Open Access Case report

Apparently synonymous substitutions in FGFR2 affect splicing and result in mild Crouzon syndrome

Aimee L Fenwick1, Jacqueline AC Goos2, Julia Rankin3, Helen Lord4, Tracy Lester4, A Jeannette M Hoogeboom5, Ans MW van den Ouweland5, Steven A Wall6, Irene MJ Mathijssen2 and Andrew OM Wilkie16*

Author Affiliations

1 Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford OX3 9DS, UK

2 Department of Plastic and Reconstructive Surgery and Hand Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

3 Clinical Genetics Department, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK

4 Genetics Laboratories, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, UK

5 Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

6 Craniofacial Unit, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, UK

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BMC Medical Genetics 2014, 15:95  doi:10.1186/s12881-014-0095-4

Published: 31 August 2014



Mutations of fibroblast growth factor receptor 2 (FGFR2) account for a higher proportion of genetic cases of craniosynostosis than any other gene, and are associated with a wide spectrum of severity of clinical problems. Many of these mutations are highly recurrent and their associated features well documented. Crouzon syndrome is typically caused by heterozygous missense mutations in the third immunoglobulin domain of FGFR2.

Case presentation

Here we describe two families, each segregating a different, previously unreported FGFR2 mutation of the same nucleotide, c.1083A>G and c.1083A>T, both of which encode an apparently synonymous change at the Pro361 codon. We provide experimental evidence that these mutations affect normal FGFR2 splicing and document the clinical consequences, which include a mild Crouzon syndrome phenotype and reduced penetrance of craniosynostosis.


These observations add to a growing list of FGFR2 mutations that affect splicing and provide important clinical information for genetic counselling of families affected by these specific mutations.

Craniosynostosis; Crouzon syndrome; Expressivity; FGFR2; Penetrance; Splicing; Synonymous substitution