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

Author

Listed:
  • Ernest Turro

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus
    University of Cambridge)

  • William J. Astle

    (University of Cambridge
    Cambridge Biomedical Campus)

  • Karyn Megy

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Stefan Gräf

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Daniel Greene

    (Cambridge Biomedical Campus
    University of Cambridge)

  • Olga Shamardina

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Hana Lango Allen

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Alba Sanchis-Juan

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Mattia Frontini

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus
    University of Cambridge)

  • Chantal Thys

    (Center for Molecular and Vascular Biology, KU Leuven)

  • Jonathan Stephens

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Rutendo Mapeta

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Oliver S. Burren

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Kate Downes

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Matthias Haimel

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Salih Tuna

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Sri V. V. Deevi

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Timothy J. Aitman

    (Imperial College London
    University of Edinburgh)

  • David L. Bennett

    (John Radcliffe Hospital
    Oxford University Hospitals Trust)

  • Paul Calleja

    (University of Cambridge)

  • Keren Carss

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Mark J. Caulfield

    (Genomics England Ltd
    NIHR Biomedical Research Centre at Barts, Queen Mary University of London)

  • Patrick F. Chinnery

    (Cambridge Biomedical Campus
    University of Cambridge, Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Peter H. Dixon

    (King’s College London)

  • Daniel P. Gale

    (University College London
    UK Renal Registry)

  • Roger James

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Ania Koziell

    (King’s College London
    Guy’s & St Thomas’ NHS Foundation Trust)

  • Michael A. Laffan

    (Imperial College Healthcare NHS Trust
    Imperial College London)

  • Adam P. Levine

    (University College London)

  • Eamonn R. Maher

    (University of Cambridge, Cambridge Biomedical Campus
    Cambridge Biomedical Campus
    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
    Cambridge Biomedical Campus)

  • Andrew D. Mumford

    (University of Bristol
    University Hospitals Bristol NHS Foundation Trust)

  • Elizabeth Ormondroyd

    (Oxford University Hospitals Trust
    University of Oxford)

  • Stuart Rankin

    (University of Cambridge)

  • Augusto Rendon

    (Cambridge Biomedical Campus
    Genomics England Ltd)

  • Sylvia Richardson

    (University of Cambridge)

  • Irene Roberts

    (Oxford University Hospitals Trust
    University of Oxford
    University of Oxford)

  • Noemi B. A. Roy

    (Oxford University Hospitals Trust
    University of Oxford
    Oxford University Hospitals NHS Foundation Trust)

  • Moin A. Saleem

    (University of Bristol
    University Hospitals Bristol NHS Foundation Trust)

  • Kenneth G. C. Smith

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Hannah Stark

    (Cambridge Biomedical Campus
    University of Cambridge)

  • 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
    Oxford University Hospitals NHS Foundation Trust
    University of Oxford)

  • Andrew R. Webster

    (Moorfields Eye Hospital NHS Trust
    University College London)

  • Martin R. Wilkins

    (Imperial College London)

  • Catherine Williamson

    (King’s College London
    Hammersmith Hospital, Imperial College Healthcare NHS Trust)

  • James Whitworth

    (University of Cambridge, Cambridge Biomedical Campus
    Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Sean Humphray

    (Illumina Cambridge)

  • David R. Bentley

    (Illumina Cambridge)

  • Nathalie Kingston

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Neil Walker

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • John R. Bradley

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus
    Cambridge Biomedical Campus
    Cambridge University Hospitals NHS Foundation Trust)

  • Sofie Ashford

    (Cambridge Biomedical Campus
    University of Cambridge)

  • Christopher J. Penkett

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Kathleen Freson

    (Center for Molecular and Vascular Biology, KU Leuven)

  • Kathleen E. Stirrups

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • F. Lucy Raymond

    (Cambridge Biomedical Campus
    University of Cambridge, Cambridge Biomedical Campus)

  • Willem H. Ouwehand

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus
    Cambridge Biomedical Campus
    University of Cambridge)

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.

Suggested Citation

  • 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 Mapet, 2020. "Whole-genome sequencing of patients with rare diseases in a national health system," Nature, Nature, vol. 583(7814), pages 96-102, July.
    • Handle: RePEc:nat:nature:v:583:y:2020:i:7814:d:10.1038_s41586-020-2434-2
    DOI: 10.1038/s41586-020-2434-2
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    Citations

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    Cited by:

    1. Peter H. Dixon & Adam P. Levine & Inês Cebola & Melanie M. Y. Chan & Aliya S. Amin & Anshul Aich & Monika Mozere & Hannah Maude & Alice L. Mitchell & Jun Zhang & Jenny Chambers & Argyro Syngelaki & Je, 2022. "GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Vincent Michaud & Eulalie Lasseaux & David J. Green & Dave T. Gerrard & Claudio Plaisant & Tomas Fitzgerald & Ewan Birney & Benoît Arveiler & Graeme C. Black & Panagiotis I. Sergouniotis, 2022. "The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    3. Wenmin Sun & Dan Xiong & Jiamin Ouyang & Xueshan Xiao & Yi Jiang & Yingwei Wang & Shiqiang Li & Ziying Xie & Junwen Wang & Zhonghui Tang & Qingjiong Zhang, 2024. "Altered chromatin topologies caused by balanced chromosomal translocation lead to central iris hypoplasia," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. Matt C. Danzi & Maike F. Dohrn & Sarah Fazal & Danique Beijer & Adriana P. Rebelo & Vivian Cintra & Stephan Züchner, 2023. "Deep structured learning for variant prioritization in Mendelian diseases," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Marsha M. Wheeler & Adrienne M. Stilp & Shuquan Rao & Bjarni V. Halldórsson & Doruk Beyter & Jia Wen & Anna V. Mihkaylova & Caitlin P. McHugh & John Lane & Min-Zhi Jiang & Laura M. Raffield & Goo Jun , 2022. "Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    6. Timofey Prodanov & Vikas Bansal, 2022. "Robust and accurate estimation of paralog-specific copy number for duplicated genes using whole-genome sequencing," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    7. Máire Ní Leathlobhair & Anna Frangou & Ben Kinnersley & Alex J. Cornish & Daniel Chubb & Eszter Lakatos & Prabhu Arumugam & Andreas J. Gruber & Philip Law & Avraam Tapinos & G. Maria Jakobsdottir & Il, 2024. "Genomic landscape of adult testicular germ cell tumours in the 100,000 Genomes Project," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    8. Molas-Gallart, Jordi & Woolley, Richard, 2022. "Research impact seen from the user side," INGENIO (CSIC-UPV) Working Paper Series 202201, INGENIO (CSIC-UPV).
    9. Mallory J. Owen & Sebastien Lefebvre & Christian Hansen & Chris M. Kunard & David P. Dimmock & Laurie D. Smith & Gunter Scharer & Rebecca Mardach & Mary J. Willis & Annette Feigenbaum & Anna-Kaisa Nie, 2022. "An automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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