Gene mutation spectrum and genotype-phenotype correlation in a cohort of Chinese osteogenesis imperfecta patients revealed by targeted next generation sequencing

Summary The achievement of more accurate diagnosis would greatly benefit the management of patients with osteogenesis imperfecta (OI). In this study, we present the largest OI sample in China as screened by next generation sequencing. In particular, we successfully identified 81 variants, which included 45 novel variants. We further did a genotype-phenotype analysis, which helps make a better understanding of OI. Introduction This study aims to reveal the gene mutation spectrum and the genotype-phenotype relationship among Chinese OI patients by next generation sequencing (NGS). Methods We developed a NGS-based panel for targeted sequencing of all exons of 14 genes related to OI, and performed diagnostic gene sequencing for a cohort of 103 Chinese OI patients from 101 unrelated families. Mutations identified by NGS were further confirmed by Sanger sequencing and co-segregation analysis. Results Of the 103 patients from 101 unrelated OI families, we identified 79 mutations, including 43 novel mutations (11 frameshift, 17 missense, 5 nonsense, 9 splice site, and 1 chromosome translocation) in 90 patients (87.4%). Mutations in genes encoding type I collagen, COL1A1 ( n = 37), and COL1A2 ( n = 29) accounts for 73.3% of all molecularly diagnosed patients, followed by IFITM5 ( n = 9, 10%), SERPINF1 ( n = 4, 4.4%), WNT1 ( n = 4, 4.4%), FKBP10 ( n = 3, 3.3%), TMEM38B ( n = 3, 3.3%), and PLOD2 ( n = 1, 1.1%). This corresponds to 75 autosomal dominant inherited (AD) OI patients and 15 autosomal recessive (AR) inherited patients. Compared with AD inherited OI patients, AR inherited patients had lower bone mineral density (BMD) at spine ( P = 0.05) and less frequent blue sclera ( P = 0.001). Patients with type I collagen qualitative defects had lower femoral neck BMD Z-score ( P = 0.034) and were shorter compared with patients with type I collagen quantitative defects ( P = 0.022). Conclusion We revealed the gene mutation spectrum in Chinese OI patients, and novel mutations identified here expanded the mutation catalog and genotype and phenotype relationships among OI patients.