Genetic Risk Factors for Folate-Responsive Neural Tube Defects

Annu Rev Nutr. 2017 Aug 21;37:269-291. doi: 10.1146/annurev-nutr-071714-034235. Epub 2017 Jun 19.


Neural tube defects (NTDs) are the most severe congenital malformations of the central nervous system. The etiology is complex, with both genetic and environmental factors having important contributions. Researchers have known for the past two decades that maternal periconceptional use of the B vitamin folic acid can prevent many NTDs. Though this finding is arguably one of the most important recent discoveries in birth defect research, the mechanism by which folic acid exerts this benefit remains unknown. Research to date has focused on the hypothesis that an underlying genetic susceptibility interacts with folate-sensitive metabolic processes at the time of neural tube closure. Little progress has been made searching for risk-causative variants in candidate genes; therefore, more complex genetic and epigenetic methodologies are now being considered. This article reviews the research to date that has been targeted on this important gene-nutrient locus.

Keywords: MTHFR; anencephaly; folic acid; spina bifida; vitamin B12.

Publication types

  • Review
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Folic Acid / metabolism
  • Folic Acid / pharmacology
  • Folic Acid / therapeutic use
  • Genetic Predisposition to Disease*
  • Humans
  • Male
  • Mice
  • Neural Tube Defects / genetics*
  • Neural Tube Defects / prevention & control
  • Risk Factors


  • Folic Acid