Rapid exome sequencing for paediatric precision medicine

By Philippa Brice

2 August 2020


A new paper outlines the use of rapid whole exome-sequencing (rWES) for children in Hong Kong, finding it improved clinical care and reduced costs.

The advantages of exomes

Whilst genome sequencing is widely discussed, in clinical practice exome sequencing – analysis only of the protein-coding regions of the genome – is often more practical. It is faster and more focused than sequencing the whole genome, but offers much more information than more limited forms of genetic testing, which can be especially valuable when trying to identify an unknown disease.

Advances in sequencing technology have also heralded rapid increases in speed and decreases in cost, making clinical exome sequencing increasingly feasible – and potentially also cost-effective as a first-line test, rather than an option to pursue if other forms of testing fail to provide a diagnosis.

The need for speed in paediatric testing

The potential of genomics to improve paediatric care has long been an area of interest; understanding precisely what underlies disease in babies and children can provide vital information to inform and improve their care; in seriously ill newborns, it may be life-saving. The UK introduced whole exome sequencing for babies in neonatal intensive care units (NICU) as part of the rollout of the NHS Genomic Medicine Service from 2019 onwards; as of January 2020, almost half of the babies had received a genetic diagnosis following WES.

Speed is often of the essence, as these babies in particular cannot wait for investigations to be completed later, but many older babies and children with suspected genetic diseases may also benefit from rapid diagnosis to help guide optimal treatment. The potential to use rapid WES as a first-line test is therefore really important to determine – and in practical terms, this means establishing whether it can deliver clinically useful results in a timely and cost-effective manner in local populations. Studies so far have focused mainly on seriously ill newborns.

Hong Kong study – clinical and cost effectiveness

The new paper from Prof Brian Chung and colleagues at the University of Hong Kong, Queen Mary Hospital and Hong Kong Children’s Hospital reports on a study to determine the diagnostic and clinical utility of rWES on children with suspected genetic diseases from paediatric intensive care units and other paediatric settings.

They were able to make a diagnosis in 32 of 102 patients in the study, a diagnostic rate of 31% - and, importantly, to do so with relative speed; the median turnaround time (from testing to return of results) was eleven days. This may not seem very rapid, but Prof Chung explained at a recent seminar in Cambridge that before development of this capacity in Hong Kong, whole genome or exome sequencing had to be undertaken by sending samples to overseas laboratories, with a turnaround time of 8-15 weeks.

The new genetic diagnoses had a direct effect on clinical management for most of the patients (28/32); the remaining four were identified as having rare diseases only recently characterised and about which little is yet known, though relevant clinical information may reasonably be expected to emerge in the coming months and years that could affect their care. In addition, all the families of patients benefited from counselling about the risks that other family members might be affected and options for action where appropriate.

A further cost analysis in eight patients found that rWES reduced the length of hospital stay for these children, yielding an estimated cost saving of HKD$5,325,187 (£527,246 – over £65,000 per patient on average) after the additional costs of rapid exome sequencing and analysis were accounted for. The authors conclude that rWES should be considered as a first-line diagnostic test for paediatric patients with urgent needs.

These findings were consistent with other studies in different countries and populations – an important consideration, given genetic variability between populations. Many internationally available genetic databases remain disproportionately weighted towards Caucasian populations; whilst this situation is changing as global genome sequencing efforts expand, it can make accurate diagnosis more difficult.

Real world utility in the face of rapid change

The numbers involved in this study were relatively small, but it nevertheless provides valuable evidence that rapid exome sequencing can have both clinical utility – enabling swift and meaningful changes to patient management in the light of diagnostic findings – and reduce costs. This is optimal precision medicine in action: more accurate and informative diagnosis enabling more tailored management to deliver better experience and outcomes for patients, and cost-effectiveness for health systems.

Importantly, the study also demonstrates the clinical utility of this diagnostic approach in a different population and healthcare system from previous published studies, making it a significant contribution to international understanding and experience.

In the face of rapid innovation in tools for genomic (and exomic) sequencing and analysis, and similarly rapid development in the capacity to analyse and make sense of the information produced by these tools, there is a corresponding need for studies such as this one from Hong Kong to appraise just how useful they are in specific settings. Generally, as costs continue to fall and speed, data and knowledge increases, they are likely to become more useful, which bodes well for early and effective precision in paediatric medicine.

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