Genotype–phenotype correlations in 294 pediatric patients with osteogenesis imperfecta

Osteogenesis imperfecta (OI) is an inherited disorder characterized by bone fragility with extraskeletal manifestations mostly due to <i>COL1A1</i> and <i>COL1A2</i> variants. Currently, 23 genes have been implicated in the pathogenesis of OI; however, literature on genotype-phenotype correlation and incidence of non-skeletal clinical features are limited. This study aims to identify genotype-phenotype correlations in patients with OI, allowing clinicians to better inform families of prognosis, optimize patient care, and facilitate evidence-based clinical decision-making. We retrospectively reviewed 294 patients with OI to collect demographic data, clinical characteristics, and genotypic information. Patients were stratified by <i>COL1A1/1A2</i> vs non-<i>COL1A1/1A2</i> variants to evaluate differences in phenotype. The majority of OI was due to variants in <i>COL1A1/1A2</i> (91%), with the remaining 9% due to non-<i>COL1A1/1A2</i> variants. Most patients in the <i>COL1A1/2</i> group were White compared to the non-<i>COL1A1/2</i> group (78% vs 50%; <i>p</i> = 0.004). <i>COL1A/1A</i>2 patients had higher incidence of blue sclerae (83% vs 58%, <i>p</i> = 0.002), dentinogenesis imperfecta (49% vs 15%, <i>p</i> < 0.001), and family history of OI (34% vs 12%, <i>p</i> = 0.03). Those in the non-<i>COL1A1/1A2</i> group have higher rates of scoliosis compared to those in the <i>COL1A1/1A2</i> group (62% vs 40%, <i>p</i> = 0.04), as well as higher rates of expressive language disorder/delay (15% vs 0.4% in non-<i>COL1A1/1A2</i> and <i>COL1A1/1A2</i> patients, respectively; <i>p</i> < 0.001). Identifying the underlying molecular etiology early is imperative for optimal clinical care, allowing for appropriate risk counseling, identification of affected relatives, and improved anticipatory care and management. These data support that rare subtypes of OI occur more frequently in non-White individuals and demonstrated genetic associations with incidence of blue sclera, dentinogenesis imperfecta, scoliosis, and expressive language disorders.