{"title":"RNA分析使报告良性同义变异的决议和重新分类。","authors":"Adina Fuchs, Inbar Kobal, Dov Popper, Shay Porat, Joshua I Rosenbloom, Mordechai Slae, Shira Yanovsky Dagan, Vardiella Meiner, Vered Molho-Pessach, Hagit Daum, Tamar Harel","doi":"10.1111/cge.14772","DOIUrl":null,"url":null,"abstract":"<p><p>Synonymous variants can significantly impact protein levels and function, particularly through alterations in RNA processing. Consequently, variant classification must consider the broader impact on RNA splicing. We present three cases where synonymous variants were detected through exome sequencing. The variants in LARS1 and POLE were located at the last nucleotide of the exon (i.e., splice donor site), while the COL2A1 variant was located three nucleotides downstream of the splice acceptor site. Two variants were previously classified in ClinVar as \"likely benign.\" Segregation analysis confirmed segregation of the variants with the phenotype in available family members, and RNA studies revealed exon skipping in conserved regions of the protein, leading to reclassification of these variants as \"likely pathogenic\" and ultimately improving clinical management. These findings highlight the importance of incorporating RNA-based testing to directly evaluate splicing effects and demonstrate the critical role of RNA analysis in the accurate interpretation of variants and their implications for diagnosis and treatment.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3000,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"RNA Analysis Enables Resolution and Reclassification of Reportedly Benign Synonymous Variants.\",\"authors\":\"Adina Fuchs, Inbar Kobal, Dov Popper, Shay Porat, Joshua I Rosenbloom, Mordechai Slae, Shira Yanovsky Dagan, Vardiella Meiner, Vered Molho-Pessach, Hagit Daum, Tamar Harel\",\"doi\":\"10.1111/cge.14772\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Synonymous variants can significantly impact protein levels and function, particularly through alterations in RNA processing. Consequently, variant classification must consider the broader impact on RNA splicing. We present three cases where synonymous variants were detected through exome sequencing. The variants in LARS1 and POLE were located at the last nucleotide of the exon (i.e., splice donor site), while the COL2A1 variant was located three nucleotides downstream of the splice acceptor site. Two variants were previously classified in ClinVar as \\\"likely benign.\\\" Segregation analysis confirmed segregation of the variants with the phenotype in available family members, and RNA studies revealed exon skipping in conserved regions of the protein, leading to reclassification of these variants as \\\"likely pathogenic\\\" and ultimately improving clinical management. These findings highlight the importance of incorporating RNA-based testing to directly evaluate splicing effects and demonstrate the critical role of RNA analysis in the accurate interpretation of variants and their implications for diagnosis and treatment.</p>\",\"PeriodicalId\":10354,\"journal\":{\"name\":\"Clinical Genetics\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2025-05-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Genetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/cge.14772\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/cge.14772","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
RNA Analysis Enables Resolution and Reclassification of Reportedly Benign Synonymous Variants.
Synonymous variants can significantly impact protein levels and function, particularly through alterations in RNA processing. Consequently, variant classification must consider the broader impact on RNA splicing. We present three cases where synonymous variants were detected through exome sequencing. The variants in LARS1 and POLE were located at the last nucleotide of the exon (i.e., splice donor site), while the COL2A1 variant was located three nucleotides downstream of the splice acceptor site. Two variants were previously classified in ClinVar as "likely benign." Segregation analysis confirmed segregation of the variants with the phenotype in available family members, and RNA studies revealed exon skipping in conserved regions of the protein, leading to reclassification of these variants as "likely pathogenic" and ultimately improving clinical management. These findings highlight the importance of incorporating RNA-based testing to directly evaluate splicing effects and demonstrate the critical role of RNA analysis in the accurate interpretation of variants and their implications for diagnosis and treatment.
期刊介绍:
Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice.
Topics of particular interest are:
• Linking genetic variations to disease
• Genome rearrangements and disease
• Epigenetics and disease
• The translation of genotype to phenotype
• Genetics of complex disease
• Management/intervention of genetic diseases
• Novel therapies for genetic diseases
• Developmental biology, as it relates to clinical genetics
• Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease