Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls

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title = "Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls",
abstract = "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.",
keywords = "ACMG/AMP guidelines, Brugada, LQTS, variant interpretation",
author = "Roddy Walsh and Najim Lahrouchi and Rafik Tadros and Florence Kyndt and Charlotte Glinge and Postema, {Pieter G.} and Amin, {Ahmad S.} and Nannenberg, {Eline A.} and Ware, {James S.} and Nicola Whiffin and Francesco Mazzarotto and Doris {\v S}kori{\'c}-Milosavljevi{\'c} and Christian Krijger and Elena Arbelo and Dominique Babuty and Hector Barajas-Martinez and Beckmann, {Britt M.} and St{\'e}phane B{\'e}zieau and Bos, {J. Martijn} and Jeroen Breckpot and Oscar Campuzano and Silvia Castelletti and Candan Celen and Sebastian Clauss and Anniek Corveleyn and Lia Crotti and Federica Dagradi and {de Asmundis}, Carlo and Isabelle Denjoy and Sven Dittmann and Ellinor, {Patrick T.} and Ortu{\~n}o, {Cristina Gil} and Carla Giustetto and Gourraud, {Jean Baptiste} and Daisuke Hazeki and Minoru Horie and Taisuke Ishikawa and Hideki Itoh and Yoshiaki Kaneko and Kanters, {J{\o}rgen K.} and Hiroki Kimoto and Kotta, {Maria Christina} and Krapels, {Ingrid P.C.} and Masahiko Kurabayashi and Julieta Lazarte and Antoine Leenhardt and Loeys, {Bart L.} and Catarina Lundin and Takeru Makiyama and Platonov, {Pyotr G.} and {Nantes Referral Center for inherited cardiac arrhythmia}",
year = "2020",
month = sep,
day = "7",
doi = "10.1038/s41436-020-00946-5",
language = "English",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Nature Publishing Group",