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Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.

Publication ,  Journal Article
Johnston, JJ; Olivos-Glander, I; Killoran, C; Elson, E; Turner, JT; Peters, KF; Abbott, MH; Aughton, DJ; Aylsworth, AS; Bamshad, MJ; Booth, C ...
Published in: Am J Hum Genet
April 2005

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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Published In

Am J Hum Genet

DOI

ISSN

0002-9297

Publication Date

April 2005

Volume

76

Issue

4

Start / End Page

609 / 622

Location

United States

Related Subject Headings

  • Zinc Fingers
  • Zinc Finger Protein Gli3
  • Transcription Factors
  • Syndrome
  • Syndactyly
  • Polydactyly
  • Phenotype
  • Nerve Tissue Proteins
  • Mutation
  • Kruppel-Like Transcription Factors
 

Citation

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Johnston, J. J., Olivos-Glander, I., Killoran, C., Elson, E., Turner, J. T., Peters, K. F., … Biesecker, L. G. (2005). Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. Am J Hum Genet, 76(4), 609–622. https://doi.org/10.1086/429346
Johnston, Jennifer J., Isabelle Olivos-Glander, Christina Killoran, Emma Elson, Joyce T. Turner, Kathryn F. Peters, Margaret H. Abbott, et al. “Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.Am J Hum Genet 76, no. 4 (April 2005): 609–22. https://doi.org/10.1086/429346.
Johnston JJ, Olivos-Glander I, Killoran C, Elson E, Turner JT, Peters KF, et al. Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. Am J Hum Genet. 2005 Apr;76(4):609–22.
Johnston, Jennifer J., et al. “Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.Am J Hum Genet, vol. 76, no. 4, Apr. 2005, pp. 609–22. Pubmed, doi:10.1086/429346.
Johnston JJ, Olivos-Glander I, Killoran C, Elson E, Turner JT, Peters KF, Abbott MH, Aughton DJ, Aylsworth AS, Bamshad MJ, Booth C, Curry CJ, David A, Dinulos MB, Flannery DB, Fox MA, Graham JM, Grange DK, Guttmacher AE, Hannibal MC, Henn W, Hennekam RCM, Holmes LB, Hoyme HE, Leppig KA, Lin AE, Macleod P, Manchester DK, Marcelis C, Mazzanti L, McCann E, McDonald MT, Mendelsohn NJ, Moeschler JB, Moghaddam B, Neri G, Newbury-Ecob R, Pagon RA, Phillips JA, Sadler LS, Stoler JM, Tilstra D, Walsh Vockley CM, Zackai EH, Zadeh TM, Brueton L, Black GCM, Biesecker LG. Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. Am J Hum Genet. 2005 Apr;76(4):609–622.
Journal cover image

Published In

Am J Hum Genet

DOI

ISSN

0002-9297

Publication Date

April 2005

Volume

76

Issue

4

Start / End Page

609 / 622

Location

United States

Related Subject Headings

  • Zinc Fingers
  • Zinc Finger Protein Gli3
  • Transcription Factors
  • Syndrome
  • Syndactyly
  • Polydactyly
  • Phenotype
  • Nerve Tissue Proteins
  • Mutation
  • Kruppel-Like Transcription Factors