title: Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.
abstract: 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.
authors.affiliation: National Institutes of Health, National Human Genome Research Institute, Bethesda, MD 20892-4472, USA. jjohnsto@mail.nih.gov
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authors.initials: MC
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authors.forename: Raoul C M
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Lewis B
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authors.lastname: Holmes
authors.forename: H Eugene
authors.initials: HE
authors.lastname: Hoyme
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Leppig
authors.forename: Angela E
authors.initials: AE
authors.lastname: Lin
authors.forename: Patrick
authors.initials: P
authors.lastname: Macleod
authors.forename: David K
authors.initials: DK
authors.lastname: Manchester
authors.forename: Carlo
authors.initials: C
authors.lastname: Marcelis
authors.forename: Laura
authors.initials: L
authors.lastname: Mazzanti
authors.forename: Emma
authors.initials: E
authors.lastname: McCann
authors.forename: Marie T
authors.initials: MT
authors.lastname: McDonald
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Mendelsohn
authors.forename: John B
authors.initials: JB
authors.lastname: Moeschler
authors.forename: Billur
authors.initials: B
authors.lastname: Moghaddam
authors.forename: Giovanni
authors.initials: G
authors.lastname: Neri
authors.forename: Ruth
authors.initials: R
authors.lastname: Newbury-Ecob
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Pagon
authors.forename: John A
authors.initials: JA
authors.lastname: Phillips
authors.forename: Laurie S
authors.initials: LS
authors.lastname: Sadler
authors.forename: Joan M
authors.initials: JM
authors.lastname: Stoler
authors.forename: David
authors.initials: D
authors.lastname: Tilstra
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Walsh Vockley
authors.forename: Elaine H
authors.initials: EH
authors.lastname: Zackai
authors.forename: Touran M
authors.initials: TM
authors.lastname: Zadeh
authors.forename: Louise
authors.initials: L
authors.lastname: Brueton
authors.forename: Graeme Charles M
authors.initials: GC
authors.lastname: Black
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004825:Epiglottis / Q000002:abnormalities; D006222:Hamartoma / Q000235:genetics; D006801:Humans; D006972:Hypertelorism / Q000235:genetics; D007027:Hypothalamic Diseases / Q000235:genetics; D051741:Kruppel-Like Transcription Factors; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D017689:Polydactyly / Q000235:genetics*; D013576:Syndactyly / Q000235:genetics; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*; D000074290:Zinc Finger Protein Gli3; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C065683:GLI3 protein, human; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D000074290:Zinc Finger Protein Gli3
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