NOTCH3 cysteine-altering variant is an important risk factor for stroke in the Taiwanese population

Objective To test the hypothesis that the prevalence and clinical effect of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have been underestimated in Asian populations. Methods The Taiwan Biobank, containing 1,517 Taiwanese genome sequences, was queried for pathogenic NOTCH3 cysteine-altering mutations. NOTCH3 mutations identified in the reference population were genotyped in 7,038 stroke- and dementia-free individuals and 800 patients with ischemic stroke. NOTCH3 genotyping, clinical manifestations, and the severity of white matter lesions on MRI were compared between the 2 groups. Results Three cysteine-altering NOTCH3 variants (p.R544C, p.C853Y, and p.C884Y) were identified from the Taiwan Biobank. We confirmed that the NOTCH3 p.R544C mutation was present in a significant number of individuals in Taiwan, including 60 of the 7,038 healthy controls (0.9%), 17 of the 800 patients with ischemic stroke (2.1%), and 16 of the 245 patients with small vessel occlusion (SVO) stroke (6.5%). The other 2 cysteine-altering mutations were rarely detected. After adjusting for vascular risk factors, harboring the p.R544C variant resulted in a 3.40-fold increased risk for overall stroke and an 11.05-fold increased risk for SVO stroke (p = 0.0001 and 3.9 x 10-10, respectively). Three symptom-free individuals carrying the p.R544C mutation had extensive leukoencephalopathy typical of CADASIL at age 59, 66, and 67, suggesting that p.R544C-related CADASIL could remain subclinical at advanced age. Conclusion The NOTCH3 p.R544C variant is an important risk factor for SVO stroke in Taiwan. Phenotypic variation among individuals carrying a NOTCH3 mutation indicates the existence of disease-modifying factors in CADASIL.