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Full genetic sequencing can improve diagnosis and care of patients with rare diseases

 

New research from the NIHR BioResource has demonstrated that sequencing whole genomes for patients with rare diseases can improve their diagnosis and care. In one example, the research identified a genetic diagnosis for early loss of vision in around 60% of patients.

The results come from two pilots that are part of the 100,000 Genomes Project, which was set up to use powerful genetic sequencing technology within the NHS to help diagnose and treat patients with rare inherited diseases and cancer. 

More than three million people in the UK have a rare disease. To tackle this challenge, the NIHR BioResource created a network of 57 NHS hospitals with a focus of care for patients with rare diseases. Nearly 1000 doctors and nurses working at these hospitals asked their patients and some parents of affected children to join the NIHR BioResource whole-genome sequencing project.

The researchers set out to decode all the 3.2 billion DNA letters for each patient, instead of the usual practice of reading only a small fraction of the genetic code. This allowed them to explore the ‘switches and dimmers’ – regulatory elements in DNA that control the activity of the thousands of genes, which are passed down by parents to their children.

Professor Willem Ouwehand, Professor of Experimental Haematology at the University of Cambridge, the NIHR Research BioResource and NHS Blood and Transplant Principal Investigator, said: “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.

“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.”

The first study, published in the journal Nature, sequenced the entire genomes of almost 10,000 NHS patients who had rare diseases. The team analysed more than 172 million genetic variants, many of which were previously undiscovered, to find the genetic changes that were the cause of each patient’s condition. They examined 15 disease groups, looking at rare conditions that affect particular tissues such as the brain, eyes, blood and the immune system. 

The researchers identified 95 genes associated with rare diseases in these tissues. For at least 79 of these diseases, variants in the genes were shown to definitively cause the disease.

In the second study, also published in Nature, researchers looked at 886 patients with primary immunodeficiency, which affects the ability to fight infections caused by microbes. The analysis identified four new genetic associations linked with this condition. 

Dr Ernest Turro from the NIHR BioResource team at Cambridge University Hospitals said: “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.

"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."

Dr Louise Wood, Director of Science, Research and Evidence at the Department of Health and Social Care, said: “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.” 

“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.”

The UK government announced In October 2018 that the NHS will offer whole-genome analysis for all seriously ill children with a suspected genetic disorder, including those with cancer. 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 can include reduced diagnostic journeys for patients, reduced costs for providers, improved understanding for patients and carers and improved provision of treatment.

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