PITX1 and familial clubfoot with or without associated lower limb anomalies: Multiple examples of haploinsufficient mutations in genes leading to disease in humans without affecting heterozygous animals are well documented in validated mammalian models such as, for example, mutations in the zinc-finger transcription factors GATA4 and GATA6 associated with congenital heart defects in humans [147], mutations in the macrophage colony-stimulating factor receptor (CSF1R) associated with adult onset leukoencephalopathy [148], or mutations in the PITX1 bicoid homeodomain transcription factor associated with clubfoot in humans [149].