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Cited by 554Genomics and Rare DiseasesGenetic Associations and EpidemiologyConnective tissue disorders research

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

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Turro, Ernest, Astle, William J., Megy, Karyn, Gräf, Stefan, Greene, Daniel, Shamardina, Olga, Allen, Hana Lango, Sanchis-Juan, Alba +504 more·2020·Nature
DOI 10.1038/s41586-020-2434-2PMC PMC7610553

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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 discovered 1. 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 participants 2, 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.

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  • Another nonsense variant, p.Gln520Ter, has also been reported in one individual.

    “Another nonsense variant, p.Gln520Ter, has also been reported in one individual98,99.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [99]

    The Extended Data caption describes a premature stop in one ITGB3 case but does not identify it as p.Gln520Ter. Searches for p.Gln520Ter, alternative Q520 notation, and a nonsense variant at position 520 found no passage in our copy establishing that this specific variant was reported in one individual. (LLM, conf=0.70)

    Experimental — accuracy not yet measured

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Turro, E., Astle, W. J., Megy, K., Gräf, S., Greene, D., Shamardina, O., Allen, H. L., Sanchis-Juan, A., Frontini, M., Thys, C., Stephens, J., Mapeta, R., Burren, O. S., Downes, K., Haimel, M., Tuna, S., Deevi, S. V. V., Aitman, T. J., Bennett, D. L., Calleja, P., Carss, K., Caulfield, M. J., Chinnery, P. F., Dixon, P. H., Gale, D. P., James, R., Koziell, A., Laffan, M. A., Levine, A. P., Maher, E. R., Markus, H. S., Morales, J., Morrell, N. W., Mumford, A. D., Ormondroyd, E., Rankin, S., Rendon, A., Richardson, S., Roberts, I., Roy, N. B. A., Saleem, M. A., Smith, K. G. C., Stark, H., Tan, R. Y. Y., Themistocleous, A. C., Thrasher, A. J., Watkins, H., Webster, A. R., Wilkins, M. R., Williamson, C., Whitworth, J., Humphray, S., Bentley, D. R., NIHR BioResource for the 100, 0. G. P., Abbs, S., Abulhoul, L., Adlard, J., Ahmed, M., Aitman, T. J., Alachkar, H., Allsup, D. J., Almeida-King, J., Ancliff, P., Antrobus, R., Armstrong, R., Arno, G., Ashford, S., Astle, W. J., Attwood, A., Aurora, P., Babbs, C., Bacchelli, C., Bakchoul, T., Banka, S., Bariana, T., Barwell, J., Batista, J., Baxendale, H. E., Beales, P. L., Bennett, D. L., Bentley, D. R., Bierzynska, A., Biss, T., Bitner-Glindzicz, M. A. K., Black, G. C., Bleda, M., Blesneac, I., Bockenhauer, D., Bogaard, H., Bourne, C. J., Boyce, S., Bradley, J. R., Bragin, E., Breen, G., Brennan, P., Brewer, C., Brown, M., Browning, A. C., Browning, M. J., Buchan, R. J., Buckland, M. S., Bueser, T., Diz, C. B., Burn, J., Burns, S. O., Burren, O. S., Burrows, N., Calleja, P., Campbell, C., Carr-White, G., Carss, K., Casey, R., Caulfield, M. J., Chambers, J., Chambers, J., Chan, M. M. Y., Cheah, C., Cheng, F., Chinnery, P. F., Chitre, M., Christian, M. T., Church, C., Clayton-Smith, J., Cleary, M., Brod, N. C., Coghlan, G., Colby, E., Cole, T. R. P., Collins, J., Collins, P. W., Colombo, C., Compton, C. J., Condliffe, R., Cook, S., Cook, H. T., Cooper, N., Corris, P. A., Furnell, A., Cunningham, F., Curry, N. S., Cutler, A. J., Daniels, M. J., Dattani, M., Daugherty, L. C., Davis, J., De Soyza, A., Deevi, S. V. V., Dent, T., Deshpande, C., Dewhurst, E. F., Dixon, P. H., Douzgou, S., Downes, K., Drazyk, A. M., Drewe, E., Duarte, D., Dutt, T., Edgar, J. D. M., Edwards, K., Egner, W., Ekani, M. N., Elliott, P., Erber, W. N., Erwood, M., Estiu, M. C., Evans, D. G., Evans, G., Everington, T., Eyries, M., Fassihi, H., Favier, R., Findhammer, J., Fletcher, D., Flinter, F. A., Floto, R. A., Fowler, T., Fox, J., Frary, A. J., French, C. E., Freson, K., Frontini, M., Gale, D. P., Gall, H., Ganesan, V., Gattens, M., Geoghegan, C., Gerighty, T. S. A., Gharavi, A. G., Ghio, S., Ghofrani, H.