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.
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