• N. Engl. J. Med. · Nov 2021

    100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.

    • 100,000 Genomes Project Pilot Investigators, Damian Smedley, Katherine R Smith, Antonio Martin, Ellen A Thomas, Ellen M McDonagh, Valentina Cipriani, Jamie M Ellingford, Gavin Arno, Arianna Tucci, Jana Vandrovcova, Georgia Chan, Hywel J Williams, Thiloka Ratnaike, Wei Wei, Kathleen Stirrups, Kristina Ibanez, Loukas Moutsianas, Matthias Wielscher, Anna Need, Michael R Barnes, Letizia Vestito, James Buchanan, Sarah Wordsworth, Sofie Ashford, Karola Rehmström, Emily Li, Gavin Fuller, Philip Twiss, Olivera Spasic-Boskovic, Sally Halsall, R Andres Floto, Kenneth Poole, Annette Wagner, Sarju G Mehta, Mark Gurnell, Nigel Burrows, Roger James, Christopher Penkett, Eleanor Dewhurst, Stefan Gräf, Rutendo Mapeta, Mary Kasanicki, Andrea Haworth, Helen Savage, Melanie Babcock, Martin G Reese, Mark Bale, Emma Baple, Christopher Boustred, Helen Brittain, Anna de Burca, Marta Bleda, Andrew Devereau, Dina Halai, Eik Haraldsdottir, Zerin Hyder, Dalia Kasperaviciute, Christine Patch, Dimitris Polychronopoulos, Angela Matchan, Razvan Sultana, Mina Ryten, Ana L T Tavares, Carolyn Tregidgo, Clare Turnbull, Matthew Welland, Suzanne Wood, Catherine Snow, Eleanor Williams, Sarah Leigh, Rebecca E Foulger, Louise C Daugherty, Olivia Niblock, Ivone U S Leong, Caroline F Wright, Jim Davies, Charles Crichton, James Welch, Kerrie Woods, Lara Abulhoul, Paul Aurora, Detlef Bockenhauer, Alexander Broomfield, Maureen A Cleary, Tanya Lam, Mehul Dattani, Emma Footitt, Vijeya Ganesan, Stephanie Grunewald, Sandrine Compeyrot-Lacassagne, Francesco Muntoni, Clarissa Pilkington, Rosaline Quinlivan, Nikhil Thapar, Colin Wallis, Lucy R Wedderburn, Austen Worth, Teofila Bueser, Cecilia Compton, Charu Deshpande, Hiva Fassihi, Eshika Haque, Louise Izatt, Dragana Josifova, Shehla Mohammed, Leema Robert, Sarah Rose, Deborah Ruddy, Robert Sarkany, Genevieve Say, Adam C Shaw, Agata Wolejko, Bishoy Habib, Gavin Burns, Sarah Hunter, Russell J Grocock, Sean J Humphray, Peter N Robinson, Melissa Haendel, Michael A Simpson, Siddharth Banka, Jill Clayton-Smith, Sofia Douzgou, Georgina Hall, Huw B Thomas, Raymond T O'Keefe, Michel Michaelides, Anthony T Moore, Sam Malka, Nikolas Pontikos, Andrew C Browning, Volker Straub, Gráinne S Gorman, Rita Horvath, Richard Quinton, Andrew M Schaefer, Patrick Yu-Wai-Man, Doug M Turnbull, Robert McFarland, Robert W Taylor, Emer O'Connor, Janice Yip, Katrina Newland, Huw R Morris, James Polke, Nicholas W Wood, Carolyn Campbell, Carme Camps, Kate Gibson, Nils Koelling, Tracy Lester, Andrea H Németh, Claire Palles, Smita Patel, Noemi B A Roy, Arjune Sen, John Taylor, Pilar Cacheiro, Julius O Jacobsen, Eleanor G Seaby, Val Davison, Lyn Chitty, Angela Douglas, Kikkeri Naresh, Dom McMullan, Sian Ellard, I Karen Temple, Andrew D Mumford, Gill Wilson, Phil Beales, Maria Bitner-Glindzicz, Graeme Black, John R Bradley, Paul Brennan, John Burn, Patrick F Chinnery, Perry Elliott, Frances Flinter, Henry Houlden, Melita Irving, William Newman, Shamima Rahman, John A Sayer, Jenny C Taylor, Andrew R Webster, Andrew O M Wilkie, Willem H Ouwehand, F Lucy Raymond, John Chisholm, Sue Hill, David Bentley, Richard H Scott, Tom Fowler, Augusto Rendon, and Mark Caulfield.
