Description) Neural tube defects represent a common, heterogeneous set of congenital malformations whose etiology is poorly understood. Although some environmental factors have been implicated, a significant genetic contribution is implied by the analysis of murmne lines with NTDs and the familial clustering in humans. Additionally, numerous syndromes and chromosomal anomalies are associated with NTDs. Both deletions and trisomies of chromosome 13 have been associated with neural tube defects raising the possibility that certain genes on chromosome 13 contribute to the etiology of NTDs when their dosage is altered. Nested sets of deletions of chromosome 1 3q, including one recently identified in the investigators clinic, implicate a fairly small region on chromosome 1 3q33-34. Although the exact genes required for producing an NTD in a 13q deletion are not known, several genes found in this region are important for early neural development in murine models, making them excellent candidates to test for involvement in human NTDs. The investigators propose to test the hypothesis that candidate genes in the chromosome 1 3g critical region are associated with NTDs in patients who lack chromosomal deletions. They will map the chromosome 1 3q critical region using patients with deletions and NTDs to narrow further the number of candidate genes. They will then choose genes to screen in detail based upon evidence of their involvement in early neural development or evidence of linkage disequilibrium. The candidates will be screened for mutations in a large set of individuals with NTDs using the resources of the NTD collaborative group. The investigators will test for linkage disequilibrium of all available candidate genes in the 1 3q critical region with the transmission disequilibrium test. These studies are likely to define mutations or polymorphisms associated with NTDs. The ability to identify genetic factors that place families at risk might help reduce the incidence of NTDs or make early intervention more feasible.
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