Congenital heart disease (CHD) is the most common major birth defect affecting 4-8 per 1000 livebirths. Left-sided cardiac defects (LSCD) include valvar aortic stenosis, coarctation of the aorta and hypoplastic left heart syndrome, and account for at least 10% of CHD. Although LSCD are associated with significant morbidity and mortality, their etiology is largely unknown. Very few, if any, environmental causes have been identified and LSCD are associated with relatively few consistent chromosomal alterations or genetic syndromes. Nonetheless, studies point to a genetic contribution to these conditions, given an increased risk of recurrence and small, multiplex families. LSCD appear to share a common genetic etiology as different defects can occur in different members of a single family. Large multiplex families or affected sibling pairs amenable to genome wide linkage analyses are very rare, consistent in part with a complex mode of inheritence. The goal of this program is to identify genetic factors that contribute to the etiology of LSCD using techniques which dissect complex disorders. This investigation proposes that there are susceptibility loci and novel mutations that contribute to the etiology of LSCD. To investigate this hypothesis, this program will: (I) identify and characterize common susceptibility loci for LSCD using family-based association studies, and (II) identify and characterize rare or novel mutations in candidate genes in subjects with LSCD. A large cohort of subjects has been recruited. Family based association analyses and mutation analyses have already identified potential disease-related alleles and mutations respectively. To accomplish our goals, we will continue to recruit subjects, genotype them for a chosen set of common variants, and test them for association to LSCD. The role of maternal genetic effects for a subset of the putative susceptibility loci will also be evaluated. To complement the association studies, we will screen subjects for mutations of candidate genes by Conformation Sensitive Gel Electrophoresis and direct sequencing. If a sequence variant is identified, control populations will be tested for the same variant to determine disease relevance. The functional significance of mutations will also be assessed. This investigation will begin to dissect the genetic factors that contribute to the development of LSCD. The findings will allow for improved understanding of the disease-mechanism, more precise family counseling, and may identify preventive measures. In addition, these investigations will lead to future studies that assess the relationship of genotype to clinical outcome, and allow us to improve upon our clinical management accordingly. ? ?
