ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000007.13) (NC_000007.14)
Evidence for haploinsufficiency phenotype
PubMed ID Description
15739154 A 2005 genotype-phenotype correlation study of mutations in the GLI3 zinc-finger transcription factor gene detected 47 distinct pathological mutations in 135 individuals affected with Greig cephalopolysyndactyly syndrome (GCPS, 89 patients) or Pallister-Hall syndrome (PHS, 46 patients), which are variable but distinct clinical entities known to be caused by pathogenic mutations in GLI3. Mutations that result in truncated functional repressor protein were shown to be associated with PHS, frameshift, nonsense and splicing mutations primarily in the second third of the gene (from open reading frame [ORF] nucleotides [nt]1998-3481), and functional haploinsufficiency (translocations, large deletions, exonic deletions and duplications, small in-frame deletions, missense, frameshift, nonsense, splicing mutations) in the first third of the gene (from ORF nt 1-1997) of GLI3 were shown to cause GCPS.
21326280 2011 report of 5 probands with Greig cephalopolysyndactyly syndrome (GCPS) caused by heterozygous mutation or deletion of GLI3. Two intragenic mutations and three complete gene deletions detected on array comparative genomic hybridization were identified. The three deletions included an 8.3 Mb deletion at 7p12.3-p14.1 encompassing GLI3 and 59 flanking RefSeq genes, a 6.8 Mb deletion of region 7p13-p14.1 encompassing GLI3 and 51 flanking RefSeq genes, and a 6.1 Mb deletion at 7p13-p14.1 encompassing GLI3 and 51 other RefSeq genes. Due to the large chromosomal deletions, the authors suggested additional clinical features may be attributable to haploinsufficiency of contiguous genes in the 7p14.1 region. In children with GCPS due to large chromosomal deletions, additional clinical features may be attributable to haploinsufficiency of contiguous genes in the region of 7p14.1. Multiple genes may contribute to the more severe developmental delay in these children, and deletion of GCK (which occurred in Patients 3?5) is potentially associated with maturity onset diabetes of the young (MODY) type 2.
29236091 A ~190 kb deletion, including the entire GLI3 gene, was detected in an individual affected with mirror image duplication (CG187717) (Supplemental Table 3) in 2018 study of copy number variations (CNV) in 340 unrelated individuals with isolated limb malformation. A total of 35 unique CNVs were detected with 43% of CNVs including a known disease gene and likely to have resulted from gene dosage effects, and 57% of the disease-associated CNVs were in noncoding cis-regulatory genomic regions.

Haploinsufficiency phenotype comments:

GLI3 encodes a zinc finger transcription factor that functions in the hedgehogsignal transduction pathway (see SHH, MIM: #600725) , which is dependent on primary cilia in many tissues (summary by Laclef et al., 2015). Allelic disorders associated with GLI3 include autosomal dominant (AD) Greig cephalopolysyndactyly syndrome (MIM: #175700), AD Pallister-Hall syndrome (MIM: #146510), AD Polydactyly, postaxial, types A1 and B (MIM: #174200), and AD Polydactyly, preaxial, type IV (174700). (For a complete description of disorders, see Additional evidence: PMID: 20672375 Ninety-three patients not previously reported from the 2005 study with either (or both) GCPS or PHS: GCPS is caused by a wide range of mutations, but PHS is caused essentially only by truncating mutations. The data presented here, combined with published cases (Borg, et al., 2007; Fujioka, et al., 2005; Furniss, et al., 2009; Johnston, et al., 2005; Mendoza-Londono, et al., 2005; Roscioli, et al., 2005; Yilmaz, et al., 2008), describe 147 mutations in patients with typical GCPS or PHS. The mutation distribution in these two phenotypes is distinct. The GCPS mutations include large deletions/duplications (n=31) and translocations (n=5), and a variety of point mutations including missense (n=9), in frame deletions (n=1), splice (n=11), and frameshift or nonsense mutations (n=54). The distribution among patients with PHS is limited to one splice mutation and thirty-five frameshift or nonsense mutations. PMID: 20301619 Greig Cephalopolysyndactyly Syndrome (GCPS) is inherited in an autosomal dominant manner and is caused by either a pathogenic variant involving GLI3 or a deletion of chromosome 7p14.1 involving GLI3. The proportion of individuals with GCPS caused by de novo genetic alteration is unknown. A heterozygous deletion of chromosome 7p14.1 involving GLI3 accounts for ~20% of affected individuals [PMID: 12794692, 20672375, 22903559, 24736735]. To date, more than 200 individuals with GCPS have been reported with a pathogenic variant in GLI3 [9520255, 10441342, 19308487, 20672375, 12794692, 23776344, 15739154, 21326280, 22903559, 25606469, 24736735, 31573334]. Note: A small number of individuals with translocations involving 7p14.1 have been reported [6316787, 2729360, 19308487].

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