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Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series

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cam.issuedOnline2018-10-02
cam.orpheus.successThu Jan 30 10:54:37 GMT 2020 - The item has an open VoR version.
dc.contributor.authorKoriath, C
dc.contributor.authorKenny, J
dc.contributor.authorDruyeh, R
dc.contributor.authorTaylor, W
dc.contributor.authorBeck, J
dc.contributor.authorQuinn, L
dc.contributor.authorMok, TH
dc.contributor.authorDimitriadis, A
dc.contributor.authorNorsworthy, P
dc.contributor.authorBass, N
dc.contributor.authorCarter, J
dc.contributor.authorWalker, Z
dc.contributor.authorKipps, C
dc.contributor.authorCoulthard, E
dc.contributor.authorPolke, JM
dc.contributor.authorBernal-Quiros, M
dc.contributor.authorDenning, N
dc.contributor.authorThomas, R
dc.contributor.authorRaybould, R
dc.contributor.authorWilliams, J
dc.contributor.authorMummery, CJ
dc.contributor.authorWild, EJ
dc.contributor.authorHoulden, H
dc.contributor.authorTabrizi, SJ
dc.contributor.authorRossor, MN
dc.contributor.authorHummerich, H
dc.contributor.authorWarren, JD
dc.contributor.authorRowe, JB
dc.contributor.authorRohrer, JD
dc.contributor.authorSchott, JM
dc.contributor.authorFox, NC
dc.contributor.authorCollinge, J
dc.contributor.authorMead, S
dc.contributor.orcidRowe, James [0000-0001-7216-8679]
dc.date.accessioned2018-10-03T04:44:05Z
dc.date.available2018-10-03T04:44:05Z
dc.date.issued2020-12
dc.description.abstractNext-generation genetic sequencing (NGS) technologies facilitate the screening of multiple genes linked to neurodegenerative dementia, but there is little guidance available about their use in clinical practice. Guidelines on which patients would most profit from testing, and information on the likelihood of discovery of a causal variant in a clinical syndrome, are conspicuously absent from the literature, mostly for a lack of large-scale studies. We applied a validated NGS dementia panel to 3241 patients with dementia and healthy aged controls; 13,152 variants were classified by likelihood of pathogenicity. We identified 354 deleterious variants (DV, 12.6% of patients); 39 were novel DVs. Age at clinical onset, clinical syndrome and family history each strongly predict the likelihood of finding a DV, but healthcare setting and gender did not. DVs were frequently found in genes not usually associated with the clinical syndrome. Patients recruited from primary referral centres were compared to those seen at higher-level research centres and a national clinical neurogenetic laboratory; rates of discovery were comparable, making selection bias unlikely and the results generalizable to clinical practice. We estimated penetrance of DVs using large-scale online genomic population databases and found 71 with evidence of reduced penetrance. Two DVs in the same patient were found more frequently than expected. These publicly-available data should provide a basis for informed counselling and clinical decision making.
dc.identifier.doi10.17863/CAM.30409
dc.identifier.eissn1476-5578
dc.identifier.issn1476-5578
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/283046
dc.language.isoeng
dc.publisherSpringer Nature
dc.publisher.urlhttp://dx.doi.org/10.1038/s41380-018-0224-0
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAged
dc.subjectDementia
dc.subjectGenomics
dc.subjectHigh-Throughput Nucleotide Sequencing
dc.subjectHumans
dc.subjectMutation
dc.subjectReferral and Consultation
dc.titlePredictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series
dc.typeArticle
dcterms.dateAccepted2018-07-18
prism.publicationNameMolecular Psychiatry
pubs.funder-project-idMedical Research Council (MR/J009482/1)
pubs.funder-project-idMedical Research Council (MC_U105597119)
pubs.funder-project-idWellcome Trust (103838/Z/14/Z)
pubs.funder-project-idMedical Research Council (MC_UU_00005/12)
pubs.funder-project-idMedical Research Council (MR/L023784/2)
pubs.funder-project-idMedical Research Council (MR/L023784/1)
rioxxterms.licenseref.startdate2018-07-18
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionofrecord10.1038/s41380-018-0224-0

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