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Diagnostic utility of next-generation sequence genetic panel testing in children presenting with a clinically
Jennifer Harrington1, Abdulmajeed AlSubaihin2, Lucie Dupuis3
1Division of Endocrinology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada. jenny.harrington@sa.gov.au.
Insights
Genetic panel testing detects causative variants in osteogenesis imperfecta (OI) in 35% of children with fractures. Early femur fractures or fractures before age two are key predictors for identifying these genetic causes.
Area of Science:
- Genetics
- Pediatrics
- Orthopedics
Background:
- Osteogenesis imperfecta (OI) is a group of genetic disorders characterized by bone fragility and fractures.
- Genetic panel testing, particularly next-generation sequencing (NGS), has emerged as a valuable tool for diagnosing genetic conditions.
- Accurate genetic diagnosis is crucial for appropriate management and counseling of patients with OI.
Purpose of the Study:
- To evaluate the diagnostic utility of NGS genetic panel testing in children presenting with a history of multiple fractures.
- To identify clinical predictors associated with the detection of pathogenic variants in genes related to OI.
Main Methods:
- Retrospective observational study involving 87 children with multiple long bone or vertebral fractures.
- Exclusion of subjects with a known family history of OI.
- Analysis of associations between genetic findings and clinical characteristics, including fracture history and skeletal/extra-skeletal features.
Main Results:
- Pathogenic variants were identified in 35% of the children studied.
- Detection rates were significantly higher in children with extra-skeletal features of OI (94%) compared to those without (20%).
- Clinical predictors for variant detection included a first fracture before age two (OR 5.5) and a history of femur fracture (OR 3.3).
Conclusions:
- NGS genetic panel testing is effective in diagnosing pathogenic variants in up to one-third of children with significant fracture histories.
- Early-onset fractures, particularly femur fractures, are strong indicators for genetic testing in suspected OI cases.
- Genetic testing aids in identifying the underlying cause of fractures in children, guiding clinical management.
Abstract:
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.
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