SIX3 and holoprosencephaly: However, only 25% of holoprosencephalic cases are due to mutations in known genes correlated with holoprosencephaly (e.g., Shh, Fgf8, Six3), leaving 75% of cases with unknown mutations (Dubourg et al., 2004, 2018; Pineda-Alvarez et al., 2010).