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DNA sequence analysis in 598 individuals with a clinical diagnosis of osteogenesis imperfecta: diagnostic yield and mutation spectrum

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Abstract

Summary

We detected disease-causing mutations in 585 of 598 individuals (98 %) with typical features of osteogenesis imperfecta (OI). In mild OI, only collagen type I encoding genes were involved. In moderate to severe OI, mutations in 12 different genes were found; 11 % of these patients had mutations in recessive genes.

Introduction

OI is usually caused by mutations in COL1A1 or COL1A2, the genes encoding collagen type I alpha chains, but mutations in at least 16 other genes have also been associated with OI. It is presently unknown what proportion of individuals with clinical features of OI has a disease-causing mutation in one of these genes.

Methods

DNA sequence analysis was performed on 598 individuals from 487 families who had a typical OI phenotype. OI type I was diagnosed in 43 % of individuals, and 57 % had moderate to severe OI, defined as OI types other than type I.

Results

Disease-causing variants were detected in 97 % of individuals with OI type I and in 99 % of patients with moderate to severe OI. All mutations found in OI type I were dominant and exclusively affected COL1A1 or COL1A2. In moderate to severe OI, dominant mutations were found in COL1A1/COL1A2 (77 %), IFITM5 (9 %), and P4HB (0.6 %). Mutations in one of the recessive OI-associated gene were observed in 12 % of individuals with moderate to severe OI. The genes most frequently involved in recessive OI were SERPINF1 (4.0 % of individuals with moderate to severe OI) and CRTAP (2.9 %).

Conclusions

DNA sequence analysis of currently known OI-associated genes identifies disease-causing variants in almost all individuals with a typical OI phenotype. About 20 % of individuals with moderate to severe OI had mutations in genes other than COL1A1/COL1A2.

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Acknowledgments

We thank Patty Mason for technical assistance and Mark Lepik for the preparation of the figures. F.R. received salary support from the Chercheur-Boursier Clinicien program of the Fonds de Recherche du Québec-Santé. This study was supported by the Shriners of North America and the Fonds de recherche Québec-Santé.

Roles of the authors

GB performed analyses. FHG contributed patient information. PM revised manuscript content. 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 the final version of the manuscript.

Conflicts of interest

Ghalib Bardai, Pierre Moffatt, Francis H Glorieux, and Frank Rauch declare that they have no conflict of interest.

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, H3G 1A6, Québec, Canada

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

Authors
  1. G. Bardai
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  2. P. Moffatt
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  3. F. H. Glorieux
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  4. F. Rauch
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Corresponding author

Correspondence to F. Rauch.

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Bardai, G., Moffatt, P., Glorieux, F.H. et al. DNA sequence analysis in 598 individuals with a clinical diagnosis of osteogenesis imperfecta: diagnostic yield and mutation spectrum. Osteoporos Int 27, 3607–3613 (2016). https://doi.org/10.1007/s00198-016-3709-1

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  • DOI: https://doi.org/10.1007/s00198-016-3709-1

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