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.
- whole genome sequencing
- paediatric intensive care unit
- rapid diagnosis
- rare disease
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LM-B and EC contributed equally.
Contributors HJW, LB, SD, PLQS and LO performed the laboratory and variant analyses. HJW, LB, EC and WDJ devised the Rapid Paediatric Sequencing (RaPS) workflow and phased variant reporting. PLB, CB, HJW and LJ initiated and supervised the RaPS workflow. AG and NJ performed the bioinformatics analysis. HJW, EC, LB and WDJ wrote the manuscript, which was critically reviewed by all authors. EC, WDJ, JAH, MP and HJW liaised with specialist paediatricians to recruit individuals to the study. WDJ, EC, MB-G, SR and JAH reviewed variants from phases I, II and III. Members of the North East Thames Regional Genetics Service and the molecular Genetics laboratory reviewed potentially pathogenic variants at the weekly multidisciplinary team meeting.
Funding The study was funded by NIHR GOSH/UCL BRC: ormbrc-2012-1.
Disclaimer The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Competing interests None declared.
Patient consent Provided.
Ethics approval The study has UK Research Ethics Committee approval REC reference 08/H0713/82.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All diagnostic variants have been uploaded to ClinVar.
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