A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling

Background: GLI2 encodes for a transcription factor that controls the expression of several genes in the Hedgehog pathway. Mutations in GLI2 have been described as causative of a spectrum of clinical phenotypes, notably holoprosencephaly, hypopituitarism and postaxial polydactyl. Methods: In order to identify causative genetic variant, we performed exome sequencing of a trio from an Italian family with multiple affected individuals presenting clinical phenotypes in the Culler-Jones syndrome spectrum. We performed a series of assays, both in vitro and in ovo (Chicken model) to test the functional properties of GLI2 mutation. Results: Here we report a novel deletion c.3493delC (p.P1167LfsX52) in the C-terminal activation domain of GLI2, and cell-based functional assays confirmed the pathogenicity of the identified variant and revealed a dominant-negative effect of mutant GLI2 on Hedgehog signalling. Conclusion: Our results highlight the variable clinical manifestation of GLI2 mutations and emphasize the value of functional characterisation of novel gene variants to assist genetic counselling and diagnosis.