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

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dc.contributor.authorTurro, E.
dc.contributor.authorAstle, W.J.
dc.contributor.authorMegy, K.
dc.contributor.authorGräf, S.
dc.contributor.authorGreene, D.
dc.contributor.authorShamardina, O.
dc.contributor.authorAllen, H.L.
dc.contributor.authorSanchis-Juan, A.
dc.contributor.authorFrontini, M.
dc.contributor.authorThys, C.
dc.contributor.authorStephens, J.
dc.contributor.authorMapeta, R.
dc.contributor.authorBurren, O.S.
dc.contributor.authorDownes, K.
dc.contributor.authorHaimel, M.
dc.contributor.authorTuna, S.
dc.contributor.authorDeevi, S.V.V.
dc.contributor.authorAitman, T.J.
dc.contributor.authorBennett, D.L.
dc.contributor.authorCalleja, P.
dc.contributor.authoret al.
dc.date.issued2020
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.description.statementofresponsibilityErnest Turro ... NIHR BioResource for the 100,000 Genomes Project : William M. Hague ... et al.
dc.identifier.citationNature, 2020; 583(7814):96-126
dc.identifier.doi10.1038/s41586-020-2434-2
dc.identifier.issn0028-0836
dc.identifier.issn1476-4687
dc.identifier.orcidHague, W. [0000-0002-5355-2955]
dc.identifier.urihttps://hdl.handle.net/2440/146089
dc.language.isoen
dc.publisherNature Research
dc.rights© The Author(s), under exclusive licence to Springer Nature Limited 2020
dc.source.urihttps://doi.org/10.1038/s41586-020-2434-2
dc.subjectComputational biology and bioinformatics; Disease genetics; Genetics research
dc.subject.meshErythrocytes
dc.subject.meshHumans
dc.subject.meshRare Diseases
dc.subject.meshAdaptor Proteins, Signal Transducing
dc.subject.meshPhenotype
dc.subject.meshAlleles
dc.subject.meshQuantitative Trait Loci
dc.subject.meshInternationality
dc.subject.meshDatabases, Factual
dc.subject.meshNational Health Programs
dc.subject.meshState Medicine
dc.subject.meshGATA1 Transcription Factor
dc.subject.meshActin-Related Protein 2-3 Complex
dc.subject.meshReceptors, Thrombopoietin
dc.subject.meshUnited Kingdom
dc.subject.meshWhole Genome Sequencing
dc.titleWhole-genome sequencing of patients with rare diseases in a national health system
dc.typeJournal article
pubs.publication-statusPublished

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