Cysteine-Altering NOTCH3 Variants Are a Risk Factor for Stroke in the Elderly Population

Abstract

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.

NOTCH3 variants are more common than expected in the general population and associated with stroke and vascular dementia: an analysis of 200 000 participants

“…A recent report from the US Geisinger database suggested NOTCH3 variants are associated with an increased risk of stroke and MRI features of SVD, although no association was found with dementia. 8 Our findings are broadly confirmatory of those in the Geisinger cohort although we reported a slightly higher prevalence of NOTCH3 variants (0.22% vs 0.14%) and our larger sample size also allowed an association with vascular dementia to be detected.…”

“…Moreover, in the subset of individuals in whom MRI scanning was performed, we correlated presence of NOTCH3 variants with MRI markers of SVD including white matter hyperintensities (WMHs) and lacunar infarcts and determined whether variant carriers had a similar spatial distribution of lesions to that seen in typical CADASIL cases. This study extends previous studies, particularly the Geisinger DiscovEHR cohort, 8 with a larger sample size providing greater power to examine associations with the risk of both stroke and dementia.…”

NOTCH3 variants are common in the general population and associated with stroke and vascular dementia: an analysis of 200,000 participants

“…A very recent report from the United States Geisinger database suggested such variants associated with an increased risk of stroke and MRI features of SVD, although no association was found with dementia. [8] Our findings provide robust evidence from a large population-based study of over 200,000 individuals that common NOTCH3 variants are associated with symptomatic cerebrovascular disease in the general population. We demonstrated that they conferred a risk equivalent to that in the top 1.6% of individuals as determined by a polygenic risk score, with the risks from common polygenic variant and NOTCH3 variants being independent.…”

“…[4] Although CADASIL is considered rare, with a reported disease prevalence of 4 per 100,000, [5,6] recently a much higher frequency of typical cysteine-altering NOTCH3 variants, as high as 1 in 400. [7,8] These could contribute to the risk of apparently sporadic lacunar stroke, but the clinical significance of these variants remains uncertain. Studies have mostly been conducted on anonymised genome-sequencing databases, [7] and it is unclear whether such apparently 'asymptomatic' variants have clinical implications.…”

Contribution of “Omic” Studies to the Understanding of Cadasil. A Systematic Review

“…In fact, because of the creation of biobanks, which are projects that aggregate and harmonize exome and genome sequencing data from a wide variety of large-scale sequencing studies, it has been possible to further profile mutations affecting cysteine residues in Notch3 in a significant number of individuals. In the Genome Aggregation Database (gnomAD, , accessed on 27 May 2021), the UK Biobank (UKB, , accessed on 27 May 2021) and the Geisinger DiscovEHR ( , accessed on 27 May 2021), a prevalence of 1.4–3.4/1000 subjects carrying NOTCH3 variants that were considered pathogenic were established [ 17 , 18 , 19 , 20 , 21 ] ( Figure 2 ), and 9/1000 in the Taiwan Biobank ( , accessed on 27 May 2021) [ 22 ], the latter high frequency is in line with the UKB observation of enrichment of pathogenic mutations in NOTCH3 in Asians [ 19 ].…”