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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • 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 Bos
  • Jeroen 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
  • Takeru Makiyama
  • Pyotr G. Platonov
  • Nantes Referral Center for inherited cardiac arrhythmia
Enheter & grupper
Externa organisationer
  • Academic Medical Center
  • Montreal Heart Institute
  • University of Nantes
  • Copenhagen University Hospital
  • Imperial College London
  • Royal Brompton and Harefield NHS Foundation Trust
  • Careggi University Hospital
  • University of Florence
  • University of Barcelona
  • Institutd' Investigacions Biomèdiques August Pi iSunyer (IDIBAPS)
  • Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV)
  • University Hospital of Tours
  • Lankenau Institute for Medical Research
  • German Center for Lung Research (DZL)
  • Mayo Clinic Minnesota
  • University Hospitals Leuven
  • University of Girona
  • Istituto Auxologico Italiano
  • Ege University Medical School
  • German Centre for Cardiovascular Research
  • World Orthopaedic Concern
  • University of Milano-Bicocca
  • Universitair Ziekenhuis Brussel
  • Hopital Bichat-Claude-Bernard AP-HP
  • Universitätsklinikum Münster
  • Massachusetts General Hospital
  • Massachusetts Institute of Technology
  • Hospital Virgen de la Arrixaca
  • Citta' della Salute e della Scienza Hospital-University of Turin
  • Kagoshima City Hospital
  • Shiga University of Medical Science
  • National Cerebral and Cardiovascular Center
  • Hiroshima University Hospital
  • Gunma University Graduate School of Medicine
  • University of Copenhagen
  • Nagasaki University Graduate School of Biomedical Sciences
  • Yukioka Hospital
  • University of Western Ontario
  • Antwerp University Hospital
  • Kyoto University
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Genetik och förädling

Nyckelord

Originalspråkengelska
TidskriftGenetics in Medicine
StatusPublished - 2020 sep 7
PublikationskategoriForskning
Peer review utfördJa