Neural tube defects (NTD) are among the most common birth defects but their etiology is unknown. Genetic models of NTDs in mice reveal the existence of several dozen possible genetic etiologies. The murine NTD lines also demonstrate the specific association of certain genetic defects with non-NTD anomalies, some of which involve neural crest-derived structures. In order to understand the genetic factors in human NTDs, we have screened a large population of children with myelodysplasia and found that anomalies of neural crest derived structures are present in a fraction (8.5 percent) of patients with NTDs, and that neural crest anomalies are inherited in a fraction (7.5 percent) of families of NTD patients. The neural crest anomalies found in the NTD patients resemble several specific human neural crest syndromes and murine lines with NTDs, suggesting the hypothesis that NTD patients with accompanying neural crest anomalies have gene defects underlying both disorders. We, therefore, propose to determine if individuals with neural crest anomalies and NTDs have mutations in genes that are associated with human and murine neural crest syndromes. Two individuals from this group who have been examined so far revealed gene defects in the PAX3 gene and mild signs of Waardenburg syndrome type III. A third patient had familial progressive deafness and a mitochondrial rRNA mutation. We will screen the remaining patients with NTDS and neural crest anomalies for deletions and point mutations in a set of ten well characterized genes known to produce neural crest anomalies, including PAX3 and the mitochondrial rRNA. Mutations will be characterized and their inheritance in families of NTD patients will be examined. Finding gene mutations associated with NTDs is an important first step toward determining the etiology of the human disorder, and in evaluating the role of genetic factors. This study also offers a means to subdivide the heterogeneous disorders that produce NTDs into clinical-genetic classifications, with the potential to improve genetic counseling or other early interventions.
