Genetic determinants of human heterotaxy and aortic arch malformation

人类异位性和主动脉弓畸形的遗传决定因素

• 批准号: 8318587
• 负责人: MARTINA BRUECKNER
• 金额: $ 70.91万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318587
• 关键词: Affect; Anatomy; Animal Model; Biological Models; Biology; Candidate Disease Gene; Cardiac; Cardiac Surgery procedures; Characteristics; Clinical; Clinical Data; Congenital Abnormality; Copy Number Polymorphism; Data Collection; Databases; Demographic Analyses; Development; Diagnosis; Enrollment; Gene Cluster; Generic Drugs; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genie; Genomics; Genotype; Goals; Human; Infant; Instruction; Laboratories; Life; Link; London; Morphogenesis; Mus; Mutation; Myocardial; Outcome; Pathway interactions; Patients; Phenotype; Physiological; Pilot Projects; Plant Roots; Recruitment Activity; Recurrence; Regression Analysis; Renal function; Role; Sample Size; Signal Transduction; Situs Inversus; Societies; Structure; System; Techniques; Technology; Testing; Thoracic Surgeon; Universities; Variant; aortic arch; base; cardiogenesis; clinically relevant; cohort; college; congenital heart disorder; directed attention; exome; glycosylation; malformation; novel

DESCRIPTION (provided by applicant): Congenital heart disease is the most common serious birth defect, affecting .8% of live born infants, and ample evidence in both humans and animal model systems supports a genetic basis for CHD. However, low recurrence rates, small sample size and limitation in genomic technology have provided a significant hurdle in defining the genetics of CHD. The goal of this proposal is to combine the state-of-the art genomic technology in the Lifton laboratory with the understanding of the developmental mechanism underlying CHD developed in the Brueckner laboratory to determine the genetic determinants of two types of CHD, Heterotaxy (Htx) and Aortic Arch Abnormalities (AAAs). We have used copy number variation (CNV) analysis in a pilot study of 288 patients with Htx and identified rare genie CNVs in -20%. Interestingly, the CNVs direct attention to novel candidate genes that cluster in 3 pathways previously identified to have a role in the development of LR asymmetry and vasculature: ciliary structure and function, TGF-P signaling and glycosylation. These observations suggest that by combining powerful genomic techniques and large patient cohorts with our understanding of the developmental pathways implicated in cardiac morphogenesis we will identify a genetic cause in a significant number of CHD patients. In Specific Aim 1, we will recruit and carefully phenotype >2,000 pts with all CHD from Yale, University of Rochester and University College London to share with the PCGC consortium. In Specific Aim 2, patients from the consortium with Htx and AAAs will first be analyzed for CNVs. Subsequently, sporadic Htx and AAA patients with no detectable copy-number changes can undergo whole exome sequencing to discover causative mutations. In Specific Aim 3, we will determine whether discrete genotype variants with shared, clinically defined Htx and AAA phenotypes have significantly different short and mid-term clinical outcomes. Here we will focus on three aspects of clinical outcome that have possible links to the causative developmental pathways: myocardial function and renal function, both of which have been associated with ciliary function in model animal systems, and aortic root size, which is prominently affected by TGF-P signaling in mice and humans. RELEVANCE (See instructions): Although a genetic etiology for congenital heart disease (CHD) has long been suspected, limitations in patient number, genomic technology and understanding of the biology governing heart development have hampered identification of generic causes of CHD. This proposal seeks to use state-of-the-art genomic technology to identify the cause of two types of major CHD, heterotaxy and aortic arch abnormalities.

描述（由申请人提供）：