Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, Switzerland (S.C., A.G., D.A., F.R., C.B.B., F.D., A.M.S.).
Swiss DNAlysis, Dubendorf, Switzerland (A.M.-D.).
Circ Genom Precis Med. 2021 Feb;14(1):e003047. doi: 10.1161/CIRCGEN.120.003047. Epub 2020 Nov 24.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy, which is associated with life-threatening ventricular arrhythmias. Approximately 60% of patients carry a putative disease-causing genetic variant, but interpretation of genetic test results can be challenging. The aims of this study were to systematically reclassify genetic variants in patients with ARVC and to assess the impact on ARVC diagnosis.
This study included patients from the Multicenter Zurich ARVC Registry who hosted a genetic variant deemed to be associated with the disease. Reclassification of pathogenicity was performed according to the modified 2015 American College of Medical Genetics criteria. ARVC diagnosis (categories: definite, borderline, possible) based on the 2010 Task Force Criteria was reclassified after genetic readjudication.
In 79 patients bearing 80 unique genetic variants, n=47 (58.8%) genetic variants were reclassified, and reclassification was judged to be clinically relevant in n=33 (41.3%). Variants in plakophilin-2 () were shown to reclassify less frequently as compared with other genes (, n=1, 8.3%; desmosomal non-, n=20, 66.7%; nondesmosomal, n=26, 68.4%; =0.001for overall comparison; versus desmosomal non-=0.001; versus nondesmosomal, <0.001). Genetic reclassification impacted ARVC diagnosis. Eight patients (10.1%) were downgraded from definite to borderline/possible disease at the time of initial genetic testing as well as last follow-up, respectively. Separate genetic reclassification in family members led to downgrading of n=5 (38.5%) variants.
Given that approximately half of genetic variants were reclassified, with 10.1% of patients losing their definite disease status, accurate determination of variant pathogenicity is of utmost importance in the diagnosis of ARVC.
致心律失常性右室心肌病（ARVC）是一种遗传性心肌病，与危及生命的室性心律失常有关。大约 60%的患者携带潜在的致病基因突变，但基因检测结果的解读具有挑战性。本研究的目的是对 ARVC 患者的基因突变进行系统重分类，并评估其对 ARVC 诊断的影响。
本研究纳入了多中心苏黎世 ARVC 注册中心的患者，这些患者携带被认为与疾病相关的基因突变。致病性的重分类是根据改良的 2015 年美国医学遗传学学院标准进行的。根据 2010 年工作组标准进行的 ARVC 诊断（类别：明确、边界、可能）在基因重新评估后进行了重新分类。
在 79 名携带 80 个独特基因突变的患者中，n=47（58.8%）基因突变被重新分类，n=33（41.3%）被认为具有临床相关性。与其他基因相比，桥粒斑蛋白-2（）基因突变的重分类频率较低（，n=1，8.3%；非桥粒连接，n=20，66.7%；非桥粒连接，n=26，68.4%；总体比较，=0.001；与非桥粒连接相比，=0.001；与非桥粒连接相比，<0.001）。基因重分类影响 ARVC 诊断。8 名患者（10.1%）在首次基因检测和最后一次随访时分别从明确疾病降为边界/可能疾病。在家族成员中进行单独的基因重分类导致 n=5（38.5%）的基因突变降级。
鉴于大约一半的基因突变被重新分类，有 10.1%的患者失去了明确的疾病状态，因此准确确定变异的致病性对 ARVC 的诊断至关重要。
