James, CA;
Jongbloed, JDH;
Hershberger, RE;
Morales, A;
Judge, DP;
Syrris, P;
Pilichou, K;
... van Tintelen, JP; + view all
(2021)
International Evidence Based Reappraisal of Genes Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome Resource Framework.
Circulation: Genomic and Precision Medicine
, 14
(3)
, Article e003273. 10.1161/CIRCGEN.120.003273.
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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 (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.
| Type: | Article |
|---|---|
| Title: | International Evidence Based Reappraisal of Genes Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome Resource Framework |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1161/CIRCGEN.120.003273 |
| Publisher version: | https://doi.org/10.1161/CIRCGEN.120.003273 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Clinical Science |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10126316 |
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