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dc.contributor.authorSmedley, D.
dc.contributor.authorSmith, K. R.
dc.contributor.authorMartin, A.
dc.contributor.authorThomas, E. A.
dc.contributor.authorMcDonagh, E. M.
dc.contributor.authorCipriani, V.
dc.contributor.authorEllingford, J. M.
dc.contributor.authorArno, G.
dc.contributor.authorTucci, A.
dc.contributor.authorVandrovcova, J.
dc.contributor.authorChan, G.
dc.contributor.authorWilliams, H. J.
dc.contributor.authorRatnaike, T.
dc.contributor.authorWei, W.
dc.contributor.authorStirrups, K.
dc.contributor.authorIbanez, K.
dc.contributor.authorMoutsianas, L.
dc.contributor.authorWielscher, M.
dc.contributor.authorNeed, A.
dc.contributor.authorBarnes, M. R.
dc.contributor.authorVestito, L.
dc.contributor.authorBuchanan, J.
dc.contributor.authorWordsworth, S.
dc.contributor.authorAshford, S.
dc.contributor.authorRehmström, K.
dc.contributor.authorLi, E.
dc.contributor.authorFuller, G.
dc.contributor.authorTwiss, P.
dc.contributor.authorSpasic-Boskovic, O.
dc.contributor.authorHalsall, S.
dc.contributor.authorFloto, R. A.
dc.contributor.authorPoole, K.
dc.contributor.authorWagner, A.
dc.contributor.authorMehta, S. G.
dc.contributor.authorGurnell, M.
dc.contributor.authorBurrows, N.
dc.contributor.authorJames, R.
dc.contributor.authorPenkett, C.
dc.contributor.authorDewhurst, E.
dc.contributor.authorGräf, S.
dc.contributor.authorMapeta, R.
dc.contributor.authorKasanicki, M.
dc.contributor.authorHaworth, A.
dc.contributor.authorSavage, H.
dc.contributor.authorBabcock, M.
dc.contributor.authorReese, M. G.
dc.contributor.authorBale, M.
dc.contributor.authorBaple, E.
dc.contributor.authorBoustred, C.
dc.contributor.authorBrittain, H.
dc.contributor.authorde Burca, A.
dc.contributor.authorBleda, M.
dc.contributor.authorDevereau, A.
dc.contributor.authorHalai, D.
dc.contributor.authorHaraldsdottir, E.
dc.contributor.authorHyder, Z.
dc.contributor.authorKasperaviciute, D.
dc.contributor.authorPatch, C.
dc.contributor.authorPolychronopoulos, D.
dc.contributor.authorMatchan, A.
dc.contributor.authorSultana, R.
dc.contributor.authorRyten, M.
dc.contributor.authorTavares, A. L. T.
dc.contributor.authorTregidgo, C.
dc.contributor.authorTurnbull, C.
dc.contributor.authorWelland, M.
dc.contributor.authorWood, S.
dc.contributor.authorSnow, C.
dc.contributor.authorWilliams, E.
dc.contributor.authorLeigh, S.
dc.contributor.authorFoulger, R. E.
dc.contributor.authorDaugherty, L. C.
dc.contributor.authorNiblock, O.
dc.contributor.authorLeong, I. U. S.
dc.contributor.authorWright, C. F.
dc.contributor.authorDavies, J.
dc.contributor.authorCrichton, C.
dc.contributor.authorWelch, J.
dc.contributor.authorWoods, K.
dc.contributor.authorAbulhoul, L.
dc.contributor.authorAurora, P.
dc.contributor.authorBockenhauer, D.
dc.contributor.authorBroomfield, A.
dc.contributor.authorCleary, M. A.
dc.contributor.authorLam, T.
dc.contributor.authorDattani, M.
dc.contributor.authorFootitt, E.
dc.contributor.authorGanesan, V.
dc.contributor.authorGrunewald, S.
dc.contributor.authorCompeyrot-Lacassagne, S.
dc.contributor.authorMuntoni, F.
dc.contributor.authorPilkington, C.
dc.contributor.authorQuinlivan, R.
dc.contributor.authorThapar, N.
dc.contributor.authorWallis, C.
dc.contributor.authorWedderburn, L. R.
dc.contributor.authorWorth, A.
dc.contributor.authorBueser, T.
dc.contributor.authorCompton, C.
dc.contributor.authorDeshpande, C.
dc.contributor.authorFassihi, H.
dc.contributor.authorHaque, E.
dc.contributor.authorIzatt, L.
dc.contributor.authorJosifova, D.
dc.contributor.authorMohammed, S.
dc.contributor.authorRobert, L.
dc.contributor.authorRose, S.
dc.contributor.authorRuddy, D.
dc.contributor.authorSarkany, R.
dc.contributor.authorSay, G.
dc.contributor.authorShaw, A. C.
dc.contributor.authorWolejko, A.
dc.contributor.authorHabib, B.
dc.contributor.authorBurns, G.
dc.contributor.authorHunter, S.
dc.contributor.authorGrocock, R. J.
dc.contributor.authorHumphray, S. J.
dc.contributor.authorRobinson, P. N.
