title: Rare mutations of FGFR2 causing apert syndrome: identification of the first partial gene deletion, and an Alu element insertion from a new subfamily.
abstract: Apert syndrome (AS) is a severe disorder, characterized by craniosynostosis and complex syndactyly of the hands and feet. Two heterozygous gain-of-function substitutions (Ser252Trp and Pro253Arg) in exon IIIa of fibroblast growth factor receptor 2 (FGFR2) are responsible for >98% of cases. Here we describe two novel mutations in FGFR2 in the two patients in whom a mutation had not previously been found in our cohort of 227 AS cases. The first is a 1.93-kb deletion, removing exon IIIc and substantial portions of the flanking introns. This is the first large FGFR2 deletion described in any individual with craniosynostosis. The other mutation is a 5' truncated Alu insertion into exon IIIc. This is the third Alu insertion identified in AS; all have occurred within an interval of only 104 bp, representing an enrichment of over a million-fold compared to the background genomic rate. We show that the inserted Alu element belongs to a small subfamily, not previously known to be mobile, which we term Alu Yk13. Both the deletion and insertion are likely to act by a similar gain-of-function mechanism in which disruption of exon IIIc leads to illegitimate mesenchymal expression of an FGFR2 spliceform containing the alternatively spliced exon IIIb. All the AS-associated Alu insertions have arisen in the paternal germline; we propose that their enrichment in FGFR2 is driven by positive selection of the mutant spermatogonial progenitors, a mechanism analogous to that explaining why the canonical AS nucleotide substitutions also reach exceptionally high levels in sperm.
authors: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors: Elena G
authors: EG
authors: Bochukova
authors: Tony
authors: T
authors: Roscioli
authors: Dale J
authors: DJ
authors: Hedges
authors: Indira B
authors: IB
authors: Taylor
authors: David
authors: D
authors: Johnson
authors: David J
authors: DJ
authors: David
authors: Prescott L
authors: PL
authors: Deininger
authors: Andrew O M
authors: AO
authors: Wilkie
mesh_terms: D000168:Acrocephalosyndactylia / Q000175:diagnosis / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D020087:Alu Elements / Q000235:genetics*; D020029:Base Pairing; D001483:Base Sequence; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005220:Fathers; D017353:Gene Deletion; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*
chemical_list: D051497:Receptor, Fibroblast Growth Factor, Type 2