Impaired FGF signaling contributes to cleft lip and palate

Bridget M. Riley, M. Adela Mansilla, Jinghong Ma, Sandra Daack-Hirsch, Brion S. Maher, Lisa M. Raffensperger, Erilynn T. Russo, Alexandre R. Vieira, Catherine Dodé, Moosa Mohammad, Mary L. Marazita, Jeffrey C. Murray

Research output: Contribution to journalArticlepeer-review

199 Scopus citations


Nonsyndromic cleft lip and palate (NS CLP) is a complex birth defect resulting from a combination of genetic and environmental factors. Several members of the FGF and FGFR families are expressed during craniofacial development and can rarely harbor mutations that result in human clefting syndromes. We hypothesized that disruptions in this pathway might also contribute to NS CLP. We sequenced the coding regions and performed association testing on 12 genes (FGFR1, FGFR2, FGFR3, FGF2, FGF3, FGF4, FGF7, FGF8, FGF9, FGF10, FGF18, and NUDT6) and used protein structure analyses to predict the function of amino acid variants. Seven likely disease-causing mutations were identified, including: one non-sense mutation (R609X) in FGFR1, a de novo missense mutation (D73H) in FGF8, and other missense variants in FGFR1, FGFR2, and FGFR3. Structural analysis of FGFR1, FGFR2, and FGF8 variants suggests that these mutations would impair the function of the proteins, albeit through different mechanisms. Genotyping of SNPs in the genes found associations between NS CLP and SNPs in FGF3, FGF7, FGF10, FGF18, and FGFR1. The data suggest that the FGF signaling pathway may contribute to as much as 3-5% of NS CLP and will be a consideration in the clinical management of CLP.

Original languageEnglish (US)
Pages (from-to)4512-4517
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number11
StatePublished - Mar 13 2007
Externally publishedYes


  • Cleft palate
  • Fibroblast growth factor
  • Fibroblast growth factor receptor
  • Single-nucleotide polymorphism

ASJC Scopus subject areas

  • General


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