Genetic Spectrum and Variability in Chinese Patients with Amyotrophic Lateral Sclerosis
Genetic Spectrum and Variability in Chinese Patients with Amyotrophic Lateral Sclerosis
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中国肌萎缩侧索硬化症患者的基因谱和变异
DOI：
10.14336/ad.2019.0215
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发表时间：
2019-12-01
影响因子：
7.4
通讯作者：
Wu, Zhi-Ying
中科院分区：
文献类型：
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作者：
Liu, Zhi-Jun;Lin, Hui-Xia;Wu, Zhi-Ying
肌萎缩性侧索硬化症（ALS）是一种进行性、致死性神经退行性疾病，其特征是上下运动神经元的选择性损伤。我们的目的是研究中国ALS患者的遗传谱和变异。共纳入24例家族性ALS （FALS）和21例中国血统的早发散发性ALS （SALS）。先证物进行靶向下一代测序（NGS），然后进行Sanger测序和共分离分析验证。存在致病性或可能致病性变异患者的临床特征。分析中国人群中als相关基因的突变频率。在该队列中，在14例FALS和6例早发性SALS中发现了17个已知突变（9个SOD1, 5个FUS， 2个TARDBP和1个SETX）。此外，还鉴定出了7个新变异（SOD1 C . 112g >C、OPTN C . 811c >T、ERBB4 C . 965t >A、DCTN1 C . 1915c >T、NEFH C . 2602g >A、NEK1 C . 3622g >A和TAF15 C . 1535g >A）。在中国东南部FALS中，SOD1、FUS和TARDBP的突变频率分别为52.9%、8.8%和8.8%。在早发性SALS中，FUS突变最为常见（22.6%）。在中国ALS病例中，p.H47R是最常见的SOD1突变，p.R521是最常见的FUS突变，p.M337V是最常见的TARDBP突变。我们的研究结果显示，SOD1、FUS和TARDBP突变是中国FALS最常见的原因，而FUS突变是早发性SALS最常见的原因。中国人与白种人ALS的遗传谱存在差异。
Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by selective impairment of upper and lower motor neurons. We aimed to investigate the genetic spectrum and variability in Chinese patients with ALS. A total of 24 familial ALS (FALS) and 21 early-onset sporadic ALS (SALS) of Chinese ancestry were enrolled. Targeted next-generation sequencing (NGS) was performed in the probands, followed by verification by Sanger sequencing and co-segregation analysis. Clinical features of patients with pathogenic or likely pathogenic variants were present. The mutation frequency of ALS-related genes was then analyzed in Chinese population. In this cohort, 17 known mutations (9 SOD1, 5 FUS, 2 TARDBP and one SETX) were identified in 14 FALS and 6 early-onset SALS. Moreover, 7 novel variants (SOD1 c.112G>C, OPTN c.811C>T, ERBB4 c.965T>A, DCTN1 c.1915C>T, NEFH c.2602G>A, NEK1 c.3622G>A, and TAF15 c.1535G>A) were identified. In southeastern Chinese FALS, the mutation frequency of SOD1, FUS, and TARDBP was 52.9%, 8.8%, 8.8% respectively. In early-onset SALS, FUS mutations were the most common (22.6%). In Chinese ALS cases, p.H47R is most frequent SOD1 mutations, while p.R521 is most common FUS mutation and p.M337V is most common TARDBP mutation. Our results revealed that mutations in SOD1, FUS and TARDBP are the most common cause of Chinese FALS, while FUS mutations are the most common cause of early-onset SALS. The genetic spectrum is different between Chinese ALS and Caucasian ALS.