does not cause the disease, determining whether the variation corresponds to a known mutation or pathogenesis.
  • the method may further include storing information about the mutation when the extracted mutation is related to a sex chromosomal recessive genetic disease and deleting the variation information when the variation is not related to a sex chromosomal recessive genetic disease. Steps. That is, information about extracted mutations in female subjects not related to sex chromosomal recessive genetic diseases may be deleted.
  • the method may further include verifying that the sequencing result of the gene in which the mutation information is stored is valid in a female subject when the mutation information is stored.
  • the method may perform the step of verifying that the sequencing result of the gene associated with the mutation information is valid before storing the mutation information if the mutation is related to sex chromosomal recessive genetic disease. As a result of the verification, if the sequencing result of the gene associated with the mutation information is valid, the mutation information is stored, and if not valid, the mutation information is deleted.
  • the method according to the other aspect comprises a method for predicting the risk of developing genetic diseases of putative progeny between a male subject and a female subject, comprising: (a) obtaining genomic sequencing data of the female subject; (b) extracting mutation information from the obtained genomic sequencing data of the female subject by mapping with standard sequences; (c) confirming whether a first variation of the extracted variation information is related to a sex chromosomal recessive genetic disease; (d) if the first variation is associated with a sex chromosomal recessive disease, store the first variation information, and if the first variation is not associated with a sex chromosomal recessive disease, the first variation information is stored.
  • step (b) Deleting; And (e) performing steps (c) to (d) on the second variation of the variation information extracted in the step (b).
  • the corresponding steps performed on the first variation with respect to the second variation may be performed in the same manner, and the corresponding steps may be the same for all the finally found variations. Can be performed.
  • the method may further include calculating a risk of developing a genetic disease associated with stored variation information of the estimated progeny based on the total stored variation information. For example, if a female subject is found to have one known mutation or pathogenic mutation, the male putative progeny may have a 50% chance of having a sex chromosomal recessive genetic disease associated with that mutation, so the risk is based on certain criteria. The probability may be scored by.
  • the method may further comprise displaying the total stored variation information results.
  • the method may further comprise providing the subject with a report comprising the total stored variation information. Calculating, displaying, and providing a report to an individual on the risk of developing the genetic disease are as described above.
  • Another aspect includes obtaining genomic sequencing data of male subjects and female subjects; Extracting mutations from the genomic sequencing data of each subject through mapping with standard sequences; Identifying whether the extracted mutation is associated with a dominant genetic disease that can be treated or prevented; And storing the variation information when the mutation is related to a treatable or preventable dominant genetic disease, and deleting the variation information when the variation is not related to a treatable or preventable genetic disease. It provides a method for predicting the risk of developing genetic diseases.
  • the genetic disease may be a dominant genetic disease.
  • the genetic disease may be a dominant genetic disease that can be treated or prevented.
  • the preventable or treatable autosomal dominant genetic disease may include a disease allowed in each country, and may include dominant genetic disease related genes according to the ethnicity or race of the test subject. can do.
  • the dominant hereditary disease that can be treated or prevented is, for example, Hereditary Breast and Ovearian Cancer, Hereditary Colorectal Cancer, Familial Adenomatous Polyposis, or Romano-Word Syndrome. (Romano-Ward Syndrome) et al. (PMID: 23788249).
  • the method discloses only the risk of developing a dominant hereditary disease that can be treated or prevented, thereby solving ethical problems resulting from the disclosure of a disease without treatment and helping to prevent, early diagnose, treat, and manage the disease before the onset. It can reduce morbidity and mortality in a given disease.
  • the method includes extracting variation information from each of the genomic sequencing data of the male subject and the female subject through mapping with standard sequences.
  • the method preferably extracts variation information from both male and female subjects.
  • the identification when the extracted mutation is related to a dominant genetic disease that can be treated or prevented, information about the mutation is stored, and when the extracted mutation is not related to a treatable or preventable genetic disease, Deleting information about.
  • criteria for determining polymorphism may include dbSNP, a polymorphism database, Exome Aggregation Server (ExAC), and Korean Reference Genome Database (KRGDB). If the extracted variation is not a polymorphism that does not cause a disease using such a database, it is checked whether the variation is a known mutation, and if the extracted variation corresponds to a polymorphism that does not develop a disease, the variation information is It is deleted.
