Exome sequencing and functional studies in familial CHD

家族性先心病的外显子组测序和功能研究

基本信息

批准号：
8550126
负责人：
Vidu Garg
金额：
$ 66.91万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-24 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8550126
关键词：
Address Adult Affect Archives Area Behavior Bioinformatics Biological Assay Cardiovascular system Cause of Death Cells Child Childhood Clinical Collection Complex Congenital Abnormality Congenital Heart Defects Copy Number Polymorphism Counseling Data Databases Development Developmental Biology Diagnosis Diagnostic Dideoxy Chain Termination DNA Sequencing Disease Enrollment Epidemiologic Studies Exhibits Family Family history of Frequencies Gene Expression Genes Genetic Genetic Counseling Genetic Predisposition to Disease Genetic Variation Genome Genomics Goals Hereditary Disease Human Human Genetics In Vitro Individual Infant Inheritance Patterns Intervention Joints Knowledge Lead Life Literature Live Birth Measures Medicine Methods Minority Mission Molecular Molecular Biology Morbidity - disease rate Mutation National Heart, Lung, and Blood Institute Nature Nucleotides Oceans Ohio Only Child Organism Outcome Study Parents Pathogenesis Pathway Analysis Persons Population Positioning Attribute Prevention Prevention Measures Preventive Recruitment Activity Research Resources Risk Strategic Planning Supercomputing Survivors Technology Testing Variant Weight Xenopus base biobank burden of illness case control cohort disability exome exome sequencing fetal diagnosis gene therapy genetic pedigree genetic variant genome sequencing genome wide association study genome-wide human disease improved in utero diagnosis in vitro Assay in vivo infancy innovation malformation mortality new technology novel research study response sample collection screening segregation statistics success transmission process

项目摘要

DESCRIPTION (provided by applicant): The development of massively parallel sequencing technologies may hold the key to personalized medicine as it allows for the identification of functional genetic variants that rende a person susceptible to disease. For this to become reality, disease-causing genes must be identified. This proposal concentrates on non-syndromic congenital heart defects (CHDs). Representing the most common type of birth defect, CHDs affect not only children but also a growing population of adult survivors. Epidemiologic studies have demonstrated genetic contributors, but few etiologic genes have been identified. Until this knowledge gap is overcome, the underlying molecular cause will remain hidden and hinder the development of new therapies and potentially prediction of long-term complications. Our long-term goal is to identify the underlying genetic causes and elucidate the molecular mechanisms leading to CHDs. The overall objective of this application is to discover the genetic variation that results in CHDs. Th central hypothesis is that CHD-causing genes can be identified by a genome-wide sequencing approach, using families exhibiting Mendelian inheritance patterns. The rationale for the proposed research is that the discovery of genetic causes of CHDs has the potential to provide better risk counseling and result in novel therapies for malformations that contribute to mortality from infancy to adulthood. Guided by recent literature supporting this premise and possession of a unique cohort of families, the central hypothesis will be tested by pursuing two Specific Aims: 1) Expand our current cohort of multiplex families and sporadic cases of CHDs; 2) Identify disease-causing genes in families exhibiting Mendelian segregation for CHDs and in trios via transmission disequilibrium tests by exome and whole genome sequencing. Methods will be developed specifically to test for rare variant associations in trio data, which aggregate over variants within a gene region and weight these variants based upon frequency and functionality. These methods will also allow for the joint analysis of unrelated individuals with a family history of CHD and trio data. The putative causal variants functional effects will be investigated by in vitro and in vivo Xenopus assays. A larger cohort with CHD will then be screened for mutations in identified genes. Our approach is innovative not only because it employs new technologies but also adds the power of Mendelian genetics through the use of families to tackle the genetic basis of a complex disease. This application focuses on part of the NHLBI Strategic Plan goals and challenges to identify key genetic variants in the human population that are associated with specific diseases. Success of this proposal will create a paradigm shift in the approach for human disease gene identification. The proposed research is significant because it is expected to vertically advance the fields of human genetics, developmental biology and cardiovascular medicine by identifying causal genes for CHDs. In the current era of fetal diagnosis and intervention, this knowledge will be used to improve prevention measures, in utero diagnosis, genetic counseling and therapy.

描述（由申请人提供）：大规模平行测序技术的发展可能是个性化医学的关键，因为它允许识别易感疾病的人的功能遗传变异。为了使这成为现实，必须确定引起疾病的基因。该建议集中于非综合性先天性心脏缺陷（CHD）。代表最常见的先天缺陷类型，CHD不仅会影响儿童，而且会影响成年幸存者的越来越多。流行病学研究表明遗传贡献者，但鉴定出病因学很少。在克服这些知识差距之前，根本的分子原因将保持隐藏，并阻碍新疗法的发展和可能对长期并发症的预测。我们的长期目标是确定潜在的遗传原因并阐明导致CHD的分子机制。该应用的总体目的是发现导致CHD的遗传变异。中心假设是，可以使用表现出Mendelian遗传模式的家族来通过全基因组测序方法来鉴定引起冠心病的基因。拟议的研究的理由是，发现CHD的遗传原因有可能提供更好的风险咨询，并为畸形的新疗法提供新的疗法，这有助于死亡率从婴儿期到成年。在最近的文献支持这一前提和拥有一系列独特家庭的文献的指导下，将通过追求两个具体的目标来检验中心假设：1）扩大我们目前的多元化家庭和零星CHD案件的同类； 2）通过外显子组和整个基因组测序的传播不平衡测试，在表现出志元和三重点的元氏隔离的家庭中确定引起疾病的基因。方法将专门用于测试三个数据中的稀有变体关联，这些数据汇总了基因区域内的变体，并基于频率和功能的重量这些变体。这些方法还将允许对具有家族史的无关个体进行联合分析 CHD和三重奏数据。假定的因果变异将通过体外和体内异武测定法研究。然后，将筛选与CHD的较大队列中的鉴定基因中的突变。我们的方法具有创新性，不仅是因为它采用了新技术，而且还通过使用家庭来解决复杂疾病的遗传基础来增加孟德尔遗传学的力量。该应用集中在NHLBI战略计划目标和挑战的一部分，以确定与特定疾病相关的人口中的关键遗传变异。该提案的成功将在人类疾病基因鉴定方法中产生范式转变。拟议的研究之所以重要，是因为有望通过鉴定CHD的因果基因来垂直垂直推进人类遗传学，发育生物学和心血管医学领域。在当前的胎儿诊断和干预时代，该知识将用于改善预防措施，子宫诊断，遗传咨询和治疗。