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

There is growing evidence that epigenetic dysregulation plays a role in neurodevelopmental disorders. In humans, folate is one of the main donors of the methyl group required for the synthesis of S-adenosylmethionine, which in turn is needed for DNA and histone methylation as key neurodevelopment processes. Folate deficiency during pregnancy has been correlated with neural tube defects and with a higher incidence of neurocognitive and/or neurobehavioral deficits. A similar outcome may be exerted by gene polymorphisms in folate or folate-related pathways. This has been documented by numerous case/control association studies performed on neurodevelopmental disorders such as autism spectrum disorder and attention deficit hyperactivity disorder. In this regard, the folate cycle represents a "perfect model" of how genetics influences epigenetics. Gene variants in folate and folate-related pathways can be considered risk factors for neurodevelopmental disorders and should therefore be assessed by genetic testing in pregnant women. High-risk women should be considered for folate supplementation during pregnancy. Here, we review all published case/control association studies on gene polymorphisms in folate and folate-related pathways performed on neurodevelopmental disorders, provide an overview of neurodevelopment and DNA methylation changes occurring at this time, and describe the biological basis of neurodevelopmental disorders and recent evidence of their epigenetic dysregulation.