100,000 Genomes Project pilot study using Monarch tools shows that whole genome sequencing improves diagnosis of rare diseases

25% of study participants received new diagnosis

Groundbreaking research co-led by Monarch Initiative PI Damian Smedley, a professor of Computational Genomics at Queen Mary University of London, demonstrated that whole genome sequencing (WGS) can help uncover rare disease diagnoses in a large range of patients. The 100,000 Genomes Project, sponsored by the U.K. government and launched in 2013, has just published its preliminary report in the New England Journal of Medicine. The report has been widely covered by news media including the BBC and the Guardian.

The 100,000 Genomes Project was established to sequence 100,000 genomes from patients in the UK with a rare disease or cancer. Rare disease is a global health challenge, with approximately 10,000 disorders, most of which have a genetic component, affecting 6% of the population in Western societies. These conditions are often disabling and expensive to manage. One third of children with a rare disease die before their fifth birthday.

The pilot study, which analyzed the genomes of 4,660 of the sequenced patients with undiagnosed rare diseases, found that using WGS, along with sophisticated analysis methods, successfully led to a new diagnosis for 25% of the participants. 14% of the responsible genetic variants were found in regions of the genome that would have been missed by existing approaches, including non-whole genomic tests.

Tools and standards developed by the Monarch Initiative played key roles in the study. The Human Phenotype Ontology (HPO) was used to encode the clinical data. The diagnostic pipeline used in the study made use of our Exomiser variant prioritization tool, which utilizes both genomic and phenomic information. Exomiser’s ontology-driven phenotype matching algorithm can identify patients who have an atypical profile for a disease, helping to solve some of the toughest cases. In this study, Exomiser found 88% of the rare disease diagnoses in its top five ranked candidates.

Dr. Smedley said, “Our novel software, together with 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. This study makes the case for healthcare systems worldwide to adopt whole genome sequencing as the genetic test of choice for rare disease patients.”

Read more:

NEJM paper: 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report (2021). 100,000 Genomes Project Pilot Investigators, Smedley D, Smith KR, et al. N Engl J Med. 2021 Nov 11;385(20):1868–1880. http://dx.doi.org/10.1056/NEJMoa2035790

Press release: Whole genome sequencing improves diagnosis of rare diseases and shortens diagnostic journeys for patients, according to world first study. November 10, 2021. https://www.genomicsengland.co.uk/100k-whole-genome-sequencing-rare-disease/



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