    • From Genomics England (D.S., K.R.S., A.M., E.A.T., E.M.M., A.T., G.C., K.I., L.M., M. Wielscher, A.N., M. Bale, E.B., C.B., H.B., M. Bleda, A. Devereau, D.H., E. Haraldsdottir, Z.H., D.K., C. Patch, D.P., A.M., R. Sultana, M.R., A.L.T.T., C. Tregidgo, C. Turnbull, M. Welland, S. Wood, C.S., E.W., S.L., R.E.F., L.C.D., O.N., I.U.S.L., C.F.W., J.C., R.H.S., T.F., A.R., M.C.), the William Harvey Research Institute, Queen Mary University of London (D.S., K.R.S., V.C., A.T., L.M., M.R.B., D.K., S. Wood, P.C., J.O.J., T.F., M.C.), University College London (UCL) Institute of Ophthalmology (V.C., G.A., M.M., A.T.M., S. Malka, N.P., P.Y.-W.-M., A.R.W.), UCL Genetics Institute (V.C., N.W.W.), GOSgene (H.J.W.), Genetics and Genomic Medicine Programme (L.V., M.R., M.D., L.C., P. Beales, M.B.-G.), National Institute for Health Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre (BRC) (M.R., S. Grunewald, S.C.-L., F.M., C. Pilkington, L.R.W., L.C., P. Beales, M.B.-G.), Infection, Immunity, and Inflammation Research and Teaching Department (P.A., L.R.W.), Stem Cells and Regenerative Medicine (N.T.), and Mitochondrial Research Group (S. Rahman), UCL Great Ormond Street Institute of Child Health, UCL Ear Institute (L.V.), the Department of Renal Medicine (D. Bockenhauer), and Institute of Cardiovascular Science (P.E.), UCL, Moorfields Eye Hospital National Health Service (NHS) Foundation Trust (V.C., G.A., M.M., A.T.M., S. Malka, N.P., A.R.W.), the National Hospital for Neurology and Neurosurgery (J.V., E.O., J.Y., K. Newland, H.R.M., J.P., N.W.W., H.H.), the Metabolic Unit (L.A., S. Grunewald, S. Rahman), London Centre for Paediatric Endocrinology and Diabetes (M.D.), and the Department of Gastroenterology (N.T.), Great Ormond Street Hospital for Children NHS Foundation Trust (L.V., D. Bockenhauer, A. Broomfield, M.A.C., T. Lam, E.F., V.G., S.C.-L., F.M., C. Pilkington, R. Quinlivan, C.W., L.R.W., A. Worth, L.C., P. Beales, M.B.-G., R.H.S.), the Clinical Genetics Department (M.R., T.B., C. Compton, C.D., E. Haque, L.I., D.J., S. Mohammed, L.R., S. Rose, D.R., G.S., A.C.S., F.F., M.I.) and St. John's Institute of Dermatology (H.F., R. Sarkany), Guy's and St. Thomas' NHS Foundation Trust, the Division of Genetics and Epidemiology, Institute of Cancer Research (C. Turnbull), Florence Nightingale Faculty of Nursing, Midwifery, and Palliative Care (T.B.), Division of Genetics and Molecular Medicine (M.A.S.), and Division of Medical and Molecular Genetics (M.I.), King's College London, NIHR BRC at Moorfields Eye Hospital (P.Y.-W.-M.), NHS England and NHS Improvement, Skipton House (V.D., A. Douglas, S. Hill), and Imperial College Healthcare NHS Trust, Hammersmith Hospital (K. Naresh), London, Open Targets and European Molecular Biology Laboratory-European Bioinformatics Institute, Wellcome Genome Campus, Hinxton (E.M.M.), the Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine, and Health, University of Manchester (J.M.E., S.B., J.C.-S., S.D., G.H., H.B.T., R.T.O., G. Black, W.N.), and the Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University NHS Foundation Trust (J.M.E., Z.H., S.B., J.C.-S., S.D., G.H., G. Black, W.N.), Manchester, the Department of Genetic and Genomic Medicine, Institute of Medical Genetics, Cardiff University, Cardiff (H.J.W.), the Department of Clinical Neurosciences (T.R., W.W., R.H., P.F.C.), the Medical Research Council (MRC) Mitochondrial Biology Unit (T.R., W.W., P.Y.-W.-M., P.F.C.), the Department of Paediatrics (T.R.), the Department of Haematology (K.S., C. Penkett, S. Gräf, R.M., W.H.O., A.R.), the School of Clinical Medicine (K.R., E.L., R.A.F., K.P., F.L.R.), the Department of Medicine (S. Gräf), and Cambridge Centre for Brain Repair, Department of Clinical Neurosciences (P.Y.