Submission Details

COL1A1 was first reported in relation to autosomal dominant Caffey Disease in 2005 (Gensure et al., PMID: 15864348). Caffey disease is characterized by an infantile episode of massive subperiosteal new bone formation that typically involves the diaphyses of the long bones, mandible, and clavicles. Painful swelling and systemic fever often accompany the episode, which usually begins before the age of 5 months and resolves before age 2 years. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, osteogenesis imperfecta, type I (OMIM:166200), osteogenesis imperfecta, type II (OMIM:166210), osteogenesis imperfecta, type III (OMIM:259420), osteogenesis imperfecta, type IV (OMIM:166220), Ehlers-Danlos Syndrome, arthrochalasia type, 1 (OMIM:130060), combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 (OMIM:619115), Ehlers-Danlos Syndrome, classic type, 1 (not associated with COL1A1 in OMIM), and Caffey disease (OMIM:114000). The split curations have been curated separately. Two variants (c.3040C>T; p.Arg1014Cys and c.2752C>T; p.Arg918Cys) that have been reported in 40 probands in 7 publications (PMIDs: 15864348, 17309652, 18704262, 21249479, 21567126, 24390061, 34272483) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (11.9/12 pts.) has been reached. COL1A1-related Caffey disease is most frequently caused by the c.3040C>T (p.Arg1014Cys) variant (previously known as p.Arg836Cys), believed to disrupt specific type I collagen-ligand interaction (PMID: 24389367). This gene-disease association is also supported by expression throughout the skeletal system and functional alteration in patient cells (PMIDs: 15864348, 19669491, 34272483). In summary, COL1A1 is definitively associated with autosomal dominant Caffey Disease. 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 11/2/2022 (SOP Version 9).

COL1A1 was first reported in relation to autosomal dominant Caffey Disease in 2005 (Gensure et al., PMID: 15864348). Caffey disease is characterized by an infantile episode of massive subperiosteal new bone formation that typically involves the diaphyses of the long bones, mandible, and clavicles. Painful swelling and systemic fever often accompany the episode, which usually begins before the age of 5 months and resolves before age 2 years. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, COL1A1-related osteogenesis imperfecta (types I-IV, OMIM:166200, OMIM:166210, OMIM:259420, OMIM:166220), COL1A1-related Ehlers-Danlos syndrome (lumped Ehlers-Danlos Syndrome, arthrochalasia type, 1 (OMIM:130060), combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 (OMIM:619115), Ehlers-Danlos Syndrome, classic type, 1 (not associated with COL1A1 in OMIM)), and Caffey disease (OMIM:114000). The split curations have been curated separately. Two variants (c.3040C>T; p.Arg1014Cys and c.2752C>T; p.Arg918Cys) that have been reported in 40 probands in 7 publications (PMIDs: 15864348, 17309652, 18704262, 21249479, 21567126, 24390061, 34272483) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (11.9/12 pts.) has been reached. COL1A1-related Caffey disease is most frequently caused by the c.3040C>T (p.Arg1014Cys) variant (previously known as p.Arg836Cys), believed to disrupt specific type I collagen-ligand interaction (PMID: 24389367). This gene-disease association is also supported by expression throughout the skeletal system and functional alteration in patient cells (PMIDs: 15864348, 19669491, 34272483). In summary, COL1A1 is definitively associated with autosomal dominant Caffey Disease. 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 11/2/2022 (SOP Version 9).