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

Abstract

BackgroundSignalling by fibroblast growth factor receptor type 2 (FGFR2) normally involves a tissue-specific alternative splice choice between two exons (IIIb and IIIc), which generates two receptor isoforms (FGFR2b and FGFR2c respectively) with differing repertoires of FGF-binding specificity. Here we describe a unique chimeric IIIb/c exon in a patient with Apert syndrome, generated by a non-allelic homologous recombination event.Case PresentationWe 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.ConclusionsBased 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.

Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants

“…To date, only four other FGFR2 mutations in five patients have been reported. [22][23][24][25][26] The entire coding region of FGFR2, and deletions or Alu events in FGFR2 have been excluded.…”

What does acne genetics teach us about disease pathogenesis?

“…51 The disorder is caused by gain-of-function mutations in FGFR2, which encodes the receptor tyrosine kinase fibroblast growth factor receptor 2. [52][53][54][55][56] In total 98% of patients carry one of the two predominant mutations in exon 7 of FGFR2 that were originally identified in 39 unrelated families and subsequently confirmed in a larger cohort of 260 patients. 50,52,57 The two predominant mutations in exon 7 are in an extracellular linker region between Ig-like domains II and III.…”

“…Apert syndrome causes a severe acne phenotype that is indistinguishable from its sporadic counterpart, responding to treatment with retinoids and oral contraceptives . The disorder is caused by gain‐of‐function mutations in FGFR2 , which encodes the receptor tyrosine kinase fibroblast growth factor receptor 2 . In total 98% of patients carry one of the two predominant mutations in exon 7 of FGFR2 that were originally identified in 39 unrelated families and subsequently confirmed in a larger cohort of 260 patients .…”

The Fibroblast Growth Factor signaling pathway

“…For example, the Crouzon syndrome mutation, FGFR2 C342Y , affects the shape of the brain, but not its overall volume. 629 The biochemical consequences of the classic Apert syndrome mutations (FGFR2 S252W and FGFR2 P253R ) and a relatively rare Alu element insertion, or deletion of an intronic splicing element in the intron between exon 8 (IIIb) and exon 9 (IIIc) of FGFR2 is to change the ligand binding affinity to an extent that mesenchymal ligands such as FGF10 are able to activate mesenchymal splice variants of FGFR2 575,630 (Figure 5(b)). Importantly, the Apert mutations all remain ligand dependent.…”