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

心律失常二尖瓣脱垂的遗传学：UCSF MVP 登记处的大量谱系收集

基本信息

批准号：
10850759
负责人：
Francesca N Delling
金额：
$ 77.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-26 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10850759
关键词：
18 year old 3-Dimensional ATAC-seq Administrative Supplement Adult Affect Ambulatory Monitoring Arrhythmia Biological Assay Biological Models Cardiac Cardiac Electrophysiologic Techniques Cardiomyopathies Case Study Cell Culture Techniques Cell model Characteristics Cilia Clinical Collection Complex Computer Models Data Data Set Detection Development Diffuse Disease Echocardiography Educational workshop Electrocardiogram Embryo FLNC gene Family Family member Fibrosis Foundations Future Gadolinium General Population Generations Genes Genetic Genetic Determinism Genetic Markers Genetic study Genotype Genotype-Tissue Expression Project Goals Heart Arrest Holter Electrocardiography Image Implantable Defibrillators In Vitro Individual Inherited Institution Investigation Knock-in Left Life Link Magnetic Resonance Malignant - descriptor Maps Mechanics Memory Minority Mitral Valve Mitral Valve Insufficiency Mitral Valve Prolapse Mutation Myocardial Myopathy National Heart, Lung, and Blood Institute Neonatal Outcome Outcome Study Participant Pathogenicity Pathology Patients Phenotype Prevention Primary Prevention Proteins Registries Research Risk Testing United States Variant Ventricular Ventricular Arrhythmia Wife cardiac magnetic resonance imaging cohort coronary fibrosis data modeling demographics exome sequencing genetic pedigree genetic variant genome wide association study heart imaging imaging biomarker in vivo multimodality novel phenotypic biomarker predictive marker proband prospective protein expression recruit risk prediction model risk stratification screening segregation sudden cardiac death

项目摘要

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.

项目概要二尖瓣脱垂 (MVP) 是一种常见的瓣膜病，具有很强的遗传性，影响超过 7 名患者在美国，每年有高达 1.8% 的 MVP 发生心脏骤停。 (SCA) 或心源性猝死 (SCD) 在之前的研究中，MVP 中的 SCD/SCA 与严重的死亡有关。二尖瓣反流 (MR) 或伴有轻度 MR 的恶性双叶表型、二尖瓣环分离 (MAD) 以及导致复杂心室异位 (ComVE) 和/或左心室异常的瓣膜心肌力学心室置换纤维化 [晚期钆增强或心脏磁共振 (CMR) 的 LGE 我们已经证明，在正在进行的 R01 的支持下，CMR/T1 映射与弥漫性纤维化有关。无论双叶表型、严重 MR 或是否存在 LGE，心律失常风险都会增加。心律失常 MVP 可能不是“纯粹的”瓣膜病，而是原发性亚临床肌病的一个组成部分。除了之前描述的纤毛相关基因（DCHS1、TNS1、LMCD1、DZIP1）的突变外， “一般”MVP、心肌病或通道病基因（FLNC、LMNA、ALPK3、SCN5A）最近已被尽管在病例报告或具有异质性表现的 GWAS 研究中提出了心律失常 MVP 的建议。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 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。补充申请，我们寻求完成全外显子组测序、心律失常特征和 CMR 我们的中心假设是，少数尚未接受这些调查的家庭成员。在 MVP 遗传变异中，心肌病或通道病基因单独作用或与纤毛联合作用相关变体增加 MVP 中 SCD/SCA 的风险，以检验我们的中心假设并实现我们的目标。总体目标，我们提出以下具体目标：目标 1：确定临床特征和遗传特征 MVP SCD/SCA 谱系中心律失常风险的决定因素，目标 2：测试遗传致病性使用蛋白质表达数据和细胞模型分析了解心律失常 MVP 的变体并了解其机制。通过此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 SCD。验证我们的遗传发现的模型测定对于了解 MVP 患者的心律失常发生至关重要。我们的提议是受到最近 NHLBI 举办的关于 MVP 和 CAROL 法案研究机会研讨会的推动纪念一位因 MVP 突然去世的美国国会议员的妻子。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cardiac Imaging for Risk Assessment of Malignant Ventricular Arrhythmias in Patients With Mitral Valve Prolapse.

DOI：
10.3389/fcvm.2021.574446
发表时间：
2021
期刊：
Frontiers in cardiovascular medicine
影响因子：
3.6
作者：
Tayal B;Delling FN;Malahfji M;Shah DJ
通讯作者：
Shah DJ

Interstitial Fibrosis and Arrhythmic Mitral Valve Prolapse: Unravelling Sex-Based Differences.

间质纤维化和心律失常二尖瓣脱垂：揭示性别差异。

DOI：
10.1101/2024.01.12.24301217
发表时间：
2024
期刊：
medRxiv : the preprint server for health sciences
影响因子：
0
作者：
Tastet,Lionel;Dixit,Shalini;Nguyen,Thuy;Lim,LisaJ;Al-Akchar,Mohammad;Bibby,Dwight;Arya,Farzin;Cristin,Luca;Anwar,Shafkat;Higuchi,Satoshi;Hsia,Henry;Lee,YooJin;Delling,FrancescaN
通讯作者：
Delling,FrancescaN

Mechanical Dispersion Discriminates Between Arrhythmic and Nonarrhythmic Sudden Death: From the POST SCD Study.

机械弥散区分心律失常性和非心律失常性猝死：来自 POST SCD 研究。

DOI：
10.1016/j.jacep.2024.01.002
发表时间：
2024
期刊：
JACC. Clinical electrophysiology
影响因子：
0
作者：
Tastet,Lionel;Ramakrishna,Satvik;Lim,LisaJ;Bibby,Dwight;Olgin,JeffreyE;Connolly,AndrewJ;Moffatt,Ellen;Tseng,ZianH;Delling,FrancescaN
通讯作者：
Delling,FrancescaN

Antemortem and Post-Mortem Characteristics of Lethal Mitral Valve Prolapse Among All Countywide Sudden Deaths.

DOI：
10.1016/j.jacep.2021.01.007
发表时间：
2021-08
期刊：
JACC. Clinical electrophysiology
影响因子：
0
作者：
Delling FN;Aung S;Vittinghoff E;Dave S;Lim LJ;Olgin JE;Connolly A;Moffatt E;Tseng ZH
通讯作者：
Tseng ZH

Left ventricular fibrosis in arrhythmic mitral valve prolapse: quantification and comparison of semi-automated techniques assessed by cardiac magnetic resonance.

心律失常二尖瓣脱垂中的左心室纤维化：通过心脏磁共振评估的半自动技术的量化和比较。

DOI：
10.1007/s10554-023-03006-6
发表时间：
2024
期刊：
The international journal of cardiovascular imaging
影响因子：
0
作者：
Cecere,Annagrazia;Cipriani,Alberto;DeLazzari,Manuel;Graziano,Francesca;Brunetti,Giulia;DeConti,Giorgio;Motta,Raffaella;Ravagnin,Alberto;Lorenzoni,Giulia;Gregori,Dario;Basso,Cristina;Tona,Francesco;Lee,YooJin;Delling,Francesca
通讯作者：
Delling,Francesca