The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review
Abstract 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...
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doaj-b3d43f28d09044c598ac8af8ada40da32020-11-25T00:57:33ZengBMCTranslational Neurodegeneration2047-91582017-10-016111110.1186/s40035-017-0098-0The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a reviewShirley Yin-Yu Pang0Kay-Cheong Teo1Jacob Shujui Hsu2Richard Shek-Kwan Chang3Miaoxin Li4Pak-Chung Sham5Shu-Leong Ho6Division of Neurology, Department of Medicine, Queen Mary Hospital, University of Hong KongDivision of Neurology, Department of Medicine, Queen Mary Hospital, University of Hong KongCentre for Genomic Sciences, University of Hong KongDivision of Neurology, Department of Medicine, Queen Mary Hospital, University of Hong KongCentre for Genomic Sciences, University of Hong KongCentre for Genomic Sciences, University of Hong KongDivision of Neurology, Department of Medicine, Queen Mary Hospital, University of Hong KongAbstract 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.http://link.springer.com/article/10.1186/s40035-017-0098-0Next generation sequencingNeurodegenerative diseasesGeneticsPleiotropy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shirley Yin-Yu Pang Kay-Cheong Teo Jacob Shujui Hsu Richard Shek-Kwan Chang Miaoxin Li Pak-Chung Sham Shu-Leong Ho |
spellingShingle |
Shirley Yin-Yu Pang Kay-Cheong Teo Jacob Shujui Hsu Richard Shek-Kwan Chang Miaoxin Li Pak-Chung Sham Shu-Leong Ho The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review Translational Neurodegeneration Next generation sequencing Neurodegenerative diseases Genetics Pleiotropy |
author_facet |
Shirley Yin-Yu Pang Kay-Cheong Teo Jacob Shujui Hsu Richard Shek-Kwan Chang Miaoxin Li Pak-Chung Sham Shu-Leong Ho |
author_sort |
Shirley Yin-Yu Pang |
title |
The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review |
title_short |
The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review |
title_full |
The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review |
title_fullStr |
The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review |
title_full_unstemmed |
The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review |
title_sort |
role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review |
publisher |
BMC |
series |
Translational Neurodegeneration |
issn |
2047-9158 |
publishDate |
2017-10-01 |
description |
Abstract 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. |
topic |
Next generation sequencing Neurodegenerative diseases Genetics Pleiotropy |
url |
http://link.springer.com/article/10.1186/s40035-017-0098-0 |
work_keys_str_mv |
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