Charcot-Marie-Tooth disease and the related disorders hereditary motor neuropathy and hereditary sensory neuropathy, collectively termed CMT, are the commonest group of inherited neuromuscular diseases, and they exhibit wide phenotypic and genetic heterogeneity. CMT is usually characterized by distal muscle atrophy, often with foot deformity, weakness and sensory loss. In the past decade, next-generation sequencing (NGS) technologies have revolutionized genomic medicine and, as these technologies are being applied to clinical practice, they are changing our diagnostic approach to CMT. In this Review, we discuss the application of NGS technologies, including disease-specific gene panels, whole-exome sequencing, whole-genome sequencing (WGS), mitochondrial sequencing and high-throughput transcriptome sequencing, to the diagnosis of CMT. We discuss the growing challenge of variant interpretation and consider how the clinical phenotype can be combined with genetic, bioinformatic and functional evidence to assess the pathogenicity of genetic variants in patients with CMT. WGS has several advantages over the other techniques that we discuss, which include unparalleled coverage of coding, non-coding and intergenic areas of both nuclear and mitochondrial genomes, the ability to identify structural variants and the opportunity to perform genome-wide dense homozygosity mapping. We propose an algorithm for incorporating WGS into the CMT diagnostic pathway.

中文翻译：

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Charcot-Marie-Tooth 病的下一代测序：机遇和挑战。

Charcot-Marie-Tooth 病及相关疾病遗传性运动神经病和遗传性感觉神经病统称为 CMT，是最常见的一组遗传性神经肌肉疾病，它们表现出广泛的表型和遗传异质性。CMT通常以远端肌肉萎缩为特征，常伴有足部畸形、无力和感觉丧失。在过去十年中，下一代测序 (NGS) 技术彻底改变了基因组医学，并且随着这些技术应用于临床实践，它们正在改变我们对 CMT 的诊断方法。在这篇综述中，我们讨论了 NGS 技术在 CMT 诊断中的应用，包括疾病特异性基因组、全外显子组测序、全基因组测序 (WGS)、线粒体测序和高通量转录组测序。我们讨论了变异解释日益严峻的挑战，并考虑如何将临床表型与遗传、生物信息学和功能证据相结合，以评估 CMT 患者遗传变异的致病性。与我们讨论的其他技术相比，WGS 有几个优势，其中包括无与伦比的核和线粒体基因组的编码、非编码和基因间区域的覆盖范围、识别结构变异的能力以及执行全基因组密集纯合性作图的机会。我们提出了一种将 WGS 纳入 CMT 诊断途径的算法。与我们讨论的其他技术相比，WGS 具有几个优势，其中包括无与伦比的核和线粒体基因组的编码、非编码和基因间区域的覆盖范围、识别结构变异的能力以及执行全基因组密集纯合性作图的机会。我们提出了一种将 WGS 纳入 CMT 诊断途径的算法。与我们讨论的其他技术相比，WGS 具有几个优势，其中包括无与伦比的核和线粒体基因组的编码、非编码和基因间区域的覆盖范围、识别结构变异的能力以及执行全基因组密集纯合性作图的机会。我们提出了一种将 WGS 纳入 CMT 诊断途径的算法。