C677T variant form at the MTHFR gene and CL/P: a risk factor for mothers?

Am J Med Genet. 2001 Feb 1;98(4):357-60. doi: 10.1002/1096-8628(20010201)98:4<357::aid-ajmg1108>3.0.co;2-f.


Maternal folic acid supplementation in early pregnancy has been suggested to play a role in the prevention of nonsyndromic orofacial cleft, i.e., cleft lip with or without cleft palate (CL/P). Moreover, some authors demonstrated association of the C-->T mutation (C677T), converting an alanine to a valine residue in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, with other congenital anomalies such as neural tube defects (NTDs). Because of MTHFR's involvement in the metabolism of folate, we investigated 64 CL/P patients and their parents for C677T MTHFR mutation. No linkage disequilibrium was found using the transmission disequilibrium test (TDT). However, a significantly higher mutation frequency was detected in mothers of CL/P patients compared to controls. The odds ratios calculated for mothers having CT or TT genotype, compared to the normal CC genotype, were 2.75 (95% confidence interval 1.30-5.57) and 2.51 (1.00-6.14), respectively. These results support the involvement of the folate pathway in the etiology of CL/P, and indicate an effect of the maternal genotype, rather than influence of the embryo's genotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Substitution
  • Cleft Lip / enzymology
  • Cleft Lip / genetics
  • Cleft Lip / pathology
  • Cleft Palate / enzymology
  • Cleft Palate / genetics
  • Cleft Palate / pathology
  • DNA / genetics
  • Family Health
  • Female
  • Gene Frequency
  • Genotype
  • Humans
  • Linkage Disequilibrium
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Mutation
  • Oxidoreductases Acting on CH-NH Group Donors / genetics*


  • DNA
  • Oxidoreductases Acting on CH-NH Group Donors
  • Methylenetetrahydrofolate Reductase (NADPH2)