  • HGVS Human Gene Mutation Database
  • ClinVar and each disease, gene-specific mutation database can be used. If the mutation is not a known mutation, check whether it corresponds to a pathogenic mutation or VUS, and if it is a known mutation, store information about the mutation. Methods for determining whether the mutation corresponds to a pathogenic mutation or VUS include 'Standards and Guidelines for the Interpretation of Sequence Variants' published by American College of Medical Genetics (ACMG) and Association for Molecular Pathology (AMP). Reference may be made (PMID 25741868). If the variation is determined to be a pathogenic variation or VUS, information about the variation is stored.
  • ACMG American College of Medical Genetics
  • AMP Association for Molecular Pathology
  • the method for predicting the risk of genetic disease development of putative progeny comprises: (a) obtaining genomic sequencing data of a male subject and a female subject; (b) extracting variation information from each of the two subjects' genomic sequencing data through mapping with standard sequences; (c) identifying whether a first variation of the extracted variation is related to a dominant genetic disease that can be treated or prevented; And (d) if the first mutation is associated with a treatable or preventable dominant genetic disease, storing information about the first mutation and if the extracted variation is not associated with a treatable or preventable genetic disease, Discarding information about the first variation.
  • the step of identifying the treatable or preventable dominant genetic disease performed on the first variation for the second variation after storing or deleting the information about the first variation may be performed in the same manner.
  • the method may further include verifying that the stored variation result is valid in the object having the stored variation information.
  • the method may further include verifying that the result of the variation information to be stored of the object is valid before storing the variation information. For example, if the first variation information result is valid, the first variation information is stored. If the first variation information result is not valid, the first variation information is not stored and each corresponding step is performed for the next second variation. Can be performed.
  • the method may further include displaying stored variation information.
  • the method may further include calculating a risk of developing dominant genetic disease associated with the stored variation information of the estimated progeny based on the total stored variation information.
  • the method may further comprise providing the subject with a report comprising the total stored variation information. Calculating, displaying, and providing a report to an individual on the risk of developing the genetic disease are as described above.
  • the method explains the outcome to the subject and identifies the risk of dominant genetic disease.
  • the method may further include performing genetic counseling including prevention and treatment methods.
  • the method of predicting the risk of genetic disease development of the estimated progeny according to the above aspect and the method of predicting the risk of developing genetic disease of the estimated progeny according to another aspect may be performed separately from each other or each step may be performed in combination with each other.
  • the step of extracting mutation information from the genomic sequencing data of one subject any variation among the extracted mutation information is selected and each is an autosomal recessive.
  • a step may be performed to determine if it is associated with a genetic disease, a sex chromosomal recessive genetic disease, or a dominant genetic disease that can be treated or prevented. Thereafter, the process may be performed according to each method.
  • Another aspect provides a computer readable recording medium having recorded thereon a program for realizing a method for predicting the risk of developing genetic diseases of the putative progeny described above.
  • the computer readable recording medium may be a computer readable recording medium.
  • Computer-readable recording media include all kinds of recording devices that store data that can be read by a computer system. Examples of computer-readable recording media include storage media such as magnetic storage media (eg, ROMs, floppy disks, hard disks, etc.), optical reading media (eg, CD-ROMs, DVDs, etc.). It also includes the implementation in the form of a carrier wave (for example, transmission over the Internet).
  • the computer readable recording medium can also be distributed over network coupled computer systems so that the computer readable code is stored and executed in a distributed fashion.
  • Another aspect includes a receiver for receiving genomic sequencing data of a male subject and a female subject; An information extraction unit for extracting variation information from the genomic sequencing data of each object through mapping with standard sequencing; An analysis unit to determine whether the extracted mutation is related to a genetic disease; And it provides a system for predicting the risk of developing genetic diseases of putative progeny of male subjects and female subjects, including a storage unit for storing the variation information.
  • the genetic disease in the system can be an autosomal recessive genetic disease, a sex chromosomal recessive genetic disease, and / or a dominant genetic disease treatable or preventable. Specifically, it may be an autosomal recessive genetic disease.
  • the system includes a receiver, an information extractor, an analyzer and a storage.
  • the receiver may receive genome sequence data of a male subject and a female subject.
  • the mutation information extracting unit may extract mutation information from genomic sequence data of an object.
  • the analysis unit may determine whether the extracted mutation is related to the genetic disease.
