(1) Department of Translational Research and New Technologies in Medicine and Surgery, Division of Medical Genetics, University of Pisa, Pisa, Italy
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In 1999, it was first hypothesised that maternal polymorphisms of genes involved in folate metabolism might represent maternal risk factors for the birth of a child with Down syndrome. Several research articles have been produced worldwide to address that question, and recent meta-analyses of the literature suggest that at least two polymorphisms, namely MTHFR c.677C>T and MTRR c.66A>G, are associated with increased maternal risk for trisomy 21. Moreover, there is indication for an additive contribution of variants in folate pathway genes to the maternal risk for having a birth with Down syndrome. In addition, lack of folate supplementation at peri-conception, in combination with genetic polymorphisms of folate pathway genes, might represent maternal risk factors for congenital heart defects in the child with Down syndrome. The aim of this critical review was to discuss advances in genetic aspects linking folate metabolism to the maternal risk of giving birth to a child with Down syndrome.
Despite encouraging results, several factors such as ethnicity, age, dietary habits, and many others, could modulate those interactions and we are still far away from a complete understanding of the relationship between folate metabolism and chromosome 21 non-disjunction.