Whole exome sequencing identifies pathogenic variants and genotype-phenotype correlations in osteogenesis imperfecta

ObjectiveOsteogenesis imperfecta (OI) is a group of connective tissue disorders with significantly clinical and genetic heterogeneity, which is characterized by low bone mineral density, recurrent fractures and skeletal deformities. This study aimed to conduct clinical and genetic analyses in a Chinese OI cohort to expand the spectrum of pathogenic variants and provide evidence for precise genetic counseling and prenatal genetic diagnosis.MethodsA total of 77 Chinese families with clinically suspected OI were enrolled in this study. Clinical assessments at enrollment included physical examinations, X-ray imaging, and bone mineral density testing. Whole exome sequencing (WES) combined with Sanger sequencing was used to detect candidate pathogenic variants. Variant pathogenicity was evaluated via bioinformatics analysis and familial co-segregation analysis. In this OI cohort, the spectra of pathogenic variants, clinical phenotypes, and genotype-phenotype correlations were analyzed.ResultsA 100% detection rate for pathogenic variants was achieved in the 77 families, with 79 variants identified in total. Among the 79 variants, 21 (26.6%) were novel variants founded across six OI-associated genes. Interestingly, apart from the correlation between different pathogenic genes and clinical phenotypes, we also discovered that the severity and phenotype of patients associated with the location of pathogenic variants within the type I collagen domain, exhibiting an aggravating trend from the amino terminus to the carboxyl terminus.ConclusionBased on previous studies of large OI cohorts, we expanded the spectrum of pathogenic variants by identifying 21 novel ones. Meanwhile, we discovered that the location of pathogenic variants, particularly missense variants, in type I procollagen is correlated with the clinical manifestations and severity of patients. These findings will provide important evidence for the precise diagnosis and genetic counseling of the disease.