  • the analyzing unit may include, for example, a first analyzing unit which checks whether the extracted mutation is related to an autosomal recessive genetic disease; If the mutation is related to a recessive genetic disease, a second analysis unit which checks whether the other subject has a mutation in the gene in which the mutation is found, from the genomic sequencing data of the other subject; When the other subject has a mutation in a gene in which a mutation is found, the third subject may include a third analysis unit to check whether the mutation of the other subject corresponds to a known mutation or pathogenesis. The determination of whether the extracted mutation is related to genetic disease is as described above. If the mutation of another subject in the third analysis unit corresponds to a known mutation or pathogenicity, the first mutation related information is stored in the storage unit.
  • the first mutation related information may be, for example, information about a first variation extracted from one subject, information about a genetic disease causing the first variation, and / or a first variation identified in another subject. Mutation information of a gene of a genetic disease.
  • system may further include a verification unit for verifying the validity of each variation when the causative mutation of autosomal recessive genetic disease is found in two subjects and finally they are known or pathogenic.
  • system may further include a calculation unit for calculating the risk of developing a genetic disease associated with the stored mutation.
  • the system may further include a display unit for reporting a risk level. Validation of the variation, risk calculation, and risk reporting in the system are as described above.
  • the method and system according to one aspect can protect the privacy of an individual's genetic information because the genetic information of the male and female genome information that is not related to the genetic disease for the future child is deleted and is not disclosed to anyone. Help prevent or early diagnose genetic disorders in future children.
  • 1 is an overall schematic diagram of a method for predicting the risk of autosomal recessive hereditary disease of an estimated progeny according to one embodiment.
  • FIG. 2 is a flow chart of a method for predicting the risk of autosomal recessive genetic disease of a presumed offspring according to one embodiment.
  • FIG. 3 is a flow chart of a method for predicting the risk of autosomal recessive genetic disease of a putative progeny in accordance with another embodiment.
  • FIG. 4 is a flow chart of a method for predicting the risk of autosomal recessive genetic disease of a putative progeny in accordance with another embodiment.
  • 5 is a flow chart of a method for predicting the risk of autosomal recessive genetic disease of a presumptive offspring according to one embodiment.
  • Figure 6 is a general schematic diagram of a method for predicting the risk of sex chromosomal recessive genetic diseases of the estimated progeny according to one embodiment.
  • FIG. 7 is a flow chart of a method for predicting the risk of sex chromosomal recessive genetic diseases of a putative offspring according to one embodiment.
  • FIG. 8 is a flow chart of a method for predicting the risk of sex chromosomal recessive genetic diseases of the estimated progeny according to one embodiment.
  • FIG. 9 is an overall schematic diagram of a method for predicting the risk of dominant genetic disease that can be treated or prevented in a progeny progeny according to one embodiment.
  • FIG. 10 is a flow chart of a method for predicting the risk of dominant genetic disease that can be treated or prevented in an estimated progeny according to one embodiment.
  • 11 is a flowchart of a method for predicting the risk of dominant genetic disease that can be treated or prevented in an estimated progeny according to one embodiment.
  • Re-alignment was performed using the RealignerTargetCreator and IndelRealigner of GATK v3.2-2, and the base quality recalibration process was performed using GATK's BaseRecalibrator.
  • the variant quality recalibration process for genotyping and variant filtering was performed using Haplotype Caller and Variant Recalibrator of GATK, respectively, and the sensitivity was applied to 99.7 level.
  • Gene annotation was performed using in-house custom-made script, and dbSNP build 141 and HGMD 2015.3 Professional version were used for annotation.
  • mutations already listed as disease-related variants in HGMD http://www.hgmd.cf.ac.uk/
  • a representative mutation database for genetic diseases are not deleted and analyzed. This proceeded.
  • mutations that are prone to mutations such as frameshift, nonsense, splicing, and initiation codon due to the nature of the mutations are not deleted, and mutations that are likely to be mutations were not deleted.
  • base variants that satisfy more stringent filtering strategies, such as allele depth ( ⁇ 10) and allele ratio (0.4-0.6 for heterozygote), to reduce base sequence errors due to sequencing errors.
  • AMP guidelines were applied to interpret and classify the meaning of base variations.
  • one base mutation (NM_000441.1 standard sequence) in SLC26A4, the gene responsible for autosomal recessive hereditary deafness and Pendred syndrome, located on chromosome 7 was analyzed during exome sequence data of the first woman.
