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

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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.

The project, the results of which were published 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.

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 integration of genetic research with NHS diagnostic systems increases the likelihood that a patient will receive a diagnosis and the chance this will be provided within weeks rather than months.

The multi-centre study, led by researchers at the National Institute for Health Research (NIHR) BioResource together with Genomics England, demonstrates how 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, including experts from the University of Bristol, studied the genomes of groups of patients with similar symptoms, affecting different tissues, such as the brain, eyes, kidney, 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.

Principal investigators Andrew Mumford, Professor of Haematology, and Moin Saleem, Professor of Paediatric Renal Medicine, led the set-up of the programme and oversaw regional enrolment in the South West. Professor Mumford provided national oversight for blood related disorders, while Professor Saleem managed inherited kidney diseases.

Professor Mumford and researchers in the School of Cellular and Molecular Medicine collaborated with the Bristol NIHR Biomedical Research Centre and the University of Cambridge to develop ways to improve the genetic identification of blood disorders, contributing significantly to the breakthrough diagnostic potential.

Professor Mumford said: “This pioneering study illustrates the power of whole genome sequencing for diagnosis of rare human diseases. The approach developed in this research has paved the way for the flagship 100,000 Genomes Project and the introduction of whole genome sequencing into standard NHS care.”

Professor Saleem established the UK National Renal Rare Disease Registry, and the national and international NephroS (Nephrotic Syndrome) groups, based within the UK Renal Registry in Bristol. These provided recruitment, essential genetic data, and DNA collection for the study. Researchers in Bristol provided functional and clinical insights leading to the discovery of causative genes relating to kidney disorders.

Professor Saleem said: “Rare diseases in their entirety are common, in that there are more than 7,000 different rare diseases in total affecting about 7 per cent of the population. Most have a genetic cause, so this research for the first time brings the most powerful genetic sequencing capabilities to apply across the whole health service, meaning all patients will now have the best possible chance of finding their individual genetic defect.”

In the study, funded mainly 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’.

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.”


‘Whole-genome sequencing of patients with rare diseases in a national health system,’ by Ernest Turro et alin Nature.


Further information

There are 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.

Based on the emerging data from the present NIHR BioResource study and other studies by Genomics England, the UK government previously announced 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.


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