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Molecular diagnosis in children with fractures but no extraskeletal signs of osteogenesis imperfecta

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Abstract

Summary

In 26 of 94 individuals (28%) below 21 years of age who had a significant fracture history but did not have extraskeletal features of osteogenesis imperfecta (OI), we detected disease-causing mutations in OI-associated genes.

Introduction

In children who have mild bone fragility but do not have extraskeletal features of OI, it can be difficult to establish a diagnosis on clinical grounds. Here, we assessed the diagnostic yield of genetic testing in this context, by sequencing a panel of genes that are associated with OI.

Methods

DNA sequence analysis was performed on 94 individuals below 21 years of age who had a significant fracture history but had white sclera and no signs of dentinogenesis imperfecta.

Results

Disease-causing variants were detected in 28% of individuals and affected 5 different genes. Twelve individuals had mutations in COL1A1 or COL1A2, 8 in LRP5, 4 in BMP1, and 2 in PLS3.

Conclusions

DNA sequence analysis of currently known OI-associated genes identified disease-causing variants in more than a quarter of individuals with a significant fracture history but without extraskeletal manifestations of OI.

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Acknowledgments

FR received salary support from the Chercheur-Boursier Clinicien program of the Fonds de Recherche du Québec—Santé. LMW is supported by the Research Chair program at the University of Ottawa and the Departments of Pediatrics and Surgery, Children’s Hospital of Eastern Ontario. This study was supported by the Shriners of North America.

Web resources

Exome Aggregation Consortium (ExAC) Browser: http://exac.broadinstitute.org/.

Online Mendelian Inheritance in Man (OMIM), http://www.omim.org

Osteogenesis Imperfecta Variant Database: https://oi.gene.le.ac.uk/

UCSC database, version hg19: http://www.genome.ucsc.edu/

Author information

Authors and Affiliations

  1. Shriners Hospital for Children and McGill University, 1003 Decarie, Montreal, Québec, H4A 0A9, Canada

    G. Bardai, P. Trejo, P. Moffatt, F. H. Glorieux & F. Rauch

  2. Children’s Hospital of Eastern Ontario, Ontario, Canada

    L. M. Ward

Authors
  1. G. Bardai
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  2. L. M. Ward
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  3. P. Trejo
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  4. P. Moffatt
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  5. F. H. Glorieux
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  6. F. Rauch
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Contributions

GB performed analyses; LMW, PT and FHG contributed patient information; PM and FHG reviewed sequencing data; and FR conceptualized the project, contributed patient information, finalized the report, and accepts responsibility for the integrity of the data analysis. All authors have read and approved of the final version of the manuscript.

Corresponding author

Correspondence to F. Rauch.

Ethics declarations

Ethics statement

The study was approved by the Institutional Review Board of McGill University and the Research Ethics Board at the Children’s Hospital of Eastern Ontario.

Conflicts of interest

None.

Additional information

This study was supported by the Shriners of North America and the Fonds de recherche du Québec – Santé.

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Bardai, G., Ward, L.M., Trejo, P. et al. Molecular diagnosis in children with fractures but no extraskeletal signs of osteogenesis imperfecta. Osteoporos Int 28, 2095–2101 (2017). https://doi.org/10.1007/s00198-017-4031-2

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  • DOI: https://doi.org/10.1007/s00198-017-4031-2

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