Submission Details

CCN6 was first reported in relation to autosomal recessive progressive pseudorheumatoid dysplasia (PPRD) in 1999 (Hurvitz et al. 1999 PMID: 10471507). PPRD is characterized by healthy at birth, onset of arthropathy early in childhood, usually between ages three and six years, enlargement of interphalangeal joints of hands, progressive restricted mobility of all joints, gait abnormalities, genu valgum / genu varum, progressive hip disease, articular pain, motor weakness and fatigability, spine involvement in late childhood and adolescence with thoracolumbar kyphoscoliosis that leads to short trunk, adult height below the third centile, and absence of signs of inflammation. To date more than 200 families with molecularly confirmed PPRD have been reported. Only one disease assertion has been made thus far therefore we curate the following disease entity progressive pseudorheumatoid arthropathy of childhood (MONDO:0008827, OMIM:208230). 29 variants (11 frameshift, 9 missense, 5 nonsense, 4 splice site) that have been reported in 50 probands in 2 publications (PMID: 12819927, 22791401) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of CCN6 protein function which likely disrupts normal cartilage maintenance and bone growth, leading to the joint problems in PPRD. In summary, there is definitive evidence supporting the relationship between CCN6 and autosomal recessive PPRD. 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 ClinGen Skeletal Disorders GCEP on the meeting date 09/04/2024 (SOP Version 10).