bench to bedside

Researchers, led by scientists at University College London, have developed a novel paediatric whole genome sequencing (WGS) workflow that could run within the current National Health Service system. This work comes just as the 100,000 Genome Project, the NHS’ large-scale sequencing effort, starts to wind down and the organisation prepares to deliver diagnostic sequencing solutions to all suitable patients. The workflow was outlined in a paper published in the Journal of Medical Genetics yesterday.

Several teams in the United States have developed and implemented healthcare systems that enable the use of WGS when diagnosing critically ill infants that are suspected of having a genetic disease. However, the team behind this new work are arguing that previous work in this area has been centred around a specialised diagnostic facility and cannot be translated into the procedures of standard diagnostic laboratory. For a universal healthcare system like the NHS, which relies heavily on standardisation and government funding, large-scale testing that relies specialised facilities isn’t feasible.

“In the UK, WGS is being extended into the healthcare environment through the 100,000 Genomes Project; however, feedback of results is currently expected to take many months,” the authors wrote. “In contrast, recent studies from the USA and the Netherlands have shown the benefit of rapid WGS in acutely ill children and have clearly demonstrated the cost effectiveness of this technique compared with standard genetic testing. In these studies, however, a rapid diagnosis was made through the use of modified laboratory equipment and working procedures incompatible with standard diagnostic laboratory practices in the UK or involved the use of a predetermined gene list that was applied to all patients.”

To resolve these problems, the team developed a new workflow that could function within the NHS and which they demonstrated was capable of diagnosing 42% of their cohort within a median of 7 days. The team, led by Hywel Williams, PhD, from UCL Great Ormond Street Institute of Child Health, developed their workflow so that they were able to use off-the-shelf products and standard practices. This enabled them to also use a standard template for gathering clinical and family data from patients, generating a level of standardisation that is needed when handling big genomic data.

Once the necessary data had been collected, the team split the analysis process into three phases. The first involved investigating genes that were considered likely to be linked to the patient’s condition. If no firm conclusions could be drawn from that analysis, the investigation was then expanded to incorporate genes from the Developmental Disorders Genotype-Phenotype database and OMIM Morbid genes. The third phase then expanded the search for any genes with any evidence of causality.

Using this approach, 10 children (42% of total cohort) received a molecular diagnosis, all of which were obtained during phase 1 analysis. By restricting the analysis process to only what was necessary, the team were able to complete the workflow in a median of 7 days and found that the cost of running a rapid WGS trio was between £6,105 and £8,605.

“We have developed a robust and readily adoptable protocol for achieving rapid end-to-end WGS-based analysis to support the diagnosis of critically ill children,” the team concluded.

“We have presented a sustainable end-to-end workflow for using WGS to rapidly diagnose critically ill individuals with likely monogenic genetic disorders. Such a workflow uses off-the-shelf products and could readily be adopted by other diagnostic centres.”