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

Roddy Walsh 1 2, Najim Lahrouchi 3 4, Rafik Tadros 5, Florence Kyndt 4 6, Charlotte Glinge 4 7, Pieter G Postema 3 4, Ahmad S Amin 3 4, Eline A Nannenberg 4 8, James S Ware 9 10 11, Nicola Whiffin 9 10 11, Francesco Mazzarotto 9 10 12 13, Doris Škorić-Milosavljević 3 4, Christian Krijger 3 4, Elena Arbelo 14 15 16, Dominique Babuty 17, Hector Barajas-Martinez 18, Britt M Beckmann 19, Stéphane Bézieau 4 6, J Martijn Bos 20, Jeroen Breckpot 4 21, Oscar Campuzano 16 22 23 24, Silvia Castelletti 25, Candan Celen 26, Sebastian Clauss 19 27 28, Anniek Corveleyn 4 29, Lia Crotti 25 30 31 32, Federica Dagradi 25, Carlo de Asmundis 33, Isabelle Denjoy 4 34 35, Sven Dittmann 4 36, Patrick T Ellinor 37 38, Cristina Gil Ortuño 4 39, Carla Giustetto 40, Jean-Baptiste Gourraud 4 6, Daisuke Hazeki 41, Minoru Horie 42, Taisuke Ishikawa 43, Hideki Itoh 44, Yoshiaki Kaneko 45, Jørgen K Kanters 46, Hiroki Kimoto 47, Maria-Christina Kotta 25 32, Ingrid P C Krapels 48, Masahiko Kurabayashi 45, Julieta Lazarte 49, Antoine Leenhardt 4 34 35, Bart L Loeys 50, Catarina Lundin 51, Takeru Makiyama 52, Jacques Mansourati 53, Raphaël P Martins 54, Andrea Mazzanti 4 55, Stellan Mörner 4 56, Carlo Napolitano 4 55, Kimie Ohkubo 57, Michael Papadakis 4 58 59, Boris Rudic 60 61, Maria Sabater Molina 4 39, Frédéric Sacher 62, Hatice Sahin 26, Georgia Sarquella-Brugada 4 23 63, Regina Sebastiano 64, Sanjay Sharma 4 58 59, Mary N Sheppard 4 58 59, Keiko Shimamoto 65, M Benjamin Shoemaker 66, Birgit Stallmeyer 4 36, Johannes Steinfurt 67, Yuji Tanaka 68, David J Tester 20, Keisuke Usuda 69, Paul A van der Zwaag 70, Sonia Van Dooren 4 71, Lut Van Laer 50, Annika Winbo 72, Bo G Winkel 4 7, Kenichiro Yamagata 65, Sven Zumhagen 4 36, Paul G A Volders 73, Steven A Lubitz 37 38, Charles Antzelevitch 18, Pyotr G Platonov 74, Katja E Odening 67 75, Dan M Roden 66 76 77, Jason D Roberts 78, Jonathan R Skinner 79, Jacob Tfelt-Hansen 4 7 80, Maarten P van den Berg 81, Morten S Olesen 82, Pier D Lambiase 4 83, Martin Borggrefe 60 61, Kenshi Hayashi 69, Annika Rydberg 4 84, Tadashi Nakajima 45, Masao Yoshinaga 68, Johan B Saenen 85, Stefan Kääb 19 27, Pedro Brugada 4 86, Tomas Robyns 4 87, Daniela F Giachino 64 88, Michael J Ackerman 20, Ramon Brugada 89, Josep Brugada 90, Juan R Gimeno 4 91, Can Hasdemir 26, Pascale Guicheney 92, Silvia G Priori 4 55, Eric Schulze-Bahr 4 36, Naomasa Makita 43, Peter J Schwartz 25 32, Wataru Shimizu 93, Takeshi Aiba 65, Jean-Jacques Schott 4 6, Richard Redon 4 6, Seiko Ohno 94, Vincent Probst 4 6, Nantes Referral Center for inherited cardiac arrhythmia; Elijah R Behr 4 58 59, Julien Barc 4 95, Connie R Bezzina 3 4

Collaborators, Affiliations

PMID: 32893267
DOI: 10.1038/s41436-020-00946-5

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.