A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling ValenzaFabiola CittaroDavide StupkaElia BiancoliniDonatella Grazia PatricelliMaria BonanomiDario LazarevićDejan 2019 <div><p>Background</p><p>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.</p><p>Methods</p><p>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 cell-based assays to test the functional properties of mutant GLI2.</p><p>Results</p><p>Here we report a novel deletion c.3493delC (p.P1167LfsX52) in the C-terminal activation domain of GLI2. Functional assays confirmed the pathogenicity of the identified variant and revealed a dominant-negative effect of mutant GLI2 on Hedgehog signalling.</p><p>Conclusions</p><p>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.</p></div>