The Hereditary Basis of Neural Tube Defects

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Birth defects are the leading cause of death in children under one year of age. Neural tube defects (NTD) have a frequency of approximately 1/1000 and are the second most common type of birth defect. Although there is strong evidence for a genetic component to NTD, little is known about the causes of these devastating disorders in humans. Plausible candidate genes come from positional data (e.g., genomic screen or cytogenetic rearrangement) or biological feasibility. For instance, at least 60 different loci predisposing to NTDs in mouse have been identified and represent biologically plausible candidate genes in humans, yet none have been established as major genes influencing human NTD risk. Furthermore, recent studies have determined that neural tube closure sites vary between mice and human, suggesting that mouse models might not be ideal for identifying genes involved in human neural tube closure. The identification of genes predisposing to human NTDs would be substantially enhanced by direct information about what genes are expressed during the process of neural tube closure. However, scientists have no knowledge of gene expression in humans during the presumably critical period from Carnegie (C) stages 7-14 when the human neural tube forms and closes. In this study we therefore propose to analyze gene expression in the anterior neuropore during the critical stages prior to or during (C9-11), and just after (C 12-14) neural tube closure using the complementary techniques of Serial Analysis of Gene Expression (SAGE) and microarrays. This approach will allow us to quantitate and advance our understanding of gene expression during these critical periods and potentially identify critical pathways and genes that may be involved in NTD. In combination with results from our genomic screen, mouse models of NTDs, and genes with biological plausibility for involvement in failed NTD closure, candidates will be prioritized for assessment in our series of patients and families with NTDs.