5 results on '"CADASIL genetics"'
Search Results
2. Imaging-based pregenetic screening for NOTCH3 p.R544C mutation in ischemic stroke in Taiwan.
- Author
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Cheng YW, Chen CH, Hu CJ, Chiou HY, Tang SC, and Jeng JS
- Subjects
- Aged, 80 and over, Asian People genetics, Brain Ischemia diagnostic imaging, CADASIL genetics, Female, Humans, Ischemic Stroke genetics, Ischemic Stroke pathology, Magnetic Resonance Imaging methods, Male, Middle Aged, Receptors, Notch genetics, Taiwan, Brain Ischemia genetics, Genetic Predisposition to Disease genetics, Mutation genetics, Receptor, Notch3 genetics, Receptor, Notch3 metabolism
- Abstract
Objective: To develop an easily applicable screening score to guide NOTCH3 p.R544C genetic testing for patients who presented with acute ischemic cerebrovascular events in Taiwan., Methods: 1734 patients who presented with ischemic cerebrovascular events were enrolled from the Formosa Stroke Genetic Consortium stroke registry and were screened for the NOTCH3 p.R544C mutation. Clinical and MRI characteristics of NOTCH3 p.R544C mutation carriers (n = 36) and a subset of noncarriers (n = 673) were tested in a logistic regression model to identify key features associated with the NOTCH3 p.R544C carrier status. Variables and their odds ratios in the regression model were used to develop the R544C screening score to predict positive NOTCH3 p.R544C test results., Results: We constructed the R544C screening score using five clinical and imaging characteristics, including stroke onset before 50 years of age, the small vessel occlusion subtype, a family history of stroke/TIA in siblings, external capsule involvement, and advanced deep white matter hyperintensity. The area under the ROC curve of the screening score was 0.867 (95% CI = 0.810-0.924). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 0.75, 0.88, 0.13, 0.99, and 0.88, respectively, for a cutoff score of 5 points. In addition, the R544C screening score was validated in another cohort composed of 235 stroke patients with comparable performance (area under the ROC curve = 0.957, 95% CI = 0.916-0.997)., Interpretations: For Taiwanese patients presenting with acute ischemic cerebrovascular events, the R544C screening score is easily applicable and can efficiently select high-risk patients for NOTCH3 p.R544C mutation test., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
- Published
- 2020
- Full Text
- View/download PDF
3. NOTCH3 cysteine-altering variant is an important risk factor for stroke in the Taiwanese population.
- Author
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Lee YC, Chung CP, Chang MH, Wang SJ, and Liao YC
- Subjects
- Adult, Age Factors, Aged, CADASIL diagnostic imaging, CADASIL genetics, Female, Genetic Variation, Genotype, Humans, Leukoencephalopathies diagnostic imaging, Leukoencephalopathies genetics, Magnetic Resonance Imaging, Male, Middle Aged, Mutation genetics, Risk Factors, Stroke diagnostic imaging, Taiwan epidemiology, White Matter diagnostic imaging, Young Adult, Cysteine genetics, Receptor, Notch3 genetics, Stroke epidemiology, Stroke genetics
- Abstract
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 × 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., (© 2019 American Academy of Neurology.)- Published
