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 (χ2 p = 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.
Highlights
Osteogenesis imperfecta (OI), known as “brittle bone disease”, is a group of hereditary connective-tissue disorders with an incidence of ∼1:15,000 births (Lindahl et al, 2015)
Physical inspections for typical OI traits, including blue sclerae, limb deformity, dentinogenesis imperfecta, scoliosis, joint laxity, flat feet, basilar invagination, etc. were recorded, which shall be discussed in later sections
We analyzed the pathogenic variants in the type I collagen of 187 patients diagnosed with OI, and revealed the correlation between genotype and phenotype
Summary
Osteogenesis imperfecta (OI), known as “brittle bone disease”, is a group of hereditary connective-tissue disorders with an incidence of ∼1:15,000 births (Lindahl et al, 2015). Patients with OI are more susceptible to long bone fractures and generally characterized by various degrees of bone deformity, blue sclerae, dentinogenesis imperfecta, scoliosis, hearing loss in young adulthood and decreased pulmonary function (Forlino et al, 2011; Marini et al, 2017). Patients with type III OI present multiple fractures and progressive skeletal deformities during the neonatal period. Type IV OI shows variable degrees of bone deformity with a severity intermediate between type I and III. This classical grading system has been re-defined, adding type V OI characterized by unique interosseous ossification, radial head dislocation and hyperplastic callus formation (Van Dijk and Sillence, 2014)
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