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A novel mutation, Ala315Ser, in FGFR2: a gene-environment interaction leading to craniosynostosis?
1Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, UK.
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.
Insights
A novel fibroblast growth factor receptor 2 (FGFR2) mutation may predispose individuals to craniosynostosis. Environmental factors, like fetal head constraint, may be required for the condition to manifest.
Area of Science:
- Genetics
- Developmental Biology
- Medical Research
Background:
- Craniosynostosis, a condition of premature skull fusion, has known genetic links to FGFR and TWIST genes in syndromic cases.
- A significant portion of non-syndromic craniosynostosis cases lack identified genetic causes, highlighting the need for further research.
Observation:
- A novel heterozygous FGFR2 mutation (Ala315Ser) was identified in a patient with non-syndromic unicoronal craniosynostosis.
- This mutation was also found in her mother and grandfather, who exhibited mild facial asymmetry but not craniosynostosis.
- The affected infant experienced fetal head constraint due to breech presentation, leading to skull compression at birth.
Findings:
- The identified FGFR2 mutation appears to confer only a predisposition to craniosynostosis.
- Environmental factors, specifically intrauterine fetal head constraint, seem necessary to trigger the condition in the presence of this mutation.
Implications:
- This study presents the first evidence of an interaction between a weakly pathogenic FGFR2 mutation and intrauterine constraint in causing craniosynostosis.
- Understanding gene-environment interactions is crucial for diagnosing and potentially preventing craniosynostosis.