  • Baseline c.2168A> G was found, and analysis of the nucleotide sequence found in the SLC26A4 gene in male exome sequence data revealed that one pathogenic mutation (NM_000441.1 baseline c.918-2A> G) was found. The variation information was found as reported in Table 1 below. Subsequent analysis of female exome data revealed a pathogenic mutation (NM_000053.3 standard c.2333G> T) in ATP7B, the causal gene for Wilson's disease, located on chromosome 13. As a result of analyzing the nucleotide sequence found in the ATP7B gene in the male exome sequencing data, the pathogenic mutation was not found, and thus the ATP7B gene mutation information found in the female was deleted. Since the analysis of female exome sequencing data continued, but no additional etiological base mutations were found, all mutation information other than the base mutations found in the SLC26A4 gene was deleted.
  • Example 1.2 the risk of developing a child was calculated in the first couple who showed the possibility of developing an autosomal recessive genetic disease. Since both men and women who report mutations in their autosomal recessive inherited diseases and their causal genes for future children are heterozygous, there is a 50% chance that each child will receive a mutated genotype. Accordingly, the risk of developing an autosomal recessive genetic disease in the future child of the man and the woman was finally calculated to be 25%, and was explained through the genetic counseling process to the first couple through the professor of genetic clinic.
  • Exome sequence data acquisition method is the same as Example 1.1.
  • the possibility of the occurrence of sex chromosomal recessive genetic disease of the future child was analyzed, and the exome sequencing data of the female was selected to extract the mutation information.
  • the method for detecting and analyzing mutations from exome base sequence data is the same as in Example 1.2 above.
  • Example 2.2 the risk of developing children was calculated in the second couple who showed the possibility of developing a sex chromosomal recessive genetic disease. Women who report mutational information on sex chromosomal recessive genetic diseases and their causal genes for future children are heterozygous, and have a 50% chance of delivering mutated genotypes to their children. Sex chromosomal recessive hereditary disease is a carrier of female children who receive genetic mutations, and the disease occurs only in male children. Therefore, the risk of developing sex chromosomal recessive genetic disease in future children of the male and female was calculated to be 0% in female children and finally to 50% in male children, and the genetic counseling process was conducted through the genetic clinic professor. It was explained through.
  • Exome sequence data acquisition method is the same as Example 1.1.
  • the possibility of the treatment or prophylactic dominant genetic disease of the future child was analyzed, and the exome sequencing data of the male and female are selected as the object to extract the mutation information It was.
  • the method for detecting and analyzing mutations from exome base sequence data is the same as in Example 1.2 above.
  • Exome sequencing data of women in the third couple found no mutated dominant genetic diseases.
  • one base mutation (NM_007294.3 standard c.196C> T) was found in BRCA1, the gene responsible for hereditary breast ovarian cancer located on chromosome 17. Final variation information was reported as shown in Table 3. Subsequent analysis of male exome sequencing data continued, but no additional etiological base mutations were found, so all mutation information except for the base mutations found in the BRCA1 gene was deleted.
  • the risk of developing children was calculated in the third couple who showed the likelihood of developing a treatable or preventable dominant genetic disease in Example 3.2. Since men with heterogeneous information reported for future cure or prophylaxis of dominant genetic diseases and their causative genes are heterozygous, there is a 50% chance of delivering a mutated genotype to their child, and for women with genetic variation 40 Breast cancer develops in -80%, ovarian cancer in 11-40%, and prostate cancer in up to 39% of men with genetic mutations. In addition, since the incidence of pancreatic cancer is estimated to be 1-7%, the probability of cancer is higher than that of people without genetic mutations, so it is recommended to periodically perform tests for early diagnosis of cancer. Surgery is also possible, so this information was explained through a genetic counseling process to a third couple through a professor of genetic clinics.

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Abstract

L'invention concerne un procédé et un système permettant de prédire un risque de développement d'un trouble génétique dans une progéniture putative entre un sujet masculin et un sujet féminin. Comme les informations génétiques d'une progéniture putative non associées à un trouble génétique sont supprimées des informations génomiques masculines et féminines et ne sont divulguées à personne, un procédé et un système selon un aspect de l'invention permettent de respecter la confidentialité concernant les informations génétiques personnelles et peuvent servir également à la prévention ou au diagnostic précoce d'un trouble génétique dans une progéniture putative.
PCT/KR2017/001245 2016-02-05 2017-02-06 Procédé et système permettant de prédire le risque de développement d'un trouble génétique dans la progéniture putative Ceased WO2017135768A1 (fr)

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