Conotruncal cardiac defects are malformations of the outflow tracts of the heart, which account for 16% of all congenital heart defects. Despite their clinical significance, their etiology is poorly understood. Studies indicate that the etiology of conotruncal defects is heterogeneous and complex, and includes both environmental and genetic factors. Because multiplex families amenable to parametric linkage analyses are extraordinarily rare, alternative approaches to identify genetic causes of these heart defects have been taken. Candidate genes and chromosomal loci have been identified through molecular analyses of genetic syndromes and from animal models. Epidemiologic studies have also suggested that the folate metabolic pathway may influence the risk of developing conotruncal defects. We have ascertained a large cohort of subjects with conotruncal cardiac defects and have identified mutations in a subset of patients in two key developmental genes: NKX2.5 and CFCI. Based on the literature and our preliminary studies, we hypothesize that three specific metabolic and developmental pathways contribute to the etiology of conotruncal defects including: (1) the folate-homocysteine metabolic axis, (2) NKX2.5 and its molecular partners, and (3) human disease genes (such as CFC1) associated with the abnormalities of left-right asymmetry. We propose to continue our efforts to define the genetic basis of conotruncal defects using family-based association studies and mutation analyses of candidate genes in these pathways. For genetic variants in the folate-homocysteine metabolic axis, novel family-based association studies will examine whether the maternal or embryonic genotype influences the risk of conotruncal defects. These studies will also begin to explore whether maternal-fetal genotype interactions, gene-gene interactions acting at the level of the mother or embryo, and gene-environment interactions influence conotruncal development. Developmental genes, such as those interacting with NKX2.5 or those participating in left-right asymmetry, will be studied for mutations and in select cases, for the influence of embryonic genotype on disease. The overall goal of this project is to further elucidate genetic factors that contribute to the etiology of conotruncal defects. With this data, the impact of genotype on clinical outcome can be assessed and improved management strategies devised for the future. ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Pulmonary Research A Study Section (CVA)
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Schramm, Charlene A
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Children's Hospital of Philadelphia
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