Mutations in the PITX1–TBX4–Hoxc pathway were proposed in familial clubfoot cases,99 and additional evidence implicated homeobox genes, including SHOX family—both of which were involved in limb and skeletal development and were associated with short stature phenotypes—in contributing to limb anomalies through interactions with TBX4. Here, TBX4 is linked to familial clubfoot with or without associated lower limb anomalies.