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Association of NOTCH3 variant position with stroke onset and other clinical features among patients with CADASIL

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cam.depositDate2022-04-05
cam.issuedOnline2022-05-31
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cam.orpheus.successWed Jun 08 08:57:08 BST 2022 - Embargo updated
dc.contributor.authorCho, Bernard Pok Him
dc.contributor.authorJolly, Amy
dc.contributor.authorNannoni, Stefania
dc.contributor.authorTozer, Daniel
dc.contributor.authorBell, Steven
dc.contributor.authorMarkus, Hugh
dc.contributor.orcidCho, Bernard PH [0000-0002-5034-3234]
dc.contributor.orcidJolly, Amy A [0000-0003-2669-4998]
dc.contributor.orcidNannoni, Stefania [0000-0002-1825-1874]
dc.contributor.orcidTozer, Daniel [0000-0002-0404-3214]
dc.contributor.orcidBell, Steven [0000-0001-6774-3149]
dc.contributor.orcidMarkus, Hugh S [0000-0002-9794-5996]
dc.date.accessioned2022-04-05T23:30:30Z
dc.date.available2022-04-05T23:30:30Z
dc.date.issued2022-08-01
dc.date.updated2022-04-05T08:27:11Z
dc.description.abstractABSTRACT Background and Objectives Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by a cysteine-altering mutation in one of the thirty-four epidermal growth factor-like repeat (EGFR) domains of the NOTCH3 protein. CADASIL has a variable phenotypic presentation and NOTCH3 mutations in EGFRs 1-6 have been found correlated with greater disease severity. We examined clinical and radiological features and performed bioinformatic annotation of mutations in a large CADASIL cohort to further understand these associations. Methods We examined the association of NOTCH3 variant position on stroke onset and other clinical features among patients with CADASIL from the United Kingdom. We also explored how in-silico predicted protein aggregation differed by variant position and the extent to which this affected stroke risk. Results We identified 76 different cysteine-altering NOTCH3 variants in our cohort of 485 patients (mean age: 50.1 years; % male: 57.5). After controlling for cardiovascular risk factors, variants in EGFRs 1-6 were associated with earlier onset of stroke (hazard ratio [HR]: 2.05, 95% CI: 1.43-2.94) and encephalopathy (HR: 2.70, 95% CI: 1.15-6.37), than variants in EGFRs 7-34. Although the risk of stroke was higher in the patients with predicted protein aggregation (HR: 1.50, 95% CI: 1.05-2.14), this association was no longer significant after controlling for variant site. Further analysis suggested lower stroke risk was observed for variants in EGFRs 10-17 compared to variants in the other EGFR domains. Discussion NOTCH3 variant position is a predictor of stroke and encephalopathy in CADASIL independent of cardiovascular risk factors. Lower stroke risk was found for variants in EGFRs 10-17. Molecular factors that influence CADASIL disease severity remain to be determined.
dc.identifier.doi10.17863/CAM.83243
dc.identifier.eissn1526-632X
dc.identifier.issn0028-3878
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/335807
dc.language.isoeng
dc.publisherLippincott, Williams & Wilkins
dc.publisher.urlhttp://dx.doi.org/10.1212/wnl.0000000000200744
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectHumans
dc.subjectMale
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectCADASIL
dc.subjectReceptor, Notch3
dc.subjectCysteine
dc.subjectProtein Aggregates
dc.subjectMutation
dc.subjectMagnetic Resonance Imaging
dc.subjectStroke
dc.subjectErbB Receptors
dc.subjectReceptors, Notch
dc.titleAssociation of NOTCH3 variant position with stroke onset and other clinical features among patients with CADASIL
dc.typeArticle
dcterms.dateAccepted2022-04-04
prism.publicationNameNeurology
pubs.funder-project-idMedical Research Council (MR/N026896/1)
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
pubs.licence-identifierapollo-deposit-licence-2-1
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1212/WNL.0000000000200744

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