International Evidence Based Reappraisal of Genes Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome Resource Framework

Cynthia A. James, Jan D. H. Jongbloed, Ray E. Hershberger, Ana Morales, Daniel P. Judge, Petros Syrris, Kalliopi Pilichou, Argelia Medeiros Domingo, Brittney Murray, Julia Cadrin-Tourigny, Ronald Lekanne Deprez, Rudy Celeghin, Alexandros Protonotarios, Babken Asatryan, Emily Brown, Elizabeth Jordan, Jennifer McGlaughon, Courtney Thaxton, C. Lisa Kurtz, J. Peter van Tintelen

OnderzoeksoutputAcademicpeer review

106 Citaten (Scopus)
53 Downloads (Pure)



Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease characterized by ventricular arrhythmias and progressive ventricular dysfunction. Genetic testing is recommended, and a pathogenic variant in an ARVC-associated gene is a major criterion for diagnosis according to the 2010 Task Force Criteria. As incorrect attribution of a gene to ARVC can contribute to misdiagnosis, we assembled an international multidisciplinary ARVC Clinical Genome Resource Gene Curation Expert Panel to reappraise all reported ARVC genes.


Following a comprehensive literature search, six 2-member teams conducted blinded independent curation of reported ARVC genes using the semiquantitative Clinical Genome Resource framework.


Of 26 reported ARVC genes, only 6 (PKP2, DSP, DSG2, DSC2, JUP, and TMEM43) had strong evidence and were classified as definitive for ARVC causation. There was moderate evidence for 2 genes, DES and PLN. The remaining 18 genes had limited or no evidence. RYR2 was refuted as an ARVC gene since clinical data and model systems exhibited a catecholaminergic polymorphic ventricular tachycardia phenotype. In ClinVar, only 5 pathogenic/likely pathogenic variants (1.1%) in limited evidence genes had been reported in ARVC cases in contrast to 450 desmosome gene variants (97.4%).


Using the Clinical Genome Resource approach to gene-disease curation, only 8 genes (PKP2, DSP, DSG2, DSC2, JUP, TMEM43, PLN, and DES) had definitive or moderate evidence for ARVC, and these genes accounted for nearly all pathogenic/likely pathogenic ARVC variants in ClinVar. Therefore, only pathogenic/likely pathogenic variants in these 8 genes should yield a major criterion for ARVC diagnosis. Pathogenic/likely pathogenic variants identified in other genes in a patient should prompt further phenotyping as variants in many of these genes are associated with other cardiovascular conditions.

Originele taal-2English
Pagina's (van-tot)273-284
Aantal pagina's12
TijdschriftCirculation-Genomic and precision medicine
Nummer van het tijdschrift3
StatusPublished - jun.-2021


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