Whole-genome sequencing of patients with rare diseases in a national health system

Ernest Turro, William J. Astle, Karyn Megy, Stefan Gräf, Daniel Greene, Olga Shamardina, Hana Lango Allen, Alba Sanchis-Juan, Mattia Frontini, Chantal Thys, Jonathan Stephens, Rutendo Mapeta, Oliver S. Burren, Kate Downes, Matthias Haimel, Salih Tuna, Sri V.V. Deevi, Timothy J. Aitman, David L. Bennett, Paul CallejaKeren Carss, Mark J. Caulfield, Patrick F. Chinnery, Peter H. Dixon, Daniel P. Gale, Roger James, Ania Koziell, Michael A. Laffan, Adam P. Levine, Eamonn R. Maher, Hugh S. Markus, Joannella Morales, Nicholas W. Morrell, Andrew D. Mumford, Elizabeth Ormondroyd, Stuart Rankin, Augusto Rendon, Sylvia Richardson, Irene Roberts, Noemi B.A. Roy, Moin A. Saleem, Kenneth G.C. Smith, Hannah Stark, Rhea Y.Y. Tan, Andreas C. Themistocleous, Adrian J. Thrasher, Hugh Watkins, Andrew R. Webster, Martin R. Wilkins, Catherine Williamson, James Whitworth, Sean Humphray, David R. Bentley, Stephen Abbs, Lara Abulhoul, Julian Adlard, Munaza Ahmed, Timothy J. Aitman, Hana Alachkar, David J. Allsup, Jeff Almeida-King, Philip Ancliff, Richard Antrobus, Ruth Armstrong, Gavin Arno, Sofie Ashford, William J. Astle, Anthony Attwood, Paul Aurora, Christian Babbs, Chiara Bacchelli, Tamam Bakchoul, Siddharth Banka, Tadbir Bariana, Julian Barwell, Joana Batista, Helen E. Baxendale, Phil L. Beales, David L. Bennett, David R. Bentley, Agnieszka Bierzynska, Tina Biss, Maria A.K. Bitner-Glindzicz, Graeme C. Black, Marta Bleda, Iulia Blesneac, Detlef Bockenhauer, Harm Bogaard, Christian J. Bourne, Sara Boyce, John R. Bradley, Eugene Bragin, Gerome Breen, Paul Brennan, Carole Brewer, Matthew Brown, Andrew C. Browning, Michael J. Browning, Rachel J. Buchan, Matthew S. Buckland, Teofila Bueser, Carmen Bugarin Diz, John Burn, Siobhan O. Burns, Oliver S. Burren, Nigel Burrows, Paul Calleja, Carolyn Campbell, Gerald Carr-White, Keren Carss, Ruth Casey, Mark J. Caulfield, Jenny Chambers, John Chambers, Melanie M.Y. Chan, Calvin Cheah, Floria Cheng, Patrick F. Chinnery, Manali Chitre, Martin T. Christian, Colin Church, Jill Clayton-Smith, Maureen Cleary, Naomi Clements Brod, Gerry Coghlan, Elizabeth Colby, Trevor R.P. Cole, Janine Collins, Peter W. Collins, Camilla Colombo, Cecilia J. Compton, Robin Condliffe, Stuart Cook, H. Terence Cook, Nichola Cooper, Paul A A. Corris, Abigail Furnell, Fiona Cunningham, Nicola S. Curry, Antony J. Cutler, Matthew J. Daniels, Mehul Dattani, Louise C. Daugherty, John Davis, Anthony De Soyza, Sri V.V. Deevi, Timothy Dent, Charu Deshpande, Eleanor F. Dewhurst, Peter H. Dixon, Sofia Douzgou, Kate Downes, Anna M. Drazyk, Elizabeth Drewe, Daniel Duarte, Tina Dutt, J. David M. Edgar, Karen Edwards, William Egner, Melanie N. Ekani, Perry Elliott, Wendy N. Erber, Marie Erwood, Maria C. Estiu, Dafydd Gareth Evans, Gillian Evans, Tamara Everington, Mélanie Eyries, Hiva Fassihi, Remi Favier, Jack Findhammer, Debra Fletcher, Frances A. Flinter, R. Andres