The Use of Next-Generation Sequencing in Movement Disorders

Abstract

New advances in genomic technology are being introduced at a greater speed and are revolutionizing the field of genetics for both complex and Mendelian diseases. For instance, during the past few years, genome-wide association studies (GWAS) have identified a large number of significant associations between genomic loci and movement disorders such as Parkinson’s disease and progressive supranuclear palsy. GWAS are carried out through the use of high-throughput SNP genotyping arrays, which are also used to perform linkage analyses in families previously considered statistically underpowered for genetic analyses. In inherited movement disorders, using this latter technology, it has repeatedly been shown that mutations in a single gene can lead to different phenotypes, while the same clinical entity can be caused by mutations in different genes. This is being highlighted with the use of next-generation sequencing technologies and leads to the search for genes or genetic modifiers that contribute to the phenotypic expression of movement disorders. Establishing an accurate genome–epigenome–phenotype relationship is becoming a major challenge in the post-genomic research that should be facilitated through the implementation of both functional and cellular analyses. In this review, we summarize the latest genetic discoveries made by the use of NGS technologies and purpose future directions and challenges to truly understand the pathophysiology of MDs.

Mutations in gamma adducin are associated with inherited cerebral palsy

“…We systematically filtered sequence variants by focusing on homozygous variants within the linkage region and filtering out known SNPs present in public databases and in control exomes 26. Within the linked regions of chromosome 10, on-target coverage was 99.24%.…”

Genetic Mutation Analysis of Parkinson’s Disease Patients Using Multigene Next-Generation Sequencing Panels

“…However, whether a second variant in another disease-causing gene might have an additive effect has not been demonstrated [11,12]. The putative synergy of variants in different genes needs to be elucidated, and additional experimental data need to be tested.…”

The ACMSD gene, involved in tryptophan metabolism, is mutated in a family with cortical myoclonus, epilepsy, and parkinsonism

“…In this context, whole exome sequencing (WES) is dramatically accelerating the field of biomedical research, particularly in Mendelian diseases, and is becoming a fruitful strategy for gene identification. Through the use of WES, novel genes have recently been identified in several neurological disease, including ET [10], and in families previously deemed statistically underpowered for positional cloning [11]. In this study we aimed to identify the genetic causes underlying FCMTE in a large Spanish family through the application of WES.…”