Non-COL1A1/2 genetic burden and osteoporosis-overlap in patients referred with osteogenesis imperfecta phenotype

Patients referred with an osteogenesis imperfecta (OI) phenotype exhibit marked genetic heterogeneity, and a substantial proportion may harbor variants associated with early-onset osteoporosis (EOO) or OI-mimicking disorders rather than classical collagenopathies. This study aimed to define the genetic spectrum and non-COL1A1/2 variant burden in a cohort clinically diagnosed with OI.

Ninety-eight unrelated patients referred with a clinical diagnosis of OI were analyzed using a targeted NGS panel on the DNBSEQ-400 platform and, when indicated, whole-exome sequencing. Variants were classified according to ACMG/AMP guidelines, and copy-number variants were assessed by microarray (Affymetrix CytoScan Optima, Thermo Fisher Scientific). Genes were categorized as COL1A1/COL1A2-related or non-collagen bone fragility genes.

Seventy-two variants affecting 60 distinct loci were identified. While most pathogenic variants involved COL1A1 and COL1A2, a substantial proportion of patients (approximately one-quarter) carried variants in non-collagen genes including FKBP10, WNT1, P3H1, PLS3, and SERPINF1, which are known to be associated with early-onset osteoporosis and OI-overlap phenotypes. Several of these variants were detected in the heterozygous state and were incompatible with classical autosomal-recessive OI, supporting an osteoporosis-predominant or modifier-based disease model.

A significant proportion of patients referred with an OI phenotype genetically represent early-onset osteoporosis or OI-overlap disorders rather than true collagenopathies. Comprehensive NGS-based testing, including copy-number analysis and non-COL1A1/2 genes, enables accurate classification across the bone fragility spectrum and improves diagnostic yield.