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

Nantes Referral Center for inherited cardiac arrhythmia, 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, Hector Barajas-Martinez, Britt M Beckmann, Stéphane Bézieau, J Martijn BosJeroen Breckpot, Oscar 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 Ortuño, 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 L Loeys, Catarina Lundin, Sonia Van Dooren, Pedro Brugada

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)47-58
Number of pages12
JournalGenetics in Medicine : Official Journal of the American College of Medical Genetics
Volume23
Issue number1
Early online date7 Sep 2020
DOIs
Publication statusPublished - Jan 2021

Keywords

  • ACMG/AMP guidelines
  • Brugada
  • LQTS
  • variant interpretation

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