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Paternal origin of FGFR3 mutations in Muenke-type craniosynostosis


Muenke syndrome, also known as FGFR3-associated coronal synostosis, is defined molecularly by the presence of a heterozygous nucleotide transversion, c.749C>G, encoding the amino acid substitution Pro250Arg, in the fibroblast growth factor receptor type 3 gene (FGFR3). This frequently occurs as a new mutation, manifesting one of the highest documented rates for any transversion in the human genome. To understand the biology of this mutation, we have investigated its parental origin, and the ages of the parents, in 19 families with de novo c.749C>G mutations. All ten informative cases originated from the paternal allele (95% confidence interval 74–100% paternal); the average paternal age at birth overall was 34.7 years. An exclusive paternal origin of mutations, and increased paternal age, were previously described for a different mutation (c.1138G>A) of the FGFR3 gene causing achondroplasia, as well as for mutations of the related FGFR2 gene causing Apert, Crouzon and Pfeiffer syndromes. We conclude that similar biological processes are likely to shape the occurrence of this c.749C>G mutation as for other mutations of FGFR3 as well as FGFR2.

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We are very grateful to the families for their participation in this study, Dr. J. Hoogeboom (Rotterdam), Dr. R. Newbury-Ecob and Dr. L. Mauceri for referral of families, A.L.W. Janssen for the original mutation analysis of the Dutch cases, and E. Bochukova, A. Goriely and R Hansen for comments on the manuscript. This work was supported by the Wellcome Trust (AOMW).

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Correspondence to Andrew O. M. Wilkie.

Additional information

S.V. Rannan-Eliya and I.B. Taylor contributed equally to this work.

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Rannan-Eliya, S.V., Taylor, I.B., de Heer, I.M. et al. Paternal origin of FGFR3 mutations in Muenke-type craniosynostosis. Hum Genet 115, 200–207 (2004). https://doi.org/10.1007/s00439-004-1151-5

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  • Craniosynostosis
  • Achondroplasia
  • Amplification Refractory Mutation System
  • Single Nucleotide Polymorphism Allele
  • Paternal Origin