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.

中文翻译：

---

使用临床基因组资源框架对与致心律失常性右心室心肌病相关的基因进行国际循证重新评估

背景：致心律失常性右心室心肌病（ARVC）是一种以室性心律失常和进行性心室功能不全为特征的遗传性疾病。建议进行基因检测，根据 2010 年工作组标准，ARVC 相关基因的致病变异是诊断的主要标准。由于基因对 ARVC 的错误归因可能导致误诊，我们组建了一个国际多学科 ARVC 临床基因组资源基因管理专家小组，重新评估所有报告的 ARVC 基因。方法：在全面的文献检索之后，六个 2 人团队进行了盲法独立管理使用半定量临床基因组资源框架报告的 ARVC 基因。结果：在 26 个报告的 ARVC 基因中，只有 6 个（PKP2，DSP, DSG2 , DSC2 , JUP , 和TMEM43 ) 有强有力的证据并被归类为 ARVC 因果关系的确定性。有 2 个基因DES和PLN的适度证据。其余 18 个基因的证据有限或没有证据。RYR2被驳斥为 ARVC 基因，因为临床数据和模型系统表现出儿茶酚胺能多态性室性心动过速表型。在 ClinVar 中，与 450 个桥粒基因变异 (97.4%) 相比，在 ARVC 病例中仅报告了有限证据基因中的 5 个致病/可能致病变异 (1.1%)。结论：使用临床基因组资源方法进行基因疾病管理，只有 8 个基因（PKP2，DSP、DSG2、DSC2、JUP、TMEM43、PLN和DES ) 具有 ARVC 的明确或适度证据，这些基因几乎解释了 ClinVar 中所有致病性/可能致病性 ARVC 变异。因此，只有这 8 个基因中的致病性/可能致病性变异才能成为 ARVC 诊断的主要标准。在患者的其他基因中发现的致病/可能致病变异应促使进一步的表型分析，因为其中许多基因的变异与其他心血管疾病有关。