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100,000 genomes pilot on rare-disease diagnosis in health care — Preliminary report

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The 100,000 Genomes Project Pilot Investigators

Original languageEnglish
Pages (from-to)1868-1880
Number of pages13
JournalNew England Journal of Medicine
Issue number20
Published11 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. Funding Information: We thank the personnel at NIHR BioResource for their partnership in this study; all the health care teams at Addenbrooke’s Hospital in Cambridge, Great Ormond Street Hospital NHS Foundation Trust, University College London NHS Foundation Trust, Guy’s and St. Thomas’ Hospital, Barts Health, Oxford University Hospitals NHS Foundation Trust, Manchester University NHS Foundation Trust, and the Newcastle Hospitals NHS Foundation Trust; the NHS patients and their families who made this work possible; all those across the world who have contributed to the PanelApp knowledge base and to the validation and reporting working group (Dr. Dom McMullan, Dr. Helen Firth, Dr. Steve Abbs, and Dr. Sian Ellard) for their role in supporting the development of the bioinformatics pipeline and reporting process; Dr. David Bick and Dr. Gil McVean for providing feedback on our work; Dr. Dame Sue Hill and the team at NHS England for the work to fund and establish the 13 GMCs, which enabled the NHS contribution that included the clinical return of results within the NHS in a standardized and validated format that led to the confirmation of the diagnoses, provided additional information, and led to the patient benefit reported; the Illumina Laboratory Services team at Hinxton for genome sequencing and secondary analysis; and the developers of the Human Phenotype Ontology (Monarch Initiative) and Exomiser (funded by the NIH Office of the Director [1R24OD011883]) for the support that was provided through these resources. Publisher Copyright: Copyright © 2021 Massachusetts Medical Society.

King's Authors


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.

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