Mestek-Boukhibar_2018_J.Med.Genet_55_721

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.