COL1A1 was first reported in relation to autosomal dominant combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 (EDS/OI) in 2005 (Cabral et al., PMID: 15728585). Combined osteogenesis imperfecta and Ehlers-Danlos syndrome-1 (OIEDS1) is an autosomal dominant generalized connective tissue disorder characterized by features of both osteogenesis imperfecta (bone fragility, long bone fractures, blue sclerae) and Ehlers-Danlos syndrome (joint hyperextensibility, soft and hyperextensible skin, abnormal wound healing, easy bruising, vascular fragility). 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 eight 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. Ten variants (missense) that have been reported in eleven probands in four publications (PMIDs: 15728585, 17078022, 17206620, 23692737) are included in this curation. The mechanism of pathogenicity is known to be due to interference with N-propeptide removal (PMID: 23692737). This gene-disease association is also supported by evidence supporting abnormal biochemical function consistent with disease, expression studies throughout the skeletal system, tendons, ligaments, and sclerae, and a mouse model recapitulating the human phenotype (animal models, expression studies, biochemical function studies) (PMIDs: 6519194, 16407265, 19669491, 24443344, 28206959). In summary, there is definitive evidence supporting the relationship between COL1A1 and autosomal dominant combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1. 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 September 7, 2022 (SOP Version 9).
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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.