In humans, SIX3 haploinsufficiency can cause holoprosencephaly (HPE), the most common forebrain malformation characterized by midline deficiencies of brain and facial structures as well as a wide spectrum of eye malformations such as cyclopia, anophthalmia, microphthalmia and coloboma13, 14, 15. Here, SIX3 is linked to holoprosencephaly.