Phenotypic Spectrum and Molecular Basis in a Chinese Cohort of Osteogenesis Imperfecta With Mutations in Type I Collagen

Abstract

Osteogenesis imperfecta (OI) is a rare inherited connective tissue dysplasia characterized with skeletal fragility, recurrent fractures and bone deformity, predominantly caused by mutations in the genes COL1A1 or COL1A2 that encode the chains of type I collagen. In the present study, clinical manifestations and genetic variants were analysed from 187 Chinese OI patients, majority of whom are of southern Chinese origin. By targeted sequencing, 63 and 58 OI patients were found carrying mutations in COL1A1 and COL1A2 respectively, including 8 novel COL1A1 and 7 novel COL1A2 variants. We validated a novel splicing mutation in COL1A1. A diverse mutational and phenotypic spectrum was observed, coupling with the heterogeneity observed in the transcriptomic data derived from osteoblasts of six patients from our cohort. Missense mutations were significantly associated (χ2p = 0.0096) with a cluster of patients with more severe clinical phenotypes. Additionally, the severity of OI was more correlated with the quality of bones, rather than the bone mineral density. Bone density is most responsive to bisphosphonate treatment during the juvenile stage (10–15 years old). In contrast, height is not responsive to bisphosphonate treatment. Our findings expand the mutational spectrum of type I collagen genes and the genotype-phenotype correlation in Chinese OI patients. The observation of effective bisphosphonate treatment in an age-specific manner may help to improve OI patient management.

Patient-reported outcomes in a Chinese cohort of osteogenesis imperfecta unveil psycho-physical stratifications associated with clinical manifestations

“…The clinical manifestations of OI represent a continuum ranging from mild or moderate, to severe or perinatal lethal, which is in line with the diverse mutational spectrum observed in this condition [ 35 ]. Genetic mutations affecting collagen production, conformation and osteoblast differentiation cause skeletal deformity and joint dysfunction, leading to different levels of functional limitation and physical disability [ 39 ].…”

“…The peripheral blood samples of 72 patients were collected for genetic tests on a panel of OI-related genes (Methods). Genetic test results of 35 patients were recently published [ 35 ], while those of the remaining 37 patients were first reported in the current study (Additional file 3 ). We detected pathogenic variants in 11 genes, among which mutations in COL1A1 (n = 24, 33.3%) and COL1A2 (n = 19, 26.4%) accounted for a combined 59.7% (n = 43) (Additional file 3 ; Fig.…”

Comprehensive risk assessments and anesthetic management for children with osteogenesis imperfecta: A retrospective review of 252 orthopedic procedures over 5 years

“…The Sillence classifications in our cohort, part of which was recently published, 26 were scored by the physicians, according to published criteria 7,27 …”

“…The Sillence classifications in our cohort, part of which was recently published, 26 were scored by the physicians, according to published criteria. 7,27 To assess intraoperative temperature variations, we selected three key readings per surgery, including t init , t min , and t max , corresponding to the initial, minimum, and maximum temperatures, respectively.…”

Perthes Disease in a Child With Osteogenesis Imperfecta From a Rare Genetic Variant: A Case Report

“…Osteogenesis imperfecta (OI) is a rare disease which is characterized by brittle bone, blue sclerae and short stature (Schindeler et al, 2022). Most of the OIs result from mutations in the COL1A1 and COL1A2 genes (Chen et al, 2022). Type I collagen is widely present in the bone, skin and tendon tissue, and nowadays, OI is recognized as a collagen-related disorder (Kaneto et al, 2014;Li et al, 2019).…”