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 Calleja, Keren 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, Nathalie Kingston, Neil Walker, John R. Bradley, Sofie Ashford, Christopher J. Penkett, Kathleen Freson, Kathleen E. Stirrups, F. Lucy Raymond () and Willem H. Ouwehand ()
Additional contact information
Ernest Turro: Cambridge Biomedical Campus
William J. Astle: University of Cambridge
Karyn Megy: Cambridge Biomedical Campus
Stefan Gräf: Cambridge Biomedical Campus
Daniel Greene: Cambridge Biomedical Campus
Olga Shamardina: Cambridge Biomedical Campus
Hana Lango Allen: Cambridge Biomedical Campus
Alba Sanchis-Juan: Cambridge Biomedical Campus
Mattia Frontini: Cambridge Biomedical Campus
Chantal Thys: Center for Molecular and Vascular Biology, KU Leuven
Jonathan Stephens: Cambridge Biomedical Campus
Rutendo Mapeta: Cambridge Biomedical Campus
Oliver S. Burren: Cambridge Biomedical Campus
Kate Downes: Cambridge Biomedical Campus
Matthias Haimel: Cambridge Biomedical Campus
Salih Tuna: Cambridge Biomedical Campus
Sri V. V. Deevi: Cambridge Biomedical Campus
Timothy J. Aitman: Imperial College London
David L. Bennett: John Radcliffe Hospital
Paul Calleja: University of Cambridge
Keren Carss: Cambridge Biomedical Campus
Mark J. Caulfield: Genomics England Ltd
Patrick F. Chinnery: Cambridge Biomedical Campus
Peter H. Dixon: King’s College London
Daniel P. Gale: University College London
Roger James: Cambridge Biomedical Campus
Ania Koziell: King’s College London
Michael A. Laffan: Imperial College Healthcare NHS Trust
Adam P. Levine: University College London
Eamonn R. Maher: University of Cambridge, Cambridge Biomedical Campus
Hugh S. Markus: University of Cambridge, Cambridge Biomedical Campus
Joannella Morales: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI)
Nicholas W. Morrell: Cambridge Biomedical Campus
Andrew D. Mumford: University of Bristol
Elizabeth Ormondroyd: Oxford University Hospitals Trust
Stuart Rankin: University of Cambridge
Augusto Rendon: Cambridge Biomedical Campus
Sylvia Richardson: University of Cambridge
Irene Roberts: Oxford University Hospitals Trust
Noemi B. A. Roy: Oxford University Hospitals Trust
Moin A. Saleem: University of Bristol
Kenneth G. C. Smith: Cambridge Biomedical Campus
Hannah Stark: Cambridge Biomedical Campus
Rhea Y. Y. Tan: University of Cambridge, Cambridge Biomedical Campus
Andreas C. Themistocleous: John Radcliffe Hospital
Adrian J. Thrasher: UCL Great Ormond Street Institute of Child Health
Hugh Watkins: University of Oxford
Andrew R. Webster: Moorfields Eye Hospital NHS Trust
Martin R. Wilkins: Imperial College London
Catherine Williamson: King’s College London
James Whitworth: University of Cambridge, Cambridge Biomedical Campus
Sean Humphray: Illumina Cambridge
David R. Bentley: Illumina Cambridge
Nathalie Kingston: Cambridge Biomedical Campus
Neil Walker: Cambridge Biomedical Campus
John R. Bradley: Cambridge Biomedical Campus
Sofie Ashford: Cambridge Biomedical Campus
Christopher J. Penkett: Cambridge Biomedical Campus
Kathleen Freson: Center for Molecular and Vascular Biology, KU Leuven
Kathleen E. Stirrups: Cambridge Biomedical Campus
F. Lucy Raymond: Cambridge Biomedical Campus
Willem H. Ouwehand: Cambridge Biomedical Campus

Nature, 2020, vol. 583, issue 7814, 96-102

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2434-2

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