title: Intronic deletion and duplication proximal of the EXT1 gene: a novel causative mechanism for multiple osteochondromas.
abstract: Multiple osteochondromas (MO) is a syndrome in which benign cartilage-capped neoplasms develop at the surface of the long bones. Most cases are caused by exonic changes in EXT1 or EXT2, but 15% are negative for these changes. Here we report for the first time a family of MO patients with germline genomic alterations at the EXT1 locus without detectable mutations or copy number alterations of EXT exonic sequences. Array-CGH showed an 80.7 kb deletion of Intron 1 of EXT1 and a 68.9 kb duplication proximal of EXT1. We identified a breakpoint between the distal end of the duplicated region and a sequence distal of the deleted region in the first intron. This breakpoint was absent in non-affected family members. The configuration of the breakpoint indicates a direct insertion of the duplicated region into the deletion. However, no other breakpoint was found, which suggests a more complex genomic rearrangement has occurred within the duplicated region. Our results reveal intronic deletion and duplication as a new causative mechanism for MO not detected by conventional diagnostic methods.
authors: Department of Pathology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
authors: Cathelijn J F
authors: CJ
authors: Waaijer
authors: Marcel G T
authors: MG
authors: Winter
authors: Christianne M A
authors: CM
authors: Reijnders
authors: Daniëlle
authors: D
authors: de Jong
authors: S
authors: S
authors: John Ham
authors: Judith V M G
authors: JV
authors: Bovée
authors: Károly
authors: K
authors: Szuhai
mesh_terms: D001483:Base Sequence; D004252:DNA Mutational Analysis; D005097:Exostoses, Multiple Hereditary / Q000235:genetics* / Q000473:pathology; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics*; D008297:Male; D017351:N-Acetylglucosaminyltransferases; D010375:Pedigree; D000099058:Exostosin 1
chemical_list: D017351:N-Acetylglucosaminyltransferases; D000099058:Exostosin 1