A world-first scientific study has shown that whole-genome sequencing (WGS) improves diagnosis of rare diseases and shortens diagnostic journeys for patients.
Rare diseases are a global health challenge. There are roughly 10,000 rare disorders that affect around 6% of the population in Western societies. Of these rare diseases, over 80% have a genetic component. These conditions can have a large impact on quality of life and are also expensive to manage. Unfortunately, one third of children with a rare disease die before their fifth birthday.
Over the past decade, with the advent of next-generation sequencing (NGS), rates of diagnosis of rare diseases have significantly improved. However, the majority of patients with rare diseases do not obtain a molecular diagnosis via standard methods. To address this problem, in 2013, the ambitious 100,000 Genomes Project was launched with the aim of sequencing 100,000 genomes from NHS patients and their families. The project, led by Genomics England and NHS England, was focussed on applying WGS to rare disease, cancer and infectious disease in national healthcare. By reaching its milestone in December 2018, the 100,000 Genomes Project has helped cement the UK and NHS as key leaders in genomics-driven healthcare.
Using WGS to shorten the diagnostic odyssey
A recent pilot study, published in NEJM and led by Genomics England and Queen Mary University of London in partnership with the National Institute for Health Research (NIHR) BioResource, studied whole genomes of rare undiagnosed diseases from early participants in the 100,000 Genomes Project. The team analysed the genes of 4,660 people from 2,183 families. Many of these participants had undergone years of appointments and tests without getting any answers.
The study reported that using WGS resulted in a new diagnosis for 25% of the participants. Of these diagnoses, 14% were also found in regions of the genome that would be missed by standard methods. In addition, for around a quarter of participants, their diagnosis resulted in them being able to receive more focussed clinical care. This included additional family screening, dietary changes and provision of vitamins/minerals and other therapies.
For many patients, this study secured a diagnosis and led to the end of their diagnostic odyssey. One such patient included a 10-year-old girl who, over a sever year period, had several intensive care admissions and 307 hospital visits at a cost of £356,571. The genetic diagnosis she received from this study enabled her to receive a curative bone marrow transplant at a cost of £70,000. Predictive testing of her siblings also showed that no further family members were at risk.
This pilot study is the first to analyse the diagnostic and clinical impact of WGS for a broad range of rare diseases, from intellectual disability to vision and hearing disorders. The findings have demonstrated that WGS can effectively obtain a diagnosis for patients, save NHS costs and resources, and pave the way for vital interventions. It has supported the adoption of WGS, not just as part of the new NHS National Genomic Test Directory, but within healthcare systems worldwide.
Professor Damian Smedley, lead author, from Queen Mary University of London, said:
“This is the first time that whole genome sequencing has been directly embedded into rare disease diagnostics in a healthcare system like the NHS and applied at scale across the full breadth of rare disease. Our novel software, together with collection of detailed clinical data, was key to us being able to solve the ‘needle in a haystack’ challenge of finding the cause of a rare disease patient’s condition amongst the millions of variants in every genome. A large proportion of the diagnoses we discovered were found outside the coding region and would not have been detected by existing approaches. This study makes the case for healthcare systems worldwide to adopt whole genome sequencing as the genetic test of choice for rare disease patients.”
The team are now hoping to continue to address unmet diagnostics needs by undertaking a pan-rare disease re-analysis of the data, incorporating additional layers i.e., RNA and protein data to gain further insights into function and ensuring that there is continued collaboration with participants at every stage of the journey. These efforts continue to demonstrate the value of paired investment in research and healthcare, along with the positive impact it can have in patient care.
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