COL1A1 was first reported in relation to AD COL1A1-related Ehlers-Danlos syndrome in 1986 (Cole et al., PMID: 3082886). COL1A1-related Ehlers-Danlos syndrome is a connective tissue disorder characterized by skin hyperextensibility, abnormal wound healing, and joint hypermobility, with or without congenital hip dislocation, extreme joint laxity, and osteogenesis imperfecta. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities (Ehlers-Danlos syndrome, classic type, 1, MIM: 130000; Ehlers-Danlos syndrome, arthrochalasia type, 1, MIM: 130060; Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1, MIM:619115) have been lumped into one disease entity, COL1A1-related Ehlers-Danlos syndrome. The split curations for Caffey disease and osteogenesis imperfecta have been curated separately.
8 missense, 3 splicing, and one indel variants that have been reported in 18 probands in 4 publications (PMIDs: 3082886, 15728585, 32091183, 34265140) 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 is known to be due to interference with N-propeptide removal or alteration of the N-proteinase cleavage site necessary for proper collagen processing (PMIDs: 23692737, 18409203). This gene-disease association is also supported by experimental evidence including a mouse model, three expression studies, two biochemical function studies, and functional alteration in patient cells (PMIDs: 24443344, 6519194, 28206959, 19669491, 16407265, 19233756, 18409203). In summary, there is definitive evidence supporting the relationship between COL1A1 and COL1A1-related Ehlers-Danlos 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 Skeletal Disorders GCEP on the meeting date October 3rd, 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).
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