Whole genome sequencing improves diagnosis of rare diseases and shortens diagnostic journeys for patients, according to world first study

LONDON – 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, 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% of the participants. Of these new diagnoses, 14% 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.

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% 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.

Professor Sir Mark Caulfield (lead author) from Queen Mary University of London, and former Chief Scientist at Genomics England, said: “We hope this major advance will enable rare disease patients worldwide to start receiving diagnostic whole genome sequencing where appropriate. Our findings show that deployment of this comprehensive and efficient genomic test at the first signs of symptoms, can improve diagnostic rates. This study has paved the way for clinical implementation of whole genome sequencing as part of the NHS Genomic Medicine Service.”

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.”

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.”

Chris Wigley, CEO of Genomics England, said: “Our mission at Genomics England is to bring the benefits of genomic healthcare to everyone – this pilot study highlights the potential it has to transform healthcare. It gives medical professionals the ability to transform the way patient care is delivered – in particular allowing them to make more accurate diagnoses and offer more personalised treatments.”

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.”

Dr Louise Wood CBE, Director of Science, Research and Evidence at the Department of Health and Social Care and Deputy CEO of the NIHR, said: “This study underpinned the UK’s 100,000 genomes project which went on to provide the evidence base for integration of whole genome sequencing into routine clinical care in the NHS. Rare diseases patients and their carers tell us one of their top priorities is getting a diagnosis. This research showed significant progress can be made in addressing this ask and, in about a quarter of cases, in enabling clinical action to be taken on the basis of the diagnosis.”

Professor John Bradley, Chief Investigator of the NIHR BioResource, said: “The NIHR BioResource is delighted to have worked in partnership with Genomics England and NHS England to deliver this study. It is transforming the approach to diagnosing rare diseases in the NHS.”

Dr David Bentley, Vice President and Chief Scientist of Illumina, said: “Illumina is extremely proud to have been part of this tremendous collaboration with Genomics England, bringing whole genome sequencing into the clinic, positively impacting many patients and families, setting sequence data quality standards and now helping to deliver genomes for the NHS Genomic Medicine Service.”

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.

About the pilot study:

Rare disease is a global health challenge, with approximately 10,000 disorders affecting six percent of the population in Western societies. Over 80% of rare diseases have a genetic component, and these conditions are disabling and expensive to manage. One third of children with a rare disease die before their fifth birthday.

The 4,660 pilot study participants were recruited and had their whole genome sequenced throughout 2014-2016.

About Genomics England (https://www.genomicsengland.co.uk)

Genomics England works with the NHS to bring forward the use of genomic healthcare and research in Britain to help people live longer, healthier lives. Genomics is a ground-breaking area of medicine that uses our unique genetic code to help diagnose, treat and prevent illnesses. Established in 2013, Genomics England launched the world-leading 100,000 Genomes Project with the NHS, demonstrating how genomic insights can help doctors across the NHS, and building a foundation for the future by assembling a unique dataset. The project was achieved thanks to patients and participants helping to shape it and guiding decisions on data and privacy.

Genomics England is now expanding its impact. Our next chapter involves working with patients, doctors and scientists to improve genomic testing in the NHS and help researchers access the health data and technology they need to make new medical discoveries and create more effective, targeted medicines for everybody.

About Queen Mary University of London

At Queen Mary University of London, we believe that a diversity of ideas helps us achieve the previously unthinkable.

In 1785, Sir William Blizard established England’s first medical school, The London Hospital Medical College, to improve the health of east London’s inhabitants. Together with St Bartholomew’s Medical College, founded by John Abernethy in 1843 to help those living in the City of London, these two historic institutions are the bedrock of Barts and The London School of Medicine and Dentistry.

Today, Barts and The London continues to uphold this commitment to pioneering medical education and research. Being firmly embedded within our east London community, and with an approach that is driven by the specific health needs of our diverse population, is what makes Barts and The London truly distinctive.

Our local community offer to us a window to the world, ensuring that our ground-breaking research in cancer, cardiovascular and inflammatory diseases, and population health not only dramatically improves the outcomes for patients in London, but also has a far-reaching global impact.

This is just one of the many ways in which Queen Mary is continuing to push the boundaries of teaching, research and clinical practice, and helping us to achieve the previously unthinkable.

About NIHR Bioresource for Translational Research

The mission of the National Institute of Health Research (NIHR) BioResource is to facilitate human health research and its transformation into medical practice. The BioResource is an NIHR initiative established at 13 local Research Centres – Birmingham, Cambridge, Exeter, Leeds, Leicester, London (Barts Health, GSTT, Maudsley, Moorfields and UCL), Manchester, Newcastle and Southampton. The NIHR BioResource is at the heart of efforts to improve healthcare and the long-term prevention and treatment of disease. More than 150,000 participants, both with and without health problems, have already joined the NIHR BioResource to help transform the genetics of health research. The enthusiasm, commitment and contribution of NIHR BioResource participants help its researcher partners in academia, industry and NHS to uncover the causes of disease. www.bioresource.nihr.ac.uk

About NIHR

The mission of the National Institute for Health Research (NIHR) is to improve the health and wealth of the nation through research. We do this by:

  • Funding high quality, timely research that benefits the NHS, public health and social care;
  • Investing in world-class expertise, facilities and a skilled delivery workforce to translate discoveries into improved treatments and services;
  • Partnering with patients, service users, carers and communities, improving the relevance, quality and impact of our research;
  • Attracting, training and supporting the best researchers to tackle complex health and social care challenges;
  • Collaborating with other public funders, charities and industry to help shape a cohesive and globally competitive research system;
  • Funding applied global health research and training to meet the needs of the poorest people in low and middle income countries.

NIHR is funded by the Department of Health and Social Care. Its work in low and middle income countries is principally funded through UK Aid from the UK government.


For Genomics England: Kevin Maxwell, 07985 351 797, [email protected] and Yufan Chen, 07534 823 151, [email protected].

For Queen Mary University of London: Sophie McLachlan, 07889 386 321, [email protected]