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

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Abstract

Summary

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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Data availability

Data has not been deposited in a data repository.

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Authors and Affiliations

  1. Division of Endocrinology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada

    Jennifer Harrington

  2. Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia

    Abdulmajeed AlSubaihin

  3. Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada

    Lucie Dupuis, Peter Kannu & Roberto Mendoza-Londono

  4. Division of Orthopedics, The Hospital for Sick Children, University of Toronto, Toronto, Canada

    Andrew Howard

Authors
  1. Jennifer Harrington
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  2. Abdulmajeed AlSubaihin
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  3. Lucie Dupuis
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  4. Peter Kannu
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  5. Roberto Mendoza-Londono
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  6. Andrew Howard
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Contributions

All authors were involved in the conception and design of the project, critically revised the manuscript and approved the final version to be published. JH and AA were also involved in data acquisition and analysis.

Corresponding author

Correspondence to Jennifer Harrington.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Research and Ethics Board at the Hospital for Sick Children. Approval to waive the need for informed consent to participate was given by the Hospital for Sick Children’s Ethics Committees, given the retrospective nature of the chart review.

Consent for publication

Approval to waive the need for informed consent to publish was given by the Hospital for Sick Children’s Ethics Committees, given the retrospective nature of the chart review.

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None.

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Harrington, J., AlSubaihin, A., Dupuis, L. et al. Diagnostic utility of next-generation sequence genetic panel testing in children presenting with a clinically significant fracture history. Arch Osteoporos 16, 88 (2021). https://doi.org/10.1007/s11657-021-00943-4

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  • DOI: https://doi.org/10.1007/s11657-021-00943-4

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