Mutations in SIX3 result in holoprosencephaly (HPE), a heterogeneous collection of forebrain malformations, with incomplete penetrance due to SIX3 haploinsufficiency or hypomorphic function (Table 1; Wallis et al., 1999; Lacbawan et al., 2009; Hehr et al., 2010; Stokes et al., 2018). Here, SIX3 is linked to holoprosencephaly.