Floto, Tom Fowler, James Fox, Amy J. Frary, Courtney E. French, Kathleen Freson, Mattia Frontini, Daniel P. Gale, Henning Gall, Vijeya Ganesan, Michael Gattens, Claire Geoghegan, Terence S.A. Gerighty, Ali G. Gharavi, Stefano Ghio, Hossein Ardeschir Ghofrani, J. Simon R. Gibbs, Kate Gibson, Kimberly C. Gilmour, Barbara Girerd, Nicholas S. Gleadall, Sarah Goddard, David B. Goldstein, Keith Gomez, Pavels Gordins, David Gosal, Stefan Gräf, Jodie Graham, Luigi Grassi, Daniel Greene, Lynn Greenhalgh, Andreas Greinacher, Paolo Gresele, Philip Griffiths, Sofia Grigoriadou, Russell J. Grocock, Detelina Grozeva, Mark Gurnell, Scott Hackett, Charaka Hadinnapola, William M. Hague, Rosie Hague, Matthias Haimel, Matthew Hall, Helen L. Hanson, Eshika Haque, Kirsty Harkness, Andrew R. Harper, Claire L L. Harris, Daniel Hart, Ahamad Hassan, Grant Hayman, Alex Henderson, Archana Herwadkar, Jonathan Hoffman, Simon Holden, Rita Horvath, Henry Houlden, Arjan C C. Houweling, Luke S. Howard, Fengyuan Hu, Gavin Hudson, Joseph Hughes, Aarnoud P. Huissoon, Marc Humbert, Sean Humphray, Sarah Hunter, Matthew Hurles, Melita Irving, Louise Izatt, Roger James, Sally A. Johnson, Stephen Jolles, Jennifer Jolley, Dragana Josifova, Neringa Jurkute, Tim Karten, Johannes Karten, Mary A. Kasanicki, Hanadi Kazkaz, Rashid Kazmi, Peter Kelleher, Anne M. Kelly, Wilf Kelsall, Carly Kempster, David G. Kiely, Nathalie Kingston, Robert Klima, Nils Koelling, Myrto Kostadima, Gabor Kovacs, Ania Koziell, Roman Kreuzhuber, Taco W. Kuijpers, Ajith Kumar, Dinakantha Kumararatne, Manju A. Kurian, Michael A. Laffan, Fiona Lalloo, Michele Lambert, Hana Lango Allen, Allan Lawrie, D. Mark Layton, Nick Lench, Claire Lentaigne, Tracy Lester, Adam P. Levine, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Eleni Louka, Paul A. Lyons, Rajiv D. Machado, Robert V. MacKenzie Ross, Bella Madan, Eamonn R. Maher, Jesmeen Maimaris, Samantha Malka, Sarah Mangles, Rutendo Mapeta, Kevin J. Marchbank, Stephen Marks, Hugh S. Markus, Hanns Ulrich Marschall, Andrew Marshall, Jennifer Martin, Mary Mathias, Emma Matthews, Heather Maxwell, Paul McAlinden, Mark I. McCarthy, Harriet McKinney, Aoife McMahon, Stuart Meacham, Adam J. Mead, Ignacio Medina Castello, Karyn Megy, Sarju G G. Mehta, Michel Michaelides, Carolyn Millar, Shehla N. Mohammed, Shahin Moledina, David Montani, Anthony T. Moore, Joannella Morales, Nicholas W. Morrell, Monika Mozere, Keith W. Muir, Andrew D. Mumford, Andrea H. Nemeth, William G. Newman, Michael Newnham, Sadia Noorani, Paquita Nurden, Jennifer O’Sullivan, Samya Obaji, Chris Odhams, Steven Okoli, Andrea Olschewski, Horst Olschewski, Kai Ren Ong, S.  