Purpose of Review

Since the advent of next-generation sequencing, the number of genes associated with dystonia has been growing exponentially. We provide here a comprehensive review of the latest genetic discoveries in the field of dystonia and discuss how the growing knowledge of biology underlying monogenic dystonias may influence and challenge current classification systems.

Recent Findings

Pathogenic variants in genes without previously confirmed roles in human disease have been identified in subjects affected by isolated or combined dystonia (KMT2B, VPS16, HPCA, KCTD17, DNAJC12, SLC18A2) and complex dystonia (SQSTM1, IRF2BPL, YY1, VPS41). Importantly, the classical distinction between isolated and combined dystonias has become harder to sustain since many genes have been shown to determine multiple dystonic presentations (e.g., ANO3, GNAL, ADCY5, and ATP1A3). In addition, a growing number of genes initially linked to other neurological phenotypes, such as developmental delay, epilepsy, or ataxia, are now recognized to cause prominent dystonia, occasionally in an isolated fashion (e.g., GNAO1, GNB1, SCN8A, RHOBTB2, and COQ8A). Finally, emerging analyses suggest biological convergence of genes linked to different dystonic phenotypes.

Summary

While our knowledge on the genetic basis of monogenic dystonias has tremendously grown, their clinical boundaries are becoming increasingly blurry. The current phenotype-based classification may not reflect the molecular structure of the disease, urging the need for new systems based on shared biological pathways among dystonia-linked genes.

中文翻译：

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遗传性肌张力障碍：分类更新和新的遗传发现

审查目的

自下一代测序技术问世以来，与肌张力障碍相关的基因数量呈指数增长。我们在这里提供对肌张力障碍领域最新遗传发现的全面综述，并讨论对单基因肌张力障碍的生物学基础的不断增长的知识如何影响和挑战当前的分类系统。

最近的发现

在受孤立或合并的肌张力障碍（KMT2B，VPS16，HPCA，KCTD17，DNAJC12，SLC18A2）和复杂肌张力障碍（SQSTM1，IRF2BPL，YY1，VPS41）影响的受试者中，已鉴定出在人类疾病中没有先前确认作用的基因的致病变异。重要的是，孤立的肌张力障碍和合并的肌张力障碍之间的经典区别变得越来越难以维持，因为已证明许多基因可以确定多种肌张力障碍表现形式（例如，ANO3，GNAL，ADCY5和ATP1A3）。此外，现在认识到越来越多的最初与其他神经系统表型（如发育延迟，癫痫或共济失调）相关的基因有时会以孤立的方式引起严重的肌张力障碍（例如GNAO1，GNB1，SCN8A，RHOBTB2和COQ8A）。最后，新兴的分析表明与不同的张力异常表型有关的基因的生物融合。

概要

尽管我们对单基因肌张力障碍的遗传学知识有了极大的发展，但它们的临床界限变得越来越模糊。当前基于表型的分类可能无法反映该疾病的分子结构，因此敦促需要基于肌张力障碍相关基因之间共享生物学途径的新系统。