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.

Background: Congenital talipes equinovarus (CTEV) is a common developmental disorder of the foot, affecting between 1 and 4.5 babies per 1000 live births. The etiology is not well elucidated. While both genetic and environmental factors are implicated, no specific genes have been identified and little is known about environmental risk factors.

Methods: We conducted a case-control study of idiopathic congenital talipes equinovarus (ICTEV) in the United Kingdom. 194 cases and 60 controls were recruited. Pedigrees were obtained for 162 cases.

Results: The rank of the index pregnancy, maternal education and cesarean delivery were significantly associated with ICTEV risk in a multivariate model. There were suggestions that maternal use of folic acid supplements in the three months before the pregnancy decreased ICTEV risk, and that parental smoking during the pregnancy increased risk. One quarter of pedigrees showed a family history of CTEV, and autosomal dominant inheritance was suggested in some of these.

Conclusion: Uterine restriction did not appear to have a strong influence on ICTEV development in our study. Large population-based studies are needed to clarify the etiology of this common developmental disorder.