Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.
ACMG/AMP guidelines
Brugada
LQTS
variant interpretation
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
01
06
2020
accepted:
11
08
2020
revised:
03
08
2020
pubmed:
8
9
2020
medline:
3
6
2021
entrez:
7
9
2020
Statut:
ppublish
Résumé
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 Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
Identifiants
pubmed: 32893267
doi: 10.1038/s41436-020-00946-5
pii: S1098-3600(21)02504-1
pmc: PMC7790744
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
47-58Subventions
Organisme : Medical Research Council
ID : MC_UP_1102/20
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL152201
Pays : United States
Investigateurs
Alain Al Arnaout
(AA)
Mathieu Amelot
(M)
Frédéric Anselme
(F)
Olivier Billon
(O)
Pascal Defaye
(P)
Jean-Marc Dupuis
(JM)
Laurence Jesel
(L)
Gabriel Laurent
(G)
Philippe Maury
(P)
Jean-Luc Pasquie
(JL)
Francois Wiart
(F)
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