The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review.
The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review.
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DOI：
10.1186/s40035-017-0098-0
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发表时间：
2017
影响因子：
12.6
通讯作者：
Ho SL
中科院分区：
文献类型：
--
作者：
Pang SY;Teo KC;Hsu JS;Chang RS;Li M;Sham PC;Ho SL
在具有重叠症状的异质条件下，基于表型的神经退行性疾病的临床诊断很困难。它没有考虑到疾病的病因或高度可变的临床病程，即使在诊断患有相同疾病的患者中也是如此。下一代测序 (NGS) 的出现允许采用全系统、无偏见的方法来同时识别基因组中的所有基因变异。随着大量新基因的发现，孟德尔疾病（如脊髓小脑性共济失调（SCA）、遗传性痉挛性截瘫（HSP）和腓骨肌萎缩症（CMT））的遗传分类而非基于表型的分类已被广泛接受。人们还清楚地知道，基因变异在帕金森病 (PD) 和肌萎缩侧索硬化症 (ALS) 等常见且主要散发的神经退行性疾病中发挥着作用。多效性的观察已经出现，同一基因的突变会产生不同的表型，这进一步增加了表型-基因型相关性的复杂性。多效性的可能机制包括同一基因中不同突变的不同下游效应、修饰基因的存在和寡基因遗传。未来的方向包括开发生物信息学工具和建立更广泛的公共基因型/表型数据库，以更好地区分有害基因变异与良性多态性，通过体外和体内研究将遗传发现转化为致病机制，并最终找到针对神经退行性疾病的疾病缓解疗法。
The clinical diagnosis of neurodegenerative disorders based on phenotype is difficult in heterogeneous conditions with overlapping symptoms. It does not take into account the disease etiology or the highly variable clinical course even amongst patients diagnosed with the same disorder. The advent of next generation sequencing (NGS) has allowed for a system-wide, unbiased approach to identify all gene variants in the genome simultaneously. With the plethora of new genes being identified, genetic rather than phenotype-based classification of Mendelian diseases such as spinocerebellar ataxia (SCA), hereditary spastic paraplegia (HSP) and Charcot-Marie-Tooth disease (CMT) has become widely accepted. It has also become clear that gene variants play a role in common and predominantly sporadic neurodegenerative diseases such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). The observation of pleiotropy has emerged, with mutations in the same gene giving rise to diverse phenotypes, which further increases the complexity of phenotype-genotype correlation. Possible mechanisms of pleiotropy include different downstream effects of different mutations in the same gene, presence of modifier genes, and oligogenic inheritance. Future directions include development of bioinformatics tools and establishment of more extensive public genotype/phenotype databases to better distinguish deleterious gene variants from benign polymorphisms, translation of genetic findings into pathogenic mechanisms through in-vitro and in-vivo studies, and ultimately finding disease-modifying therapies for neurodegenerative disorders.
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影响因子：
3.1
作者：
Ho, Philip Wing-Lok;Pang, Shirley Yin-Yu;Li, Miaoxin;Tse, Zero Ho-Man;Kung, Michelle Hiu-Wai;Sham, Pak-Chung;Ho, Shu-Leong
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影响因子：
14.5
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影响因子：
3.5
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通讯作者：
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影响因子：
4.5
作者：
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影响因子：
2
作者：
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通讯作者：
Kennerson, Marina L.