International Evidence Based Reappraisal of Genes Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome Resource Framework.
Circ Genom Precis Med
; 14(3): e003273, 2021 06.
Article
em En
| MEDLINE
| ID: mdl-33831308
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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Arritmias Cardíacas
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Displasia Arritmogênica Ventricular Direita
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Predisposição Genética para Doença
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article