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

Mestek-Boukhibar, Lamia, Clement, Emma, Jones, Wendy D., Drury, Suzanne, Ocaka, Louise, Gagunashvili, Andrey, Le Quesne Stabej, Polona, Bacchelli, Chiara, Jani, Nital, Rahman, Shamima, Jenkins, Lucy, Hurst, Jane A., Bitner-Glindzicz, Maria, Peters, Mark, Beales, Philip L. and Williams, Hywel J. ORCID: https://orcid.org/0000-0001-7758-0312 2018. Rapid Paediatric Sequencing (RaPS): Comprehensive real-life workflow for rapid diagnosis of critically ill children. Journal of Medical Genetics 55 (11) , pp. 721-728. 10.1136/jmedgenet-2018-105396

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Abstract

Background Rare genetic conditions are frequent risk factors for, or direct causes of, paediatric intensive care unit (PICU) admission. 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. Our aim was to develop 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 team for case selection, trio WGS, rapid bioinformatics sequence analysis and a phased analysis and reporting system to prioritise genes with a high likelihood of being causal. Results Trio WGS in 24 critically ill children led to a molecular diagnosis in 10 (42%) through the identification of causative genetic variants. In 3 of these 10 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 4 days (median 8.5 days). Conclusion Rapid WGS can be used to diagnose and inform management of critically ill children 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. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	BMJ Publishing Group
ISSN:	0022-2593
Date of Acceptance:	10 June 2018
Last Modified:	26 Oct 2022 08:47
URI:	https://orca.cardiff.ac.uk/id/eprint/128300

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