Genotype and Phenotype of 198 Korean Patients With Nonlethal Osteogenesis Imperfecta: A Retrospective Cohort Study

Abstract

Osteogenesis imperfecta (OI) is a heterogeneous group of genetic skeletal disorders characterized by bone fragility and low bone mass, manifesting as multiple fractures and deformities of the spine and extremities. Although genotype-phenotype correlations have been studied in various populations, large-scale data in Koreans have been lacking. This study is aimed at characterizing the clinical and genetic spectrum of nonlethal OI in the Korean population and explore genotype–phenotype associations. This retrospective cohort study analyzed 198 genetically confirmed Korean OI probands evaluated at a single center between 2004 and 2024, with clinical features reviewed and genetic testing performed using Sanger sequencing and targeted next-generation sequencing. A total of 160 distinct pathogenic variants were identified, including 44 novel variants. Variant pathogenicity was assessed according to the ACMG/AMP variant classification guidelines. Pathogenic variants of COL1A1 and COL1A2 accounted for 87.4% of cases, with COL1A1 variants being the most prevalent (66.7%). Only 4.0% of cases had autosomal recessive OI. Glycine substitution (GS) variants were associated with significantly more severe phenotypes than other variants, including shorter height (median z-score−3.67 [IQR −8.37 to −1.78] vs. −1.17 [−1.96 to −0.16], p < 0.001) and earlier fracture onset (1.00 [0.00–8.25] vs. 15.00 [7.00–24.75] months, p < 0.001). In COL1A1, GS variants closer to the C-terminus correlated with significantly more severe height reduction (Spearman ρ = −0.478, p = 0.005). The genotype–phenotype analysis confirmed the phenotypic severity of GS, particularly for variants closer to the C-terminus of COL1A1, consistent with previous studies. Additionally, the identification of 44 novel variants expands the variant spectrum of OI. These findings provide valuable insights into genetic diagnosis, prognostic assessment, and clinical management of OI.