Trio-based whole exome sequence (WES) has been used as an efficient genetic tool to identify de novo causative mutations for clinical diagnosis, as shown in our recent reports on various brain development-related conditions.[15,16] In the present study, we report a previously undescribed missense mutation in the ZIC2 gene that is identified in an infant girl with HPE and arachnoid cyst. Here, ZIC2 is linked to holoprosencephaly.