Background and Purpose:
Cysteine altering
NOTCH3
variants, which have previously been exclusively associated with the rare hereditary small vessel disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, have a population frequency of 1:300 worldwide. Using a large population database, and taking genotype as a starting point, we aimed to determine whether individuals harboring a
NOTCH3
cysteine altering variant have a higher load of small vessel disease markers on brain magnetic resonance imaging than controls, as well as a higher risk of stroke and cognitive impairment.
Methods:
A cross-sectional study using integrated clinical, neuroimaging, and whole-exome sequencing data of 92 456 participants from the Geisinger DiscovEHR initiative cohort. The case group consisted of individuals harboring a
NOTCH3
cysteine altering variant (n=118). The control group consisted of randomly selected age- and sex-matched individuals who did not have any nonsynonymous variants in
NOTCH3
(n=184). Medical records including brain magnetic resonance imagings were evaluated for clinical and neuroimaging findings associated with small vessel disease. Group comparisons were done using Fisher exact test and ordinal logistic regression models. Risk of stroke was assessed using Cox regression.
Results:
Of the 118 cases, 39.0% were men, mean age 58.1±16.9 years; 12.6% had a history of stroke, compared with 4.9% of controls. The risk of stroke was significantly increased after age 65 years (hazard ratio, 6.0 [95% CI, 1.4–26.3]). Dementia, mild cognitive impairment, migraine with aura and depression were equally prevalent in cases and controls. Twenty-nine cases (25%) and 45 controls (24%) had an available brain magnetic resonance imaging. After age 65 years, cases had a higher white matter lesion burden and more lacunes. A severe small vessel disease phenotype compatible with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy was rarely seen.
Conclusions:
Cysteine altering
NOTCH3
variants are an important contributor to the risk of stroke, lacunes, and white matter hyperintensities in the elderly population.
Comparison of brain magnetic resonance imaging between myotonic dystrophy type 1 and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy