Multiple Epiphyseal Dysplasia and Stickler Syndrome, Autosomal Recessive, via the COL9A2 Gene

Multiple epiphyseal dysplasia (MED) 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. Adult height is either in the lower range of normal or mildly shortened (Briggs et al. GeneReviews 2011). Stickler syndrome (STL) is a multisystem connective tissue disorder that may include ocular findings of myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial underdevelopment and cleft palate (either alone or as part of the Robin sequence); and mild spondyloepiphyseal dysplasia or precocious arthritis (Robin et al. GeneReviews, 2010). STL has been described with both dominant and recessive forms. The recessive form of STL is very rare (Van Camp et al. Am J Hum Genet 79: 449-457, 2006; Baker et al. Am J Med Genet 155A: 1668-1672, 2011).

A number of genes are linked to autosomal dominant MED and STL. Rare cases of dominant MED and recessive STL are caused by variants in the COL9A2 gene, which encodes the alpha 2 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 COL9A2 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).

The clinical sensitivity for COL9A2-related MED or STL is currently unknown.

This test provides full coverage of all coding exons of the COL9A2 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).