Submission Details

COL2A1 was first reported in relation to autosomal dominant spondyloperipheral dysplasia in 1996 (Zabel et al., PMID: 8723097). Spondyloperipheral dysplasia is a disorder that impairs bone growth. This condition is characterized by flattened bones of the spine (platyspondyly) and unusually short fingers and toes (brachydactyly), with the exception of the first (big) toes. Other skeletal abnormalities associated with spondyloperipheral dysplasia include short stature, shortened long bones of the arms and legs, exaggerated curvature of the lower back (lordosis), and an inward- and upward-turning foot (clubfoot). Additionally, some affected individuals have nearsightedness (myopia), hearing loss, and intellectual disability. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, COL2A1-related spondyloepiphyseal dysplasia (OMIM:609162, OMIM:183900, OMIM:184254, OMIM:184250), dysplasia of the proximal femoral epiphyses (OMIM:608805, OMIM:150600), spondyloperipheral dysplasia (OMIM:271700), Stickler syndrome type 1 (OMIM:108300), Kniest dysplasia (OMIM:156550), Achondrogenesis type II (OMIM:200610), and platyspondylic skeletal dysplasia, Torrance type (OMIM:151210). The split curations have been curated separately. 7 variants (nonsense, frameshift, and canonical splice site) that have been reported in 7 probands in 6 publications (PMIDs: 15316962, 15895462, 17347327, 21356074, 23545312, 25604898) are included in this curation. The Zabel publication includes an additional proband which cannot be scored due to accession errors (PMID: 8723097). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. COL2A1 was shown to be normally expressed in the extracellular matrix surrounding chondrocytes, marrow cells, osteoblasts, fibroblasts and some osteocytes, in addition to chondrocytes in otic capsule (PMIDs: 3033664, 7806485). In summary, there is definitive evidence to support the relationship between COL2A1 and autosomal dominant spondyloperipheral 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 10/4/21 (SOP version 9).

COL2A1 was first reported in relation to autosomal dominant spondyloperipheral dysplasia in 1996 (Zabel et al., PMID: 8723097). Spondyloperipheral dysplasia is a disorder that impairs bone growth. This condition is characterized by flattened bones of the spine (platyspondyly) and unusually short fingers and toes (brachydactyly), with the exception of the first (big) toes. Other skeletal abnormalities associated with spondyloperipheral dysplasia include short stature, shortened long bones of the arms and legs, exaggerated curvature of the lower back (lordosis), and an inward- and upward-turning foot (clubfoot). Additionally, some affected individuals have nearsightedness (myopia), hearing loss, and intellectual disability. 7 variants (nonsense, frameshift, and canonical splice site) that have been reported in 7 probands in 6 publications (PMIDs: 15316962, 15895462, 17347327, 21356074, 23545312, 25604898) are included in this curation. The Zabel publication includes an additional proband which cannot be scored due to accession errors (PMID: 8723097). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Notably, COL2A1 has been definitively associated with Achondrogenesis type 2-hypochondrogenesis, Platyspondylic dysplasia, Spondyloepiphyseal dysplasia congenita, and Kniest dysplasia after curation by the ClinGen Skeletal Disorders GCEP. This gene has also been associated with SED with metatarsal shortening (Czech dysplasia), Stickler syndrome type I, and Dysplasia of the proximal femoral epiphyses (PMID: 31633310), which will be assessed separately. The mechanism of pathogenicity is known to be loss of function. COL2A1 was shown to be normally expressed in the extracellular matrix surrounding chondrocytes, marrow cells, osteoblasts, fibroblasts and some osteocytes, in addition to chondrocytes in otic capsule (PMIDs: 3033664, 7806485). In summary, there is definitive evidence to support the relationship between COL2A1 and autosomal dominant spondyloperipheral 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 10/4/21 (SOP version 9).