Association of NOTCH3 variant position with stroke onset and other clinical features among patients with CADASIL
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Publication Date
2022-05-31Journal Title
Neurology
ISSN
0028-3878
Publisher
Lippincott, Williams & Wilkins
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Cho, B. P. H., Jolly, A., Nannoni, S., Tozer, D., Bell, S., & Markus, H. (2022). Association of NOTCH3 variant position with stroke onset and other clinical features among patients with CADASIL. Neurology https://doi.org/10.1212/WNL.0000000000200744
Abstract
ABSTRACT
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.
Embargo Lift Date
2023-05-31
Identifiers
External DOI: https://doi.org/10.1212/WNL.0000000000200744
This record's URL: https://www.repository.cam.ac.uk/handle/1810/335807
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