Splice‑site variant c.3531+1G>T in COL1A1 in a family with osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by high genetic and phenotypic heterogeneity. Notably, 90% of cases of OI are caused by pathogenic variants in the COL1A1 and COL1A2 genes, with those in COL1A1 being the most common. The present study aimed to investigate the genetic etiology of OI in a family and the pathogenicity of the splice‑site variant. Whole‑exome sequencing was performed for the proband and Sanger sequencing was performed for all family members to validate the results. Reverse transcription (RT)‑PCR on lymphocyte strains was performed on the proband and an age‑matched control, and minigene experiments were performed to verify the splicing patterns. A heterozygous variant, c.3531+1G>T, was detected in COL1A1 in all patients in the family. RT‑PCR showed an increase in abnormal transcript expression and a decrease in normal transcript expression in the proband. Minigene splicing assays revealed that the mutant gene exhibited four splicing patterns, whereas the normal gene exhibited three splicing patterns. This finding indicated that the c.3531+1G>T variant site affected intron 47 splicing. To the best of our knowledge, this variant was first reported in the Palestinian population, whereas the present study is the first to report this variant in the Chinese population and to clarify the effect of this variant. The results expand the spectrum of pathogenic variants associated with OI.