Aims In this study, we aimed to clinically and genetically characterize LVNC patients and investigate the prevalence of variants in known and novel LVNC disease genes. Introduction Left ventricular non-compaction cardiomyopathy (LVNC) is an increasingly recognized cause of heart failure, arrhythmia, thromboembolism, and sudden cardiac death. We sought here to dissect its genetic causes, phenotypic presentation and outcome. Methods and results In our registry with follow-up of in the median 61 months, we analysed 95 LVNC patients (68 unrelated index patients and 27 affected relatives; definite familial LVNC = 23.5%) by cardiac phenotyping, molecular biomarkers and exome sequencing. Cardiovascular events were significantly more frequent in LVNC patients compared with an age-matched group of patients with non-ischaemic dilated cardiomyopathy (hazard ratio = 2.481, P = 0.002). Stringent genetic classification according to ACMG guidelines revealed that TTN, LMNA, and MYBPC3 are the most prevalent disease genes (13 patients are carrying a pathogenic truncating TTN variant, odds ratio = 40.7, Confidence interval = 21.6-76.6, P < 0.0001, percent spliced in 76-100%). We also identified novel candidate genes for LVNC. For RBM20, we were able to perform detailed familial, molecular and functional studies. We show that the novel variant p.R634L in the RS domain of RBM20 co-segregates with LVNC, leading to titin mis-splicing as revealed by RNA sequencing of heart tissue in mutation carriers, protein analysis, and functional splice-reporter assays. Conclusion Our data demonstrate that the clinical course of symptomatic LVNC can be severe. The identified pathogenic variants and distribution of disease genes-a titin-related pathomechanism is found in every fourth patient-should be considered in genetic counselling of patients. Pathogenic variants in the nuclear proteins Lamin A/C and RBM20 were associated with worse outcome.

中文翻译：

---

左室致密化不全心肌病的临床遗传学和预后

目的 在这项研究中，我们旨在对 LVNC 患者进行临床和遗传表征，并调查已知和新型 LVNC 疾病基因中变异的流行情况。简介 左室致密化不全心肌病 (LVNC) 是越来越公认的导致心力衰竭、心律失常、血栓栓塞和心源性猝死的原因。我们试图在这里剖析其遗传原因、表型表现和结果。方法和结果 在我们的登记中，中位随访时间为 61 个月，我们通过心脏表型、分子生物标志物和外显子组测序分析了 95 名 LVNC 患者（68 名无关指标患者和 27 名受影响的亲属；明确的家族性 LVNC = 23.5%）。与年龄匹配的非缺血性扩张型心肌病患者组相比，LVNC 患者的心血管事件发生率明显更高（风险比 = 2.481，P = 0.002）。根据 ACMG 指南的严格遗传分类显示，TTN、LMNA 和 MYBPC3 是最普遍的疾病基因（13 名患者携带致病性截短 TTN 变异，优势比 = 40.7，置信区间 = 21.6-76.6，P < 0.0001，剪接百分比76-100%）。我们还确定了 LVNC 的新候选基因。对于 RBM20，我们能够进行详细的家族、分子和功能研究。我们表明，RBM20 的 RS 结构域中的新变体 p.R634L 与 LVNC 共分离，导致通过对突变载体心脏组织的 RNA 测序、蛋白质分析、和功能性剪接报告基因分析。结论 我们的数据表明，症状性 LVNC 的临床过程可能很严重。在患者的遗传咨询中应考虑已确定的致病变异和疾病基因的分布 - 在每四个患者中发现与肌联蛋白相关的病理机制。核蛋白 Lamin A/C 和 RBM20 的致病变异与较差的结果相关。