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Diagnostics
Original article
Clinical genetic testing using a custom-designed steroid-resistant nephrotic syndrome gene panel: analysis and recommendations
  1. Ethan S Sen1,2,
  2. Philip Dean3,
  3. Laura Yarram-Smith3,
  4. Agnieszka Bierzynska1,
  5. Geoff Woodward3,
  6. Chris Buxton3,
  7. Gemma Dennis3,
  8. Gavin I Welsh1,
  9. Maggie Williams3,
  10. Moin A Saleem1,2
  1. 1 Bristol Renal, School of Clinical Sciences, University of Bristol, Bristol, UK
  2. 2 Bristol Royal Hospital for Children, Bristol, UK
  3. 3 Bristol Genetics Laboratory, Southmead Hospital, Bristol, UK
  1. Correspondence to Professor Moin A Saleem, Bristol Renal, School of Clinical Sciences, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY; M.Saleem{at}bristol.ac.uk

Abstract

Background There are many single-gene causes of steroid-resistant nephrotic syndrome (SRNS) and the list continues to grow rapidly. Prompt comprehensive diagnostic testing is key to realising the clinical benefits of a genetic diagnosis. This report describes a bespoke-designed, targeted next-generation sequencing (NGS) diagnostic gene panel assay to detect variants in 37 genes including the ability to identify copy number variants (CNVs).

Methods This study reports results of 302 patients referred for SRNS diagnostic gene panel analysis. Phenotype and clinical impact data were collected using a standard proforma. Candidate variants detected by NGS were confirmed by Sanger sequencing/Multiplex Ligation-dependent Probe Amplification with subsequent family segregation analysis where possible.

Results Clinical presentation was nephrotic syndrome in 267 patients and suspected Alport syndrome (AS) in 35. NGS panel testing determined a likely genetic cause of disease in 44/220 (20.0%) paediatric and 10/47 (21.3%) adult nephrotic cases, and 17/35 (48.6%) of haematuria/AS patients. Of 71 patients with genetic disease, 32 had novel pathogenic variants without a previous disease association including two with deletions of one or more exons of NPHS1 or NPHS2.

Conclusion Gene panel testing provides a genetic diagnosis in a significant number of patients presenting with SRNS or suspected AS. It should be undertaken at an early stage of the care pathway and include the ability to detect CNVs as an emerging mechanism for genes associated with this condition. Use of clinical genetic testing after diagnosis of SRNS has the potential to stratify patients and assist decision-making regarding management.

  • Podocyte
  • Steroid-resistant nephrotic syndrome
  • Next generation sequencing
  • Alport syndrome
  • Gene panel testing
  • SRNS
  • Focal segmental glomerulosclerosis
  • FSGS

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-2017-104811

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    Footnotes

    • Contributors MW and MAS conceived and designed the study. ESS, PD and LY-S collected and analysed the clinical data. PD, LY-S, AB, GW, CB, GD and MW performed the genetic analysis. ESS and PD created the tables and figures. ESS, PD and MW wrote the first draft of the manuscript. ESS, PD, AB, GIW, MW and MAS were involved in manuscript editing. All authors read and approved the final version.

    • Funding ESS is funded by a National Institute for Health Research (NIHR) Rare Diseases Translational Research Collaboration (RD-TRC) Clinical Research Fellowship. AB was supported by Kids Kidney Research and Kidney Research UK.

    • Disclaimer The views expressed are those of the authors and not necessarily those of the UK National Health Service, the NIHR or the Department of Health.

    • Competing interests MAS has external consultancy roles with UCB, Retrophin and Pfizer. All other authors declare no conflicts ofinterest.

    • Patient consent Obtained.

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