The Hereditary Basis of Neural Tube Defects

描述(由调查员提供)：出生缺陷是一岁以下儿童死亡的主要原因。神经管缺陷(NTD)的发生率约为千分之一，是第二种最常见的出生缺陷类型。尽管有强有力的证据表明NTD具有遗传成分，但人们对这些人类破坏性疾病的原因知之甚少。看似合理的候选基因来自位置数据(例如，基因组筛选或细胞遗传学重排)或生物学可行性。例如，在小鼠中，至少有60个不同的基因座被鉴定为NTDS的易感基因，它们代表了人类生物学上看似合理的候选基因，但没有一个基因被确定为影响人类NTD风险的主要基因。此外，最近的研究确定了神经管关闭的位置在小鼠和人类之间不同，这表明小鼠模型可能不是识别与人类神经管关闭有关的基因的理想方法。通过对神经管闭合过程中哪些基因表达的直接信息，将大大加强对人类NTDS易感基因的识别。然而，科学家们并不知道在卡内基(C)7-14期人类神经管形成和关闭的关键时期内人类的基因表达。因此，在这项研究中，我们建议使用基因表达序列分析(SAGE)和基因芯片的互补技术来分析神经管闭合之前或期间(C9-11)和紧接(C12-14)神经管关闭后的关键阶段的前神经孔中的基因表达。这种方法将使我们能够量化和提高我们对这些关键时期基因表达的理解，并潜在地识别可能涉及NTD的关键途径和基因。结合我们基因组筛查的结果、NTDS的小鼠模型以及与失败的NTD闭合有关的生物学上可信的基因，我们将在我们的NTDS患者和家庭系列中优先评估候选患者。

DESCRIPTION (provided by investigator): 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.