The pilot study, published today in New England Journal of Medicine, 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.

Experts at Newcastle University were involved in the ground-breaking project, and the study identified that using whole genome sequencing led to a new diagnosis for 25% of the participants.

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

Vital help for patients

Scientists at Newcastle University’s Centre of Research Excellence for Rare Disease were involved in the study, with Professor John Sayer, Deputy Dean of Clinical Medicine at the University, leading recruitment for the North East.

Professor Sayer, also a Consultant Nephrologist at Newcastle Hospitals NHS Foundation Trust, said: “Our study is a world-first confirming a definitive genetic diagnosis can vitally help patients and their families, giving them access to specific information about prognosis, treatment, genetic counselling and reproductive options.

“As one of the key contributing centres for this study, Newcastle University’s Centre of Research Excellence for Rare Disease has enabled patients with rare genetic diseases to receive diagnostic whole genome sequencing, which improves both diagnosis and clinical care.

“I am delighted that our work has paved the way for patients to receive whole genome sequencing testing within the NHS as this has been truly transformational.”

Many of the study’s 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 whole genome sequencing can effectively secure a diagnosis for patients, save the NHS vital resources, and pave the way for other interventions.

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 whole genome sequencing for a broad range of rare diseases within a national healthcare system. The findings support its widespread adoption in health systems worldwide.

Improved knowledge

A wide variety of conditions were observed in the pilot study, including intellectual disability, vision and hearing disorders. 

Professors Gráinne Gorman, Bobby McFarland, Rob Taylor and team at the Wellcome Centre for Mitochondrial Research at Newcastle University and Newcastle Hospitals NHS Foundation Trust, were also part of the pilot study to identify patients with mitochondrial disease. 

Professor Gorman said: “We would like to thank our patients for their important contribution to the study. This project has confirmed that mitochondrial disease is more common than previously thought and supports our commitment to continue our research towards finding a cure.” 

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.” 

The pilot study was led by Genomics England and Queen Mary University of London and conducted in partnership with the National Institute for Health Research (NIHR) BioResource, the NIHR and Illumina who undertook the sequencing. 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. 

Dr Louise Wood CBE, 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.” 

Family among first to benefit

A family in the North East was the among the first to benefit from the study’s ground-breaking developments in whole genome sequencing.

Leslie Hedley, of Fenham, Newcastle, has a life-long history of high blood pressure, causing kidney failure. His first kidney transplant failed, and he has received a second transplant.

The 63-year-old’s father, brother and uncle all died of the same rare genetic kidney condition and his daughter Terri Hedley, 41, has developed kidney damage.

There was a concern that Leslie’s granddaughter, Katie, 20, could also be affected but whole genome sequencing revealed she had not inherited the disease and could cease regular, costly NHS check-ups.

Terri, an emergency care assistant, also of Fenham, Newcastle, said: “It’s so important that experts gain as much insight as possible into rare diseases and it’s fantastic that Newcastle University has been involved in this study.

“I wanted to be part of it for the benefit of my daughter, Katie, and it was such a relief when we found out that she did not have the same rare kidney disease as myself and other family members.

“We were so worried that Katie would have to go through what we have - to be told that this is not the case was fantastic news.

“Our family is so lucky to live in Newcastle and to be able to have been part of this study.”

Reference: 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care – Preliminary Report. Damian Smedley et al. New England Journal of Medicine. DOI: 10.1056/NEJMoa2035790