100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report
Open accessAbstract
BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection. METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis. RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives. CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).
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Targeted genetic testing currently has an 11.5% yield.
“This framework will support targeted genetic testing, which currently has an 11.5% yield [7], and improved consistency when researching epidemiology, symptom evolution, complications, and interventions.”
From Pediatric joint hypermobility: a diagnostic framework and narrative review (2023) · cites this paper as [7]
The Results (Diagnostic Yield; page unavailable) say that previous tests mostly involved targeted single-gene or panel-based testing, but give no diagnostic yield for those tests. Searches for “11.5% yield” and the yield of previous targeted testing found no supporting passage; the reported percentages concern genome sequencing or other outcomes. (LLM, conf=0.72)
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- Authors
- The 100, 0. G. P. P. I.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2021-11-11
- Volume
- 385
- Issue
- 20
- Pages
- 1868-1880
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC7613219
- OpenAlex
- W3212464243
- Cited by
- 716
- References
- 29
- Citations by year
- 2026: 78 · 2025: 153 · 2024: 176 · 2023: 160 · 2022: 139 · 2021: 6 · 2013: 1
- FWCI
- 68.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Figshare (submittedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Open Research Exeter (University of Exeter) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion, other-oa)
- Science and Technology Facilities Council (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
- Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion, other-oa)
- Explore Bristol Research (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Department of Health and Social Care
- NIH Office of the Director (1R24OD011883, 5-UM1-HG006370)
- National Institute for Health Research
- Wellcome Trust
- Medical Research Council
- Cancer Research U.K.
- NHS England
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- 100,000 Genomes Project, rare diseases, undiagnosed disease, diagnostic yield, variant prioritization, novel pathogenic variant, monogenic disorders, intellectual disability, hearing disorders, visual disturbances, non-coding variants, structural variants, mitochondrial DNA variants, disease gene discovery, family trios, National Health Service
- MeSH terms
- Whole Genome Sequencing, Adolescent, Adult, Child, Child, Preschool, Family Characteristics, Female, United Kingdom, Humans, Male, Middle Aged, Pilot Projects, Sensitivity and Specificity, State Medicine, Genetic Variation, Genome, Human, Polymerase Chain Reaction, Rare Diseases, Young Adult
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