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Whole genome sequencing improves diagnosis of rare diseases and shortens diagnostic journeys for patients

A world-first scientific study, published today in the New England Journal of Medicine, has shown that whole genome sequencing (WGS) can uncover new diagnoses for people across the broadest range of rare diseases investigated to date and could deliver enormous benefits across the NHS.

The pilot study of rare undiagnosed diseases involved analysing the genes of 4,660 people from 2,183 families - all of whom were early participants in the 100,000 Genomes Project. The ground-breaking Project, led by Genomics England and NHS England and involving the University of Exeter, was established in 2013 to sequence 100,000 whole genomes from NHS patients and their families.

The pilot study, led by Genomics England and Queen Mary University of London and undertaken in partnership with the National Institute for Health Research (NIHR) BioResource, found that using WGS led to a new diagnosis for 25 per cent of the participants. Of these new diagnoses, 14 per cent were found in regions of the genome that would be missed by other conventional methods, including other types of non-whole genomic tests.

Many of the participants had gone through years of appointments, without getting any answers. By having their whole genome sequenced diagnoses were uncovered that would not have previously been detectable. The pilot study shows that WGS can effectively secure a diagnosis for patients, save the NHS vital resources and pave the way for other interventions.

Dr Emma Baple and Professor Caroline Wright, of the University of Exeter, were clinical lead and scientific lead respectively for Rare Disease Validation and Feedback at Genomics England during the pilot project. Dr Baple is now Rare Disease Medical Lead for the South West Genomic Laboratory Hub, and said:  "This work demonstrates the remarkable patient benefits that can stem from collaborative working across academia and the NHS. We are now reaping the benefits of this approach in the new Genomic Medicine Service, with whole genome sequencing now embedded as a diagnostic test for patients affected by rare disease in England".

Participants who received a diagnosis through the pilot include:

• a 10-year-old girl whose previous seven-year search for a diagnosis had multiple intensive care admissions over 307 hospital visits at a cost of £356,571. Genomic diagnosis enabled her to receive a curative bone marrow transplant (at a cost of £70,000). In addition, predictive testing of her siblings showed no further family members were at risk.
• a man in his 60s who had endured years of treatment for a serious kidney disease, including two kidney transplants. Already knowing his daughter had inherited the same condition, a genomic diagnosis made by looking at the whole genome for him and his daughter enabled his 15-year-old granddaughter to be tested. This revealed she had not inherited the disease and could cease regular costly check-ups.
• a baby who became severely ill immediately after birth and sadly died at four months but with no diagnosis and healthcare costs of £80,000. Analysis of his whole genome uncovered a severe metabolic disorder due to inability to take vitamin B12 inside cells explaining his illness. This enabled a predictive test to be offered to his younger brother within one week of his birth. The younger child was diagnosed with the same disorder but was able to be treated with weekly vitamin B12 injections to prevent progression of the illness.

For around a quarter of study participants, their diagnosis meant they were able to receive more focused clinical care. This included further family screening, dietary change, provision of vitamins and / or minerals and other therapies.

The study is the first to analyse the diagnostic and clinical impact of WGS for a broad range of rare diseases within a national healthcare system. The findings support its widespread adoption in health systems worldwide.

The high performance of WGS for specific conditions observed in the pilot study - including intellectual disability, vision and hearing disorders of 40-55 per cent diagnostic yield - has underpinned the case for the inclusion of WGS to diagnose specific rare diseases as part of the new NHS National Genomic Test Directory.

The pilot study was also conducted in partnership with the National Institute for Health Research (NIHR) and Illumina who undertook the sequencing, and it was funded by the NIHR, the Wellcome Trust, the Medical Research Council, Cancer Research UK, the Department of Health and Social Care, and NHS England.

Jillian Hastings Ward, Chair of the Genomics England Participant Panel, said: “The people who signed up for whole genome sequencing in this pilot study were hoping to find new diagnoses for their loved ones, and were willing to share their precious data with Genomics England so that rare diseases could be better understood. The pilot has helped on both of these fronts and we are delighted that whole genome sequencing is now being routinely offered by the NHS to more families across England as a result. This is the beginning of a great leap forward and it needs families, clinicians and researchers to continue to work together for its full potential to be realised.”

Dr Richard Scott, Chief Medical Officer at Genomics England, said: “Historically, diagnosis of rare diseases has often been reliant on clinicians doing multiple different targeted tests - an approach that can delay diagnosis and access to more tailored care. Improved knowledge of genomics and the whole genome sequencing and data infrastructure that the government and NHS have invested in now offers us the ability to radically transform the process. This paper provides evidence of that transformation and where it has most impact. We’re proud at Genomics England to be working in partnership with the NHS to bring the benefits of whole genome sequencing to patients.”

Professor Dame Sue Hill, Chief Scientific Officer for England and SRO for NHS Genomics, said: “Understanding the role a person's genome plays in disease holds the key to finding treatments for not only the conditions we know about but also for those we are yet to discover.

“This pilot study highlights the importance of whole genome sequencing within a healthcare system. It can fundamentally change how we think about disease, lead to faster, more comprehensive and accurate diagnoses, provide the missing pieces for families who have a loved one living with a rare disease and pave the way for more tailored and effective treatments for patients.”

These major findings were only possible due to the support of patients and healthcare staff at Barts Health NHS Trust, Queen Mary, Addenbrooke’s Hospital in Cambridge, Cambridge University, Great Ormond Street Hospital NHS Foundation Trust, University College London NHS Foundation Trust, Moorfield’s Hospital NHS Foundation Trust, University College London, Guy’s and St Thomas’ NHS Foundation Trust, King’s College London, Oxford University Hospitals NHS Foundation Trust, Oxford University, Manchester University NHS Foundation Trust, Manchester University and Newcastle Hospitals NHS Foundation Trust and Newcastle University.

Date: 10 November 2021