Why the study?
Stringent variant interpretation guidelines lead to high rates of variants of uncertain significance for genetically heterogeneous diseases like long QT syndrome and Brugada syndrome.
Does quantitative and disease-specific customization of ACMG/AMP guidelines improve variant interpretation and reduce VUS in inherited arrhythmias?
Does quantitative and disease-specific customization of ACMG/AMP guidelines improve variant interpretation and reduce VUS in inherited arrhythmias?
Disease-specific customization of ACMG/AMP guidelines using large case-control datasets significantly improves diagnostic yield and reduces variants of uncertain significance in inherited arrhythmias.
May reduce VUS rates in LQTS/BrS via disease-specific ACMG/AMP customization; hypothesis-generating and requires independent validation.
PURPOSE Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. METHODS We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. RESULTS Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. CONCLUSION Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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Walsh et al. (2021) studied this question.
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