-A., Gibbs, J. S. R., Gibson, K., Gilmour, K. C., Girerd, B., Gleadall, N. S., Goddard, S., Goldstein, D. B., Gomez, K., Gordins, P., Gosal, D., Gräf, S., Graham, J., Grassi, L., Greene, D., Greenhalgh, L., Greinacher, A., Gresele, P., Griffiths, P., Grigoriadou, S., Grocock, R. J., Grozeva, D., Gurnell, M., Hackett, S., Hadinnapola, C., Hague, W. M., Hague, R., Haimel, M., Hall, M., Hanson, H. L., Haque, E., Harkness, K., Harper, A. R., Harris, C. L., Hart, D., Hassan, A., Hayman, G., Henderson, A., Herwadkar, A., Hoffman, J., Holden, S., Horvath, R., Houlden, H., Houweling, A. C., Howard, L. S., Hu, F., Hudson, G., Hughes, J., Huissoon, A. P., Humbert, M., Humphray, S., Hunter, S., Hurles, M., Irving, M., Izatt, L., James, R., Johnson, S. A., Jolles, S., Jolley, J., Josifova, D., Jurkute, N., Karten, T., Karten, J., Kasanicki, M. A., Kazkaz, H., Kazmi, R., Kelleher, P., Kelly, A. M., Kelsall, W., Kempster, C., Kiely, D. G., Kingston, N., Klima, R., Koelling, N., Kostadima, M., Kovacs, G., Koziell, A., Kreuzhuber, R., Kuijpers, T. W., Kumar, A., Kumararatne, D., Kurian, M. A., Laffan, M. A., Lalloo, F., Lambert, M., Allen, H. L., Lawrie, A., Layton, D. M., Lench, N., Lentaigne, C., Lester, T., Levine, A. P., Linger, R., Longhurst, H., Lorenzo, L. E., Louka, E., Lyons, P. A., Machado, R. D., MacKenzie Ross, R. V., Madan, B., Maher, E. R., Maimaris, J., Malka, S., Mangles, S., Mapeta, R., Marchbank, K. J., Marks, S., Markus, H. S., Marschall, H.-U., Marshall, A., Martin, J., Mathias, M., Matthews, E., Maxwell, H., McAlinden, P., McCarthy, M. I., McKinney, H., McMahon, A., Meacham, S., Mead, A. J., Castello, I. M., Megy, K., Mehta, S. G., Michaelides, M., Millar, C., Mohammed, S. N., Moledina, S., Montani, D., Moore, A. T., Morales, J., Morrell, N. W., Mozere, M., Muir, K. W., Mumford, A. D., Nemeth, A. H., Newman, W. G., Newnham, M., Noorani, S., Nurden, P., O’Sullivan, J., Obaji, S., Odhams, C., Okoli, S., Olschewski, A., Olschewski, H., Ong, K. R., Oram, S. H., Ormondroyd, E., Ouwehand, W. H., Palles, C., Papadia, S., Park, S.-M., Parry, D., Patel, S., Paterson, J., Peacock, A., Pearce, S. H., Peden, J., Peerlinck, K., Penkett, C. J., Pepke-Zaba, J., Petersen, R., Pilkington, C., Poole, K. E. S., Prathalingam, R., Psaila, B., Pyle, A., Quinton, R., Rahman, S., Rankin, S., Rao, A., Raymond, F. L., Rayner-Matthews, P. J., Rees, C., Rendon, A., Renton, T., Rhodes, C. J., Rice, A. S. C., Richardson, S., Richter, A., Robert, L., Roberts, I., Rogers, A., Rose, S. J., Ross-Russell, R., Roughley, C., Roy, N. B. A., Ruddy, D. M., Sadeghi-Alavijeh, O., Saleem, M. A., Samani, N., Samarghitean, C., Sanchis-Juan, A., Sargur, R. B., Sarkany, R. N., Satchell, S., Savic, S., Sayer, J. A., Sayer, G., Scelsi, L., Schaefer, A. M., Schulman, S., Scott, R., Scully, M., Searle, C., Seeger, W., Sen, A., Sewell, W. A. C., Seyres, D., Shah, N., Shamardina, O., Shapiro, S. E., Shaw, A. C., Short, P. J., Sibson, K., Side, L., Simeoni, I., Simpson, M. A., Sims, M. C., Sivapalaratnam, S., Smedley, D., Smith, K. R., Smith, K. G. C., Snape, K., Soranzo, N., Soubrier, F., Southgate, L., Spasic-Boskovic, O., Staines, S., Staples, E., Stark, H., Stephens, J., Steward, C., Stirrups, K. E., Stuckey, A., Suntharalingam, J., Swietlik, E. M., Syrris, P., Tait, R. C., Talks, K., Tan, R. Y. Y., Tate, K., Taylor, J. M., Taylor, J. C., Thaventhiran, J. E., Themistocleous, A. C., Thomas, E., Thomas, D., Thomas, M. J., Thomas, P., Thomson, K., Thrasher, A. J., Threadgold, G., Thys, C., Tilly, T., Tischkowitz, M., Titterton, C., Todd, J. A., Toh, C.