Breakpoint characterization of large deletions in EXT1 or EXT2 in 10 Multiple Osteochondromas families

Here we report on the first molecular characterization of ten large EXT1- and EXT2-deletions in MO-patients. Deletions were initially indentified using MLPA or FISH analysis and were subsequently characterized using an MO-specific tiling path array, allele-specific PCR-amplification and sequencing analysis.Within the set of ten large deletions, the deleted regions ranged from 2.7 to 260 kb. One EXT2 exon 8 deletion was found to be recurrent. All breakpoints were located outside the coding exons of EXT1 and EXT2. Non-allelic homologous recombination (NAHR) mediated by Alu-sequences, microhomology mediated replication dependent recombination (MMRDR) and non-homologous end-joining (NHEJ) were hypothesized as the causal mechanisms in different deletions.Molecular characterization of EXT1- and EXT2-deletion breakpoints in MO-patients indicates that NAHR between Alu-sequences as well as NHEJ are causal and that the majority of these deletions are nonrecurring. These observations emphasize once more the huge genetic variability which is characteristic for MO. To our knowledge, this is the first study characterizing large genomic deletions in EXT1 and EXT2.Osteochondromas (cartilage-capped bone tumors) are by far the most commonly treated of all primary benign bone tumors (50%) [1]. Most osteochondromas appear as solitary, nonhereditary lesions, but in 15% of cases these tumors occur as multiple lesions in the context of multiple osteochondromas (MO) [2] (OMIM 133700-133701), previously known as osteocartilaginous exostosis or multiple hereditary exostosis (MHE/HME). The prevalence of this autosomal dominant skeletal disorder is estimated to be 1/50.000 in the Western population [3]. MO is characterized by the formation of multiple osteochondromas mainly arising from the growth plate area in the juxta-epiphyseal region of long tubular bones. These bone neoplasmas are caused by an increased chondrocyte proliferation and bone growth at children's metaphyses [4]. During the fi