Intronic deletion and duplication proximal of the EXT1 gene: a novel causative mechanism for multiple osteochondromas

Genes Chromosomes Cancer. 2013 Apr;52(4):431-6. doi: 10.1002/gcc.22041. Epub 2013 Jan 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • DNA Mutational Analysis
  • Exostoses, Multiple Hereditary / genetics*
  • Exostoses, Multiple Hereditary / pathology
  • Family Health
  • Female
  • Gene Deletion*
  • Gene Duplication*
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Introns / genetics*
  • Male
  • N-Acetylglucosaminyltransferases
  • Pedigree

Substances

  • N-Acetylglucosaminyltransferases
  • exostosin-1