中国隐性遗传性痉挛性截瘫患者的临床特征及基因谱

Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia.

作者信息

Wei Qiao, Dong Hai-Lin, Pan Li-Ying, Chen Cong-Xin, Yan Yang-Tian, Wang Rou-Min, Li Hong-Fu, Liu Zhi-Jun, Tao Qing-Qing, Wu Zhi-Ying

机构信息

1Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009 China.

2Longyan First Hospital, Fujian Medical University, Longyan, China.

出版信息

Transl Neurodegener. 2019 Jun 26;8:19. doi: 10.1186/s40035-019-0157-9. eCollection 2019.

DOI:10.1186/s40035-019-0157-9

PMID:31289639

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6593507/

Abstract

BACKGROUND

Although many causative genes of hereditary spastic paraplegia (HSP) have been uncovered in recent years, there are still approximately 50% of HSP patients without genetically diagnosis, especially in autosomal recessive (AR) HSP patients. Rare studies have been performed to determine the genetic spectrum and clinical profiles of recessive HSP patients in the Chinese population.

METHODS

In this study, we investigated 24 Chinese index AR/sporadic patients by targeted next-generation sequencing (NGS), Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Further functional studies were performed to identify pathogenicity of those uncertain significance variants.

RESULTS

We identified 11 mutations in HSP related genes including 7 novel mutations, including two (p.V1979_L1980delinsX, p.F2343 fs) in , two (p.T55 M, p.S308 T) in , one (p.S242 N) in one (p.D597fs) in , and one (p.Q486X) in in 8 index patients and their family members. Mutations in and genes were firstly reported in the Chinese population. Furthermore, the clinical phenotypes of the patients carrying mutations were described in detail. The mutation (p.S242 N) in decreased enzyme activity of P5CS and mutations (p.T55 M, p.S308 T) in induced lysosomal dysfunction.

CONCLUSION

Our results expanded the genetic spectrum and clinical profiles of AR-HSP patients and further demonstrated the efficiency and reliability of targeted NGS diagnosing suspected HSP patients.

摘要

背景

尽管近年来已发现许多遗传性痉挛性截瘫（HSP）的致病基因，但仍有大约50%的HSP患者未得到基因诊断，尤其是常染色体隐性（AR）HSP患者。针对中国人群中隐性HSP患者的遗传谱和临床特征的研究较少。

方法

在本研究中，我们通过靶向二代测序（NGS）、桑格测序和多重连接依赖探针扩增（MLPA）对24例中国AR/散发患者进行了研究。进一步进行功能研究以确定那些意义不明确变异的致病性。

结果

我们在HSP相关基因中鉴定出11个突变，包括7个新突变，其中8例先证者及其家庭成员中有2个（p.V1979_L1980delinsX，p.F2343 fs）在，2个（p.T55 M，p.S308 T）在，1个（p.S242 N）在，1个（p.D597fs）在，1个（p.Q486X）在。和基因中的突变首次在中国人群中报道。此外，详细描述了携带突变患者的临床表型。中的突变（p.S242 N）降低了P5CS的酶活性，中的突变（p.T55 M，p.S308 T）诱导了溶酶体功能障碍。