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.

Genetic spectrum and clinical features of adult leukoencephalopathies in a Chinese cohort

“…In addition, most of our CADASIL patients presented with ischemic stroke or recurrent TIA and a few suffered from migraine, which was different from Caucasians due to the higher proportion of migraine in Caucasians. 40 Inherited metabolic disorders are common causes of child leukoencephalopathies, 41 but they were found not to be rare in our adult leukoencephalopathies cohort. Several metabolic disorders were identified that affected very long chain fatty acid profile (ALD), serum cholestanol/urinary bile alcohols (CTX), specific enzyme activities (PKU and Krabbe disease) and plasma amino acid profile (homocystinuria).…”

“…Some novel cysteine‐sparing mutations in NOTCH3 , such as p.R90H and p.V237M, were also found in our study. In addition, most of our CADASIL patients presented with ischemic stroke or recurrent TIA and a few suffered from migraine, which was different from Caucasians due to the higher proportion of migraine in Caucasians 40 …”

Modifiable vascular risk factors contribute to stroke in 1080 NOTCH3 R544C carriers in Taiwan Biobank

“…Among the symptomatic NOTCH3 R607C variant carriers, the prevalence of vascular risk factors was around one-third, but the relationship with stroke was not elaborated. 21 From a community-based perspective, our biobank study provides information on the cardiovascular risk factors impact on NOTCH3 variants in greater magnitude.…”

“…The NOTCH3 variant landscape in the East Asian population was diverse, yet the NOTCH3 R544C variant (EGFr 13/14) and the NOTCH3 R607C variant (EGFr 15) top the most frequent variants. 21 In hospital-recruited studies of the NOTCH3 R544C carriers, sibling history of stroke and hypertension was related to intracerebral hemorrhage incidence. 9,22 Given the unavailable information on the NOTCH3 R544C carriers with hemorrhagic stroke in Taiwan Biobank, it may be suggested that further studies of the cohort are needed with vascular risk contributions to specific stroke types.…”

Case report: Mild leukoencephalopathy caused by a new mutation of NOTCH3 gene

“…[1] NOTCH3 was identified as a pathogenic gene for CADASIL. [2] The NOTCH3 gene encodes a membrane-bound receptor protein, and to date, several different NOTCH3 gene mutations have been identified. [3] Here, we report a case of CADASIL with a heterozygous mutation c.931T > G (thymine > guanine) on the exon region of the NOTCH3 gene, resulting in an amino acid change p.C311G (cysteine > glycine).Case report: We report a case of a female patient with CADASIL whose genetic sequencing revealed a mutation in the NOTCH3 gene.…”