Many studies have investigated the ZIC2 mutations in patients with HPE. A recent meta-analysis study of previously published results showed that the vast majority of ZIC2 mutations (98%) cause significant loss-of-function7. This suggests that HPE is caused by severely impaired function of ZIC2. Interestingly, only the very few cases (three families), in which the function of ZIC2 was shown to be null, included two independent parents with normal brain imaging despite the identification of ZIC2 missense mutations (Q36P or D152F)7. Together with these results, our findings raise the possibility that mildly impaired ZIC2 function does not result in HPE, but in psychiatric illnesses.