Inherited Cardiac Arrhythmia Program, Department of Cardiology, Boston Children's Hospital (R.J.H., D.Q., S.F.C., T.M.R., W.T.P., V.J.B., D.J.A.), Harvard Medical School, Boston MA.
Department of Genetics (A.C.P., D.Q., J.G.S., C.E.S.), Harvard Medical School, Boston MA.
Circ Genom Precis Med. 2022 Jun;15(3):e003507. doi: 10.1161/CIRCGEN.121.003507. Epub 2022 May 10.
Truncating variants in the desmosomal gene tv) cause arrhythmogenic right ventricular cardiomyopathy (ARVC) yet display varied penetrance and expressivity.
We identified individuals with tv from the UK Biobank (UKB) and determined the prevalence of an ARVC phenotype and other cardiovascular traits based on clinical and procedural data. The tv minor allelic frequency in the UKB was compared with a second cohort of probands with a clinical diagnosis of ARVC (ARVC cohort), with a figure of 1:5000 assumed for disease prevalence. In silico predictors of variant pathogenicity (combined annotation-dependent depletion and Splice AI [Illumina, Inc.]) were assessed.
tv were identified in 193/200 643 (0.10%) UKB participants, with 47 unique tv. Features consistent with ARVC were present in 3 (1.6%), leaving 190 with tv without manifest disease (UKB cohort; minor allelic frequency 4.73×10). The ARVC cohort included 487 ARVC probands with 144 distinct tv, with 25 tv common to both cohorts. The odds ratio for ARVC for the 25 common tv was 0.047 (95% CI, 0.001-0.268; 2.43×10), and only favored ARVC (odds ratio >1) for a single variant, p.Arg79*. In silico variant analysis did not differentiate tv between the 2 cohorts. Atrial fibrillation was over-represented in the UKB cohort in those with tv (7.9% versus 4.3%; odds ratio, 2.11; =0.005).
tv are prevalent in the population and associated with ARVC in only a small minority, necessitating a more detailed understanding of how tv cause ARVC in combination with associated genetic and environmental risk factors.
桥粒蛋白基因 tv 的截断变异可导致致心律失常性右室心肌病（ARVC），但其表现出不同的外显率和表现度。
我们从英国生物库（UKB）中鉴定出携带 tv 的个体，并根据临床和程序数据确定 ARVC 表型和其他心血管特征的患病率。UKB 中 tv 的次要等位基因频率与第二个临床诊断为 ARVC 的先证者队列（ARVC 队列）进行了比较，假定疾病患病率为 1:5000。评估了变异致病性的预测因子（综合注释依赖性耗尽和 Splice AI[Illumina，Inc.])。
在 200003 名 UKB 参与者中鉴定出 193 名携带 tv（0.10%），其中 47 名具有独特的 tv。在 3 名参与者中存在与 ARVC 一致的特征（1.6%），其余 190 名携带 tv 而无显性疾病（UKB 队列；次要等位基因频率为 4.73×10）。ARVC 队列包括 487 名 ARVC 先证者，其中 144 名具有独特的 tv，两个队列中有 25 名 tv 相同。25 个共同 tv 发生 ARVC 的比值比为 0.047（95%CI，0.001-0.268；2.43×10），仅对单个变体 p.Arg79* 有利（比值比>1）。在两个队列之间，基于计算机的变异分析并未区分 tv。在携带 tv 的 UKB 队列中，心房颤动更为常见（7.9%对 4.3%；比值比，2.11；=0.005）。
tv 在人群中很普遍，但仅在一小部分人群中与 ARVC 相关，这需要更详细地了解 tv 如何与相关遗传和环境风险因素一起导致 ARVC。
