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

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.

Keywords: desmosomes; diagnosis; genes; genetic testing; tachycardia.

Figure 1.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) gene curation approach. Two-member teams conducted blinded independent dual curation using the semiquantitative Clinical Genome Resource (ClinGen) framework with ARVC-specific rules for required minor allele frequency of variants detected in patients and phenotypic evaluation of model systems. Each summarized their analysis in separate presentations for the entire ARVC gene curation expert panel (GCEP) who arrived by consensus at the final gene classification.

Figure 2.

Level of evidence scores for genes reported for arrhythmogenic right ventricular cardiomyopathy (ARVC). Final genetic (dark blue) and experimental (light blue) evidence scores for 26 genes reported in the literature as associated with ARVC. Only 8 genes (bold font) had strong or moderate evidence for ARVC causality. The granular scores for each gene along with a complete list of references used are available in Table IV in the Data Supplement.

Figure 3.

Variants in ClinVar in arrhythmogenic right ventricular cardiomyopathy (ARVC) gene curation expert panel (GCEP) curated genes. A, Distribution of variants in each gene curated—pathogenic and likely pathogenic (P/LP) variants (blue) were reported primarily in genes encoding the cardiac desmosome. B, Nearly all P/LP variants reported in ClinVar for ARVC are in the genes categorized as definitive or moderate evidence ARVC genes while refuted/disputed/limited evidence genes account for a higher proportion of variant of uncertain significance (VUS) and benign/likely benign (B/LB) variants.