Cardiomyopathy Genomes Project

心肌病基因组计划

基本信息

批准号：
9061822
负责人：
Elizabeth M McNally
金额：
$ 54.36万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9061822
关键词：
Affect Algorithms Area Benign Biological Blood specimen Cardiac Cardiomyopathies Cessation of life Chicago Code Congenital cardiomyopathy Congestive Heart Failure DNA Sequence Alteration Data Databases Development Disease Early Diagnosis Early Intervention Exons Family Frequencies Gene Expression Genes Genetic Materials Genetic Polymorphism Genetic Variation Genetic screening method Genetic study Genome Health Heart Heart failure Hospitalization Human Genome Individual Institution Knowledge Laboratories Link Medical Medical Genetics Methods MicroRNAs Mutate Mutation Nuclear Nucleic Acid Regulatory Sequences Pathogenicity Patients Population Positioning Attribute Production Proteins RNA Splicing Research Personnel Resources Sampling Sequence Analysis Site Somatic Mutation Supercomputing Surveys Terminator Codon Testing Thick Filament Thin Filament Universities Untranslated RNA Variant Work clinical decision-making clinical material cohort connectin experience genetic disorder diagnosis genetic variant genome sequencing genome-wide human genome sequencing improved insertion/deletion mutation medical schools novel novel strategies prognostic rare variant response segregation tool transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（通过应用程序提供）：心力衰竭是住院和死亡的主要原因。自1995年以来，心力衰竭没有显着下降，这反映出缺乏新的医疗发展治疗。因此，开发新的心力衰竭方法是一种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，这种疾病是具有较高的遗传成分的疾病。家庭心肌病的遗传研究已经确定了70多种不同的基因，这些基因在突变后会引起心肌病和心力衰竭。对基于心力衰竭和心肌病的基础遗传缺陷的遗传缺陷的理解提供了预后的信息，以指导临床决策，并提供有关心力衰竭生物学基础的更好信息。心肌病的遗传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，遗传诊断为早期发现和早期干预提供了机会。当前的遗传诊断策略依赖于基因面板，其中简单地对多个基因进行了测序，几乎所有这些基因编码蛋白质都是已知的心脏功能，包括厚和薄丝蛋白，以及对细胞骨架和核完整性重要的心脏功能。我们建议在心肌病患者中进行全面的基因组测序，以定义心肌病受试者中存在的致病性变异范围。最初的分析将集中于影响基因编码区域的稀有变体，尤其是那些预计会破坏蛋白质产生的变体。为此，还将对非编码区域进行调查，重点是删除或重复（也称为结构变体），该区域破坏了已知基因的调节区域与心肌病有关的基因以及影响MicroRNAS和长期不编码RNA的基因。来自单个心肌病基因组的数据将通过家庭隔离研究来验证。这种心肌病遗传变异的数据库将产生公开可用的资源，有助于解释临床基因检测，确定已知基因的新突变以及新的突变对心肌病重要的基因。