GLI2 is a large and highly polymorphic gene, with a number of rare/family-specific heterozygous missense, non-sense, and frameshift mutations detected in individuals presenting with a spectrum of clinical phenotypes that include HPE, craniofacial abnormalities, polydactyly, panhypopituitarism, secondary hypogonadism or isolated growth hormone deficiency [20–24]. Here, GLI2 is linked to holoprosencephaly.