Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Desmosomal Variants Are Rarely De Novo

Circulation. Genomic and Precision Medicine
Freyja H M van LintCynthia A James

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with pathogenic/likely pathogenic (P/LP) variants in genes encoding the cardiac desmosomal proteins. Origin of these variants, including de novo mutation rate and extent of founder versus recurrent variants has implications for variant adjudication and clinical care, yet this has never been systematically investigated. We identified arrhythmogenic right ventricular cardiomyopathy probands who met 2010 Task Force Criteria and had undergone genotyping that included sequencing of the desmosomal genes (PKP2, DSP, DSG2, DSC2, and JUP) from 3 arrhythmogenic right ventricular cardiomyopathy registries in America and Europe. We classified the desmosomal variants, defined the contribution of unique versus nonunique (ie, not family-specific) P/LP variants, and identified the frequency and characteristics of de novo variants. Next, we haplotyped nonunique variants to determine how often they likely represent a single mutation event in a common ancestor (implied by shared haplotypes) versus multiple mutation events at the same genetic location. Of 501 arrhythmogenic right ventricular cardiomyopathy probands, 322 (64.3%) carried 327 desmosomal P/LP variants. Most variants ...Continue Reading

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Citations

Mar 20, 2020·European Heart Journal·Cynthia A JamesHugh Calkins
May 30, 2020·Journal of Cardiovascular Development and Disease·Tyler L StevensPeter J Mohler
Sep 18, 2020·Circulation. Genomic and Precision Medicine·Brittney MurrayCynthia A James
Jan 19, 2021·The American Journal of Cardiology·Paul J ScheelNisha A Gilotra
Jun 14, 2021·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Annika M DriesVictoria N Parikh

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