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Rapid Paediatric Sequencing (RaPS): Comprehensive real-life workflow for rapid diagnosis of critically ill children

Lamia Boukhibar, Emma Clement, Wendy Jones, Suzanne Drury, Louise Ocaka, Andrey Gagunashvili, Polona Le Quesne Stabej, Chiara Bacchelli, Nital Jani, Shamima Rahman, Lucy Jenkins, Jane Hurst, Maria Bitner-Glindzicz, Mark Peters, Philip Beales, View ORCID ProfileHywel J Williams
doi: https://doi.org/10.1101/283697
Lamia Boukhibar
1GOSgene, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
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Emma Clement
2Clinical Genetics and Genomic Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
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Wendy Jones
2Clinical Genetics and Genomic Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
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Suzanne Drury
3Congenica Ltd, Bioinnovation Data Centre, Wellcome Genome Campus, Cambridge, United Kingdom
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Louise Ocaka
1GOSgene, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
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Andrey Gagunashvili
1GOSgene, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
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Polona Le Quesne Stabej
1GOSgene, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
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Chiara Bacchelli
1GOSgene, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
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Nital Jani
1GOSgene, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
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Shamima Rahman
4Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
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Lucy Jenkins
5NE Thames Regional Genetics Laboratory, Great Ormond Street Hospital, London, United Kingdom
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Jane Hurst
2Clinical Genetics and Genomic Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
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Maria Bitner-Glindzicz
4Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
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Mark Peters
6UCL Great Ormond Street Institute of Child Health and Great Ormond Street NHS Foundation Trust, London, United Kingdom
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Philip Beales
1GOSgene, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
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Hywel J Williams
1GOSgene, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
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  • ORCID record for Hywel J Williams
  • For correspondence: hywel.williams@ucl.ac.uk
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Abstract

Background Rare genetic conditions are frequent risk factors for, or direct causes of, organ failure requiring paediatric intensive care unit (PICU) support. Such conditions are frequently suspected but unidentified at PICU admission. Compassionate and effective care is greatly assisted by definitive diagnostic information. There is therefore a need to provide a rapid genetic diagnosis to inform clinical management.

To date, Whole Genome Sequencing (WGS) approaches have proved successful in diagnosing a proportion of children with rare diseases, but results may take months to report or require the use of equipment and practices not compatible with a clinical diagnostic setting. We describe an end-to-end workflow for the use of rapid WGS for diagnosis in critically ill children in a UK National Health Service (NHS) diagnostic setting.

Methods We sought to establish a multidisciplinary Rapid Paediatric Sequencing (RaPS) team for case selection, trio WGS, a rapid bioinformatics pipeline for sequence analysis and a phased analysis and reporting system to prioritise genes with a high likelihood of being causal. Our workflow was iteratively developed prospectively during the analysis of the first 10 children and applied to the following 14 to assess its utility.

Findings Trio WGS in 24 critically ill children led to a molecular diagnosis in ten (42%) through the identification of causative genetic variants. In three of these ten individuals (30%) the diagnostic result had an immediate impact on the individual’s clinical management. For the last 14 trios, the shortest time taken to reach a provisional diagnosis was four days (median 7 days).

Interpretation Rapid WGS can be used to diagnose and inform management of critically ill children using widely available off the shelf products within the constraints of an NHS clinical diagnostic setting. We provide a robust workflow that will inform and facilitate the rollout of rapid genome sequencing in the NHS and other healthcare systems globally.

Funding The study was funded by NIHR GOSH/UCL BRC: ormbrc-2012-1

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted March 19, 2018.
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Rapid Paediatric Sequencing (RaPS): Comprehensive real-life workflow for rapid diagnosis of critically ill children
Lamia Boukhibar, Emma Clement, Wendy Jones, Suzanne Drury, Louise Ocaka, Andrey Gagunashvili, Polona Le Quesne Stabej, Chiara Bacchelli, Nital Jani, Shamima Rahman, Lucy Jenkins, Jane Hurst, Maria Bitner-Glindzicz, Mark Peters, Philip Beales, Hywel J Williams
bioRxiv 283697; doi: https://doi.org/10.1101/283697
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Rapid Paediatric Sequencing (RaPS): Comprehensive real-life workflow for rapid diagnosis of critically ill children
Lamia Boukhibar, Emma Clement, Wendy Jones, Suzanne Drury, Louise Ocaka, Andrey Gagunashvili, Polona Le Quesne Stabej, Chiara Bacchelli, Nital Jani, Shamima Rahman, Lucy Jenkins, Jane Hurst, Maria Bitner-Glindzicz, Mark Peters, Philip Beales, Hywel J Williams
bioRxiv 283697; doi: https://doi.org/10.1101/283697

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