COL1A1 was first reported in relation to AD osteogenesis imperfecta in 1986 (Cohn et al., PMID: 3016737). Osteogenesis imperfecta is a disorder of connective tissues characterized by increased susceptibility to bone fractures and decreased bone density. 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 (osteogenesis imperfecta, type I, MIM:166200; osteogenesis imperfecta, type II, MIM:166210; osteogenesis imperfecta, type III, MIM:259420; osteogenesis imperfecta, type IV, MIM:166220) have been lumped into one disease entity, osteogenesis imperfecta. The split curations for Caffey disease and COL1A1-related Ehlers-Danlos syndrome have been curated separately.
11 missense, 4 frameshift, 3 splicing, 1 nonsense variants that have been reported in 19 probands in 6 publications (PMIDs: 3016737, 7942841, 25633413, 35113812, 17078022, 31653500) 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 disease is reported to be haploinsufficiency or dominant negative. This gene-disease association is also supported by experimental evidence including three mouse models, three expression studies, and a biochemical function study (PMIDs: 10608859, 2450280, 24443344, 6519194, 28206959, 19669491, 16407265). In summary, there is definitive evidence supporting the relationship between COL1A1 and AD osteogenesis imperfecta. 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 June 6th, 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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