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dc.contributor.authorCarss, KJ
dc.contributor.authorArno, G
dc.contributor.authorErwood, M
dc.contributor.authorStephens, J
dc.contributor.authorSanchis-Juan, A
dc.contributor.authorHull, S
dc.contributor.authorMegy, K
dc.contributor.authorGrozeva, D
dc.contributor.authorDewhurst, E
dc.contributor.authorMalka, S
dc.contributor.authorPlagnol, V
dc.contributor.authorPenkett, C
dc.contributor.authorStirrups, K
dc.contributor.authorRizzo, R
dc.contributor.authorWright, G
dc.contributor.authorJosifova, D
dc.contributor.authorBitner-Glindzicz, M
dc.contributor.authorScott, RH
dc.contributor.authorClement, E
dc.contributor.authorAllen, L
dc.contributor.authorArmstrong, R
dc.contributor.authorBrady, AF
dc.contributor.authorCarmichael, J
dc.contributor.authorChitre, M
dc.contributor.authorHenderson, RHH
dc.contributor.authorHurst, J
dc.contributor.authorMacLaren, RE
dc.contributor.authorMurphy, E
dc.contributor.authorPaterson, J
dc.contributor.authorRosser, E
dc.contributor.authorThompson, DA
dc.contributor.authorWakeling, E
dc.contributor.authorOuwehand, WH
dc.contributor.authorMichaelides, M
dc.contributor.authorMoore, AT
dc.contributor.authorNIHR-BioResource Rare Diseases Consortium
dc.contributor.authorWebster, AR
dc.contributor.authorRaymond, FL
dc.date.accessioned2017-02-21T10:07:42Z
dc.date.available2017-02-21T10:07:42Z
dc.date.issued2017-01-05
dc.identifier.issn0002-9297
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/262688
dc.description.abstractInherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.
dc.description.sponsorshipThis work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre.
dc.languageeng
dc.language.isoen
dc.publisherElsevier (Cell Press)
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectretinal dystrophy
dc.subjectwhole-genome sequence
dc.subjectcopy-number variants
dc.subjectrare sequence variant
dc.titleComprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease
dc.typeArticle
prism.endingPage90
prism.issueIdentifier1
prism.publicationDate2017
prism.publicationNameAmerican Journal of Human Genetics
prism.startingPage75
prism.volume100
dc.identifier.doi10.17863/CAM.7967
dcterms.dateAccepted2016-11-29
rioxxterms.versionofrecord10.1016/j.ajhg.2016.12.003
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
rioxxterms.licenseref.startdate2017-01-05
dc.contributor.orcidRaymond, Lucy [0000-0003-2652-3355]
dc.identifier.eissn1537-6605
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MR/L006197/1)
pubs.funder-project-idWellcome Trust (206618/Z/17/Z)
pubs.funder-project-idBritish Heart Foundation (None)
cam.issuedOnline2016-12-29
rioxxterms.freetoread.startdate2017-06-29


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