Diagnostic utility of next-generation sequence genetic panel testing in children presenting with a clinically significant fracture history

We assessed the diagnostic utility of genetic panel testing to detect pathogenic variants associated with osteogenesis imperfecta in children presenting with multiple fractures. Thirty-five percent of children had a pathogenic variant. A history of a femur fracture or a first fracture occurring under 2 years of age were significant clinical predictors.

Purpose: The use of next-generation sequencing (NGS) genetic panels offers a comprehensive rapid diagnostic test to evaluate for pathogenic variants in the expanding list of genes associated with osteogenesis imperfecta (OI). We aimed to assess the diagnostic utility of this method in children with a clinically significant fracture history.

Methods: NGS panel testing was performed in 87 children presenting with multiple long bone or vertebral fractures. Subjects with a known family history of OI were excluded. Associations between genetic findings and clinical characteristics were analyzed in a retrospective observational study.

Results: Thirty-five percent of patients were found to have a disease-causing variant, with a higher detection rate in those patients with extra-skeletal features of OI (94 vs. 20%, p < 0.001). In subjects with extra-skeletal clinical OI features, 69% were found to have pathogenic variants in COL1A1 or COL1A2. In children without extra-skeletal features, 14 of 70 (20%) had pathogenic variants, of which 7 were variants in type 1 collagen, and the remaining 7 variants were associated with osteoblast function or signaling (PLS3, SP7, LRP5). Clinical predictors for detecting a disease-causing variant included a history of having a first fracture that occurred under 2 years of age (Odds ratio 5.5, 95%CI 1.8, 16.9) and a history of a femur fracture (Odds ratio 3.3, 95%CI 1.0, 11.1).

Conclusion: NGS panel testing will detect causative pathogenic variants in up to a third of children with a clinically significant fracture history, particularly where there is a history of early femur fracture.