Article Text

Download PDFPDF
Non-collagen pathogenic variants resulting in the osteogenesis imperfecta phenotype in children: a single-country observational cohort study
  1. Patrick Thornley1,
  2. Nicholas Bishop2,3,
  3. Duncan Baker4,
  4. Joanna Brock4,
  5. Paul Arundel3,
  6. Christine Burren5,
  7. Sarah Smithson6,
  8. Catherine DeVile7,
  9. Belinda Crowe7,
  10. Jeremy Allgrove8,
  11. Vrinda Saraff9,
  12. Nick Shaw9,10,
  13. Meena Balasubramanian2,3,11
  1. 1The University of Sheffield Faculty of Medicine Dentistry and Health, Sheffield, UK
  2. 2Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK
  3. 3Highly Specialised Osteogenesis Imperfecta Service, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK
  4. 4Sheffield Diagnostic Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK
  5. 5Department of Paediatric Endocrinology and Diabetes, Bristol Royal Hospital for Children, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
  6. 6Department of Clinical Genetics, St Michaels Hospital, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
  7. 7Department of Neurosciences, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
  8. 8Department of Endocrinology, Great Ormond Street Hospital For Children NHS Foundation Trust, London, UK
  9. 9Department of Endocrinology and Diabetes, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK
  10. 10Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
  11. 11Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK
  1. Correspondence to Dr Meena Balasubramanian, Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK; m.balasubramanian{at}


Background/Objectives In England, children (0–18 years) with severe, complex and atypical osteogenesis imperfecta (OI) are managed by four centres (Birmingham, Bristol, London, Sheffield) in a ‘Highly Specialised Service’ (HSS OI); affected children with a genetic origin for their disease that is not in COL1A1 or COL1A2 form the majority of the ‘atypical’ group, which has set criteria for entry into the service. We have used the data from the service to assess the range and frequency of non-collagen pathogenic variants resulting in OI in a single country.

Methods Children with atypical OI were identified through the HSS OI service database. All genetic testing for children with OI in the service were undertaken at the Sheffield Diagnostic Genetics Service. Variant data were extracted and matched to individual patients. This study was done as part of a service evaluation project registered with the Sheffield Children’s Hospital Clinical Governance Department.

Results One hundred of 337 children in the HSS met the ‘atypical’ criteria. Eighty have had genetic testing undertaken; 72 had genetic changes detected, 67 in 13 genes known to be causative for OI. The most frequently affected genes were IFITM5 (22), P3H1 (12), SERPINF1 (8) and BMP1 (6).

Conclusion Among children with more severe forms of OI (approximately one-third of all children with OI), around 20% have pathogenic variants in non-collagen genes. IFITM5 was the most commonly affected gene, followed by genes within the P3H1 complex. These data provide additional information regarding the likelihood of different genetic origins of the disease in children with OI, which may influence clinical care.

  • paediatrics
  • genetics
  • epidemiology
  • child health

Data availability statement

Data are available upon reasonable request. Data can be made publicly available on request.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Data availability statement

Data are available upon reasonable request. Data can be made publicly available on request.

View Full Text


  • Contributors NB, PT and MB conceived the study and established the study design. PT collated and analysed all the data. All authors contributed to data collection and manuscript write-up and approved the final manuscript. NB and MB take full responsibility for overall content and act as guarantor for the data included in this manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.