Evaluation of C677T and A1298C polymorphisms of the MTHFR gene as maternal risk factors for Down syndrome and congenital heart defects

Am J Med Genet A. 2009 Oct;149A(10):2080-7. doi: 10.1002/ajmg.a.32989.


Abnormal folate/homocysteine metabolism due to polymorphisms in genes involved in this pathway has been implicated as an etiologic factor in Down syndrome (DS). This case-control study aimed to evaluate the effect of maternal C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) as risk factors for the development of DS and congenital heart defects (CHD). The distribution of these genotypic variants was similar between mothers of children with DS (n = 239) and control mothers of normal children (n = 197), but the combined genotypes 677CT or TT and 1298AA increased the risk of having offspring with DS (OR = 1.99; 95% CI 1.11-3.55). The presence of the 677T allele in case mothers resulted in a 2.07-fold higher odds of CHD in the offspring (P < 0.01). Among the 57 mothers of CHD-affected children with DS who carried the MTHFR 677CT or TT genotypes and did not have periconceptional folic acid intake, we observed a 2.26-fold increased odds (95% CI 1.25-4.09) of having any CHD-affected child with DS. Our results show that MTHFR genetic polymorphisms may be involved in the etiology of DS in our population when controlling for age. We noted a borderline significant association for the C677T polymorphism (P = 0.05). Maternal 677T allele may be associated with an increased occurrence of CHD in children with DS and we anticipate that women who carry this polymorphism would benefit from periconceptional folic acid supplementation. (c) 2009 Wiley-Liss, Inc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Case-Control Studies
  • Child
  • Down Syndrome / epidemiology
  • Down Syndrome / genetics*
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Heart Defects, Congenital / epidemiology
  • Heart Defects, Congenital / genetics*
  • Humans
  • Inheritance Patterns / genetics
  • Inheritance Patterns / physiology
  • Maternal Age
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Middle Aged
  • Mothers*
  • Polymorphism, Single Nucleotide*
  • Prevalence
  • Risk Factors


  • Methylenetetrahydrofolate Reductase (NADPH2)