title: A novel mutation, Ala315Ser, in FGFR2: a gene-environment interaction leading to craniosynostosis?
abstract: Mutations in the fibroblast growth factor receptor 1, 2 and 3 (FGFR1, -2 and -3) and TWIST genes have been identified in several syndromic forms of craniosynostosis. There remains, however, a significant number of patients with non-syndromic craniosynostosis in whom no genetic cause can be identified. We describe a novel heterozygous mutation of FGFR2 (943G --> T, encoding the amino acid substitution Ala315Ser) in a girl with non-syndromic unicoronal craniosynostosis. The mutation is also present in her mother and her maternal grandfather who have mild facial asymmetry but do not have craniosynostosis. None of these individuals has the Crouzonoid appearance typically associated with FGFR2 mutations. However, the obstetric history revealed that the proband was in persistent breech presentation in utero and was delivered by Caesarean section, at which time compression of the skull was apparent. We propose that this particular FGFR2 mutation only confers a predisposition to craniosynostosis and that an additional environmental insult (in this case foetal head constraint associated with breech position) is necessary for craniosynostosis to occur. To our knowledge, this is the first report of an interaction between a weakly pathogenic mutation and intrauterine constraint, leading to craniosynostosis.
authors.affiliation: Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, UK.
authors.forename: D
authors.initials: D
authors.lastname: Johnson
authors.forename: S A
authors.initials: SA
authors.lastname: Wall
authors.forename: S
authors.initials: S
authors.lastname: Mann
authors.forename: A O
authors.initials: AO
authors.lastname: Wilkie
mesh_terms: D000409:Alanine / Q000737:chemistry; D000595:Amino Acid Sequence; D001483:Base Sequence; D003398:Craniosynostoses / Q000000981:diagnostic imaging / Q000235:genetics*; D017931:DNA Primers / Q000737:chemistry; D004781:Environmental Exposure; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D011859:Radiography; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D012694:Serine / Q000737:chemistry
chemical_list: D017931:DNA Primers; D017468:Receptors, Fibroblast Growth Factor; D012694:Serine; C496353:FGFR2 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; D000409:Alanine