Folate pathway and nonsyndromic cleft lip and palate

Birth Defects Res A Clin Mol Teratol. 2011 Jan;91(1):50-60. doi: 10.1002/bdra.20740. Epub 2010 Dec 1.


Background: Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common complex birth defect. Periconceptional supplementation with folic acid, a key component in DNA synthesis and cell division, has reduced the birth prevalence of neural tube defects and may similarly reduce the birth prevalence of other complex birth defects including NSCLP. Past studies investigating the role of two common methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs), C677T (rs1801133) and A1298C (rs1801131), in NSCLP have produced conflicting results. Most studies of folate pathway genes have been limited in scope, as few genes/SNPs have been interrogated. Here, we asked whether variations in a more comprehensive group of folate pathway genes were associated with NSCLP, and were there detectable interactions between these genes and environmental exposures?

Methods: Fourteen folate metabolism-related genes were interrogated using 89 SNPs in multiplex and simplex non-Hispanic white and Hispanic NSCLP families.

Results: Evidence for a risk association between NSCLP and SNPs in NOS3 and TYMS was detected in the non-Hispanic white group, whereas associations with MTR, BHMT2, MTHFS, and SLC19A1 were detected in the Hispanic group. Evidence for over-transmission of haplotypes and gene interactions in the methionine arm was detected.

Conclusions: These results suggest that perturbations of the genes in the folate pathway may contribute to NSCLP. There was evidence for an interaction between several SNPs and maternal smoking, and for one SNP with gender of the offspring. These results provide support for other studies that suggest that high maternal homocysteine levels may contribute to NSCLP and should be further investigated.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / genetics
  • Betaine-Homocysteine S-Methyltransferase / genetics
  • Carbon-Nitrogen Ligases / genetics
  • Cleft Lip / complications*
  • Cleft Lip / ethnology
  • Cleft Lip / genetics
  • Cleft Palate / complications*
  • Cleft Palate / ethnology
  • Cleft Palate / genetics
  • Folic Acid / metabolism*
  • Genes / genetics*
  • Genetic Predisposition to Disease*
  • Hispanic or Latino / genetics
  • Humans
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Nitric Oxide Synthase Type III / genetics
  • Polymorphism, Single Nucleotide / genetics*
  • Reduced Folate Carrier Protein / genetics
  • Thymidylate Synthase / genetics
  • White People / genetics


  • BHMT2 protein, human
  • Reduced Folate Carrier Protein
  • SLC19A1 protein, human
  • Folic Acid
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
  • Thymidylate Synthase
  • Betaine-Homocysteine S-Methyltransferase
  • Carbon-Nitrogen Ligases
  • 5,10-methenyltetrahydrofolate synthetase