Finding the genetic mechanisms of folate deficiency and neural tube defects—Leaving no stone unturned

Abstract

Neural tube defects (NTDs) occur secondary to failed closure of the neural tube between the third and fourth weeks of gestation. The worldwide incidence ranges from 0.3 – 200 per 10,000 births with the United States of American NTD incidence at around 3–6.3 per 10,000 dependent on race and socioeconomic background. Human NTD incidence has fallen by 35–50% in North America due to mandatory folic acid fortification of enriched cereal grain products since 1998. The US Food and Drug Administration has approved the folic acid fortification of corn masa flour with the goal to further reduce the incidence of NTDs, especially among individuals who are Hispanic. However, the genetic mechanisms determining who will benefit most from folate enrichment of the diet remains unclear despite volumes of literature published on studies of association of genes with functions related to folate metabolism and risk of human NTDs. The advances in omics technologies provides hypothesis-free tools to interrogate every single gene within the genome of NTD affected individuals to discover pathogenic variants and methylation targets throughout the affected genome. By identifying genes with expression regulated by presence of folate through transcriptome profiling studies, the genetic mechanisms leading to human NTDs due to folate deficiency may begin to be more efficiently revealed.

Insights into the Etiology of Mammalian Neural Tube Closure Defects from Developmental, Genetic and Evolutionary Studies

“…Despite many genetic studies, the etiology is not well understood [ 11 ], and likely involves combinations of deleterious versions of genes in affected individuals, with the combinations differing between individuals [ 12 ]. We discuss examples of similar genetic complexity in mouse mutant models.…”

Deletion of the neural tube defect–associated gene disrupts one-carbon and central energy metabolism in mouse embryos

“…One-carbon metabolism is indispensable during embryonic development, and maternal deficiency of folic acid is strongly associated with neural tube defects (NTDs). 2 Periconceptional intake of supplemental folic acid can reduce the incidence of NTDs by as much as 70%, and many countries now fortify their food supply with folic acid to ensure that women of child-bearing age consume adequate quantities of the vitamin. Although folic acid fortification has decreased NTD incidence in most populations, an estimated 30% of NTD cases do not respond to folic acid supplementation (1).…”

“…Although folic acid fortification has decreased NTD incidence in most populations, an estimated 30% of NTD cases do not respond to folic acid supplementation (1). Moreover, despite the strong clinical links between folate and NTDs, the biochemical mechanisms through which folic acid acts during neural tube development remain largely undefined (2).…”

Linking genetics to epigenetics: The role of folate and folate‐related pathways in neurodevelopmental disorders

“…Trascriptome profiling studies may also be useful to identify genes whose expression is regulated by folate. 101 As the genetics of mothers relative to polymorphisms in genes involved in folate and folate-related pathways can influence the developing fetus, it would be important to investigate a panel of genetic variants in the mother to identify possibility of folate deficiency in the fetus. Gene panels will allow the identification of high-risk mothers who should then be considered for folic acid supplementation during peri-conception and pregnancy.…”