International Evidence Based Reappraisal of Genes Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome Resource Framework.
International Evidence Based Reappraisal of Genes Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome Resource Framework.
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使用临床基因组资源框架对心律失常性右室心肌病相关基因进行基于国际证据的重新评估。
DOI：
10.1161/circgen.120.003273
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发表时间：
2021-06
期刊：
影响因子：
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通讯作者：
van Tintelen JP
中科院分区：
文献类型：
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作者：
James CA;Jongbloed JDH;Hershberger RE;Morales A;Judge DP;Syrris P;Pilichou K;Domingo AM;Murray B;Cadrin-Tourigny J;Lekanne Deprez R;Celeghin R;Protonotarios A;Asatryan B;Brown E;Jordan E;McGlaughon J;Thaxton C;Kurtz CL;van Tintelen JP
补充数字内容可在文本中找到。致心律失常性右室心肌病是一种以室性心律失常和进行性心室功能障碍为特征的遗传性疾病。建议进行基因检测，根据2010年工作队标准，抗逆转录病毒相关基因的致病变异是诊断的主要标准。由于基因对ARVC的不正确归因可能导致误诊，我们组建了一个国际多学科ARVC临床基因组资源基因治疗专家小组，重新评估所有报告的ARVC基因。在全面的文献检索后，六个2人小组使用半定量临床基因组资源框架对报告的ARVC基因进行了盲法独立治疗。在26个已报道的ARVC基因中，只有6个（PKP 2、DSP、DSG 2、DSC 2、JUP和TMEM 43）具有强有力的证据，并被归类为ARVC因果关系的确定性基因。有2个基因，DES和PLN的中度证据。其余18个基因的证据有限或没有证据。由于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，RYR 2被反驳为ARVC基因。在ClinVar中，在ARVC病例中仅报告了5种有限证据基因的致病性/可能致病性变异（1.1%），而桥粒基因变异为450种（97.4%）。使用临床基因组资源方法进行基因-疾病治疗，只有8个基因（PKP 2、DSP、DSG 2、DSC 2、JUP、TMEM 43、PLN和DES）具有ARVC的明确或中度证据，这些基因几乎占ClinVar中所有致病性/可能致病性ARVC变体。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鉴定出的致病性/可能致病性变体应促使进一步的表型分析，因为许多这些基因中的变体与其他心血管疾病相关。
Supplemental Digital Content is available in the text. 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. Following a comprehensive literature search, six 2-member teams conducted blinded independent curation of reported ARVC genes using the semiquantitative Clinical Genome Resource framework. 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%). 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.