NOTCH3 and ischemic stroke: Cerebral small vessel disease (SVD) is a major cause of stroke and dementia.1 2 Most cases are sporadic, although polygenic risk factors appear important.3 SVD is the most common type of ischaemic stroke caused by single-gene disorders; the most common is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which results in early-onset lacunar stroke and dementia, and is caused by distinctive NOTCH3 variants that lead to an extra unpaired cysteine residue in one of 34 epidermal growth factor-like repeat (EGFR) domains.4