dc.contributor.authorHaendel, M.
dc.contributor.authorSimpson, M. A.
dc.contributor.authorBanka, S.
dc.contributor.authorClayton-Smith, J.
dc.contributor.authorDouzgou, S.
dc.contributor.authorHall, G.
dc.contributor.authorThomas, H. B.
dc.contributor.authorO'Keefe, R. T.
dc.contributor.authorMichaelides, M.
dc.contributor.authorMoore, A. T.
dc.contributor.authorMalka, S.
dc.contributor.authorPontikos, N.
dc.contributor.authorBrowning, A. C.
dc.contributor.authorStraub, V.
dc.contributor.authorGorman, G. S.
dc.contributor.authorHorvath, R.
dc.contributor.authorQuinton, R.
dc.contributor.authorSchaefer, A. M.
dc.contributor.authorYu-Wai-Man, P.
dc.contributor.authorTurnbull, D. M.
dc.contributor.authorMcFarland, R.
dc.contributor.authorTaylor, R. W.
dc.contributor.authorO'Connor, E.
dc.contributor.authorYip, J.
dc.contributor.authorNewland, K.
dc.contributor.authorMorris, H. R.
dc.contributor.authorPolke, J.
dc.contributor.authorWood, N. W.
dc.contributor.authorCampbell, C.
dc.contributor.authorCamps, C.
dc.contributor.authorGibson, K.
dc.contributor.authorKoelling, N.
dc.contributor.authorLester, T.
dc.contributor.authorNémeth, A. H.
dc.contributor.authorPalles, C.
dc.contributor.authorPatel, S.
dc.contributor.authorRoy, N. B. A.
dc.contributor.authorSen, A.
dc.contributor.authorTaylor, J.
dc.contributor.authorCacheiro, P.
dc.contributor.authorJacobsen, J. O.
dc.contributor.authorSeaby, E. G.
dc.contributor.authorDavison, V.
dc.contributor.authorChitty, L.
dc.contributor.authorDouglas, A.
dc.contributor.authorNaresh, K.
dc.contributor.authorMcMullan, D.
dc.contributor.authorEllard, S.
dc.contributor.authorTemple, I. K.
dc.contributor.authorMumford, A. D.
dc.contributor.authorWilson, G.
dc.contributor.authorBeales, P.
dc.contributor.authorBitner-Glindzicz, M.
dc.contributor.authorBlack, G.
dc.contributor.authorBradley, J. R.
dc.contributor.authorBrennan, P.
dc.contributor.authorBurn, J.
dc.contributor.authorChinnery, P. F.
dc.contributor.authorElliott, P.
dc.contributor.authorFlinter, F.
dc.contributor.authorHoulden, H.
dc.contributor.authorIrving, M.
dc.contributor.authorNewman, W.
dc.contributor.authorRahman, S.
dc.contributor.authorSayer, J. A.
dc.contributor.authorTaylor, J. C.
dc.contributor.authorWebster, A. R.
dc.contributor.authorWilkie, A. O. M.
dc.contributor.authorOuwehand, W. H.
dc.contributor.authorRaymond, F. L.
dc.contributor.authorChisholm, J.
dc.contributor.authorHill, S.
dc.contributor.authorBentley, D.
dc.contributor.authorScott, R. H.
dc.contributor.authorFowler, T.
dc.contributor.authorRendon, A.
dc.contributor.authorCaulfield, M.
dc.date.accessioned2021-12-15T14:23:05Z
dc.date.available2021-12-15T14:23:05Z
dc.date.issued2021-11-11
dc.identifier.citationN Engl J Med. 2021 Nov 11;385(20):1868-1880. doi: 10.1056/NEJMoa2035790.
dc.identifier.pmid34758253
dc.identifier.doi10.1056/NEJMoa2035790
dc.identifier.urihttps://rde.dspace-express.com/handle/11287/622253
dc.description.abstractBACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection. METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis. RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives. CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).
dc.language.isoeng
dc.publisherMassachusetts Medical Society
dc.relation.urlhttps://www.nejm.org/doi/10.1056/NEJMoa2035790?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
dc.rights© 2021 Massachusetts Medical Society.
dc.subjectAdolescent
dc.subjectAdult
dc.subjectChild
dc.subjectChild, Preschool
dc.subjectFamily Characteristics
dc.subjectFemale
dc.subjectGenetic Variation
dc.subject*Genome, Human
dc.subjectHumans
dc.subjectMale
dc.subjectMiddle Aged
dc.subjectPilot Projects
dc.subjectPolymerase Chain Reaction
dc.subjectRare Diseases/diagnosis/*genetics
dc.subjectSensitivity and Specificity
dc.subjectState Medicine
dc.subjectUnited Kingdom
dc.subjectWhole Genome Sequencing
dc.subjectYoung Adult
dc.title100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report
dc.typeJournal Article
dc.identifier.journalThe New England journal of medicine
dc.description.noteRD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted.
dc.type.versionppublish
dc.description.admin-notePublished version (6 month embargo)
dc.date.epub2021-11-11
dc.citation.volume385
dc.citation.issue20
dc.citation.spage1868-1880


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