NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients

Hu, Yacen; Sun, Qiying; Zhou, Yifei; Fang, Yi; Tang, Haiyun; Yao, Lingyan; Tian, Yun; Xie, Nina; Luo, Mingyao; Wang, Zhiqin; Liao, Xinxin; Xu, Hongwei; Zhou, Lin

doi:10.3389/fgene.2021.705284

Cited by 23 publications

(30 citation statements)

References 39 publications

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“…Although other studies have shown EGFRs 7-34 variants to be associated with very mild phenotype, [24][25][26][27][28] EGFRs 18-34 variants appeared to be as severe as EGFRs 1-9 with respect to stroke in our study. However, there were fewer patients with variants in EGFRs 18-34 which reduces confidence in this comparison.…”

Section: Discussioncontrasting

confidence: 99%

Association of NOTCH3 Variant Position With Stroke Onset and Other Clinical Features Among Patients With CADASIL

et al. 2022

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Background and Objectives:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by a cysteine-altering mutation in one of the thirty-four epidermal growth factor-like repeat (EGFR) domains of the NOTCH3 protein. CADASIL has a variable phenotypic presentation and NOTCH3 mutations in EGFRs 1-6 have been found correlated with greater disease severity. We examined clinical and radiological features and performed bioinformatic annotation of mutations in a large CADASIL cohort to further understand these associations.Methods:We examined the association of NOTCH3 variant position on stroke onset and other clinical features among patients with CADASIL from the United Kingdom. We also explored how in-silico predicted protein aggregation differed by variant position and the extent to which this affected stroke risk.Results:We identified 76 different cysteine-altering NOTCH3 variants in our cohort of 485 patients (mean age: 50.1 years; % male: 57.5). After controlling for cardiovascular risk factors, variants in EGFRs 1-6 were associated with earlier onset of stroke (hazard ratio [HR]: 2.05, 95% CI: 1.43-2.94) and encephalopathy (HR: 2.70, 95% CI: 1.15-6.37), than variants in EGFRs 7-34. Although the risk of stroke was higher in the patients with predicted protein aggregation (HR: 1.50, 95% CI: 1.05-2.14), this association was no longer significant after controlling for variant site. Further analysis suggested lower stroke risk was observed for variants in EGFRs 10-17 compared to variants in the other EGFR domains.Discussion:NOTCH3 variant position is a predictor of stroke and encephalopathy in CADASIL independent of cardiovascular risk factors. Lower stroke risk was found for variants in EGFRs 10-17. Molecular factors that influence CADASIL disease severity remain to be determined.

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Section: Discussioncontrasting

confidence: 99%

Association of NOTCH3 Variant Position With Stroke Onset and Other Clinical Features Among Patients With CADASIL

et al. 2022

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“…14,15 Previous work has pointed out that the proportion of migraine with aura was 20%-40% in Caucasian while in Chinese patients it was often around or lower than 20%. 7,[16][17][18][19] Our results showed that the proportion in Caucasian was over 50%, which meant the difference between Asians and Caucasians might bigger than we know. Also, work from Taiwan pointed out that less frequent temporal pole involvement was associated with p.Arg544Cys.…”

Section: Clinical Features Of Cadasil Patients In Different Populationsmentioning

confidence: 60%

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

Wang

Zhang

et al. 2022

CNS Neurosci Ther

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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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“…This is reflected at the neuroanatomical level, as patients with pathogenic variants in EGFR domains 1-6 showed more severe white matter hyperintensity on brain MRI and an earlier onset of stroke than those with mutations in EGFR domains 7-34 [1]. In addition, patients carrying cysteine-affecting variants reported to show more severe clinical severity than those carrying cysteine-sparing variants [7,8]. Patients with the cystine-sparing p.Arg75Pro mutation showed a significantly lower stroke frequency and white matter hyperintensity than patients with p.Arg141Cys or p.Arg182Cys, although all three such mutations were located in EGFR domains 1-6 [7].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Concerning the genotype-phenotype correlation, the determinants of clinical severity in CADASIL remain unknown [1,[6][7][8]. However, several factors seem to be associated with clinical severity, including the location of the mutation, whether the variant affects cysteine residues, as well as other cardiovascular risk factors [1,[6][7][8]. Specifically, a severe disease course is associated with variants in EGFR domains 1-6, whereas mutations located in the EGFR domains 7-34 are associated with milder phenotypes [1].…”

Section: Discussionmentioning

confidence: 99%

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A case of mild CADASIL patient with a novel heterozygous NOTCH3 variant

2022

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a single-gene disease caused by mutations in the neurogenic locus notch homolog protein 3 (NOTCH3) gene. The spectrum of clinical manifestations is broad, ranging from asymptomatic to typical ischemic stroke, and mainly depends on the location of the mutations. We describe the case of a 76-year-old female without apparent neurological deficits. However, brain magnetic resonance imaging revealed confluent lesions in the white matter. Direct sequencing of the NOTCH3 gene revealed a novel pathogenic mutation, c.811T>A, which results in a mild phenotype. Therefore, this report will expand the current knowledge in regards to the mutations that can cause CADASIL.

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NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients

Cited by 23 publications

References 39 publications

Association of NOTCH3 Variant Position With Stroke Onset and Other Clinical Features Among Patients With CADASIL

Association of NOTCH3 Variant Position With Stroke Onset and Other Clinical Features Among Patients With CADASIL

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

A case of mild CADASIL patient with a novel heterozygous NOTCH3 variant

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