Closing in on Mechanisms of Open Neural Tube Defects

Neural tube defects (NTDs) are the most common birth anomaly of the CNS. They result from a failure of the neural plate to complete the developmental transition to a neural tube. Mandatory folic acid (FA) supplementation of dietary grains led to a significant decrease in the incidence of NTDs, but the mechanisms involved remain disputed. NTD is a relatively common phenotype in mouse knockouts, showing both simple and complex inheritance, as well as responses to folate, yet few of the genes identified in mouse models have been established as causes in human NTDs. Candidate gene approaches in human studies support a role for Wnt/planar cell polarity, cilia, Sonic Hedgehog (Shh), and bone morphogenetic protein (BMP) signaling factors in NTD risk. Whole-genome sequencing, as opposed to SNP genotyping or candidate gene resequencing, allows for detection of most coding, noncoding, and structural variants, including rare, common, de novo, and somatic variants. Recently, there have been collaborative efforts to assemble larger cohorts of phenotypically diverse patients from diverse ethnic groups, both prior to and after FA fortification, for comprehensive risk assessment. Neural tube defects (NTDs) represent a failure of the neural plate to complete the developmental transition to a neural tube. NTDs are the most common birth anomaly of the CNS. Following mandatory folic acid fortification of dietary grains, a dramatic reduction in the incidence of NTDs was observed in areas where the policy was implemented, yet the genetic drivers of NTDs in humans, and the mechanisms by which folic acid prevents disease, remain disputed. Here, we discuss current understanding of human NTD genetics, recent advances regarding potential mechanisms by which folic acid might modify risk through effects on the epigenome and transcriptome, and new approaches to study refined phenotypes for a greater appreciation of the developmental and genetic causes of NTDs. Neural tube defects (NTDs) represent a failure of the neural plate to complete the developmental transition to a neural tube. NTDs are the most common birth anomaly of the CNS. Following mandatory folic acid fortification of dietary grains, a dramatic reduction in the incidence of NTDs was observed in areas where the policy was implemented, yet the genetic drivers of NTDs in humans, and the mechanisms by which folic acid prevents disease, remain disputed. Here, we discuss current understanding of human NTD genetics, recent advances regarding potential mechanisms by which folic acid might modify risk through effects on the epigenome and transcriptome, and new approaches to study refined phenotypes for a greater appreciation of the developmental and genetic causes of NTDs. a condition of absent skull and major portion of brain due to developmental abnormality. a condition whereby the neural tube is not closed along both the brain and spinal cord. sum of any modifications on DNA or histones without alterations in the DNA sequence itself. many countries mandate manufacturers to add FA to various dietary grains based on the previous clinical trials showing the effect of FA on neural tube defect prevention. Concentration of fortified FA varies from country to country, but is typically in the range 140–220 μg/100 g of flour. a generic term referring to any kinds of natural food folate (in tetrahydrofolate form). Folate in fortified foods and most of dietary supplements is in the form of folic acid, which is artificially synthesized as a pure chemical compound. understanding of the genetic factors responsible for heritable phenotypic variability, which also includes their interactions with each other (genetic interaction) and with the environment (gene–environment interaction). an approach to associate genetic variations with particular diseases. a single copy of a certain gene that does not produce sufficient protein product for normal phenotypes. an approach to find co-segregated genetic segments within a family. mutations (usually coding ones) that result in the gene product having no function, including stopgain, frameshift, or splicing mutations. inheritance patterns of single gene (monogenic) diseases. relatively small chromosomal deletion/duplication that usually cannot be detected by conventional cytogenetic method under light microscope. statistical problem whereby an increase in simultaneous tests increases the likelihood of an erroneous result. a condition of protrusion of meninges and spinal cord through vertebra and skin defects. Also known as 'spina bifida'. a group of developmental disorders that is caused by failed neural tube closure during development. an inheritance model involving several genes. a systematic difference in allele frequencies of genetic variants among subpopulations due to different ancestry. an evolutionary tendency to eliminate protein-altering or -damaging gene variants. genetic regions that control the transcription of nearby genes. see myelomeningocele.