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dc.contributor.authorRutten, Julie W
dc.contributor.authorVan Eijsden, Bastian J
dc.contributor.authorDuering, Marco
dc.contributor.authorJouvent, Eric
dc.contributor.authorOpherk, Christian
dc.contributor.authorPantoni, Leonardo
dc.contributor.authorFederico, Antonio
dc.contributor.authorDichgans, Martin
dc.contributor.authorMarkus, Hugh
dc.contributor.authorChabriat, Hugues
dc.contributor.authorLesnik Oberstein, Saskia AJ
dc.date.accessioned2018-11-07T00:31:19Z
dc.date.available2018-11-07T00:31:19Z
dc.date.issued2019-03
dc.identifier.issn1098-3600
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284713
dc.description.abstractPURPOSE: CADASIL is a small-vessel disease caused by a cysteine-altering pathogenic variant in one of the 34 epidermal growth factor-like repeat (EGFr) domains of the NOTCH3 protein. We recently found that pathogenic variant in EGFr domains 7-34 have an unexpectedly high frequency in the general population (1:300). We hypothesized that EGFr 7-34 pathogenic variant more frequently cause a much milder phenotype, thereby explaining an important part of CADASIL disease variability. METHODS: Age at first stroke, survival and white matter hyperintensity volume were compared between 664 CADASIL patients with either a NOTCH3 EGFr 1-6 pathogenic variant or an EGFr 7-34 pathogenic variant. The frequencies of NOTCH3 EGFr 1-6 and EGFr 7-34 pathogenic variant were compared between individuals in the genome  Aggregation Database and CADASIL patients. RESULTS: CADASIL patients with an EGFr 1-6 pathogenic variant have a 12-year earlier onset of stroke than those with an EGFr 7-34 pathogenic variant, lower survival, and higher white matter hyperintensity volumes. Among diagnosed CADASIL patients, 70% have an EGFr 1-6 pathogenic variant, whereas EGFr 7-34 pathogenic variant strongly predominate in the population. CONCLUSION: NOTCH3 pathogenic variant position is the most important determinant of CADASIL disease severity, with EGFr 7-34 pathogenic variant predisposing to a later onset of stroke and longer survival.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectBrain
dc.subjectHumans
dc.subjectCADASIL
dc.subjectDisease Progression
dc.subjectPhenotype
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectNetherlands
dc.subjectFemale
dc.subjectMale
dc.subjectStroke
dc.subjectReceptor, Notch3
dc.subjectProtein Domains
dc.titleThe effect of NOTCH3 pathogenic variant position on CADASIL disease severity: NOTCH3 EGFr 1-6 pathogenic variant are associated with a more severe phenotype and lower survival compared with EGFr 7-34 pathogenic variant.
dc.typeArticle
prism.endingPage682
prism.issueIdentifier3
prism.publicationDate2019
prism.publicationNameGenet Med
prism.startingPage676
prism.volume21
dc.identifier.doi10.17863/CAM.32085
dcterms.dateAccepted2018-06-04
rioxxterms.versionofrecord10.1038/s41436-018-0088-3
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2019-03
dc.contributor.orcidMarkus, Hugh [0000-0002-9794-5996]
dc.identifier.eissn1530-0366
rioxxterms.typeJournal Article/Review
cam.issuedOnline2018-07-22


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International