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 (TFC). As incorrect attribution of a gene to ARVC can contribute to misdiagnosis, we assembled an international multidisciplinary ARVC ClinGen Gene Curation Expert Panel to reappraise all reported ARVC genes. Methods - Following a comprehensive literature search, six two-member teams conducted blinded independent curation of reported ARVC genes using the semi-quantitative ClinGen framework. Results - Of 26 reported ARVC genes, only six ( PKP2 , DSP , DSG2 , DSC2 , JUP , TMEM43 ) had strong evidence and were classified as definitive for ARVC causation. There was moderate evidence for two 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 (CPVT) phenotype. In ClinVar, only 5 pathogenic / likely pathogenic (P/LP) 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 ClinGen approach to gene-disease curation, only eight genes, ( PKP2 , DSP , DSG2 , DSC2 , JUP , TMEM43 , PLN , DES ) had definitive or moderate evidence for ARVC and these genes accounted for nearly all P/LP ARVC variants in ClinVar. Therefore, only P/LP variants in these eight genes should yield a major criterion for ARVC diagnosis. P/LP 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.

Evidence-Based Assessment of Genes in Dilated Cardiomyopathy

“…Genes encoding proteins of the desmosome have also been proposed to be relevant for DCM, 37 and DSP , DSG2 , and PKP2 , considered definitive when curating an ARVC phenotype strictly defined by the Task Force criteria, 38 had various degrees of evidence when curated strictly for DCM. 15 In the case of DCM, DSP was scored as strong and may likely move to a definitive classification in future re-evaluation. DSG2 was scored as limited, and the lack of monogenic DCM evidence for PKP2 resulted in a disputed classification.…”

“…The National Institute of Health Clinical Genome Resource (ClinGen) 12 has provided a semiquantitative method to assess the clinical validity of gene-disease relationships. 13 A panel of cardiologists, genetic counselors, and genetics and laboratory scientists with relevant expertise applied this method to published evidence in DCM, one implemented by other ClinGen cardiovascular domain gene curation panels, including HCM, 14 ARVC, 15 thoracic aortic aneurysm, 16 and the long-QT 17 and Brugada syndromes. 18 Here, we report the results of the evidence-based appraisal of genes associated with DCM and the implications of these findings.…”

Altered Electrical, Biomolecular, and Immunologic Phenotypes in a Novel Patient-Derived Stem Cell Model of Desmoglein-2 Mutant ARVC

“…In this study we established a novel patient-specific hiPSC model of ARVC from an individual with a pathogenic variant in DSG2 , the second most common gene associated with ARVC [ 49 ]. We performed a broad characterization of cardiomyocytes derived from these hiPSCs, evaluating their biomolecular features as well as their electrophysiological behaviors in monolayer cultures.…”

Sudden Unexpected Death Associated with Arrhythmogenic Cardiomyopathy: Study of the Cardiac Conduction System

“…Mutations in the genes plakophilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2), desmocollin-2 (DSC2), junction plakoglobin (JUP), and transmembrane protein 43 (TMEM43) are strongly associated with ACM [10]. The possible ACM-associated mutations linked to conduction system impairments have been little, if at all, investigated.…”