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24 June, 2020 - 16:05 By Tony Quested

Genomes front and centre of rare disease diagnosis

A Cambridge-led research consortium has shown that standardised sequencing in the NHS can mean that patients without a diagnosis for a rare disease might receive one and that parents of children might face shorter diagnostic odysseys and better treatment options.

The study, published online in the science journal Nature, was part of a UK pilot installing standardised whole-genome sequencing in the NHS. The results now include diagnosis of hundreds of patients and discovery of new genetic causes of rare diseases. 

The project was led by Professor Willem Ouwehand from Cambridge, working for the NIHR BioResource on the Addenbrooke’s site, and many colleagues in Cambridge, but is a collaboration of many child health specialists, including GOSH and Guy’s/Evelina.

The 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 per cent of individuals in one group of patients with early loss of vision.

Offering whole-genome sequencing as a diagnostic test to patients with rare diseases across an integrated health system is 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.

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. 

Dr Ernest Turro from the University of Cambridge and the NIHR BioResource, 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.”

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.

Whole-genome sequencing is to 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.

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