Association of NOTCH3 Variant Position With Stroke Onset and Other Clinical Features Among Patients With CADASIL.
Neurology
; 2022 May 31.
Article
em En
| MEDLINE
| ID: mdl-35641310
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Revista:
Neurology
Ano de publicação:
2022
Tipo de documento:
Article