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

Cathelijn J F Waaijer1, Marcel G T Winter, Christianne M A Reijnders

  • 1Department of Pathology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.

Genes, Chromosomes & Cancer
|January 24, 2013
PubMed

Insights

Multiple osteochondromas (MO) is a genetic disorder. A novel intronic deletion and duplication in the EXT1 gene was identified as a new cause of MO, missed by standard genetic testing.

Area of Science:

  • Genetics
  • Oncology
  • Molecular Biology

Background:

  • Multiple osteochondromas (MO) is a genetic disorder characterized by benign cartilage-capped neoplasms on long bones.
  • Most MO cases are linked to EXT1 or EXT2 gene mutations, but a subset remains genetically unexplained.

Purpose of the Study:

  • To investigate the genetic basis of MO in a family with unexplained cases.
  • To identify novel causative genetic alterations in MO beyond exonic mutations or copy number variations.

Main Methods:

  • Array comparative genomic hybridization (Array-CGH) was used to analyze the genomic DNA of affected family members.
  • Breakpoint analysis was performed to characterize the identified genomic alterations.

Main Results:

  • A novel germline genomic rearrangement at the EXT1 locus was identified in MO patients.
  • This rearrangement involved an 80.7 kb deletion of EXT1 Intron 1 and an 80.7 kb duplication proximal to EXT1.
  • A complex breakpoint within the intron suggested a direct insertion of the duplicated region into the deletion.

Conclusions:

  • Intronic deletion and duplication within the EXT1 gene represent a new causative mechanism for multiple osteochondromas.
  • These complex genomic rearrangements can be missed by conventional diagnostic methods focusing on exonic sequences.

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