Expanded mutational spectrum of the GLI3 gene substantiates genotype-phenotype correlations.
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.
Department of Medical Genetics, University of Medical Sciences, ul. Grunwaldzka 55 paw. 15, 60-352 Poznań, Poland. jamsheer@wp.pl
Aleksander
A
Jamsheer
Anna
A
Sowińska
Tomasz
T
Trzeciak
Małgorzata
M
Jamsheer-Bratkowska
Anita
A
Geppert
Anna
A
Latos-Bieleńska
D000168:Acrocephalosyndactylia / Q000175:diagnosis / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D056726:Genetic Association Studies / Q000379:methods*; D005820:Genetic Testing / Q000379:methods; D006579:Heterozygote; D006801:Humans; D007223:Infant; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D054975:Pallister-Hall Syndrome / Q000235:genetics; D010375:Pedigree; D017354:Point Mutation; D017689:Polydactyly / Q000175:diagnosis / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D013933:Thumb / Q000002:abnormalities; D055815:Young Adult; D000074290:Zinc Finger Protein Gli3
C065683:GLI3 protein, human; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000074290:Zinc Finger Protein Gli3