News Release

Genomes front and center of rare disease diagnosis

UK NIHR BioResource study discovers novel genetic causes of rare diseases, leading to improved diagnosis and better patient care

Peer-Reviewed Publication

Don Powell Associates Ltd

Cambridge UK, 24 June 2020: A research programme pioneering the use of whole genome sequencing in the NHS has diagnosed hundreds of patients and discovered new genetic causes of disease. Whole genome sequencing is the technology used by the 100,000 Genomes Project, a service set up by the government which aims to introduce routine genetic diagnostic testing in the NHS.

The present study, led by researchers at the National Institute for Health Research BioResource together with Genomics England, demonstrates that sequencing the whole genomes of large numbers of individuals in a standardised way can improve the diagnosis and treatment of patients with rare diseases.

The researchers studied the genomes of groups of patients with similar symptoms, affecting different tissues, such as the brain, eyes, blood or the immune system. They identified a genetic diagnosis for 60% of individuals in one group of patients with early loss of vision.

The programme, the results of which were published today in two articles in the journal Nature, offered whole-genome sequencing as a diagnostic test to patients with rare diseases across an integrated health system, a world first in clinical genomics. The integration of genetic research with NHS diagnostic systems increases the likelihood that a patient will receive a diagnosis and the chance that a diagnosis will be provided within weeks rather than months.

"Around 40,000 children are born each year with a rare inherited disease in the UK alone. Sadly, it takes more than two years, on average, for them to be diagnosed," says Willem Ouwehand, Professor of Experimental Haematology at the University of Cambridge, the National Institute for Health Research BioResource and NHS Blood and Transplant Principal Investigator. "We felt it was vital to shorten this odyssey for patients and parents."

"This research shows that quicker and better genetic diagnosis will be possible for more NHS patients."

In the study, funded principally by the National Institute for Health Research, the entire genomes of almost 10,000 NHS patients with rare diseases were sequenced and searched for genetic causes of their conditions. Previously unobserved genetic differences causing known rare diseases were identified, in addition to genetic differences causing completely new genetic diseases.

The team identified more than 172 million genetic differences in the genomes of the patients, many of which were previously unknown. Most of these genetic differences have no effect on human health, so the researchers used new statistical methods and powerful supercomputers to search for the differences which cause disease - a few hundred 'needles in the haystack'.

In one study from the programme, published as a standalone article in Nature, researchers examined 886 patients with primary immunodeficiency - a condition that affects the ability of the immune system to fight infections by microbes - and identified four novel associated genes.

"Providing the best treatment and the most appropriate care for patients with inherited immune disorders depends absolutely on a conclusive molecular diagnosis," says Professor Adrian Thrasher of the UCL Great Ormond Street Institute of Child Health (ICH) in London. "Our study demonstrates the value of whole-genome sequencing in this context and provides a suite of new diagnostic tools, some of which have already led to improved patient care."

Using a new analysis method developed specifically for the project, the team identified 95 genes in which rare genetic differences are statistically very likely to be the cause of rare diseases. Genetic differences in at least 79 of these genes have been shown definitively to cause disease.

The team searched for rare genetic differences in almost all of the 3.2 billion DNA letters that make up the genome of each patient. This contrasts with current clinical genomics tests, which usually examine a small fraction of the letters, where genetic differences are thought most likely to cause disease. By searching the entire genome researchers were able to explore the 'switches and dimmers' of the genome - the regulatory elements in DNA that control the activity of the thousands of genes.

The team showed that rare differences in these switches and dimmers, rather than disrupting the gene itself, affect whether or not the gene can be switched on at the correct intensity. Identifying genetic changes in regulatory elements that cause rare disease is not possible with the clinical genomics tests currently used by health services worldwide. It is only possible if the whole of the genetic code is analysed for each patient.

"We have shown that sequencing the whole genomes of patients with rare diseases routinely within a health system provides a more rapid and sensitive diagnostic service to patients than the previous fragmentary approach, and, simultaneously, it enhances genetics research for the future benefit of patients still waiting for a diagnosis," says Dr Ernest Turro from the University of Cambridge and the NIHR BioResource.

"Thanks to the contributions of hundreds of physicians and researchers across the UK and abroad, we were able to study patients in sufficient numbers to identify the causes of even very rare diseases."

