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.
(c) 2008 Wiley-Liss, Inc.