Cardiomyopathy Genomes Project

项目摘要 心力衰竭是住院和死亡的主要原因。自1995年以来，这一数字没有显著下降 在心力衰竭方面，反映出其治疗缺乏新的医学发展。因此，发展 治疗心力衰竭的新方法是一个巨大的、尚未得到满足的需求。充血性心力衰竭的主要原因之一 是心肌病，一种具有很高遗传成分的疾病。家族性心肌病的遗传学研究 已经确定了70多种不同的基因，当突变时，会导致心肌病和心力衰竭。一个 对导致心力衰竭和心肌病的遗传缺陷的更好的理解提供了 预后信息，以指导临床决策，并提供更好的生物学信息 心力衰竭的基础。心肌病的基因诊断也可能有助于确定亚类 以更好地指导心肌病的治疗。重要的是，基因诊断为早期诊断提供了机会 及时发现和早期干预。目前的基因诊断策略依赖于基因面板，其中 多个基因同时测序，几乎所有这些基因都编码已知的心脏蛋白。 功能包括粗丝蛋白和细丝蛋白，以及那些对细胞骨架和核完整性至关重要的蛋白。 我们建议对心肌病患者进行全面的基因组测序，以确定 心肌病受试者存在病原学变异。初步分析将重点放在罕见的变种上 影响基因的编码区，特别是那些被预测会扰乱蛋白质生产的区域。对这件事 最后，还将对非编码区进行调查，重点是缺失或复制(也称为 结构变体)，扰乱了已知的与心肌病相关的基因的调节区 与影响微小RNA和长非编码RNA的那些一样。来自单个心肌病基因组的数据将 被家庭隔离研究证实。这个心肌病遗传变异的数据库将产生一个 公共可用的资源，将帮助解释临床基因检测，识别新的突变 已知基因以及对心肌病重要的新基因。

Project Summary Heart failure is a leading cause of hospitalization and death. Since 1995, there has been no significant decline in heart failure, reflecting the absence of new medical developments for its treatment. Therefore, developing new approaches to heart failure is a large, unmet need. One of the leading causes of congestive heart failure is cardiomyopathy, a disorder with a high heritable component. Genetic studies of familial cardiomyopathy have identified more than 70 different genes that, when mutated, cause cardiomyopathy and heart failure. An improved understanding of the genetic defects that underlie heart failure and cardiomyopathy provides prognostic information to guide clinical decision-making and to provide better information about the biological underpinnings of heart failure. Genetic diagnosis in cardiomyopathy may also help define subclasses of cardiomyopathy to better guide therapy. Importantly, genetic diagnosis affords the opportunity for early detection and early intervention. The current strategy for genetic diagnosis relies on gene panels, where multiple genes are sequenced simultaneously, and nearly all these genes encode proteins are known cardiac function including thick and thin filament proteins and those important for cytoskeletal and nuclear integrity. We propose to conduct comprehensive genome sequencing in cardiomyopathy patients to define the range of pathogenic variation present in subjects with cardiomyopathy. Initial analysis will focus on rare variants that affect the coding regions of genes, especially those that are predicted to disrupt protein production. To this end, noncoding regions will also be surveyed with emphasis on deletions or duplication (also known as structural variants) that disrupt regulatory regions for the genes known to be linked to cardiomyopathy as well as those that affect microRNAs and long noncoding RNAs. Data from individual cardiomyopathy genomes will be verified by family segregation studies. This database of genetic variation in cardiomyopathy will generate a publically available resource that will aid in interpretation of clinical genetic testing, identify new mutations in known genes as well as new genes important for cardiomyopathy.