Whole genome sequencing improves rare disease diagnosis in world first study

A world-first study at UCLH and UCL 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 for the NHS.

The pilot study of rare undiagnosed diseases, which analysed the genes of 4,660 people from 2,183 families, found that using WGS led to a new diagnosis for 25% of 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. The study was published in the New England Journal of Medicine.

All of the study participants had been early participants in the 100,000 Genomes Project. This 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.

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.

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, vision and hearing disorders of 40-55% diagnostic yield - 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 also conducted in partnership with the National Institute for Health Research (NIHR) and Illumina who 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.

Professor Nick Wood, consultant neurologist at UCLH and research director of the UCL Institute of Genetics, said: “This represents a tremendous milestone in dissecting a range of rare, often significantly disabling, conditions. Identifying the genes and mutations responsible empowers the patient their families and of course illuminates the causes of disease. For me, as clinician scientist, to now be able to accurately diagnose the patients who come to our clinics and guide the counselling for at risk individuals is hugely satisfying. This large-scale detailed approach allows a real opportunity for identifying new targets for therapeutic intervention.”

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.”