- 2020
- Full Text
- View/download PDF
4. Population-specific spectrum of NOTCH3 mutations, MRI features and founder effect of CADASIL in Chinese.
- Author
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Lee YC, Liu CS, Chang MH, Lin KP, Fuh JL, Lu YC, Liu YF, and Soong BW
- Subjects
- Adult, Aged, Asian People ethnology, Asian People genetics, Brain metabolism, Brain physiopathology, CADASIL ethnology, DNA Mutational Analysis, Female, Founder Effect, Gene Frequency genetics, Genetic Markers genetics, Genetic Testing, Genotype, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Receptor, Notch3, Taiwan, Brain pathology, CADASIL genetics, CADASIL pathology, Genetic Predisposition to Disease genetics, Mutation genetics, Receptors, Notch genetics
- Abstract
Background and Purpose: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disorder caused by NOTCH3 mutations and characterized by recurrent subcortical infarctions, dementia and leukoencephalopathy. So far, most clinical, molecular and neuroimaging information has come from Caucasians. Therefore, we investigated the spectrum of NOTCH3 mutations and MRI features in CADASIL patients of Chinese origin on Taiwan., Methods: Mutational analysis of NOTCH3 exons 2 to 23 by direct nucleotide sequencing was performed in patients with clinically suspected CADASIL. MRI findings were retrospectively evaluated and scored using a modified Schelten's scale., Results: Nine different point mutations of NOTCH3 were identified in 21 unrelated patients. Intriguingly, 47.6 % were in exon 11, and 19 % in each of exon 4 and 18. R544C was very common and present in all patients with a mutation in exon 11. Many patients with NOTCH3 R544C share the same haplotype linked to the mutation using markers D19S929 and D19S411, which flank the NOTCH3. The sensitivity of T2-weighted MRI detecting anterior temporal abnormality was only 42.9 %. Furthermore, the neuroimaging evidence of intracerebral hemorrhage (ICH) was present in 23.8 % of the 21 patients., Conclusions: A population-specific mutational spectrum of CADASIL was found in the Chinese patients on Taiwan. The Chinese patients carrying NOTCH3 R544C may descend from a common ancestor. Anterior temporal hyperintensity on T2-weighted MRI may not be a sensitive marker for CADASIL. ICH is a relatively common manifestation of CADASIL in East Asians, especially in the presence of hypertension.
- Published
- 2009
- Full Text
- View/download PDF
5. Arg332Cys mutation of NOTCH3 gene in the first known Taiwanese family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
- Author
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Tang SC, Lee MJ, Jeng JS, and Yip PK
- Subjects
- Asian People, Brain pathology, Brain physiopathology, CADASIL ethnology, CADASIL physiopathology, China ethnology, DNA Mutational Analysis, Dementia genetics, Dementia pathology, Dementia physiopathology, Depressive Disorder genetics, Depressive Disorder pathology, Depressive Disorder physiopathology, Exons genetics, Female, Genetic Testing, Genotype, Humans, Male, Microscopy, Electron, Transmission, Middle Aged, Pedigree, Phenotype, Receptor, Notch3, Receptors, Notch, Skin pathology, Skin ultrastructure, Stroke genetics, Stroke pathology, Stroke physiopathology, Taiwan epidemiology, Amino Acid Substitution genetics, CADASIL genetics, Mutation genetics, Proto-Oncogene Proteins genetics, Receptors, Cell Surface genetics
- Abstract
The phenotype and genotype of cerebral autosomal dominant arteriopathy and subcortical infarcts and leukoencephalopathy (CADASIL) in Caucasians have been well characterized, but CADASIL is less recognized in Asian populations. Here we investigated the first known Taiwanese family affected by CADASIL and identified an uncommon NOTCH3 mutation. The family had clinical manifestations in affected members including recurrent strokes, early dementia, and depression, but not migraine. A skin biopsy in the proband patient showed characteristic pathological findings of CADASIL on electron microscopy. Afterward, genetic analysis found an Arg332Cys mutation at exon 6 of NOTCH3. Neuropsychological evaluation showed vascular dementia in two of four affected people. Head MRI showed multiple infarcts in bilateral basal ganglia, thalami, periventricular white matter, external capsules, and brainstem, but involvement of the anterior temporal pole was found only in two people with milder symptoms. To our knowledge, the Arg332Cys NOTCH3 mutation at exon 6, which was identified in the studied family, has not been reported in Asian populations. Our findings emphasize the importance of genetic analysis of NOTCH3 for Asians with a phenotype typical of CADASIL.
- Published
- 2005
- Full Text
- View/download PDF
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