Multiple Epiphyseal Dysplasia via the COL9A3 Gene

Multiple epiphyseal dysplasia is a clinically and genetically heterogeneous chondrodysplasia with either autosomal dominant or recessive inheritance. Dominant MED presents early in childhood, usually with pain in the hips or knees after exercise. Waddling gait may be present. Adult height is either in the lower range of normal or mildly shortened. The limbs are relatively short in comparison to the trunk. Pain and joint deformity can progress, resulting in early-onset osteoarthritis (Briggs et al. GeneReviews 2011).

A number of genes are linked to autosomal dominant MED. A minority of dominant MED is caused by variants in the COL9A3 gene, which encodes the alpha 3 chain of type IX collagen, a minor component of cartilaginous tissues. Type IX collagen is an integral component of cartilage and comprises three collagenous domains (COL1-COL3) separated by four non-collagenous domains (NC1-NC4) and is closely associated with type II collagen fibrils, where it is thought to act as a molecular bridge between collagen fibrils and other cartilage matrix components. All the reported variants in COL9A3 are splice site variants, causing exon skipping in the COL3 domain, which may affect its ability to fold correctly or interact with other components of the cartilage extracellular matrix (Fresquet et al. J Biol Chem 282:34634–34643, 2007).

Variants in three type IX collagen genes (COL9A1, COL9A2, COL9A3) together account for probably ~10% of dominant MED cases (Briggs et al. GeneReviews 2011).

This test provides full coverage of all coding exons of the COL9A3 gene 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 full 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).