Although individual rare diseases affect a very small proportion of the population, there exist thousands of rare diseases and, together, they affect more than three million people in the UK. To tackle this challenge, the NIHR BioResource created a network of 57 NHS hospitals which focus on the care of patients with rare diseases. Nearly 1000 doctors and nurses working at these hospitals made the project possible by asking their patients and, in some cases, the parents of affected children to join the NIHR BioResource.

"In setting up the NIHR BioResource Project, we were taking uncharted steps in a determined effort to improve diagnosis and treatment for patients in the NHS and further afield" says Dr Louise Wood, Director of Science, Research and Evidence at the Department of Health and Social Care and who together with the Chief Medical Officer Professor Chris Whitty has the overall responsibility for the National Institute for Health Research.

"The NIHR-funded researchers on this scientific report were part of those earliest discussions as we sought to ensure we could deliver the science and transform it into clinical practice across the NHS. This research has demonstrated that patients, their families and the health service can all benefit from placing genomic sequencing at the forefront of clinical care in appropriate settings.

"The pioneering work undertaken by the NHS in partnership with Genomics England and academic researchers across the UK has laid the foundation for applying the same genome test to patients with COVID-19, with the hope of finding clues why some patients experience such a severe form of this new disease."

Based on the emerging data from the present NIHR BioResource study and other studies by Genomics England, the UK government announced in October 2018 that the NHS will offer whole-genome sequencing analysis for all seriously ill children with a suspected genetic disorder, including those with cancer. The sequencing of whole genomes will expand to one million genomes per year by 2024.

Whole-genome sequencing will be phased in nationally for the diagnosis of rare diseases as the 'standard of care', ensuring equivalent care across the country.

The benefits include a hastened diagnosis for patients, reduced costs for health services, improved understanding of the reasons they suffer from disease for patients and their carers and improved provision of treatment.


Notes to Editors

Study and history

Turro E et al. (2020) Whole-genome sequencing of patients with rare diseases in a national health system.


URL when live:

Thaventhiran J et al. (2020). Whole-genome sequencing of a sporadic primary immunodeficiency cohort. Early online publication in Nature, 6 May 2020.

This international genomics study took place under the umbrella and oversight of the National Institute of Health Research (NIHR) BioResource, based in Cambridge, UK. The main study was coordinated by Lucy Raymond, Professor in Medical Genetics and Neurodevelopment at the University of Cambridge and Cambridge University Hospitals, and Willem H Ouwehand, Professor in Experimental Haematology at the University of Cambridge and NHS Blood and Transplant.

The study is one of two major pilots for the 100,000 Genomes Project, conceived in 2012, following development of whole-genome sequencing and analysis at scale.

Funding and support

The two pilot studies for rare diseases for the 100,000 Genomes Project were mainly funded by grants from the NIHR in England to the NIHR Cambridge Biomedical Research Centre and Genomics England. Additional funding was provided by the British Heart Foundation, the Medical Research Council, NHS England, the Wellcome Trust and many other fund providers.

This research was made possible through access to the data and findings generated by two pilot studies for the 100,000 Genomes Project. The enrolment was coordinated for one by the NIHR BioResource and for the other by Genomics England Limited, a wholly owned company of the Department of Health and Social Care.

Full details of support for this research and for individual authors are listed in the paper and supplementary material.

The NIHR BioResource for Translational Research

The mission of the National Institute for Health Research BioResource is to facilitate human health research and its transformation into medical practice. The BioResource is an NIHR initiative established at thirteen local Research Centres - Birmingham, Cambridge, Exeter, Leeds, Leicester, London - includes 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 BioResource to help transform the genetics of health research. The enthusiasm, commitment and contribution of BioResource participants help its researcher partners in academia, industry and NHS to uncover the causes of disease.


The National Institute for Health Research (NIHR) is the nation's largest funder of health and care research. The NIHR:

  • Funds, supports and delivers high quality research that benefits the NHS, public health and social care

  • Engages and involves patients, carers and the public in order to improve the reach, quality and impact of research

  • Attracts, trains and supports the best researchers to tackle the complex health and care challenges of the future

  • Invests in world-class infrastructure and a skilled delivery workforce to translate discoveries into improved treatments and services

  • Partners with other public funders, charities and industry to maximise the value of research to patients and the economy

The NIHR was established in 2006 to improve the health and wealth of the nation through research, and is funded by the Department of Health and Social Care. In addition to its national role, the NIHR commissions applied health research to benefit the poorest people in low- and middle-income countries, using Official Development Assistance funding.

