Failed closure of the neural tube, the embryonic structure from which the brain and spinal cord are formed, leads to neural tube defects (NTDs). The NTD complex includes the two most common forms of NTDs, spina bifida and anencephaly, as well as other less frequent manifestations such as encephalocele, craniorachischisis, and iniencephaly. The frequency of NTD births in the United States is approximately 1/1000. Numerous studies have implicated both environmental and genetic factors. Multiple lines of evidence in humans and studies in experimental organisms provide compelling evidence that the predisposition to the development of NTDs includes a hereditary component. For instance, the increase in risk to siblings over the general population rate (lambda), frequently used as one measure of the genetic contribution to a disorder, is estimated at 25-50. In this application, the investigators propose to identify genetic factors involved in NTD development from factors and pathways identified through the sister projects. The candidate genes will be investigated using mutation screening and/or detection techniques. The investigators will also perform a high density genomic screen on a single large pedigree with six affected family members to identify regions of the genome that may harbor NTD susceptibility loci. These regions may identify novel regions of interest to be investigated in model systems. In addition, the investigators will expand their available dataset of NTD families to include the phenotype of anencephaly, at the severe spectrum of the NTD phenotype. Extensive family history data and blood for DNA extraction will be obtained from these pedigrees in which one or more members are affected with anencephaly. These pedigrees will be exhaustively characterized clinically, including radiographic assessment of level of lesion, assessment of facial dysmorphology, and cytogenetic assessments. In addition, the investigators will collect and database information on key environmental risk factors such as folic acid supplementation, maternal weight, and paternal military exposures to allow assessment of gene/environment interactions. The goal of this proposal is to illuminate the hereditary factors predisposing to NTDs, with the ultimate aim of characterizing interactions between genes and between genes and the environment, eventually leading to mechanisms for the prevention of these frequent birth defects.
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