COMP-Related Disorders via the COMP Gene

Pseudoachondroplasia (PSACH) (OMIM #177170) is characterized by normal length at birth and normal facies. Often the presenting feature is a waddling gait, recognized at the onset of walking. Typically, approximately by the age of two years, the growth rate falls below the standard growth curve, leading to a moderately severe form of disproportionate short-limb short stature (Cohn GeneReviews 2010). Joint pain, particularly in the large joints of the lower extremities, is common. Degenerative joint disease in PSACH is progressive and will eventually require hip replacement. Multiple epiphyseal dysplasia is a clinically and genetically heterogeneous chondrodysplasia with either autosomal dominant or recessive inheritance. Please refer to the MED panel description for more information.

Pseudoachondroplasia (PSACH) is inherited in an autosomal dominant manner with complete penetrance. COMP gene is the only gene associated with PSACH and is the major gene responsible for dominant multiple epiphyseal dysplasia (MED). The majority of COMP variants are missense variants and small in-frame deletions and duplications found in exons 8-14 (encoding the eight calmodulin-like calcium-binding repeats) or exons 15-19 (encoding the carboxyl-terminal globular domain) (Briggs et al. Am J Hum Genet 62:311–319, 1998; Briggs & Chapman Hum Mutat 19:465–478, 2002; Mabuchi et al. Hum Genet 112:84–90, 2003). Approximately 30% of individuals with PSACH have the same recurrent variant: a deletion of a single GAC codon in exon 13 (p.Asp473del) corresponding to the seventh calmodulin-like calcium-binding repeat domain of the protein (Hecht et al. Nat Genet 10:325–329, 1995). COMP encodes cartilage oligomeric matrix protein, a multifunctional structural protein that is composed of an amino-terminal coiled-coil domain, four type II (EGF-like) repeats, eight type III (calmodulin-like calcium binding) repeats, and a carboxyl-terminal globular domain. The type III repeats cooperatively bind calcium, and the globular domain interacts with both fibrillar (types I, II, and III) and non-fibrillar (type IX) collagens. COMP is a homopentameric adhesive glycoprotein found predominantly in the cartilage extracellular matrix (Hedbom et al. J Biol Chem 267:6132–6136, 1992) and also in tendon and ligament. It is the fifth member of the thrombospondin protein family and is also known as thrombospondin 5 (TSP5).

This test is predicted to detect disease variants in >99% of clinically confirmed cases of PSACH (Briggs & Chapman Hum Mutat 19:465–478, 2002; Kennedy et al. Eur J Hum Genet 13:547-555, 2005) and about 70% of cases with dominant MED (Briggs et al. GeneReviews 2011).

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