Insights into the Genetics of Clubfoot

Clubfoot, a common complex birth defect, affects 135,000 newborns each year worldwide. While tremendous strides have been made in treatment with the Ponsetti nonsurgical method, the post-treatment foot generally remains small with hypoplastic calf musculature. Even though clubfoot has been studied for more than 100 years, only a few contributing factors have been identified. Prenatal tobacco smoke exposure is the only consistently associated environmental factor and confers an increased risk in a dose dependent manner. Moreover, maternal smoking and a family history of clubfoot increases the risk 20-fold confirming that genetic factors play a role. Genetic studies have shown that variation in TBX4 and PITX1 cause syndromic forms of clubfoot; however, there is no evidence that variation in these genes contribute to nonsyndromic clubfoot. Recent work suggests that variants in the regulatory regions of muscle-specific genes play a role by subtly affecting gene expression and it is hypothesized that variation in the expression of multiple genes is necessary for clubfoot development. This mechanism is consistent with the multifactorial model first proposed for clubfoot over 50 years ago. Confirmation of this work should enable identification of unique gene risk signatures that will aid in genetic counseling. Next generation approaches should speed gene identification in clubfoot