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dc.contributor.authorTurro Bassols, Ernest
dc.contributor.authorAstle, William J
dc.contributor.authorMegy, Karyn
dc.contributor.authorGräf, Stefan
dc.contributor.authorGreene, Daniel
dc.contributor.authorShamardina, Olga
dc.contributor.authorLango Allen, Hana
dc.contributor.authorSanchis-Juan, Alba
dc.contributor.authorFrontini, Mattia
dc.contributor.authorThys, Chantal
dc.contributor.authorStephens, Jonathan
dc.contributor.authorMapeta, Rutendo
dc.contributor.authorBurren, Oliver
dc.contributor.authorDownes, Kate
dc.contributor.authorHaimel, Matthias
dc.contributor.authorTuna, Salih
dc.contributor.authorDeevi, Sri VV
dc.contributor.authorAitman, Timothy J
dc.contributor.authorBennett, David L
dc.contributor.authorCalleja, Paul
dc.contributor.authorCarss, Keren
dc.contributor.authorCaulfield, Mark J
dc.contributor.authorChinnery, Patrick F
dc.contributor.authorDixon, Peter H
dc.contributor.authorGale, Daniel P
dc.contributor.authorJames, Roger
dc.contributor.authorKoziell, Ania
dc.contributor.authorLaffan, Michael A
dc.contributor.authorLevine, Adam P
dc.contributor.authorMaher, Eamonn R
dc.contributor.authorMarkus, Hugh S
dc.contributor.authorMorales, Joannella
dc.contributor.authorMorrell, Nicholas W
dc.contributor.authorMumford, Andrew D
dc.contributor.authorOrmondroyd, Elizabeth
dc.contributor.authorRankin, Stuart
dc.contributor.authorRendon, Augusto
dc.contributor.authorRichardson, Sylvia
dc.contributor.authorRoberts, Irene
dc.contributor.authorRoy, Noemi BA
dc.contributor.authorSaleem, Moin A
dc.contributor.authorSmith, Kenneth GC
dc.contributor.authorStark, Hannah
dc.contributor.authorTan, Rhea YY
dc.contributor.authorThemistocleous, Andreas C
dc.contributor.authorThrasher, Adrian J
dc.contributor.authorWatkins, Hugh
dc.contributor.authorWebster, Andrew R
dc.contributor.authorWilkins, Martin R
dc.contributor.authorWilliamson, Catherine
dc.contributor.authorWhitworth, James
dc.contributor.authorHumphray, Sean
dc.contributor.authorBentley, David R
dc.contributor.authorNIHR BioResource for the 100,000 Genomes Project
dc.contributor.authorKingston, Nathalie
dc.contributor.authorWalker, Neil
dc.contributor.authorBradley, John
dc.contributor.authorAshford, Sofie
dc.contributor.authorPenkett, Christopher J
dc.contributor.authorFreson, Kathleen
dc.contributor.authorStirrups, Kathleen E
dc.contributor.authorRaymond, Lucy
dc.contributor.authorOuwehand, Willem
dc.date.accessioned2020-07-01T23:30:20Z
dc.date.available2020-07-01T23:30:20Z
dc.date.issued2020-07
dc.identifier.issn0028-0836
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/307472
dc.description.abstractMost 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.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAll rights reserved
dc.subjectNIHR BioResource for the 100,000 Genomes Project
dc.subjectErythrocytes
dc.subjectHumans
dc.subjectRare Diseases
dc.subjectAdaptor Proteins, Signal Transducing
dc.subjectPhenotype
dc.subjectAlleles
dc.subjectQuantitative Trait Loci
dc.subjectInternationality
dc.subjectDatabases, Factual
dc.subjectNational Health Programs
dc.subjectState Medicine
dc.subjectGATA1 Transcription Factor
dc.subjectActin-Related Protein 2-3 Complex
dc.subjectReceptors, Thrombopoietin
dc.subjectUnited Kingdom
dc.subjectWhole Genome Sequencing
dc.titleWhole-genome sequencing of patients with rare diseases in a national health system.
dc.typeArticle
prism.endingPage102
prism.issueIdentifier7814
prism.publicationDate2020
prism.publicationNameNature
prism.startingPage96
prism.volume583
dc.identifier.doi10.17863/CAM.54566
dcterms.dateAccepted2020-05-05
rioxxterms.versionofrecord10.1038/s41586-020-2434-2
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2020-07
dc.contributor.orcidTurro Bassols, Ernest [0000-0002-1820-6563]
dc.contributor.orcidLango Allen, Hana [0000-0002-7803-8688]
dc.contributor.orcidBurren, Oliver [0000-0002-3388-5760]
dc.contributor.orcidBradley, John [0000-0002-7774-8805]
dc.contributor.orcidRaymond, Lucy [0000-0003-2652-3355]
dc.contributor.orcidOuwehand, Willem [0000-0002-7744-1790]
dc.identifier.eissn1476-4687
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MR/L019027/1)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017)
pubs.funder-project-idMedical Research Council (MR/K020919/1)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
pubs.funder-project-idFondation Botnar (Project 603)
pubs.funder-project-idCystic Fibrosis Trust (IH 001)
pubs.funder-project-idWellcome Trust (109915_A_15_Z)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)
pubs.funder-project-idWellcome Trust (212219/Z/18/Z)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (BRC)
pubs.funder-project-idCancer Research UK (C20/A20917)
pubs.funder-project-idBritish Heart Foundation (RG/16/4/32218)
pubs.funder-project-idMedical Research Council (MR/N025431/2)
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idMedical Research Council (MC_PC_14089)
pubs.funder-project-idMedical Research Council (MC_PC_18030)
cam.issuedOnline2020-06-24
cam.orpheus.successMon Jul 06 08:36:47 BST 2020 - Embargo updated
rioxxterms.freetoread.startdate2020-12-24


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