Molecular and clinical findings in Osteogenesis Imperfecta: A cohort study from a single tertiary center

Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous skeletal fragility disorder. Although COL1A1/COL1A2 variants account for most cases, non-COL1A genes and overlapping monogenic bone fragility conditions complicate diagnosis and genotype-phenotype interpretation in routine practice. We aimed to describe the clinical spectrum and molecular findings of patients evaluated for suspected or confirmed OI at a tertiary referral center, and to assess phenotype patterns across genotype-informed groups.

We conducted a single-center retrospective cohort study at Ankara City Hospital. Pediatric and adult patients evaluated for suspected/confirmed OI were included. Clinical, radiologic, and treatment data were extracted from medical records. All patients underwent targeted next-generation sequencing panel testing, and variants were interpreted according to ACMG criteria. Findings were summarized descriptively and analyzed across COL1A1/COL1A2, non-COL1A OI-associated genes, and non-OI bone-related genes.

Forty-two individuals were included (age range at genetic evaluation: 0.1-47 years). The most common referral indication was recurrent long-bone fractures (81.0%), while 31.0% presented with or additional vertebral compression fractures and/or osteoporosis. Variants in OI-associated genes were identified in 30/42 patients (71.4%); 23/42 (54.7%) had molecularly confirmatory pathogenic/likely pathogenic variants in established OI-associated genes. Among genetically confirmed OI cases, 17/23 (73.9%) involved COL1A1/COL1A2. In the non-COL1A subgroup, biallelic pathogenic/likely pathogenic variants were found in CRTAP, P3H1, and FKBP10 (n=5), and one patient had a heterozygous WNT1 variant. Seven patients (16.7%) had negative panel results. At last follow-up, 83.3% were independently ambulatory.

In this tertiary-center cohort, integrating phenotype with molecular testing improved diagnostic stratification in suspected OI and highlighted the predominance of COL1A-related disease. However, the continued clinical relevance of VUS and panel-negative results underscores the need for broader second-tier genetic testing and periodic reanalysis in cases where clinical suspicion persists.