Whole genome sequencing (WGS) improves the diagnosis of rare diseases and could deliver enormous benefits across the NHS, according to a world first study.

The research found the technique proved to be a better way to diagnose rare diseases than usual genomic testing methods.

It led to new rare disease diagnoses for NHS patients, ending decades-long diagnosis journeys for some.

Scientists say the study represents a significant step towards the goal of precision medicine – a transition that will have a huge impact across the NHS and globally.

The pilot study of rare undiagnosed diseases involved analysing the genes of 4,660 people from 2,183 families – all of whom were early participants in the 100,000 Genomes Project.

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

Researchers found that of these new diagnoses, 14% were discovered 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 of the study participants had gone through years of appointments, without getting any answers.

Researchers suggest sequencing the whole genome produced diagnoses that previously would not have been detectable.

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

Among those who received a diagnosis as a result of the study were:

– A girl aged 10 whose previous seven-year search for a diagnosis had multiple intensive care admissions, and more than307 hospital visits at a cost of £356,571.

Genomic diagnosis enabled her to receive a curative bone marrow transplant, costing £70,000, and testing of her siblings showed no further family members were at risk.

– A baby who became severely ill after birth and 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.

A predictive test was offered to his younger brother within one week of his birth, and he 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.

Researchers suggest the high performance of WGS for specific conditions observed in the pilot study has underpinned the case for the inclusion of WGS to diagnose specific rare diseases as part of the new NHS National Genomic Test Directory.

Professor Sir Mark Caulfield, lead author, from Queen Mary University of London, and former chief scientist at Genomics England, 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.”

Lead author, Professor Damian Smedley, Queen Mary University of London, 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.”

Professor Dame Sue Hill, chief scientific officer for NHS England and NHS Improvement, said: “This pilot study highlights the importance of whole genome sequencing within a healthcare system.

“It can fundamentally change how we think about disease, lead to faster, more comprehensive and accurate diagnoses, provide the missing pieces for families who have a loved one living with a rare disease and pave the way for more tailored and effective treatments for patients.“

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

It was undertaken in partnership with the National Institute for Health Research (NIHR) BioResource, and also 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 is published in the New England Journal of Medicine.