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Cited by 36Cerebrovascular and genetic disordersGenetic Neurodegenerative DiseasesHereditary Neurological Disorders

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

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Ni, Wang, Zhang, Yi, Zhang, Liang, Xie, Juan‐Juan, Li, Hong‐Fu, Wu, Zhi‐Ying·2022·CNS Neuroscience & Therapeutics
DOI 10.1111/cns.13917PMC PMC9532899
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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.

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  • CADASIL in Asian patients often lacks classic radiologic phenotype, such as anterior temporal pole involvement, and may present later in life with confluent WMHs and cognitive impairment, increasing the risk of misdiagnosis.

    “Moreover, CADASIL in Asian patients often lacks classic radiologic phenotype, such as anterior temporal pole involvement, and may present later in life with confluent WMHs and cognitive impairment, increasing the risk of misdiagnosis.16-18”

    From Multiple Sclerosis Misdiagnosis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (2026) · cites this paper as [16]

    The Results (Clinical features of CADASIL patients in different populations; page unavailable) report later age at onset, more cognitive impairment, and less frequent temporal-pole involvement in Asian than Caucasian patients, though temporal-pole involvement still occurred in 68.64% of Asian patients. The Introduction describes white matter hyperintensities, but our copy does not establish that they are confluent or that this presentation increases misdiagnosis risk. (LLM, conf=0.87)

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Research works printed but not linked: 21

  1. [1]Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations in CADASIL, a hereditary adult‐onset condition causing stroke and dementia. Nature. 1996; 383(6602): 707‐ 710. 8878478
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Cited by

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Authors
Ni, W., Zhang, Y., Zhang, L., Xie, J., Li, H., & Wu, Z.
Affiliations
  • Department of Neurology and Department of Medical Genetics in the Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province Zhejiang University School of Medicine Hangzhou China
  • Second Affiliated Hospital of Zhejiang University (CN)
Corresponding author
Wu, Zhi‐Ying
ORCID
Venue
CNS Neuroscience & Therapeutics
Publisher
Wiley
Published
2022-07-13
Volume
28
Issue
11
Pages
1779-1789
ISSN
  • 1755-5930 (ISSN-L)
  • 1755-5949
DOI
10.1111/cns.13917
PMC
PMC9532899
OpenAlex
W4285086584
Cited by
36
References
6
Citations by year
2026: 4 · 2025: 9 · 2024: 9 · 2023: 13 · 2022: 1
FWCI
4.21
Type
journal article
Language
en
Open access
Licence
Locations
  • CNS Neuroscience & Therapeutics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
CADASIL, NOTCH3 mutations, mutation spectrum, genetic heterogeneity, clinical phenotype, cerebral small vessel disease, novel mutations, ischemic stroke, migraine, cognitive impairment, psychiatric disturbances, temporal lobe involvement, leukoencephalopathy, white matter lesions, genetic counseling, genotype-phenotype correlation
MeSH terms
Receptor, Notch3, Cysteine, Humans, Magnetic Resonance Imaging, Mutation, Phenotype, CADASIL, Receptors, Notch

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