ONLINE MUTATION REPORT Maternal 677CT/1298AC genotype of the MTHFR gene as a risk factor for cleft lip

Non-syndromic cleft lip with or without cleft palate (CL/P) is one of the most common congenital anomalies world wide. It has a prevalence of approximately 1/1000 among white populations and 1/600 among Thai newborns. Environmental and genetic factors have been implicated in CL/P and several different loci and genes have been associated with them. Maternal folic acid supplementation during early pregnancy may reduce the risk for oral clefts, 5 but this is controversial. One of the mechanisms by which low folate levels predispose some subjects to oral clefts could be the presence of polymorphisms in the genes encoding enzymes of the folate pathway, such as 5,10-methylenetetrahydrofolate reductase (MTHFR, MIM 236250). MTHFR catalyses the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate and the carbon donor for the remethylation of homocysteine to methionine. Two polymorphisms, 677C>T and 1298A>C, in the MTHFR gene have been shown to have reduced MTHFR activity. 8 The 677C>T transition, producing an alanine to valine amino acid substitution within the catalytic domain of the MTHFR enzyme, has been associated with many disorders and conditions including neural tube defects, vascular disease, migraine, smoking behaviour, and oral clefts. 13 However, the last is controversial. Recent studies reported an association between the maternal polymorphism and the anomalies, 16 but this again is not a consistent finding. 18 No studies have investigated 1298A>C, the second most common polymorphism in MTHFR resulting in a glutamate to alanine substitution, in CL/P patients and their parents. We therefore carried out a case-control study to determine whether the two MTHFR polymorphisms in Thai patients with CL/P or their parents were associated with an increased risk of the anomaly.