-H., Tolhuis, B., Tomlinson, I. P., Toshner, M., Traylor, M., Treacy, C., Treadaway, P., Trembath, R., Tuna, S., Turek, W., Turro, E., Twiss, P., Vale, T., Geet, C. V., Zuydam, N. V., Vandekuilen, M., Vandersteen, A. M., Vazquez-Lopez, M., von Ziegenweidt, J., Vonk Noordegraaf, A., Wagner, A., Waisfisz, Q., Walker, S. M., Walker, N., Walter, K., Ware, J. S., Watkins, H., Watt, C., Webster, A. R., Wedderburn, L., Wei, W., Welch, S. B., Wessels, J., Westbury, S. K., Westwood, J.-P., Wharton, J., Whitehorn, D., Whitworth, J., Wilkie, A. O. M., Wilkins, M. R., Williamson, C., Wilson, B. T., Wong, E. K. S., Wood, N., Wood, Y., Woods, C. G., Woodward, E. R., Wort, S. J., Worth, A., Wright, M., Yates, K., Yong, P. F. K., Young, T., Yu, P., Yu-Wai-Man, P., Zlamalova, E., Kingston, N., Walker, N., Bradley, J. R., Ashford, S., Penkett, C. J., Freson, K., Stirrups, K. E., Raymond, F. L., & Ouwehand, W. H.
Affiliations
  • King's College London (GB)
  • Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
  • Royal Devon & Exeter NHS Foundation Trust (GB)
  • University of Cambridge (GB)
  • Great Ormond Street Hospital (GB)
  • Royal Brompton & Harefield NHS Foundation Trust (GB)
  • Royal Free London NHS Foundation Trust (GB)
  • University Hospitals Birmingham NHS Foundation Trust (GB)
  • Guy's Hospital (GB)
  • Queen Mary University of London (GB)
  • Imperial College Healthcare NHS Trust (GB)
  • University of Leicester (GB)
  • Royal Victoria Infirmary (GB)
  • John Radcliffe Hospital (GB)
  • Illumina (United Kingdom) (GB)
  • Southampton General Hospital (GB)
  • Royal Hallamshire Hospital (GB)
  • European Bioinformatics Institute (GB)
  • Centre for Human Genetics (GB)
  • Nottingham University Hospitals NHS Trust (GB)
  • Royal Liverpool University Hospital (GB)
  • Golden Jubilee National Hospital (GB)
  • University of Bristol (GB)
  • Salisbury District Hospital (GB)
  • Barts Health NHS Trust (GB)
  • Guy's and St Thomas' NHS Foundation Trust (GB)
  • Hôpital Armand-Trousseau (FR)
  • Justus-Liebig-Universität Gießen (DE)
  • Oxford University Hospitals NHS Trust (GB)
  • The University of Western Australia (AU)
  • University of Perugia (IT)
  • Kent and Canterbury Hospital (GB)
  • Inserm (FR)
  • Leeds Teaching Hospitals NHS Trust (GB)
  • Cambridge University Hospitals NHS Foundation Trust (GB)
  • Salford Royal NHS Foundation Trust (GB)
  • Birmingham Women’s and Children’s NHS Foundation Trust (GB)
  • UCL Queen Square Institute of Neurology (GB)
  • University of Oxford (GB)
  • Université Paris-Sud (FR)
  • University Hospitals of North Midlands NHS Trust (GB)
  • Hull University Teaching Hospitals NHS Trust (GB)
  • Universitätsmedizin Greifswald (DE)
  • NHS Greater Glasgow and Clyde (GB)
  • St George’s University Hospitals NHS Foundation Trust (GB)
  • Epsom and St Helier University Hospitals NHS Trust (GB)
  • National Health Service (GB)
  • Children's Hospital of Philadelphia (US)
  • Congenica Ltd. (United Kingdom) (GB)
  • University College Hospital (GB)
  • St Thomas' Hospital (GB)
  • Hampshire Hospitals NHS Foundation Trust (GB)
  • University College London Hospitals NHS Foundation Trust (GB)
  • Moorfields Eye Hospital (GB)
  • Sandwell & West Birmingham Hospitals NHS Trust (GB)
  • Ludwig Boltzmann Institute for Lung Vascular Research (AT)
  • Medical University of Graz (AT)
  • Cancer Research UK (GB)
  • University of Manchester (GB)
  • University of California, San Francisco (US)
  • University College London (GB)
  • Chelsea and Westminster Hospital NHS Foundation Trust (GB)
  • University Hospital of Wales (GB)
  • Genomics England (GB)
  • North Bristol NHS Trust (GB)
  • University of Leeds (GB)
  • Beth Israel Deaconess Medical Center (US)
