Department of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
DZHK (German Centre for Cardiovascular Research), Heidelberg, Germany.
Eur Heart J. 2017 Dec 7;38(46):3449-3460. doi: 10.1093/eurheartj/ehx545.
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.
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.
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.
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.
本研究旨在对左室心肌致密化不全（LVNC）患者进行临床和基因特征分析，并探讨已知和新型 LVNC 疾病基因变异的发生率。
左室心肌致密化不全（LVNC）是心力衰竭、心律失常、血栓栓塞和心源性猝死的一个日益被认识的病因。我们在此旨在剖析其遗传病因、表型表现和结局。
在我们的登记处，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 名无关联的首发患者和 27 名受累亲属；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相比，LVNC 患者心血管事件明显更为频繁（风险比=2.481，P=0.002）。根据 ACMG 指南进行严格的遗传分类显示，TTN、LMNA 和 MYBPC3 是最常见的疾病基因（13 名患者携带致病性截断 TTN 变异，优势比=40.7，置信区间=21.6-76.6，P<0.0001，76-100%剪接百分比）。我们还鉴定了 LVNC 的新型候选基因。对于 RBM20，我们能够进行详细的家族性、分子和功能研究。我们表明，RBM20 的 RS 结构域中新发现的变异 p.R634L 与 LVNC 共分离，导致突变携带者心脏组织的 RNA 测序、蛋白分析和功能剪接报告试验中肌联蛋白错误剪接。
我们的数据表明，有症状的 LVNC 的临床病程可能很严重。鉴定的致病性变异和疾病基因的分布（每四个患者中就有一个存在与肌联蛋白相关的发病机制）应在患者的遗传咨询中考虑。核蛋白 Lamin A/C 和 RBM20 的致病性变异与预后较差相关。
