Expanded mutational spectrum of the GLI3 gene substantiates genotype-phenotype correlations

J Appl Genet. 2012 Nov;53(4):415-22. doi: 10.1007/s13353-012-0109-x. Epub 2012 Aug 18.


Greig cephalopolysyndactyly syndrome (GCPS) and isolated preaxial polydactyly type IV (PPD-IV) are rare autosomal dominant disorders, both caused by mutations in the GLI3 gene. GCPS is mainly characterised by craniofacial abnormalities (macrocephaly/prominent forehead, hypertelorism) and limb malformations, such as PPD-IV, syndactyly and postaxial polydactyly type A or B (PAPA/B). Mutations in the GLI3 gene can also lead to Pallister-Hall syndrome (PHS) and isolated PAPA/B. In this study, we investigated 16 unrelated probands with the clinical diagnosis of GCPS/PPD-IV and found GLI3 mutations in 12 (75%) of them (nine familial and three sporadic cases). We also performed a detailed clinical evaluation of all 12 GLI3-positive families, with a total of 27 patients. The hallmark triad of GCPS (preaxial polydactyly, macrocephaly/prominent forehead, hypertelorism) was present in 14 cases (52%), whereas at least one typical dysmorphic feature was manifested in 17 patients (63%). Upon sequencing of the GLI3 gene, we demonstrated eight novel and two previously reported heterozygous point mutations. We also performed multiplex ligation-dependent probe amplification (MLPA) to screen for intragenic copy number changes and identified heterozygous deletions in the two remaining cases (16.7%). Our findings fully support previous genotype-phenotype correlations, showing that exonic deletions, missense mutations, as well as truncating variants localised out of the middle third of the GLI3 gene result in GCPS/PPD-IV and not PHS. Additionally, our study shows that intragenic GLI3 deletions may account for a significant proportion of GCPS/PPD-IV causative mutations. Therefore, we propose that MLPA or quantitative polymerase chain reaction (qPCR) should be implemented into routine molecular diagnostic of the GLI3 gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrocephalosyndactylia / diagnosis
  • Acrocephalosyndactylia / genetics*
  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • DNA Copy Number Variations
  • Genetic Association Studies / methods*
  • Genetic Testing / methods
  • Heterozygote
  • Humans
  • Infant
  • Kruppel-Like Transcription Factors / genetics*
  • Kruppel-Like Transcription Factors / metabolism
  • Male
  • Middle Aged
  • Mutation, Missense
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Pallister-Hall Syndrome / genetics
  • Pedigree
  • Point Mutation*
  • Polydactyly / diagnosis
  • Polydactyly / genetics*
  • Real-Time Polymerase Chain Reaction / methods
  • Thumb / abnormalities
  • Young Adult
  • Zinc Finger Protein Gli3


  • GLI3 protein, human
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • Zinc Finger Protein Gli3

Supplementary concepts

  • Greig cephalopolysyndactyly syndrome
  • Polydactyly preaxial type 1