Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
GLI2 heterozygous variants have been identified in patients with Culler-Jones syndrome, also known as postaxial polydactyly–anterior pituitary anomalies–facial dysmorphism syndrome. A novel missense variant c.527A>G (p.Tyr176Cys) was detected in a patient presenting with anosmia [PMID:36936162]. Additionally, a truncating variant c.3493delC (p.Gln1165SerfsTer52) co-segregated with disease in an Italian family [PMID:30629636]. Overall, these represent 2 probands with segregation in 1 family supporting a limited evidence base.
Functional studies demonstrate that the truncating GLI2 mutant exerts a dominant-negative effect on Hedgehog signaling, consistent with loss-of-function pathogenicity [PMID:30629636]. No conflicting evidence has been reported. Although current case numbers are limited, these findings support inclusion of GLI2 sequencing in the diagnostic evaluation of patients with pituitary anomalies and polydactyly. Key take-home: GLI2 heterozygous variants underlie Culler-Jones syndrome and warrant consideration in clinical genetic testing.
Gene–Disease AssociationLimited2 probands (one novel missense, one truncating variant), segregation in 1 family Genetic EvidenceLimitedCase-level evidence from 2 unrelated probands with GLI2 variants and co-segregation in one pedigree Functional EvidenceModerateCell-based assays show dominant-negative impairment of Hedgehog signaling by the truncating GLI2 variant |