Genetic spectrum of NOTCH3 and clinical phenotype of CADASIL patients in different populations

Abstract Introduction Cerebral autosomal‐dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a relatively common cerebral small vessel disease. NOTCH3 has been identified as the causative gene of CADASIL. Clinical variability and genetic heterogeneity were observed in CADASIL patients and need to be further clarified. Aims The aim of the study was to clarify genetic spectrum of NOTCH3 and clinical phenotype of CADASIL patients. Methods Suspected CADASIL patients were collected by our center between 2016 and 2021. Whole exome sequencing was performed to screen NOTCH3 mutations of these patients. Genetic and clinical data of CADASIL patients from previous studies were also analyzed. Studies between 1998 and 2021 that reported more than 9 pedigrees with detailed genetic data or clinical data were included. After excluding patients carrying cysteine‐sparing mutations, genetic data of 855 Asian pedigrees (433 Chinese; 226 Japanese, and 196 Korean) and 546 Caucasian pedigrees, in a total of 1401 CADASIL pedigrees were involved in mapping mutation spectrum. Clinical data of 901 Asian patients (476 Chinese patients, 217 Japanese patients, and 208 Korean patients) and 720 Caucasian patients, in a total of 1621 patients were analyzed and compared between different populations. Results Two novel mutations (c.400T>C, p.Cys134Arg; c.1511G>A, p.Cys504Tyr) and 24 known cysteine‐affecting variants were identified in 36 pedigrees. Genetic spectrums of Asians (Chinese, Japanese, and Korean) and Caucasians were clarified, p.R544C and p.R607C were the most common mutations in Asians while p.R1006C and p.R141C in Caucasians. For clinical features, Asians were more likely to develop symptoms of TIA or ischemic stroke ( p < 0.0001) and cognitive impairment ( p < 0.0001). Nevertheless, Caucasians had a higher tendency to present migraine ( p < 0.0001) and psychiatric disturbance ( p < 0.0001). The involvement of temporal pole was more likely to happen in Caucasians ( p < 0.0001). Conclusion The findings help to better understand the clinical variability and genetic heterogeneity of CADASIL.