Mutations in GLI3 have been confirmed to be associated with various human congenital malformations, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, and isolated polydactyly.
These results support a critical role of MED12 in regulating Gli3-dependent SHH signaling and in developing ID and related congenital malformations in XLID syndromes.
Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects.
Mutations in the transcription factor GLI3, a downstream target of Sonic Hedgehog (SHH) signaling, are responsible for the development of malformation syndromes such as Greig-cephalopolysyndactyly-syndrome (GCPS), or Pallister-Hall-syndrome (PHS).
Greig cephalopolysyndactyly syndrome (GCPS) is a rare multiple congenital anomaly syndrome that is inherited in an autosomal dominant pattern and is caused by haploinsufficiency of the GLI3 gene.
The Greig cephalopolysyndactyly contiguous gene syndrome (GCPS-CGS) is a multiple malformation syndrome caused by haploinsufficiency of GLI3 and adjacent genes.
Since hemizygosity of 7p13 resulting in complete loss of one copy of GLI3 causes GCPS as well, haploinsufficiency of this gene was implicated as a mechanism to cause this developmental malformation.