Molecular spectrum of autosomal recessive osteogenesis imperfecta in 93 Italian children with bone fragility: a monocentric experience

Purpose: Osteogenesis imperfecta (OI) usually follows an autosomal dominant inheritance pattern. We aimed to explore the epidemiological impact of autosomal recessive OI in a pediatric population and expand the mutational repertoire in this cohort. Methods: We presented our six-year (2018–2024) monocentric next-generation sequencing diagnostic activity on 93 unrelated children with a suspicion of OI. Variants were classified according to the American College of Medical Genetics and Genomics recommendations. Results: (Likely) pathogenic variants (PLP) or variants of uncertain significance were identified in 61.3% cases (57/93), with conclusive results (i.e. a heterozygous PLP in dominant genes, or biallelic PLP in recessive genes) in 59.1% (55/93). According to age, the rate of conclusive results was 84.0% (21/25), 52.7% (24/46) and 45.4% (10/22) in individuals aged 0–3 years, 4–12 years and 13–16 years, respectively. Six individuals out of 55 (11.0%) with conclusive results had biallelic PLP variants in autosomal recessive genes, among which we found three novel variants in SERPINF1 and WNT1, and confirmed OI as a possible phenotype due to PLOD2 abnormalities. Conclusions: In our cohort of 93 Italian patients with a suspicion of OI, autosomal recessive OI was epidemiologically significant. Such a diagnostic perspective represents the prerequisite to combine multiprofessional and extended genetic testing assessments in children with OI to improve their diagnosis, management and treatment.