COL1A1 was first reported in relation to autosomal dominant osteogenesis imperfecta type IV in 1989 (Marini et al., PMID: 2745420). 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. Twelve variants (missense and in-frame insertion-deletion) that have been reported in twelve probands in five publications (PMIDs: 2745420, 8456809, 9007315, 17078022, 35113812) are included in this curation meeting phenotypic criteria including short stature, fragile bones that fracture easily (before puberty), mild-moderate bone malformations, wormian bones, scoliosis/kyphosis, bowed limbs straighten with age, triangular face (some cases), hearing loss, otosclerosis, normal sclerae (common), and dentinogenesis imperfecta. Glycine substitutions in COL1A1 affect the triple helix structure formed by the pro-alpha 1(I) chains encoded by COL1A1 and the pro-alpha 2(I) chain encoded by COL2A1, and ultimately disrupt the function of type 1 collagen. This gene-disease relationship is also supported by mouse models recapitulating the human phenotype and molecular mechanism as well as functional alteration in patient cells (PMIDs: 3759085, 10608859, 15246109, 23802117). In summary, there is definitive evidence supporting the relationship between COL1A1 and autosomal dominant osteogenesis imperfecta type IV. 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 6, 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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