COMP has been first reported in association with autosomal dominant COMP-related skeletal dysplasia in 1993 (Hecht et al., PMID: 8307577). COMP has also been associated with multiple epiphyseal dysplasia and pseudoachondroplasia. There is no clear locus specificity of variation within the gene to determine a clear genotype-phenotype correlation and there is substantial phenotypic overlap between the two disease entities. Therefore, per criteria outlined by the ClinGen Lumping and Splitting guidelines, they have been lumped as one disease entity, COMP-related skeletal dysplasia. Evidence supporting this gene-disease relationship includes case-level, segregation, and experimental data.
At least 15 unique variants (missense, inframe indels) in COMP have been identified in 15 patients with skeletal dysplasia in 10 publications (PMIDs: 8307577, 9388247, 21644213, 21922596, 27330822, 29899997, 26920793, 21965141, 11565064, 15756302). Additionally, variants in COMP segregated with disease in 15 additional family members (PMIDs: 8307577, 11565064, 15756302, 26920793). This gene-disease relationship is supported by mouse models, expression studies, and in vitro functional assays (PMIDs: 20578249, 18576344, 11084047, 12801484, 17570134, 22006726, 10753957, 1556121). In summary, COMP is definitively associated with autosomal dominant COMP-related skeletal dysplasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the Skeletal Disorders Gene Curation Expert Panel on the meeting date February 28th, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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