The genetics of folate metabolism and maternal risk of birth of a child with Down syndrome and associated congenital heart defects

Abstract

Almost 15 years ago it was hypothesized that polymorphisms of genes encoding enzymes involved in folate metabolism could lead to aberrant methylation of peri-centromeric regions of chromosome 21, favoring its abnormal segregation during maternal meiosis. Subsequently, more than 50 small case-control studies investigated whether or not maternal polymorphisms of folate pathway genes could be risk factors for the birth of a child with Down syndrome (DS), yielding conflicting and inconclusive results. However, recent meta-analyses of those studies suggest that at least three of those polymorphisms, namely MTHFR 677C>T, MTRR 66A>G, and RFC1 80G>A, are likely to act as maternal risk factors for the birth of a child with trisomy 21, revealing also complex gene-nutrient interactions. A large-cohort study also revealed that lack of maternal folic acid supplementation at peri-conception resulted in increased risk for a DS birth due to errors occurred at maternal meiosis II in the aging oocyte, and it was shown that the methylation status of chromosome 21 peri-centromeric regions could favor recombination errors during meiosis leading to its malsegregation. In this regard, two recent case-control studies revealed association of maternal polymorphisms or haplotypes of the DNMT3B gene, coding for an enzyme required for the regulation of DNA methylation at centromeric and peri-centromeric regions of human chromosomes, with risk of having a birth with DS. Furthermore, congenital heart defects (CHD) are found in almost a half of DS births, and increasing evidence points to a possible contribution of lack of folic acid supplementation at peri-conception, maternal polymorphisms of folate pathway genes, and resulting epigenetic modifications of several genes, at the basis of their occurrence. This review summarizes available case-control studies and literature meta-analyses in order to provide a critical and up to date overview of what we currently know in this field.

Keywords: DNA methylation; Down syndrome; MTHFR; congenital heart defects; epigenetics; folate; folic acid supplementation; polymorphisms.

Figure 1

Overview of the folate metabolic pathway. The diagram illustrates the enzymes, metabolites and cofactors discussed in this article. Enzymes: BHMT, betaine-homocysteine methyltransferase; CBS, cystathionine β-synthase; DHFR, dihydrofolate reductase; MTs, Methyltransferases; MTHFD1, methylenetetrahydrofolate dehydrogenase; MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase; MTRR, methionine synthase reductase; RFC1, reduced folate carrier; SHMT, serine hydroxymethyltransferase; TC, transcobalamin; TCR, tanscobalamin receptor; TYMS, thymidilate synthase. Metabolites: DHF, dihydrofolate; GSH, glutathione; THF, tetrahydrofolate; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; SAH, S-adenosyl homocysteine; SAM, S-adenosylmethionine. Cofactors: B2, vitamin B2; B6, vitamin B6; B12, vitamin B12 or cobalamin.

Figure 2

Trans-generational contribution of folate metabolism to the risk of birth of a child with Down syndrome. The maternal grandmother's diet during pregnancy provides dietary folates, i.e., the one-carbon units required for the correct development of the mother which is still a developing embryo in the maternal grandmother's body, including those required for the initiation of meiosis of primordial oocytes. Chromosome 21 recombination errors, leading to either meiosis I (MI) or meiosis II (MII) malsegregation events, occur during the prophase of the first meiotic division of primordial maternal oocytes in the maternal grandmother's body. Therefore, the predisposition to those errors is likely to result from complex interactions among the maternal grandmother's dietary provision of folate, her lifestyles such as smoking and drinking that can impair folate metabolism, and both the grandmother's genotype and the genotype of the mother (i.e., the different alleles of folate pathway genes that can account for inter-individual differences in folate absorption and metabolism). The maternal diet and lifestyles at peri-conception and during pregnancy can account for MII errors, as well as for the correct provision of dietary folates to the developing embryo. In this regard, it was hypothesized that complex interactions among maternal diet, lifestyles and genotype, and the metabolic demands of fetuses with trisomy 21, that overexpress several folate pathway genes mapping to chromosome 21, could account for either abortion or survival up to the birth. Those complex gene-environment interactions can also result in epigenetic changes in the developing embryo potentially affecting the birth and/or the complexity of the phenotype.