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

• 批准号: 8892228
• 负责人: Vidu Garg
• 金额: $ 64.95万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8892228
• 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; Massive Parallel Sequencing; 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; genomic variation; human disease; identity by descent; improved; in utero diagnosis; in vitro Assay; in vivo; infancy; innovation; malformation; mortality; new technology; novel; personalized medicine; rare variant; research study; response; sample collection; screening; segregation; statistics; success; targeted treatment; transmission process

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）： 大规模并行测序技术的发展可能是个性化医疗的关键，因为它可以识别使人容易患病的功能性遗传变异。为了使这成为现实，必须确定致病基因。该提案重点关注非综合征性先天性心脏缺陷（CHD）。先天性心脏病是最常见的出生缺陷类型，它不仅影响儿童，还影响越来越多的成年幸存者。流行病学研究已经证明了遗传因素，但几乎没有确定病因基因。在克服这一知识差距之前，潜在的分子原因将仍然隐藏，并阻碍新疗法的开发和长期并发症的潜在预测。我们的长期目标是确定潜在的遗传原因并阐明导致先心病的分子机制。该应用程序的总体目标是发现导致先心病的遗传变异。中心假设是，可以通过全基因组测序方法，使用表现出孟德尔遗传模式的家族来鉴定导致冠心病的基因。拟议研究的基本原理是，发现先心病的遗传原因有可能提供更好的风险咨询，并为导致死亡率的畸形提供新的治疗方法 从婴儿期到成年期。在支持这一前提和拥有独特家庭队列的最新文献的指导下，中心假设将通过追求两个具体目标来检验：1）扩大我们当前的多重家庭和散发性先心病病例队列； 2) 通过外显子组和全基因组测序进行传递不平衡测试，识别表现出先心病孟德尔分离的家族和三重奏中的致病基因。将专门开发方法来测试三重数据中的罕见变异关联，这些数据聚合基因区域内的变异，并根据频率和功能对这些变异进行加权。这些方法还可以对有家族史的无关个体进行联合分析 CHD 和三重奏数据。将通过体外和体内非洲爪蟾检测来研究假定的因果变异的功能影响。然后将对更大的先天性心脏病患者群体进行筛查，以确定是否存在已识别基因的突变。我们的方法具有创新性，不仅因为它采用了新技术，而且还通过利用家庭来解决复杂疾病的遗传基础，从而增强了孟德尔遗传学的力量。该应用程序重点关注 NHLBI 战略计划的部分目标和挑战，以识别人群中与特定疾病相关的关键遗传变异。该提案的成功将为人类疾病基因识别方法带来范式转变。这项研究意义重大，因为它有望通过识别先心病的致病基因，垂直推进人类遗传学、发育生物学和心血管医学领域的发展。在当今胎儿诊断和干预的时代，这些知识将用于改进预防措施、宫内诊断、遗传咨询和治疗。

项目成果

Genetics of valvular heart disease.

• DOI: 10.1007/s11886-014-0487-2
• 发表时间: 2014
• 期刊: Current cardiology reports
• 影响因子: 3.7
• 作者: LaHaye S;Lincoln J;Garg V
• 通讯作者: Garg V

Familial co-occurrence of congenital heart defects follows distinct patterns.

• DOI: 10.1093/eurheartj/ehx314
• 发表时间: 2018-03-21
• 期刊: European heart journal
• 影响因子: 39.3
• 作者: Ellesøe SG;Workman CT;Bouvagnet P;Loffredo CA;McBride KL;Hinton RB;van Engelen K;Gertsen EC;Mulder BJM;Postma AV;Anderson RH;Hjortdal VE;Brunak S;Larsen LA
• 通讯作者: Larsen LA

Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease.

• DOI: 10.1016/j.yjmcc.2013.04.001
• 发表时间: 2013-07
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: Bosse K;Hans CP;Zhao N;Koenig SN;Huang N;Guggilam A;LaHaye S;Tao G;Lucchesi PA;Lincoln J;Lilly B;Garg V
• 通讯作者: Garg V

Novel pathogenic GATA6 variant associated with congenital heart disease, diabetes mellitus and necrotizing enterocolitis.

• DOI: 10.1038/s41390-023-02811-y
• 发表时间: 2023-09
• 期刊: Pediatric research
• 影响因子: 3.6
• 作者: J. Yasuhara;Sathiya N Manivannan;Uddalak Majumdar;David M. Gordon;Patrick J. Lawrence;Mona Aljuhani;K. Myers;C. Stiver;Amee M. Bigelow;M. Galantowicz;Hiroyuki Yamagishi;Kim L McBride;Peter White;V. Garg

Generation and characterization of a human induced pluripotent stem cell (iPSC) line from a patient with congenital heart disease (CHD).

• DOI: 10.1016/j.scr.2022.102958
• 发表时间: 2022-12
• 期刊: STEM CELL RESEARCH
• 影响因子: 1.2
• 作者: Lin, Hui;Ye, Shi-Qiao;Xu, Zhao-Hui;Penaloza, Jacqueline S.;Aljuhani, Mona;Vetter, Tatyana;Zhao, Ming -Tao;McBride, Kim L.
• 通讯作者: McBride, Kim L.