Genetic Basis of Neural Tube Defects

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Neural tube defects (NTDs) represent a common group of severe congenital malformations of the central nervous system. They result from failure of neural tube closure during early embryonic life. Their etiology is complex, involving environmental and genetic factors that interact to modulate the incidence and severity of the developing phenotype. Despite a long history of etiologic studies, the molecular and cellular pathogenic mechanisms underlining NTDs remain poorly understood. The major epidemiologic finding in NTDs is the protective effect of perinatal folic acid supplementation that reduces their risk by 60%-70%. Genetic studies in NTDs have focused mainly on folate-related genes and identified a few significant associations between variants in these genes and an increased risk for NTDs. The candidate gene approach investigating genes involved in neurulation and inferred from animal models has faced limited success in identifying major causative genes predisposing to NTDs. However, we are witnessing a rapid and impressive progress in understanding the genetic basis of NTDs, based mainly on the development of whole genome innovative technologies and the powerful tool of animal models.

Section snippets

Overview of Vertebrate Neurulation

Neurulation is a fundamental embryonic process that leads to the development of the neural tube, which is the precursor of the brain and spinal cord. Building a neural tube is an extremely complex phenomenon in which cells need to change in shape, migrate, and differentiate to transform a flat sheet of thickened epithelial cells (the neural plate) into a hollow tube (neural tube). In human beings, neurulation occurs through 2 distinct phases that occur at distinct sites along the rostrocaudal

Evidence for a Genetic Basis to NTDs

Several lines of evidence support a genetic component to NTDs. First, NTDs are associated with chromosomal abnormalities, most frequently trisomy 13, trisomy 18, and triploidy. NTDs are also associated with known genetic syndromes, including Meckel's syndrome, anterior sacral meningocele, Currarino syndrome, and anal stenosis.31 Second, NTDs show ethnic and racial differences in incidence rates. In the United States, the incidence of spina bifida, for example, is very low in African Americans

Studies of Folate-Related Genes in NTDs

The most significant epidemiologic finding relevant to NTDs is the protective effect of periconceptional administration of folic acid, which reduces their incidence as much as 60%-70%.39 This finding was initiated by a series of clinical studies that demonstrated an association between reduced folate status and elevated maternal homocysteine and an increased risk for NTDs, followed by randomized control trials and population-based folate fortification programs that confirmed the efficacy of

Candidate NTD Genes From Animal Studies

Although genetic variants have been identified in folate-related genes that increase the risk of developing an NTD, the total genetic variation identified to date in these genes does not account for the overall genetic contribution to NTD incidence observed in human populations. It is clear that other genes that are not related to folate play an important role in the pathogenesis of NTDs. As briefly described in this review, neurulation is a complex developmental process that involves distinct

Gene Identification in NTDs: Challenges and Future Directions

Candidate gene studies in human NTDs have faced limited success primarily because of the multifactorial causation of NTDs where the genotype at 1 locus cannot explain the resulting phenotype. Other limiting factors reside in the nature of such studies, where, to date, 2 major kinds have been adopted: association studies of candidate SNPs and direct resequencing. Association studies are often underpowered by small sample size that often leads to negative or inconsistent results. Concerted

Conclusions

We are still in the early stages of identifying the genetic factors predisposing to NTDs, due mainly to the complexity of this trait and the kinds of etiologic studies conducted so far. However, we are witnessing an explosion of high-resolution technologies that, coupled with animal models, will help define these genetic factors and better understand the pathophysiology of NTDs. The ultimate goal and hope is to develop better counseling and management strategies for the thousands of families

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