Submission Details

COL9A1 was first reported in relation to autosomal recessive Stickler Syndrome in 2006 (Van Camp et al., PMID: 16909383). This condition is characterized by moderate-to-severe hearing loss, which may be progressive and accompanied by ocular phenotypes (including vision issues, retinal degeneration, vitreous anomalies) and skeletal features (including epiphyseal dysplasia). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found clear differences in inheritance pattern and phenotypes. Therefore, the following disease entities have been split into two disease entities, Stickler Syndrome (OMIM: 614134) and multiple epiphyseal dysplasia (OMIM: 614135). The split curation for multiple epiphyseal dysplasia will be evaluated separately. 8 variants (missense, nonsense, frameshift) that have been reported in at least 8 probands in 6 publications (PMIDs: 16909383, 21421862, 31315069, 33951325, 36597107, 39406934) are included in this curation. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence (mouse models, expression-level data; PMIDs: 8197187, 8464901, 15802199; gEAR expression database). Mouse models indicate that mutants have hearing loss, cochlear structural anomalies, and skeletal anomalies. Expression-level evidence in mice shows strong expression throughout the cochlea. In summary, there is definitive evidence supporting the relationship between COL9A1 and autosomal recessive Stickler Syndrome. 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 Hearing Loss GCEP on the meeting date 10/8/2025 (SOP Version 11).