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.