A deletion of FGFR2 creating a chimeric IIIb/IIIc exon in a child with Apert syndrome

We present a child with Apert syndrome in whom routine genetic testing had excluded the FGFR2 missense mutations commonly associated with this disorder. The patient was found to harbour a heterozygous 1372 bp deletion between FGFR2 exons IIIb and IIIc, apparently originating from recombination between 13 bp of identical DNA sequence present in both exons. The rearrangement was not present in the unaffected parents.Based on the known pathogenesis of Apert syndrome, the chimeric FGFR2 protein is predicted to act in a dominant gain-of-function manner. This is likely to result from its expression in mesenchymal tissues, where retention of most of the residues essential for FGFR2b binding activity would result in autocrine activation. This report adds to the repertoire of rare cases of Apert syndrome for which a pathogenesis based on atypical FGFR2 rearrangements can be demonstrated.Apert syndrome (AS) is a severe malformation disorder with a birth prevalence of ~1 in 65,000, characterised by craniosynostosis (premature fusion of the cranial sutures) and bony or cutaneous syndactyly of the hands and feet [1]. Over 98% of cases are caused by one of two heterozygous mutations in exon IIIa of the fibroblast growth factor receptor 2 gene (FGFR2), encoding the amino acid substitutions Ser252Trp or Pro253Arg (Figure 1A; [2]). Many other pathogenic missense mutations of FGFR2 have been described in patients with craniosynostosis (typically with diagnoses of Crouzon, Pfeiffer or Beare-Stevenson syndromes) but these are associated with less severe abnormalities of the limbs than are present in Apert syndrome [3]. FGFR2 is one of four transmembrane FGFRs that mediate signalling downstream of fibroblast growth factor ligands (FGFs) and plays an important role in skeletal development and disease [4].The mechanism underlying the exquisite genotype-phenotype correlation of Apert syndrome mutations (Figure 1A) needs to be understood in terms of the biology of FGF/receptor signalling an