Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls
Roddy Walsh, Najim Lahrouchi, Rafik Tadros, Florence Kyndt, Charlotte Glinge, Pieter G. Postema, Ahmad S. Amin, Eline A. Nannenberg, James S. Ware, Nicola Whiffin, Francesco Mazzarotto, Doris Škorić‐Milosavljević, Christian Krijger, Elena Arbelo, Dominique Babuty, Héctor Barajas-Martínez, Britt Maria Beckmann, Stéphane Bezieau, J. Martijn Bos, Jeroen Breckpot, Óscar Campuzano, Silvia Castelletti, Candan Celen, Sebastian Clauß, Anniek Corveleyn, Lia Crotti, Federica Dagradi, Carlo de Asmundis, Isabelle Denjoy, Sven Dittmann, Patrick T. Ellinor, Cristina Gil, Carla Giustetto, Jean‐Baptiste Gourraud, Daisuke Hazeki, Minoru Horie, Taisuke Ishikawa, Hideki Itoh, Yoshiaki Kaneko, Jørgen K. Kanters, Hiroki Kimoto, Maria‐Christina Kotta, Ingrid P.C. Krapels, Masahiko Kurabayashi, Julieta Lazarte, Antoine Leenhardt, Bart Loeys, Catarina Lundin, Takeru Makiyama, Jacques Mansourati, Raphaël P. Martins, Andrea Mazzanti, Stellan Mörner, Carlo Napolitano, Kimie Ohkubo, Michael Papadakis, Boris Rudic, María Sabater‐Molina, Frédéric Sacher, Hatice Şahin, Georgia Sarquella‐Brugada, Regina Sebastiano, Sanjay Sharma, Mary N. Sheppard, Keiko Shimamoto, M. Benjamin Shoemaker, Birgit Stallmeyer, Johannes Steinfurt, Yuji Tanaka, David J. Tester, Keisuke Usuda, Paul A. van der Zwaag, Sonia Van Dooren, Lut Van Laer, Annika Winbo, Bo Gregers Winkel, Kenichiro Yamagata, Sven Zumhagen, Paul G.A. Volders, Steven A. Lubitz, Charles Antzelevitch, Pyotr G. Platonov, Katja E. Odening, Dan M. Roden, Jason D. Roberts, Jonathan R. Skinner, Jacob Tfelt-Hansen, Maarten P. van den Berg, Morten S. Olesen, Pier D. Lambiase, Martin Borggrefe, Kenshi Hayashi, Annika Rydberg, Tadashi Nakajima, Masao Yoshinaga, Johan Saenen, Stefan Kääb, Pedro Brugada, Tomas Robyns, Daniela Giachino
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: ). 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.