Multiple Epiphyseal Dysplasia and Stickler Syndrome, Autosomal Recessive via the COL9A1 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). At least three types of autosomal dominant and one type of autosomal recessive Stickler syndrome have been described. The autosomal recessive form of STL is very rare (Van Camp et al. Am J Hum Genet 79: 449-457, 2006).

Rare cases of dominant MED and autosomal recessive STL are caused by variants in the COL9A1 gene. COL9A1 encodes the alpha 1 chain of type IX collagen, a quantitatively minor component of cartilaginous tissues. Homozygous or compound heterozygous COL9A1 variants result in loss of function of collagen alpha-1(IX) chain. The STL-associated COL9A1 variant is a nonsense variant in the reported case (Van Camp et al. Am J Hum Genet 79:449-457, 2006), while the MED-associated variant is a splice site variant (Czarny-Ratajczak et al. Am J Hum Genet 69:969-980, 2001).

The clinical sensitivity for COL9A1-related Stickler syndrome or MED is currently unknown.

This test provides full coverage of all coding exons of the COL9A1 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).