Journal Article

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

Gimeno, Juan R., Hazeki, Daisuke, Lundin, Catarina, van den Berg, Maarten P., Shimizu, Wataru, Corveleyn, Anniek, Walsh, Roddy, Tanaka, Yuji, Barc, Julien, Guicheney, Pascale, Amin, Ahmad S., Kyndt, Florence, Sacher, Frédéric, Brugada, Josep, Glinge, Charlotte, Campuzano, Oscar, Van Laer, Lut, Sahin, Hatice, Priori, Silvia G., Schulze-Bahr, Eric, Martins, Raphaël P., Zumhagen, Sven, Itoh, Hideki, Breckpot, Jeroen, Ware, James S., Papadakis, Michael, Volders, Paul G.A., Jesel, Laurence, Tfelt-Hansen, Jacob, Lahrouchi, Najim, Mansourati, Jacques, Sarquella-Brugada, Georgia, Platonov, Pyotr G., Babuty, Dominique, Gourraud, Jean-Baptiste, Ellinor, Patrick T., Nannenberg, Eline A., Celen, Candan, Kimoto, Hiroki, Rudic, Boris, Robyns, Tomas, Hasdemir, Can, Ohno, Seiko, de Asmundis, Carlo, Krijger, Christian, Whiffin, Nicola, Schott, Jean-Jacques, Roden, Dan M., Lazarte, Julieta, Skinner, Jonathan R., Maury, Philippe, Leenhardt, Antoine, Mazzarotto, Francesco, Kotta, Maria-Christina, Olesen, Morten S., Bézieau, Stéphane, Van Dooren, Sonia, Stallmeyer, Birgit, Wiart, Francois, van der Zwaag, Paul A., Arnaout, A

2021

Overview

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. 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. 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. Large case–control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.

• Publisher: Elsevier Inc,Nature Publishing Group US,Elsevier Limited,Nature Publishing Group
• Subject: ACMG/AMP guidelines / Agricultural and Veterinary sciences / Agricultural Biotechnology / Arrhythmias, Cardiac / Arrhythmias, Cardiac - diagnosis / Arrhythmias, Cardiac - epidemiology / Arrhythmias, Cardiac - genetics / Biomedical and Life Sciences / Biomedicine / Bioteknologi med applikationer på växter och djur / Brugada / Brugada Syndrome / Brugada Syndrome - genetics / Cardiac arrhythmia / Consortia / Disease / Genes / Genetic Testing / Genetics / Genetics and Breeding in Agricultural Sciences / Genetik och förädling inom lantbruksvetenskap / Genomics / Human Genetics / Humans / Laboratory Medicine / Lantbruksvetenskap och veterinärmedicin / Life Sciences / Long QT Syndrome / Long QT Syndrome - diagnosis / Long QT Syndrome - epidemiology / Long QT Syndrome - genetics / LQTS / Mutation / Pathology / Population / Population Control / Quantitative analysis / variant interpretation