Whole genome sequencing improves diagnosis of rare diseases – study

Whole genome sequencing (WGS) improves the diagnosis of rare diseases and could bring huge benefits in the NHS, according to a first global study.

Research has found that the technique has proven to be a better way to diagnose rare diseases than usual genomic testing methods.

This has led to new rare disease diagnoses for NHS patients, ending decades-long diagnostic journeys for some.

Scientists say the study represents an important step towards the goal of precision medicine – a transition that will have a huge impact on the NHS and around the world.

The pilot study on undiagnosed rare diseases involved analyzing the genes of 4,660 people from 2,183 families, all of whom were the first participants in the 100,000 genomes project.

Led by Genomics England and Queen Mary University in London, it revealed that the WGS had led to a new diagnosis for a quarter of the participants.

The researchers found that of these new diagnoses, 14% were found in regions of the genome – the genetic code – that would be missed by other conventional methods, including other types of non-whole genomic tests.

Many study participants had spent years on dates without getting answers.

The researchers suggest that sequencing the entire genome has produced diagnoses that previously would not have been detectable.

They say the study shows the WGS can effectively get a diagnosis for patients, save vital NHS resources, and pave the way for other interventions.

Among those who were diagnosed as a result of the study were:

– A 10-year-old girl whose search for a diagnosis over the past seven years has had multiple intensive care admissions and over 307 hospital visits at a cost of £ 356,571.

The genomic diagnosis allowed him to receive a curative bone marrow transplant, costing £ 70,000, and tests from his siblings showed that no other family member was at risk.

– A baby who became seriously ill after birth and died at four months but without a diagnosis and without a health charge of £ 80,000.
Analysis of his entire genome revealed a severe metabolic disorder due to the inability to take vitamin B12 inside cells, which explains his illness.

His younger brother was offered a predictive test within a week of his birth, and he was diagnosed with the same disorder but could be treated with weekly vitamin B12 injections to prevent progression of the disease.

For about a quarter of study participants, their diagnosis meant they could receive more focused clinical care.

The researchers suggest that the high performance of WGS for specific conditions seen in the pilot study supported the case for including WGS to diagnose specific rare diseases under the new NHS National Genomic Test Directory.

Professor Sir Mark Caulfield, senior author from Queen Mary University in London and former Chief Scientist at Genomics England, said: “We hope this major breakthrough will allow rare disease patients around the world to start receiving a whole genome diagnostic sequencing, if applicable.

“Our results show that deploying this comprehensive and effective genomic test at the first sign of symptoms can improve diagnostic rates.

“This study paved the way for the clinical implementation of whole genome sequencing within the framework of the NHS Genomic Medicine Service. “

Lead author Professor Damian Smedley, Queen Mary University, London, said: “This is the first time that whole genome sequencing has been directly integrated into the diagnosis of rare diseases in a healthcare system such as NHS and widely applied across the spectrum of rare diseases. sickness.

“Our new software, along with the collection of detailed clinical data, has been instrumental in enabling us to solve the ‘needle in a haystack’ challenge of finding the cause of a patient’s condition. rare disease among the millions of variants of each genome.

“Much of the diagnoses we discovered were found outside the coding region and would not have been detected by existing approaches.

“This study advocates for healthcare systems around the world to adopt whole genome sequencing as the genetic test of choice for patients with rare diseases. “

Professor Dame Sue Hill, Scientific Director of NHS England and NHS Improvement, said: “This pilot study highlights the importance of whole genome sequencing in a healthcare system.

“It can fundamentally change our perception of the disease, lead to faster, more complete and more accurate diagnoses, provide the missing pieces to families with a loved one living with a rare disease and pave the way for more appropriate and effective treatments. for patients. “

The project, led by Genomics England and NHS England, was established in 2013 to sequence 100,000 entire genomes of NHS patients and their families.

It was undertaken in partnership with BioResource of the National Institute for Health Research (NIHR), and also funded by the NIHR, the Wellcome Trust, the Medical Research Council, Cancer Research UK, the Department of Health and Welfare and the NHS England.

The study is published in the New England Journal of Medicine.

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