COL1A1 was first reported in relation to autosomal dominant Ehlers-Danlos Syndrome, arthrochalasia type, 1 in 1986 (Cole et al., PMID: 3082886). Arthrochalasia-type EDS is distinguished from other types of EDS by the frequency of congenital hip dislocation and extreme joint laxity with recurrent joint subluxations and minimal skin involvement. 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. Six variants (missense, in-frame indel, canonical splice site) that have been reported in eight probands in five publications (PMIDs: 1867198, 3082886, 9295084, 18409203, 32091183) 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 alteration of the N-proteinase cleavage site necessary for proper collagen processing (PMID: 18409203). This gene-disease association is also supported by variants in patients affecting the N-proteinase cleavage site, expression throughout the skeletal system, tendons, and ligaments, and functional alterations in patient collagen fibrils (biochemical function, expression studies, and functional alteration) (PMIDs: 18409203, 19233756, 19669491, 24443344, 28206959). In summary, COL1A1 is definitively associated with autosomal dominant Ehlers-Danlos Syndrome, arthrochalasia type, 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 8/1/22 (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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