The rapid evolution of molecular genetic diagnostics in neuromuscular diseases.
The rapid evolution of molecular genetic diagnostics in neuromuscular diseases.
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DOI：
10.1097/wco.0000000000000478
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发表时间：
2017-10
影响因子：
4.8
通讯作者：
A. Volk;C. Kubisch
中科院分区：
文献类型：
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作者：
A. Volk;C. Kubisch
综述目的大规模平行测序（MPS）的发展彻底改变了单基因疾病的分子遗传学诊断。本文综述了神经肌肉疾病（NMD）临床诊断中使用的不同MPS为基础的方法，并强调了其优点和局限性。最近的发现基于MPS的方法，如基因组测序，（全）外显子组测序，（全）基因组测序和RNA测序已被用于确定NMD的遗传原因。尽管基因组测序已经发展成为异质性疾病的标准测试，但仍然存在争议，主要是因为财务问题和变异解释的未解决问题，单个患者的基因组测序（以及较小程度上的外显子组测序）是否已经被视为常规诊断。然而，已经表明，在全外显子组/全基因组MPS方法中，包括父母和额外的家庭成员通常导致诊断产率的大幅增加。此外，基于MPS的RNA测序刚刚进入研究和诊断领域。下一代测序越来越多地使得能够以有效且负担得起的方式检测高度异质性疾病（如NMD）的遗传原因。基因组测序和基于家族的外显子组测序已被证明是有效且具有成本效益的诊断工具。尽管基因组测序的临床验证和解释仍然具有挑战性，但诊断性RNA测序代表了一种有前途的工具，可以绕过使用基因组DNA进行诊断的一些障碍。
PURPOSE OF REVIEW The development of massively parallel sequencing (MPS) has revolutionized molecular genetic diagnostics in monogenic disorders. The present review gives a brief overview of different MPS-based approaches used in clinical diagnostics of neuromuscular disorders (NMDs) and highlights their advantages and limitations. RECENT FINDINGS MPS-based approaches like gene panel sequencing, (whole) exome sequencing, (whole) genome sequencing, and RNA sequencing have been used to identify the genetic cause in NMDs. Although gene panel sequencing has evolved as a standard test for heterogeneous diseases, it is still debated, mainly because of financial issues and unsolved problems of variant interpretation, whether genome sequencing (and to a lesser extent also exome sequencing) of single patients can already be regarded as routine diagnostics. However, it has been shown that the inclusion of parents and additional family members often leads to a substantial increase in the diagnostic yield in exome-wide/genome-wide MPS approaches. In addition, MPS-based RNA sequencing just enters the research and diagnostic scene. SUMMARY Next-generation sequencing increasingly enables the detection of the genetic cause in highly heterogeneous diseases like NMDs in an efficient and affordable way. Gene panel sequencing and family-based exome sequencing have been proven as potent and cost-efficient diagnostic tools. Although clinical validation and interpretation of genome sequencing is still challenging, diagnostic RNA sequencing represents a promising tool to bypass some hurdles of diagnostics using genomic DNA.