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

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Abstract

Background: 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. Methods: Following a comprehensive literature search, six 2-member teams conducted blinded independent curation of reported ARVC genes using the semiquantitative Clinical Genome Resource framework. Results: 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%). Conclusions: 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.

Original languageEnglish
Article numbere003273
Pages (from-to)273-284
Number of pages12
JournalCirculation. Genomic and precision medicine
Volume14
Issue number3
Early online date8 Apr 2021
DOIs
Publication statusPublished - Jun 2021

Keywords

  • desmosomes
  • diagnosis
  • genes
  • genetic testing
  • tachycardia

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