Hereditary Multiple Osteochondromas (HMO) Panel

Hereditary multiple osteochondromas, also known as hereditary multiple exostoses (OMIM#133700 for type I and #133701 for type II), are benign cartilage-capped bone tumors (exostoses) that grow outward from the metaphyses of long bones. Osteochondromas can be associated with a reduction in skeletal growth, bony deformity, restricted joint motion, shortened stature, premature osteoarthrosis, and compression of peripheral nerves (Schmale et al. GeneReviews. 2008). The lifetime risk for malignant osteochondrosarcoma is low (1-5%), but the risk increases with age (Vink et al. Eur J Hum Genet 13:470-474, 2005).

HMO is inherited as an autosomal dominant trait with high penetrance (~95%). About 10% of affected individuals have HMO as the result of a de novo variant. Two genes (EXT1 and EXT2) are known to be associated with HMO. A possible third locus is thought to account for a small number of cases, but the gene has not yet been identified. Both EXT gene products (exostosin-1, exostosin-2) are involved in the biosynthesis of heparan sulfate. EXT1 and EXT2 encode glycosyltransferases that interact as heterooligomeric complexes and participates in cell signaling and chondrocyte proliferation and differentiation (McCormick et al. Proc Natl Acad Sci 97:668–673, 2000). EXT1 variants account for 56-78% of HMO cases, and EXT2 variants account for 21-44% of HMO cases (Schmale et al. GeneReviews 2008). In both genes, most of reported variants are nonsense, frameshift, and splice site variants. Individuals with EXT1 variants were found to have a greater number of exostoses, a greater incidence of limb malalignment with shorter limb segments and height, and more frequent pelvic and flat bone involvement than those with EXT2 variants (Alvarez et al. Clin Genet 70:122–130, 2006). The risk of chondrosarcoma may also be higher in individuals with an EXT1 variant (Porter et al. J Bone Joint Surg Br 86:1041–1046, 2004).

Combining EXT1 and EXT2, this test is predicted to detect disease variants in 70-85% of affected individuals with HMO (Schmale et al. GeneReviews 2008). Large deletions that are not detectable by sequencing may be found in up to 10% of patients with HMO (Vink et al. Eur J Hum Genet 13:470-474, 2005).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).