  • Churchill Hospital (GB)
  • Scunthorpe General Hospital (GB)
  • Wellcome Sanger Institute (GB)
  • University Hospital Southampton NHS Foundation Trust (GB)
  • Assistance Publique – Hôpitaux de Paris (FR)
  • St George's, University of London (GB)
  • Dalhousie University (CA)
  • Amsterdam University Medical Centers (NL)
  • NIHR Great Ormond Street Hospital Biomedical Research Centre (GB)
  • University Hospitals Bristol NHS Foundation Trust (GB)
  • Imperial College London (GB)
  • St Mary's Hospital (GB)
  • Frimley Park Hospital (GB)
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2020-06-24
Volume
583
Issue
7814
Pages
96-102
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-020-2434-2
PMC
PMC7610553
OpenAlex
W3038072559
Cited by
554
References
7
Citations by year
2026: 46 · 2025: 85 · 2024: 95 · 2023: 78 · 2022: 108 · 2021: 86 · 2020: 46 · 2019: 10
FWCI
46.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • UWA Profiles and Research Repository (UWA) (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • Bristol Research (University of Bristol) (publishedVersion, other-oa)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
  • St George's Online Research Archive (St George's University of London) (acceptedVersion)
  • Oxford University Research Archive (ORA) (University of Oxford) (acceptedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • HAL (submittedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion, other-oa)
  • Lirias (KU Leuven) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
  • Newcastle University ePrints (Newcastle Univesity)
Funders
  • NHS Blood and Transplant
  • Wellcome Trust (109915, 095908, 201064, 212219/Z/18/Z, 202747, 098519, WT098519MA, 212219, 202747/Z/16/Z, 206617/A/17/Z, 098519/Z/12/Z, 109915/A/15/Z, WT200990/Z/16/Z, 200990, 107469, 204809/Z/16/Z, 090532, 204809, WT108749/Z/15/Z, 104807/Z/14/Z, 108749, 107469/Z/15/Z, 206617/Z/17/Z, 201064/Z/16/Z, 109915/Z/15/Z)
  • Scottish Government
  • Bowel Cancer UK (18PG0019)
  • UK Research and Innovation (MC_PC_18030)
  • Barts Charity (MGU0284)
  • Cancer Research UK (29034, C20/A20917, 28051)
  • National Institute for Health and Care Research (NF-SI-0512-10019, NF-SI-0617-10006, RP-2016-07-019, NF-SI-0515-10035, CL-2012-21-004, NF-SI-0510-10282, NIHR200254, CL-2019-13-009, NF-SI-0617-10154, CL-2019-14-002, NF-SI-0616-10099, ICA-CDRF-2015-01-046, NF-SI-0513-10087)
  • British Heart Foundation (FS/13/48/30453, FS/18/53/33863, SP/12/12/29836, RG/16/4/32218, FS/18/52/33808, CH/1992001/6764)
  • Kidney Research UK (Paed_RP_001_20180925, RP45/2008, SG_KS_IN_007_20180914, KKR/Paed2017/04)
  • Cystic Fibrosis Trust (IH 001)
  • Sight Research UK (SEE 003)
  • Diabetes UK
  • Rosetrees Trust (M375‐F1)
  • Cambridge University Hospitals (BRC 2012-2017, 146281)
  • Northwest Regional Development Agency
  • Fondation Botnar (Project 603)
  • NIHR BioResource
  • Medical Research Council (MR/J011711/1, MR/N010035/1, MR/R002363/1, MC_PC_14089, MR/S025502/1, MR/K020919/1, MR/R013942/1, MC_EX_MR/M009203/1, MR/L019027/1, MC_PC_17228, MC_PC_15080, MR/N025431/2, MR/P02002X/1, MR/N025431/1, MR/S021329/1, MR/L006340/1, MR/M012212/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
Keywords
rare diseases, whole genome sequencing, molecular diagnosis, non-coding variants, ARPC1B, GATA-1, LRBA, MPL, UK Biobank, National Health System
MeSH terms
Whole Genome Sequencing, Alleles, Erythrocytes, United Kingdom, Humans, National Health Programs, Phenotype, State Medicine, Databases, Factual, Rare Diseases, Internationality, Quantitative Trait Loci, Adaptor Proteins, Signal Transducing, GATA1 Transcription Factor, Actin-Related Protein 2-3 Complex, Receptors, Thrombopoietin

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