THE GENETICS OF SPINA BIFIDA

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DESCRIPTION (Adapted from investigator's abstract): The goal of the proposed project is to delineate the genetic architecture of spina bifida (SB), a developmental malformation resulting from abnormal or incomplete closure of the caudal end of the neural tube. A comprehensive program, integrating molecular, statistical and epidemiological methods will be used to evaluate the potential genetic determinants of SB in a large, well-characterized sample of families drawn from a defined geographic region. A data resource will be created including approximately 500 families consisting (minimally) of a proband affected with SB, along with the biological parents and an unaffected sibling should one or both of the parents be unavailable. Extended relatives to be studied come primarily from the material side, such as the grandmother of the proband and maternal aunts; these data will be used to attempt to tease apart maternal from fetal genotypic effects. This data resource will be useful for testing of presently identified candidate loci as well as future evaluation of putative susceptibility loci. There is also the potential to interact with other scientists, such as Dr. Marcy Speer at Duke University, also studying SB to provide replication opportunities for each other. Recent studies in humans as well as animal models suggest the biochemical and developmental pathways that control neural tube development and provide several excellent candidate susceptibility loci. These highly motivated and prioritized loci will be evaluated using an approach that detects association using a transmission disequilibrium test. Data will also be collected on several environmental factors, chosen on the basis of previous evidence of their potential involvement, to evaluate any interactions with a specific variant in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. Finally, any variants found to be associated with SB will be evaluated with respect to several criteria in an attempt to determine whether they have direct functional significance.