不同人群中 NOTCH3 基因突变谱与 CADASIL 患者的临床表型。
Genetic spectrum of NOTCH3 and clinical phenotype of CADASIL patients in different populations.
机构信息
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.
出版信息
CNS Neurosci Ther. 2022 Nov;28(11):1779-1789. doi: 10.1111/cns.13917. Epub 2022 Jul 13.
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.
简介
伴有皮质下梗死和白质脑病的脑常染色体显性动脉病（CADASIL）是一种相对常见的脑小血管病。NOTCH3 已被确定为 CADASIL 的致病基因。CADASIL 患者存在临床变异性和遗传异质性，需要进一步阐明。
目的
本研究旨在阐明 NOTCH3 的遗传谱和 CADASIL 患者的临床表型。
方法
本中心于 2016 年至 2021 年期间收集疑似 CADASIL 患者。对这些患者进行全外显子组测序，以筛查 NOTCH3 突变。还分析了来自先前研究的 CADASIL 患者的遗传和临床数据。纳入了 1998 年至 2021 年期间发表的超过 9 个具有详细遗传数据或临床数据的家系的研究。在排除携带半胱氨酸保存突变的患者后，共有 855 个亚洲家系（433 个中国人；226 个日本人，196 个韩国人）和 546 个高加索家系的遗传数据被纳入突变谱的映射。共涉及 1401 个 CADASIL 家系。对 901 名亚洲患者（476 名中国人，217 名日本人，208 名韩国人）和 720 名高加索患者的临床数据进行了分析，并在不同人群之间进行了比较。
结果
在 36 个家系中发现了 2 个新突变（c.400T>C，p.Cys134Arg；c.1511G>A，p.Cys504Tyr）和 24 个已知的半胱氨酸影响变异。阐明了亚洲人（中国人、日本人、韩国人）和高加索人的遗传谱，p.R544C 和 p.R607C 是亚洲人中最常见的突变，而 p.R1006C 和 p.R141C 在高加索人中。就临床特征而言，亚洲人更容易出现 TIA 或缺血性中风（p<0.0001）和认知障碍（p<0.0001）的症状。然而，高加索人更容易出现偏头痛（p<0.0001）和精神障碍（p<0.0001）。颞极受累在高加索人中更常见（p<0.0001）。
结论
这些发现有助于更好地理解 CADASIL 的临床变异性和遗传异质性。
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