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， 心力衰竭，反映了缺乏新的医疗发展，其治疗。因此开发 治疗心力衰竭的新方法是一个巨大的未满足的需求。充血性心力衰竭的主要原因之一 是心肌病，一种高度遗传的疾病家族性心肌病的遗传学研究 已经确定了超过70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进一步了解， 预后信息，以指导临床决策，并提供更好的信息， 心力衰竭的基础心肌病的基因诊断也可能有助于定义心肌病的亚类。 以更好地指导治疗。重要的是，基因诊断提供了机会， 发现和早期干预。目前的遗传诊断策略依赖于基因组， 多个基因同时测序，几乎所有这些基因编码的蛋白质都是已知的心脏 功能包括粗丝和细丝蛋白以及对细胞骨架和核完整性重要的那些。 我们建议对心肌病患者进行全面的基因组测序，以确定心肌病患者的基因组范围。 在患有心肌病的受试者中存在致病变异。初步分析将集中在罕见的变异， 影响基因的编码区，特别是那些被预测会破坏蛋白质生产的基因。本 最后，还将调查非编码区，重点是缺失或重复（也称为 结构变异），破坏已知与心肌病有关的基因的调控区 与影响microRNA和长链非编码RNA的基因一样。来自个体心肌病基因组的数据将 通过家庭隔离研究加以证实。这个心肌病遗传变异的数据库将产生一个 医学上可用的资源，这将有助于解释临床基因检测，确定新的突变， 已知的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.