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

Fabio Coppedè

doi:10.3389/fgene.2015.00223

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.

Highlights

Two studies conducted nearly 15 years ago in North America (James et al, 1999; Hobbs et al, 2000) have suggested that polymorphisms of genes encoding enzymes involved in the folate metabolic pathway, known as one-carbon metabolism, may be maternal risk factors for the birth of a child with Down syndrome (DS)
The original hypothesis linking impaired folate metabolism and abnormal methylation levels of chromosome 21 peri-centromeric regions (James et al, 1999) has not yet been demonstrated, even if in vitro studies revealed that cells under folate deprivation increase the rate of chromosome 21 aneuploidy (Wang et al, 2004; Beetstra et al, 2005), and recent evidence suggests that DNA methylation levels of peri-centromeric regions of chromosome 21 might be responsible of recombination errors leading to its malsegregation during meiosis (Oliver et al, 2014)
Since 1999, it was suggested that maternal polymorphisms in folate pathway genes could contribute to the epigenetic regulation of the chromatin structure in those regions, acting as maternal risk factors for the birth of a child with DS (James et al, 1999)

Summary

Introduction

Two studies conducted nearly 15 years ago in North America (James et al, 1999; Hobbs et al, 2000) have suggested that polymorphisms of genes encoding enzymes involved in the folate metabolic pathway, known as one-carbon metabolism, may be maternal risk factors for the birth of a child with Down syndrome (DS). That hypothesis (James et al, 1999) has been revised and implemented over the years, leading researchers to hypothesize that maternal polymorphisms of genes involved in folate metabolism could favor chromosome 21 malsegregation but, when transmitted to a DS embryo, could account for the probability that it will survive up to the birth (Martínez-Frías et al, 2006), or contribute to the onset of congenital defects (Brandalize et al, 2009; Locke et al, 2010), such as congenital heart defects (CHD) (Table 4) This article summarizes both casecontrol studies and literature meta-analyses in order to provide a critical and up to date review of what we currently know about maternal polymorphisms of folate-related genes and risk of birth of a child with DS and associated CHD, highlighting the strengths and the limitations of our current knowledge in this field

Methods

Findings

Discussion and Conclusions