Genetics of arrhythmic mitral valve prolapse: large pedigree collection within the UCSF MVP registry

项目总结 二尖瓣脱垂(MVP)是一种常见的瓣膜病，有很强的遗传性成分，影响超过7 在美国有一百万人。每年，多达1.8%的MVP会发生心脏骤停 (SCA)或心源性猝死(SCD)。在先前的研究中，MVP的SCD/SCA要么与严重的 二尖瓣返流(MR)或恶性双叶表型伴轻度MR，二尖瓣环分离(MAD) 以及瓣膜-心肌力学异常导致复杂的室性异位(ComVE)和/或左 心脏磁共振(CMR)的晚期Gd增强或LGE 成像]。我们已经证明，在正在进行的R01的支持下，通过CMR/T1映射进行的弥漫性纤维化与 心律失常风险增加，与双叶型、严重MR或LGE的存在无关。因此， 心律失常的MVP可能不是一种“纯粹的”瓣膜病，而是一种原发亚临床肌病的组成部分。 除了纤毛相关基因(DCHS1、TNS1、LMCD1、DZIP1)的突变外 “一般的”MVP、心肌病或通道病基因(FLNC、LMNA、ALPK3、SCN5A)是最近发现的 在心律失常的MVP中提出，尽管是在病例报告中，或者在具有不同表现的GWAS研究中。 通过我们机构正在进行的R01和不断扩大的MVP注册，我们总共确定了14个 心律失常MVP先证者和家系，以及50例散发性心律失常MVP病例。在这个管理部门中 补充应用，我们寻求完成完整的外显子组测序，心律失常的特征，和CMR 在尚未接受这些调查的少数家庭成员中。我们的中心假设是 在MVP基因变异中，心肌病或通道病基因单独或与纤毛结合起作用。 相关变异增加了MVP中SCD/SCA的风险。来检验我们的中心假设并实现我们的 总体目标，我们提出以下具体目标：目标1：确定临床特征和基因 MVP SCD/SCA家系发生心律失常风险的决定因素，以及目标2：检验基因的致病性 通过蛋白质表达数据和细胞模型分析，了解心律失常MVP的变异和机制。 通过本行政补充获得的数据对于更好地进行MVP SCD/SCA风险分层至关重要， 从而能够通过在适当选择的MVP患者中放置ICD来预防未来的SCD。使用单元格 验证我们的遗传学发现的模型分析对于理解MVP患者的心律失常发生是至关重要的。 我们的建议是受到最近NHLBI关于MVP和Carol法案研究机会的研讨会的推动 纪念一位突然死于MVP的美国国会议员的妻子。

PROJECT SUMMARY Mitral valve prolapse (MVP) is a common valvulopathy with a strong hereditary component affecting over 7 million individuals in the United States. Every year, up to 1.8% of MVPs will develop sudden cardiac arrest (SCA) or sudden cardiac death (SCD). In prior studies, SCD/SCA in MVP has either been linked to severe mitral regurgitation (MR) or to a malignant bileaflet phenotype with mild MR, mitral annular disjunction (MAD) and abnormal valvular-myocardial mechanics leading to complex ventricular ectopy (ComVE) and/or left ventricular replacement fibrosis [late gadolinium enhancement or LGE by cardiac magnetic resonance (CMR) imaging]. We have shown, supported by an ongoing R01, that diffuse fibrosis by CMR/T1 mapping is linked to increased arrhythmic risk, regardless of bileaflet phenotype, severe MR, or presence of LGE. Hence, arrhythmic MVP may not be a “pure” valvulopathy, but rather a component of a primary subclinical myopathy. In addition to mutations in cilia-related genes (DCHS1, TNS1, LMCD1, DZIP1) previously described in “general” MVP, cardiomyopathy or channelopathy genes (FLNC, LMNA, ALPK3, SCN5A) have been recently proposed in arrhythmic MVP, albeit in case reports, or GWAS studies with heterogeneous presentations. Through an ongoing R01 and an expanding MVP registry at our institution, we have identified a total of 14 arrhythmic MVP probands and pedigrees, and 50 sporadic arrhythmic MVP cases. In this administrative supplement application, we seek to complete whole exome sequencing, arrhythmic characterization, and CMR in a minority of family members that have yet to undergo these investigations. Our central hypothesis is that among MVP genetic variants, cardiomyopathy or channelopathy genes act alone or in combination with cilia- related variants to increase the risk of SCD/SCA in MVP. To test our central hypothesis and accomplish our overall objective, we propose the following Specific Aims: Aim 1: To identify clinical features and genetic determinants of arrhythmic risk in MVP SCD/SCA pedigrees, and Aim 2: To test pathogenicity of genetic variants and understand mechanisms of arrhythmic MVP using protein expression data and cell model assays. Data obtained through this administrative supplement is essential for better MVP SCD/SCA risk stratification, thus enabling future prevention of SCD via ICD placement in appropriately selected MVP patients. Use of cell model assays to validate our genetic findings is essential to understand arrhythmogenesis in MVP patients. Our proposal is motivated by a recent NHLBI workshop on research opportunities in MVP and the CAROL Act in memory of a US congressman’s wife who died suddenly from MVP.