Genetic Basis of Neural Tube Defects

Abstract

Neural tube defects (NTDs) are common, often severe congenital malformations of the central nervous system. Anencephaly and open spina bifida (myelomeningocele) arise from faulty neural tube closure, encephalocele involves brain herniation through a skull defect, and closed 'dysraphism' of the low spine results from abnormal secondary neurulation. Most cases of anencephaly and open spina bifida have multifactorial causation, with contributions from two or more genetic risk variants plus interacting non-genetic factors. Occipital encephalocele by contrast is often a single gene disorder and is now considered a `ciliopathy', resulting from defects in genes required for primary cilium function. The genetic basis of spinal dysraphism is unknown. Clues to the genetic basis of NTDs come from chromosomal anomalies, that can pinpoint critical genes within aberrant chromosomal regions, family studies that have identified single gene-related NTDs, and mouse models where more than 200 different genes are known to be essential for neural tube closure. Genes of folate one-carbon metabolism, especially those functioning in the mitochondria, have been implicated in causation of anencephaly and open spina bifida. Genes of the planar cell polarity pathway are required for initiation of neural tube closure in mice, and unique variants occur in a range of open human NTDs. However, only a small proportion of all NTDs have an established genetic causation, and ongoing research is seeking associations with candidate genes, as well as undertaking exome, and increasingly whole-genome, sequencing of cases compared with controls. Quantitative alterations in gene expression level resulting from mutations of cis-regulatory sequences, as well as epigenetic mechanisms (e.g. DNA methylation), may also play key roles in NTD causation. Such studies are important both to reveal the causation of a group of important human birth defects, and also to enable development of genetic tests to predict the risk of NTDs for prospective parents.