ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000002.11) (NC_000002.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
14581620 Roessler et al (2003) reported 3 likely loss of function GLI2 variants in a cohort of 390 patients with holoprosencephaly (HPE). A W113X variant was described in a patient with bilateral cleft lip and palate, microcephaly, single central incisor, postaxial polydactyly and growth hormone deficiency. A deceased sibling had a single nostril, hypoplastic palate, alobar HPE and absent anterior lobe of the pituitary. However, DNA was not available for testing. The variant was not found in either parent. Additional variants identified include R168X in a proband referred for HPE findings and a splice site variant IVS5+1 G>A in a proband with hypotelorism, single nares, microcephaly, and growth hormone deficiency. The variants were found to be inherited from apparently normal fathers in both cases. Functional studies performed in Roessler et al (2005) suggest these three variants result in loss of function. Functional studies for additional truncating variants identified in the C-terminal activating domain suggested they may function as a dominant-negative. Reported variants were not found in >200 control chromosomes.
21204792 Bertolacini et al. (2012) report 2 patients with frameshift/nonsense variants. The first, p.Ser511fsX536, was described in a woman with midline facial dysmorphic features, postaxial polydactyly, and a normal MRI; the same change was also found in her mother with hypotelorism. The second, p.P288fsX301, was found in a patient with semilobar HPE, midline dysmorphic facial features, and postaxial polydactyly; the same change was also found in the patient's mother, who had postaxial polydactyly.
24744436 Bear et al (2014) screened ~400 individuals with HPE spectrum disorders, endocrine disorders or craniofacial anomalies for variants in GLI2. Two large deletions were identified involving most of the gene. The first was a 118 kb deletion including coding exons 3-13 in a mother and two daughters. The mother had midface hypoplasia and short stature and both daughters had polydactyly and growth hormone deficiency. A 151 kb deletion of coding exons 2-13 was detected in a patient with bilateral cleft lip and palate. Additionally, 7 nonsense variants, 8 frame shift variants and 1 splice site variant were identified in this cohort.

Haploinsufficiency phenotype comments:

There are known issues of variable expressivity and reduced penetrance associated with this phenotype. Additional reports of GLI2 deletions: PMID: 31862539 Melitza et al (2020) identified a de novo 229.9 kb deletion of chromosome 2q14.2 including coding exons 2-13 of GLI2 in a patient with combined pituitary hormone deficiency, pituitary anomalies and polydactyly. No additional genes were contained in the deletion. PMID: 33235745 A 90 kb deletion of exons 3-13 was reported by Elward et al (2020) in a mother and two daughters. The mother had polydactyly and both daughters had growth hormone deficiency and polydactyly.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity