COMP – COMP-related Multiple Epiphyseal Dysplasia

Multiple epiphyseal dysplasia (MED) is an autosomal dominant skeletal dysplasia characterized by delayed and irregular ossification of the epiphyses, joint pain, and early‐onset osteoarthritis. Heterozygous mutations in the cartilage oligomeric matrix protein (COMP) gene account for >60% of AD-MED cases, establishing COMP as a primary locus for MED (PMID:32460719).

Inheritance is autosomal dominant with strong cosegregation: for example, a four‐generation Chinese family with 10 affected members demonstrated perfect co‐segregation of a novel COMP variant with disease in 9 additional relatives (PMID:32460719). Across >20 unrelated families (>60 probands), COMP mutations cluster in calmodulin-like repeat domains, and no protein-truncating variants have been reported (PMID:9463320; PMID:15756302).

The mutation spectrum is dominated by missense changes in the calcium‐binding type III repeats; a recurrent example is c.1153G>T (p.Asp385Tyr), which segregates with MED in multiple pedigrees (PMID:32460719).

Functional assays reveal that MED-associated COMP mutants have impaired calcium binding and reduced affinity for collagens I, II, and IX, leading to dominant‐negative disruption of extracellular matrix assembly. Recombinant D361Y and Asp374del variants bind fewer calcium ions and show attenuated collagen interactions in vitro (PMID:10852928; PMID:11084047).

No studies have refuted the COMP–MED relationship, and consistent genotype–phenotype correlations underscore the pathogenicity of CLR-domain missense variants.

Together, genetic and experimental evidence meet ClinGen definitive criteria, confirming that dominant‐negative COMP missense variants cause MED. Genetic testing for COMP enables precise diagnosis, prognostic counseling, and informs therapeutic development.

Key take‐home: COMP missense variants in calmodulin‐like repeats are definitively implicated in autosomal dominant MED, supporting routine COMP analysis in MED diagnostic panels.

References

• BMC medical genetics • 2020 • A novel COMP mutation in a Chinese family with multiple epiphyseal dysplasia. PMID:32460719
• American journal of human genetics • 1998 • Diverse mutations in the gene for cartilage oligomeric matrix protein in the pseudoachondroplasia-multiple epiphyseal dysplasia disease spectrum. PMID:9463320
• European journal of human genetics • 2005 • COMP mutation screening as an aid for the clinical diagnosis and counselling of patients with a suspected diagnosis of pseudoachondroplasia or multiple epiphyseal dysplasia. PMID:15756302
• The Journal of Biological Chemistry • 2000 • Cartilage oligomeric matrix protein is a calcium-binding protein, and a mutation in its type 3 repeats causes conformational changes. PMID:10852928
• The Journal of Biological Chemistry • 2001 • Mutations in cartilage oligomeric matrix protein causing pseudoachondroplasia and multiple epiphyseal dysplasia affect binding of calcium and collagen I, II, and IX. PMID:11084047

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