Molecular and Clinical Analyses of Greig Cephalopolysyndactyly and Pallister-Hall Syndromes: Robust Phenotype Prediction from the Type and Position of GLI3 Mutations

National Institutes of Health, National Human Genome Research Institute, Bethesda, MD 20892-4472, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 05/2005; 76(4):609-22. DOI: 10.1086/429346
Source: PubMed


Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. Mutations in the first third of the gene (from open reading frame [ORF] nucleotides [nt] 1-1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3' third of the gene (after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis.

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Available from: Jennifer J Johnston
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    • "Many of the features of ACS, including polydactyly, cutaneous syndactyly, macrocephaly with prominent forehead, and widely spaced eyes are also seen in patients with Greig cephalopolysyndactyly syndrome (GCPS), and it has been suggested that the two syndromes might be allelic [Schinzel, 1982; Legius et al., 1985; Philip et al., 1988; Hall, 1990]. The GCPS phenotype is caused by mutations in the gene encoding GLI3, a transcriptional repressor and activator of the Sonic hedgehog signal transduction pathway [Johnston et al., 2005]. GLI3 mutations can lead to a large spectrum *Correspondence to: Marja W. Wessels, M.D., Ph.D., Department of Clinical Genetics, Erasmus MC University Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. "
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