-W.-M.), University of Cambridge, NIHR BioResource, Cambridge University Hospitals (K.S., S.A., R.J., C. Penkett, E.D., S. Gräf, R.M., M.K., J.R.B., P.F.C., W.H.O., F.L.R.), and Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust (G.F., P.T., O.S.-B., S. Halsall, K.P., A. Wagner, S.G.M., N.B., M.K.), Cambridge Biomedical Campus, Wellcome-MRC Institute of Metabolic Science and NIHR Cambridge BRC (M.G.), Congenica (A.H., H.S.), Illumina Cambridge (A. Wolejko, B.H., G. Burns, S. Hunter, R.J.G., S.J.H., D. Bentley), NHS Blood and Transplant (W.H.O.), and Wellcome Sanger Institute (W.H.O.), Cambridge, the Health Economics Research Centre (J. Buchanan, S. Wordsworth) and the Wellcome Centre for Human Genetics (C. Camps, J.C.T.), University of Oxford, NIHR Oxford BRC (J. Buchanan, S. Wordsworth, J.D., C. Crichton, J.W., K.W., C. Camps, S.P., N.B.A.R., A.S., J.T., J.C.T.), the Oxford Centre for Genomic Medicine (A. de Burca, A.H.N.), and the Departments of Haematology (N.B.A.R.) and Neurology (A.S.), Oxford University Hospitals NHS Foundation Trust, Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital (C. Campbell, K.G., T. Lester, J.T.), the MRC Weatherall Institute of Molecular Medicine (N.K., N.B.A.R., A.O.M.W.) and the Oxford Epilepsy Research Group (A.S.), Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford, and the Department of Clinical Immunology (S.P.), John Radcliffe Hospital, Oxford, Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Foundation Trust (E.B.), and the University of Exeter Medical School (E.B., C.F.W.), Royal Devon and Exeter Hospital (S.E.), Exeter, Newcastle Eye Centre, Royal Victoria Infirmary (A.C.B.), the Institute of Genetic Medicine, Newcastle University, International Centre for Life (V.S., P. Brennan), Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University (G.S.G., R.H., A.M.S., D.M.T., R. Quinton, R.M., R.W.T., J.A.S.), Highly Specialised Mitochondrial Service (G.S.G., A.M.S., D.M.T., R.M., R.W.T.) and Northern Genetics Service (J. Burn), Newcastle upon Tyne Hospitals NHS Foundation Trust (J.A.S.), and NIHR Newcastle BRC (G.S.G., D.M.T., J.A.S.), Newcastle upon Tyne, the Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, University of Birmingham (C. Palles), and Birmingham Women's Hospital (D.M.), Birmingham, the Genomic Informatics Group (E.G.S.), University Hospital Southampton (I.K.T.), and the University of Southampton (I.K.T.), Southampton, Liverpool Women's NHS Foundation Trust, Liverpool (A. Douglas), the School of Cellular and Molecular Medicine, University of Bristol, Bristol (A.D.M.), and Yorkshire and Humber, Sheffield Children's Hospital, Sheffield (G.W.) - all in the United Kingdom; Fabric Genomics, Oakland (M. Babcock, M.G.R.), and the Ophthalmology Department, University of California, San Francisco School of Medicine, San Francisco (A.T.M.) - both in California; the Jackson Laboratory for Genomic Medicine, Farmington, CT (P.N.R.); and the Center for Genome Research and Biocomputing, Environmental and Molecular Toxicology, Oregon State University, Corvallis (M.H.).
    • N. Engl. J. Med. 2021 Nov 11; 385 (20): 186818801868-1880.

    BackgroundThe 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.MethodsWe 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.ResultsDiagnostic 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.ConclusionsOur 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.).Copyright © 2021 Massachusetts Medical Society.

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