Genetic Analysis of Human Outflow Tract Malformations

人类流出道畸形的遗传分析

基本信息

批准号：
7582368
负责人：
Deborah Anne Driscoll
金额：
$ 36.68万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7582368
关键词：
22q11 22q11 Deletion Syndrome Affect Animal Model Anterior Attention Bioinformatics Bone Morphogenetic Proteins Candidate Disease Gene Cardiac Child Code Congenital Heart Defects Correlation Studies DNA DNA Sequence Analysis Databases Defect Development Disease Exons FGF8 gene Family Fibroblast Growth Factor Fibroblast Growth Factor 8 First Degree Relative Functional RNA Gene Frequency Genes Genetic Genetic Polymorphism Genetic Variation Genotype Haplotypes Heart Human Individual Introns Investigation Knockout Mice Linkage Disequilibrium Mesoderm Messenger RNA Mus Mutation Analysis Neural Crest Neural Crest Cell Newborn Infant Parents Pathway interactions Patients Penetrance Phenotype Population Recruitment Activity Recurrence Relative Risks Research Personnel Risk Role Sampling Screening procedure Semaphorins Severities Signaling Molecule Single Nucleotide Polymorphism Single Nucleotide Polymorphism Map Susceptibility Gene Syndrome Testing Variant Vascular Endothelial Growth Factors base clinical phenotype cohort density genetic analysis genetic association malformation novel strategies proband programs protein function receptor transmission process

项目摘要

Malformations of the outflow tract comprise approximately one-third of cardiac defects in newborns. Familial aggregation and increased recurrence risk of cardiac defects in first degree relatives supports a substantial genetic component that may involve one or more genes each with a variable contribution and relative risk. Further, incomplete penetrance and variable severity of the cardiac phenotype in disorders such as the 22q11 deletion syndrome supports a role for genetic modifiers. Recent advances in the understanding of the genes and pathways involved in the development of the outflow tract and the availability of new approaches to identifying susceptibility genes open new avenues of investigation of outflow defects in humans. While previous attention focused on the role of the cardiac neural crest cell in the development of outflow tract malformations, more recent studies suggest that an anterior heart-forming field (AHF) consisting of pharyngeal and splanchnic mesoderm is also critical. We propose that the genes involved in the AHF including signaling molecules such as bone morphogenetic proteins, fibroblast growth factors, vascular endothelial growth factor, semaphorins and their receptors may contribute to the development of CHD in humans. Recent evidence suggests that some of these genes influence the cardiac phenotype. The major objective of this proposal is to assess the contribution and relative risk of these genes in human outflow tract defects using an epidemioiogical approach. To accomplish this, in Specific Aims 1 and 2 single nucleotide polymorphisms (SNPs) in these genes will be identified in SNP databases and by screening genornic DNA, verified and priotorized based on their predicted functional significance, hapiotype analysis, and allele frequency. In Specific Aims 3 and 4, DNA samples from over 700 children with outflow tract malformations and their parents, and at least 300 individuals with the 22q11 deletion syndrome will be genotyped at each SNP, respectively. We will look for a statistical correlation between these genes and outflow tract malformations using the transmission disequilibrium test. We will also determine if the variability and severity of the cardiac defects in patients with the 22q11 deletion can be attributed to genetic variation using population-based and family-based genetic association studies.

流出道的畸形包括新生儿中大约三分之一的心脏缺陷。在一级亲属中，家族性聚集和增加心脏缺陷的复发风险支持一个大量的遗传成分，该成分可能涉及一个或多个基因，每个基因具有可变的贡献和相对风险。此外，诸如22q11缺失综合征等疾病中心脏表型的不完整的外观和心脏表型的严重程度可变，这支持了遗传修饰剂的作用。了解流出道发展的基因和途径的最新进展以及鉴定易感基因的新方法的可用性开放了对人类流出缺陷的研究的新途径。虽然先前的注意力集中在心脏神经rest细胞在流出道畸形发展中的作用，但最新的研究表明，由咽和中胚层组成的前心形成场（AHF）也很关键。我们提出，涉及AHF的基因，包括信号分子，例如骨形态发生蛋白，成纤维细胞生长因子，血管内皮生长因子，词信号及其受体可能有助于人类CHD的发展。最近的证据表明，其中一些基因影响心脏表型。该提案的主要目的是使用流行病方法评估这些基因在人流出缺陷中的贡献和相对风险。为此，将在SNP数据库中鉴定出这些基因中的1和2单核苷酸多态性（SNP），并通过筛选Genornic DNA，基于其预测的功能意义，Hapiotype，Hapiotype分析和等位基因频率进行了验证和实现。在特定的目标3和4中，来自700多名流出道畸形的儿童及其父母的DNA样本以及至少300个患有22q11缺失综合征的人将分别在每个SNP上进行基因分型。我们将寻找这些基因与流出道畸形之间的统计相关性使用传输不平衡测试。我们还将确定使用基于人群和基于家庭的遗传关联研究的22q11缺失患者心脏缺陷的变异性和严重程度是否归因于遗传变异。