CADASIL is classically recognized as a rare hereditary cerebral small vessel disease with a prevalence of 2-5/100,000 in North Europe. The NOTCH3 p.R544C mutation accounts for around 70% of CADASIL cases in Taiwan. We previously identified four unrelated CADASIL patients harboring the homozygous p.R544C mutation, implying a high allele frequency of the p.R544C mutation in Taiwan. Furthermore, a recent study analyzed the exome aggregation consortium (ExAC) database and found that the frequency of pathogenic cysteine-altering NOTCH3 mutations in East Asians is 0.9%. Therefore, the patient numbers and the clinical impact of CADASIL, at least in East Asians, are underestimated. 

To investigate the frequency of NOTCH3 p.R544C mutation and its contribution to ischemic stroke in Taiwanese population.

The study participants included 6488 anonymous healthy community controls from Taiwan Biobank, 551 stroke and dementia-free individuals enrolled from Taipei Veterans General Hospital, and 849 ischemic stroke patients recruited from two medical centers in Taiwan. Genotyping for NOTCH3 p.R544C was performed using Applied Biosystems TaqMan technology. The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification was used to define stroke subtypes.

The NOTCH3 p.R544C mutation was presented in 0.8% (59) of all the 7039 control subjects, 2% (17) of all the 849 individuals with ischemic stroke, and 6.1% (16) of the 248 patients with small vessel occlusion (SVO) stroke. After adjusting other vascular risk factors, the odds ratio of individuals with a NOTCH3 p.R544C mutation to have a stroke or SVO stroke are 3.12 and 10.36, respectively. All the stroke patients and the three non-anonymous controls with NOTCH3 p.R544C in the study had a variable degree of leukoencephalopathy.

CADASIL is not rare and is a significant cause of SVO stroke in Taiwan.