Helen Oram, Elizabeth Ormondroyd, Willem H. Ouwehand, Claire Palles, Sofia Papadia, Soo Mi Park, David Parry, Smita Patel, Joan Paterson, Andrew Peacock, Simon H H. Pearce, John Peden, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, Romina Petersen, Clarissa Pilkington, Kenneth E.S. Poole, Radhika Prathalingam, Bethan Psaila, Angela Pyle, Richard Quinton, Shamima Rahman, Stuart Rankin, Anupama Rao, F. Lucy Raymond, Paula J. Rayner-Matthews, Christine Rees, Augusto Rendon, Tara Renton, Christopher J. Rhodes, Andrew S.C. Rice, Sylvia Richardson, Alex Richter, Leema Robert, Irene Roberts, Anthony Rogers, Sarah J. Rose, Robert Ross-Russell, Catherine Roughley, Noemi B. A Roy, Deborah M. Ruddy, Omid Sadeghi-Alavijeh, Moin A. Saleem, Nilesh Samani, Crina Samarghitean, Alba Sanchis-Juan, Ravishankar B. Sargur, Robert N. Sarkany, Simon Satchell, Sinisa Savic, John A. Sayer, Genevieve Sayer, Laura Scelsi, Andrew M. Schaefer, Sol Schulman, Richard Scott, Marie Scully, Claire Searle, Werner Seeger, Arjune Sen, W. A.Carrock Sewell, Denis Seyres, Neil Shah, Olga Shamardina, Susan E. Shapiro, Adam C. Shaw, Patrick J. Short, Keith Sibson, Lucy Side, Ilenia Simeoni, Michael A A. Simpson, Matthew C. Sims, Suthesh Sivapalaratnam, Damian Smedley, Katherine R. Smith, Kenneth G.C. Smith, Katie Snape, Nicole Soranzo, Florent Soubrier, Laura Southgate, Olivera Spasic-Boskovic, Simon Staines, Emily Staples, Hannah Stark, Jonathan Stephens, Charles Steward, Kathleen E. Stirrups, Alex Stuckey, Jay Suntharalingam, Emilia M. Swietlik, Petros Syrris, R. Campbell Tait, Kate Talks, Rhea Y.Y. Tan, Katie Tate, John M. Taylor, Jenny C. Taylor, James E. Thaventhiran, Andreas C. Themistocleous, Ellen Thomas, David Thomas, Moira J. Thomas, Patrick Thomas, Kate Thomson, Adrian J. Thrasher, Glen Threadgold, Chantal Thys, Tobias Tilly, Marc Tischkowitz, Catherine Titterton, John A. Todd, Cheng Hock Toh, Bas Tolhuis, Ian P. Tomlinson, Mark Toshner, Matthew Traylor, Carmen Treacy, Paul Treadaway, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Philip Twiss, Tom Vale, Chris Van Geet, Natalie van Zuydam, Maarten Vandekuilen, Anthony M. Vandersteen, Marta Vazquez-Lopez, Julie von Ziegenweidt, Anton Vonk Noordegraaf, Annette Wagner, Quinten Waisfisz, Suellen M. Walker, Neil Walker, Klaudia Walter, James S. Ware, Hugh Watkins, Christopher Watt, Andrew R. Webster, Lucy Wedderburn, Wei Wei, Steven B. Welch, Julie Wessels, Sarah K. Westbury, John Paul Westwood, John Wharton, Deborah Whitehorn, James Whitworth, Andrew O. M Wilkie, Martin R. Wilkins, Catherine Williamson, Brian T. Wilson, Edwin K.S. Wong, Nicholas Wood, Yvette Wood, Christopher Geoffrey Woods, Emma R R. Woodward, Stephen J. Wort, Austen Worth, Michael Wright, Katherine Yates, Patrick F.K. Yong, Timothy Young, Ping Yu, Patrick Yu-Wai-Man, Eliska Zlamalova, Nathalie Kingston, Neil Walker, John R. Bradley, Sofie Ashford, Christopher J. Penkett, Kathleen Freson, Kathleen E. Stirrups, F. Lucy Raymond, Willem H. Ouwehand, NIHR BioResource for the 100,000 Genomes Project

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

Original languageEnglish
Pages (from-to)96-102
Number of pages7
JournalNature
Volume583
Issue number7814
DOIs
Publication statusPublished - 2 Jul 2020

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