Introduction: Between 1 and 4 per 1000 births worldwide are affected by clubfoot. Clubfoot etiology is unclear, but both genetic and environmental factors are thought to be involved. Low folate status in pregnant women has been implicated in several congenital malformations and folate metabolism may be affected by polymorphisms in the MTHFR gene.

Methods: Using a case-parent triad design, we investigated whether the MTHFR C677T polymorphism, and maternal peri-conceptional folic acid supplement use, influenced risk of isolated clubfoot. 375 case-parent triads took part.

Results: Among children there was a significant trend of decreasing clubfoot risk with increasing number of Talleles: relative risk (RR ) CT vs CC=0.75 (95% CI: 0.57,0.97); RR TT vs CC=0.57 (95% CI: 0.37,0.91); p trend=0.006. This association was not modified by maternal folic acid use.

Conclusion: Maternal MTHFR genotype did not influence risk of clubfoot in the offspring overall, although a possible interaction with folic acid use was found. This is the first report of a specific genetic polymorphism associated with clubfoot. The direction of the association is intriguing and suggests DNA synthesis may be relevant in clubfoot development. However, clubfoot mechanisms are poorly understood and the folate metabolism pathway is complex. Further research is needed to elucidate these relationships.