Next-generation sequencing in Charcot-Marie-Tooth disease: opportunities and challenges

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 dista...

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Bibliographic Details
Published in:Nature reviews. Neurology 2019-11, Vol.15 (11), p.644-656
Main Authors: Pipis, Menelaos, Rossor, Alexander M, Laura, Matilde, Reilly, Mary M
Format: Article
Language:English
Subjects:
Charcot-Marie-Tooth disease
Charcot-Marie-Tooth Disease - diagnosis
Charcot-Marie-Tooth Disease - genetics
Diagnosis
Disease
DNA sequencing
Forecasts and trends
Genetic aspects
Genetic Testing - methods
Genetic Testing - trends
Genetic Variation - genetics
Genomes
Health aspects
High-Throughput Nucleotide Sequencing - methods
High-Throughput Nucleotide Sequencing - trends
Humans
Neuromuscular diseases
Nucleotide sequencing
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Summary: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.
ISSN:1759-4758
1759-4766
DOI:10.1038/s41582-019-0254-5