This work uses data provided by patients and collected by the NHS as part of their care and support and would not have been possible without access to this data. The NIHR recognises and values the role of patient data, securely accessed and stored, both in underpinning and leading to improvements in research and care.

Cambridge University Hospitals

Cambridge University Hospitals (CUH) is one of the largest and most renowned NHS Trust Hospitals in the United Kingdom. In addition to delivering care through Addenbrooke's and The Rosie Hospitals, CUH is also a leading national centre for specialist treatment, a University teaching hospital, and has formed in partnership with the University of Cambridge one of the government-designated NIHR Biomedical Research Centre, with a worldwide reputation for translating new discoveries into delivering better health for citizens in the UK and beyond.

The University of Cambridge

The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. It admits the very best and brightest students, regardless of background, and offers one of the UK's most generous bursary schemes. The University of Cambridge's reputation for excellence is known internationally and reflects the scholastic achievements of its academics and students, as well as the world-class original research carried out by its staff. Some of the most significant scientific breakthroughs occurred at the University, including the splitting of the atom, invention of the jet engine and the discoveries of stem cells, plate tectonics, pulsars and the structure of DNA. From Isaac Newton to Stephen Hawking, the University has nurtured some of history's greatest minds and has produced more Nobel Prize winners than any other UK institution with over 80 laureates.

About Great Ormond Street Hospital for Children NHS Foundation Trust

Founded in 1852, Great Ormond Street Hospital is one of the world's leading children's hospitals with the broadest range of dedicated, children's healthcare specialists under one roof in the UK. With more than 252,000 outpatient and 43,000 inpatient visits every year, the hospital's pioneering research and treatment gives hope to children from across the UK with the rarest, most complex and often life-threatening conditions. As an international centre of excellence in child healthcare, our patients and families are central to everything we do - from the moment they come through the door and for as long as they need us.Visit

Research at GOSH is underpinned by support from the National Institute of Health Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre (BRC) and GOSH Charity.

About the UCL Great Ormond Street Institute of Child Health (ICH)

The UCL Great Ormond Street Institute of Child Health (ICH) is part of the Faculty of Population Health Sciences within the School of Life and Medical Sciences at University College London. Together with its clinical partner Great Ormond Street Hospital for Children NHS Foundation Trust (GOSH), it forms the UK's only paediatric National Institute for Health Research (NIHR) Biomedical Research Centre and has the largest concentration of children's health research in Europe. For more information visit

NHS Blood and Transplant

NHS Blood and Transplant (NHSBT) is a Special Health Authority. Its remit includes the provision of a reliable, efficient supply of blood, and associated services to the NHS in England. It is also the organ donor organisation for the UK and is responsible for matching and allocating donated organs. Involving donors in research is a key aim of NHSBT's planned Research & Development Strategy. The main research sites, in collaboration with leading NIHR Biomedical Research Centres, are at Cambridge, Oxford, London and Bristol, with specialist activity in Birmingham and Liverpool.

British Heart Foundation

With donations from the public, the BHF funds ground breaking research that will get us closer than ever to a world free from the fear of heart and circulatory diseases. A world where broken hearts are mended, where millions more people survive a heart attack, where the number of people dying from or disabled by a stroke is slashed in half. A world where people affected by heart and circulatory diseases get the support they need. And a world of cures and treatments we can't even imagine today. We are backing the best ideas, the brightest minds and the biggest ambitions - because that's how we'll beat heartbreak forever.

Find out more at


A full list of authors and affiliations are listed in the paper and supplementary material.

Contact information

NIHR BioResource
Professor Willem H Ouwehand
Mobile: 44 (0)7730 53 5974

National Institute for Health Research
Eleanor Barrie
Communications Manager, NIHR
Mobile: + 44 (0)7387 106 748

NHS Blood and Transplant
Sian Edwards
Senior Communications Officer - Media and PR
Mobile: +44 (0)7384 919 180
Press Office 01923 367600

Great Ormond Street Hospital
Kate Hazlehurst
Research Communications Manager, GOSH
Mobile: +44 (0)0751 402 4238

British Heart Foundation
BHF press office
Desk: +44 (0)20 7554 0164
Mobile: +44 (0)7764 290 381 (out of hours)

Moorfields Eye Hospital Trust
Press office
Desk: +44 (0)20 7566 2628

Media coordinator
Don Powell
Don Powell Associates
Mobile: +44 (0)7786 858 220

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