Submission Details

COL1A2 was first reported in relation to autosomal dominant combined Osteogenesis Imperfecta Syndrome and Ehlers-Danlos/ syndrome (OIEDS) in 1997 (Nathanson et al.). Combined osteogenesis imperfecta and Ehlers-Danlos syndrome-2 (OIEDS2) 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 molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, osteogenesis imperfecta type II (OMIM:166210), osteogenesis imperfecta type III (OMIM:259420), osteogenesis imperfecta, type IV (OMIM:166220), Ehlers-Danlos syndrome, arthrochalasia type, 2 (OMIM:617821), Ehlers-Danlos syndrome, cardiac valvular type (OMIM:225320), and Osteoporosis, postmenopausal (OMIM:166710). The split curations have been curated separately. Fifteen variants (missense and splice site) that have been reported in 17 probands in six publications (PMIDs: 10694924, 23692737, 10982177, 11288717, 23692737) are included in this curation. The mechanism of pathogenicity is known to be loss of function due to interference with N-propeptide removal. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date 10/3/22 (SOP Version 9).