GSE186141
Phenotypic spectrum and molecular basis in a Chinese cohort of osteogenesis imperfecta with mutations in type I collagen
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 188 Chinese OI patients, majority of which are of southern China origin. By targeted sequencing, 64 and 58 OI patients were found carrying mutations in COL1A1 and COL1A2 respectively, including 12 novel COL1A1 and 8 novel COL1A2 variants. We identified a COL1A1 hotspot (c.G2461A; p.G821S) in 8 patients and validated two novel splicing mutations. A diverse mutational and phenotypic spectrum was observed, coupling with heterogeneity observed in the transcriptomic data (n=6) derived from osteoblasts of our cohort. Missense mutations were significantly associated (?2 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 (BP) treatment during the juvenile stage (10-15 y/o). 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 BP treatment in an age-specific manner may help to improve OI patient management. Overall design: We conducted bulk transcriptomic profiling on osteoblasts derived from 6 OI individuals with Collagen 1 mutations and two non-OI samples