Abstract
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.).
| Original language | English |
|---|---|
| Pages (from-to) | 1868-1880 |
| Number of pages | 13 |
| Journal | New England Journal of Medicine |
| Volume | 385 |
| Issue number | 20 |
| DOIs | |
| Publication status | Published - 11 Nov 2021 |
Bibliographical note
Funding Information:Supported by the NIHR, the Wellcome Trust, the Medical Research Council (MRC), Cancer Research U.K., the Department of Health and Social Care, and NHS England. The NIHR Bio-Resource is funded by the NIHR. Drs. Caulfield and Ouwehand are NIHR senior investigators. Dr. Chinnery is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z) and an NIHR Senior Investigator who receives support from the MRC Mitochondrial Biology Unit (MC_UU_00015/9), the MRC International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), and the NIHR Biomedical Research Centre (BRC). Dr. Wedderburn’s work is supported by grants from Versus Arthritis (21593), the NIHR BRC at Great Ormond Street Hospital, and the MRC (MR/ R013926/1). Drs. Smedley, Cacheiro, and Cipriani receive support from the National Institutes of Health (NIH, grant 5-UM1-HG006370). Dr. Smedley’s team that performed much of the analysis was supported by grants from the NIH (1R24OD011883, U54 HG006370, and 1R01HD103805-01). Dr. Arno’s work is supported by a Fight for Sight (United Kingdom) Early Career Investigator Award (5045/46), NIHR BRC at Great Ormond Street Hospital Institute for Child Health, and Moorfields Eye Charity (Stephen and Elizabeth Archer in memory of Marion Woods). The Moorfields–University College London (UCL) Institute of Ophthalmology team is additionally funded by NIHR BRC at Moorfields Eye Hospital and UCL Institute of Ophthalmology.
Publisher Copyright:
Copyright © 2021 Massachusetts Medical Society.
Keywords
- Adolescent
- Adult
- Child
- Child, Preschool
- Family Characteristics
- Female
- Genetic Variation
- Genome, Human
- Humans
- Male
- Middle Aged
- Pilot Projects
- Polymerase Chain Reaction
- Rare Diseases/diagnosis
- Bristol
- State Medicine
- United Kingdom
- Whole Genome Sequencing
- Young Adult
Access to Document
- Full-text PDF (final published version)
This is the final published version of the article (version of record). It first appeared online via Massachusetts Medical Society at https://www.nejm.org/doi/full/10.1056/NEJMoa2035790 . Please refer to any applicable terms of use of the publisher.