![]() 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. 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. Mutations in the first third of the gene (from open reading frame nucleotides 1–1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998–3481) caused primarily PHS. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. 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. We detected 47 pathological mutations (among 60 probands) when these were combined with previously published mutations, two genotype-phenotype correlations were evident. ![]() The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. Alignments of the rpoB sequences were performed using Sequencher 5.3 software (Gene Codes Corporation, Ann Arbor, MI). 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. ![]()
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