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Whole genome sequencing improves diagnosis of rare diseases, study says

11/11/2021

A world-first scientific study has shown that whole genome sequencing (WGS) can uncover new diagnoses for people across the broadest range of rare diseases investigated to date and could deliver enormous benefits across the NHS.

The pilot study of rare undiagnosed diseases, published on 11 November 2021 in the New England Journal of Medicine, involved analysing the genes of 4,660 people from 2,183 families - all of whom were early participants in the 100,000 Genomes Project. The ground-breaking project, led by Genomics England and NHS England, was established in 2013 to sequence 100,000 whole genomes from NHS patients and their families.

University of Oxford genomics researchers, supported by the NIHR Oxford Biomedical Research Centre (BRC), are among the authors on the study. Oxford University Hospitals NHS Foundation Trust was one of the centres what recruited patients to the 100,000 Genomes Project.

Rare disease is a global health challenge, with approximately 10,000 disorders affecting six percent of the population in Western societies. More than 80 percent of rare diseases have a genetic component, and these conditions are disabling and expensive to manage. One third of children with a rare disease die before their fifth birthday.

The pilot study, led by Genomics England and Queen Mary University of London (QMUL) and undertaken in partnership with the National Institute for Health Research (NIHR) BioResource, found that using WGS led to a new diagnosis for 25 percent of the participants. Of these new diagnoses, 14 percent were found in regions of the genome that would be missed by other conventional methods, including other types of non-whole genomic tests.

Many of the participants had gone through years of appointments, without getting any answers. By having their whole genome sequenced, diagnoses were uncovered that would not have previously been detectable. The pilot study shows that WGS can effectively secure a diagnosis for patients, save the NHS vital resources and pave the way for other interventions.

Participants who received a diagnosis through the pilot include:

  • a 10-year-old girl whose previous seven-year search for a diagnosis had multiple intensive care admissions over 307 hospital visits at a cost of £356,571. Genomic diagnosis enabled her to receive a curative bone marrow transplant (at a cost of £70,000). In addition, predictive testing of her siblings showed no further family members were at risk.
  • a man in his 60s who had endured years of treatment for a serious kidney disease, including two kidney transplants. Already knowing his daughter had inherited the same condition, a genomic diagnosis made by looking at the whole genome for him and his daughter enabled his 15-year-old granddaughter to be tested. This revealed she had not inherited the disease and could cease regular costly check-ups.
  • a baby who became severely ill immediately after birth and sadly died at four months but with no diagnosis and healthcare costs of £80,000. Analysis of his whole genome uncovered a severe metabolic disorder due to inability to take vitamin B12 inside cells explaining his illness. This enabled a predictive test to be offered to his younger brother within one week of his birth. The younger child was diagnosed with the same disorder but was able to be treated with weekly vitamin B12 injections to prevent progression of the illness.

For around a quarter of study participants, their diagnosis meant they were able to receive more focused clinical care. This included further family screening, dietary change, provision of vitamins and/or minerals and other therapies. 

The study is the first to analyse the diagnostic and clinical impact of WGS for a broad range of rare diseases within a national healthcare system. The findings support its widespread adoption in health systems worldwide. 

The high performance of WGS for specific conditions observed in the pilot study - including intellectual disability, and vision and hearing disorders - has underpinned the case for the inclusion of WGS to diagnose specific rare diseases as part of the new NHS National Genomic Test Directory

The pilot study was conducted in partnership with the NIHR and Illumina, which undertook the sequencing, and it was funded by the NIHR, the Wellcome Trust, the Medical Research Council, Cancer Research UK, the Department of Health and Social Care, and NHS England.

The study's lead author, Professor Sir Mark Caulfield of QMUL, said: "We hope this major advance will enable rare disease patients worldwide to start receiving diagnostic whole genome sequencing where appropriate.

"Our findings show that deployment of this comprehensive and efficient genomic test at the first signs of symptoms can improve diagnostic rates. This study has paved the way for clinical implementation of whole genome sequencing as part of the NHS Genomic Medicine Service."

Another lead author, Professor Damian Smedley from QMUL, said: "This is the first time that whole genome sequencing has been directly embedded into rare disease diagnostics in a healthcare system like the NHS and applied at scale across the full breadth of rare disease.

"Our novel software, together with collection of detailed clinical data, was key to us being able to solve the 'needle in a haystack' challenge of finding the cause of a rare disease patient's condition amongst the millions of variants in every genome. A large proportion of the diagnoses we discovered were found outside the coding region and would not have been detected by existing approaches. This study makes the case for healthcare systems worldwide to adopt whole genome sequencing as the genetic test of choice for rare disease patients."

Jillian Hastings Ward, Chair of the Genomics England Participant Panel, said: "The people who signed up for whole genome sequencing in this pilot study were hoping to find new diagnoses for their loved ones, and were willing to share their precious data with Genomics England so that rare diseases could be better understood. The pilot has helped on both of these fronts and we are delighted that whole genome sequencing is now being routinely offered by the NHS to more families across England as a result. This is the beginning of a great leap forward and it needs families, clinicians and researchers to continue to work together for its full potential to be realised."

Dr Richard Scott, Chief Medical Officer at Genomics England, said: "Historically, diagnosis of rare diseases has often been reliant on clinicians doing multiple different targeted tests - an approach that can delay diagnosis and access to more tailored care. Improved knowledge of genomics and the whole genome sequencing and data infrastructure that the government and NHS have invested in now offers us the ability to radically transform the process. This paper provides evidence of that transformation and where it has most impact."

Dr Louise Wood, Director of Science, Research and Evidence at the Department of Health and Social Care and Deputy CEO of the NIHR, said: "This study underpinned the UK's 100,000 genomes project which went on to provide the evidence base for integration of whole genome sequencing into routine clinical care in the NHS. Rare diseases patients and their carers tell us one of their top priorities is getting a diagnosis. This research showed significant progress can be made in addressing this ask and, in about a quarter of cases, in enabling clinical action to be taken on the basis of the diagnosis."