Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy.
Int J Cardiol. 2018 Jan 1;250:139-145. doi: 10.1016/j.ijcard.2017.10.016. Epub 2017 Oct 5.
Ventricular fibrillation (VF) is a major cause of sudden cardiac death. In some cases clinical investigations fail to identify the underlying cause and the event is classified as idiopathic (IVF). Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility, screening for disease-predisposing variants could improve IVF diagnostics.
The study included 76 Finnish and Italian patients with a mean age of 31.2years at the time of the VF event, collected between the years 1996-2016 and diagnosed with idiopathic, out-of-hospital VF. Using whole-exome sequencing (WES) and next-generation sequencing (NGS) approaches, we aimed to identify genetic variants potentially contributing to the life-threatening arrhythmias of these patients. Combining the results from the two study populations, we identified pathogenic or likely pathogenic variants residing in the RYR2, CACNA1C and DSP genes in 7 patients (9%). Most of them (5, 71%) were found in the RYR2 gene, associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). These genetic findings prompted clinical investigations leading to disease reclassification. Additionally, in 9 patients (11.8%) we detected 10 novel or extremely rare (MAF<0.005%) variants that were classified as of unknown significance (VUS).
The results of our study suggest that a subset of patients originally diagnosed with IVF may carry clinically-relevant variants in genes associated with cardiac channelopathies and cardiomyopathies. Although misclassification of other cardiac channelopathies as IVF appears rare, our findings indicate that the possibility of CPVT as the underlying disease entity should be carefully evaluated in IVF patients.
心室颤动（VF）是心源性猝死的主要原因。在某些情况下，临床检查未能确定潜在原因，此类事件被归类为特发性（IVF）。由于心律失常相关基因的突变常导致心律失常易感性，因此筛查致病变异可能会改善 IVF 的诊断。
本研究纳入了 76 名芬兰和意大利患者，他们在 1996 年至 2016 年间发生院外 VF 时的平均年龄为 31.2 岁，被诊断为特发性 VF。我们使用外显子组测序（WES）和下一代测序（NGS）方法，旨在鉴定可能导致这些患者危及生命的心律失常的遗传变异。结合两个研究人群的结果，我们在 7 名患者（9%）中发现了位于 RYR2、CACNA1C 和 DSP 基因中的致病性或可能致病性变异。其中大多数（5 名，71%）位于 RYR2 基因中，与儿茶酚胺多形性室性心动过速（CPVT）有关。这些遗传发现促使进行临床调查，从而重新分类疾病。此外，在 9 名患者（11.8%）中，我们检测到了 10 种新的或非常罕见的（MAF<0.005%）变异，被归类为意义不明的变异（VUS）。
我们的研究结果表明，最初诊断为 IVF 的患者中，有一部分可能携带有与心脏通道病和心肌病相关基因中的临床相关变异。尽管其他心脏通道病误诊为 IVF 的情况似乎很少，但我们的发现表明，CPVT 作为潜在疾病实体的可能性应在 IVF 患者中仔细评估。
