Conotruncal cardiac defects (CTCD) account for approximately 17 percent of congenital heart defects. However, in the majority of patients with CTCD a specific cause has not been identified. This laboratory demonstrated that one of the etiologies of CTCD is haploinsufficiency for chromosomal region 22q11.2. Recent animal studies suggest that there are multiple genes involved in conotruncal development. Several excellent candidate genes for CTCD have been identified based on their expression pattern in the heart and the observation of mouse models and transgenic mice with abnormalities of the outflow tracts and aortic arches. In addition, several genes have been identified within 22q11.2 which may play a role in cardiac development. Hence, the major goal of this project is to determine which of the recently identified genes on 22 and on other chromosomal loci contribute to the development of conotruncal malformations. The investigators propose to use several novel approaches including non-parametric linkage analysis (transmission disequilibrium test) and population association studies to accomplish this goal. Based on the significant association of CTCD with deletions of 22q11, the investigators propose that some non-deleted CTCD patients may have point mutations or smaller deletions in candidate genes within 22q11.2. Therefore, the investigators will also screen for mutations in these genes in non-deleted CTCD patients. Furthermore, the investigators propose that the presence and severity of the cardiac lesion in deleted CTCD patients may result from differences in genetic background. Potential genetic modifiers of the cardiac phenotype in individuals with 22q11 deletions will be evaluated using a population association, or traditional case-control study design. These factors may also act as cardiac susceptibility loci in non-deleted CTCD patients. Through the efforts of Core A and B the investigators have significant resources including banked DNA samples from over 400 CTCD patients which make them one of the few centers capable of performing the proposed studies.
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