MTHFR and trisomy 21: However, several case-control studies revealed that haplotypes or combined genotypes generated by MTHFR 677C>T and 1298A>C polymorphisms increase the maternal risk for a birth of a child with trisomy 21 more than the presence of the MTHFR 677C>T one alone, strengthening the evidence of a functional interaction of both polymorphisms on protein stability and activity (Grillo et al., 2002; Acácio et al., 2005; Scala et al., 2006; Brandalize et al., 2009; Zampieri et al., 2012b).