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Copy-number variation
Original Article
Assessment of the incorporation of CNV surveillance into gene panel next-generation sequencing testing for inherited retinal diseases
  1. Jamie M Ellingford1,2,
  2. Bradley Horn1,
  3. Christopher Campbell1,
  4. Gavin Arno3,
  5. Stephanie Barton1,
  6. Catriona Tate4,
  7. Sanjeev Bhaskar1,
  8. Panagiotis I Sergouniotis1,
  9. Rachel L Taylor1,2,
  10. Keren J Carss5,6,
  11. Lucy F L Raymond6,7,
  12. Michel Michaelides3,8,
  13. Simon C Ramsden1,
  14. Andrew R Webster3,8,
  15. Graeme C M Black1,2
  1. 1 Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Manchester University NHS Foundation Trust, St Mary’s Hospital, Manchester, UK
  2. 2 Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
  3. 3 Department of Genetics, UCL Institute of Ophthalmology, London, UK
  4. 4 Congenica, Wellcome Genome Campus, Hinxton, Cambridge, UK
  5. 5 Department of Haematology, University of Cambridge NHS Blood and Transplant Centre, Cambridge, UK
  6. 6 Department of NIHR BioResource – Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK
  7. 7 Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
  8. 8 Moorfields Eye Hospital NHS Foundation Trust, London, UK
  1. Correspondence to Graeme C M Black, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, St Mary’s Hospital, Manchester M13 9WL, UK; graeme.black{at}manchester.ac.uk

Abstract

Background Diagnostic use of gene panel next-generation sequencing (NGS) techniques is commonplace for individuals with inherited retinal dystrophies (IRDs), a highly genetically heterogeneous group of disorders. However, these techniques have often failed to capture the complete spectrum of genomic variation causing IRD, including CNVs. This study assessed the applicability of introducing CNV surveillance into first-tier diagnostic gene panel NGS services for IRD.

Methods Three read-depth algorithms were applied to gene panel NGS data sets for 550 referred individuals, and informatics strategies used for quality assurance and CNV filtering. CNV events were confirmed and reported to referring clinicians through an accredited diagnostic laboratory.

Results We confirmed the presence of 33 deletions and 11 duplications, determining these findings to contribute to the confirmed or provisional molecular diagnosis of IRD for 25 individuals. We show that at least 7% of individuals referred for diagnostic testing for IRD have a CNV within genes relevant to their clinical diagnosis, and determined a positive predictive value of 79% for the employed CNV filtering techniques.

Conclusion Incorporation of CNV analysis increases diagnostic yield of gene panel NGS diagnostic tests for IRD, increases clarity in diagnostic reporting and expands the spectrum of known disease-causing mutations.

  • copy-number variation
  • next-generation sequencing
  • molecular genetics
  • inherited retinal disease

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1136/jmedgenet-2017-104791

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    Footnotes

    • Contributors JME and GCMB designed and coordinated the study. All authors contributed genetic and/or phenotypic data. JME wrote the manuscript, and all authors provided important revisions and intellectual content.

    • Funding This work was supported by the Biotechnology and Biological Sciences Research Council Biotechnology and Biological Sciences Research Council [grant code BB/J014478/1], the Manchester Biomedical Research Centre, the National Institute for Health Research Biomedical Centre at Moorfields Eye Hospital and the UCL Institute of Ophthalmology, RP Fighting Blindness and Fight for Sight (RP Genome Project GR586), the Cambridge Biomedical Research Centre, and an independent research grant funded by the Manchester Academic Health Science Centre.

    • Competing interests CT is an employee of Congenica Ltd. All other authors declare no competing interests.

    • Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

    • Ethics approval Greater Manchester West Research Ethics Committee.

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

    • Correction notice This article has been corrected since it was published Online First. A typo has been corrected.