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

• 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: 631/1647/514/2254; 692/420/248; 692/699/375/374; 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; Medicine; Medicine & Public Health; Neurology; Neuromuscular diseases; Nucleotide sequencing; Review Article
• ISSN: 1759-4758; 1759-4766
• DOI: 10.1038/s41582-019-0254-5

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. Charcot–Marie–Tooth disease (CMT) encompasses a group of inherited neuropathies that exhibit phenotypic and genetic heterogeneity. The authors discuss the application of next-generation sequencing (NGS) to the diagnosis of CMT and present a method for incorporating NGS into CMT clinical practice. Key points In Charcot–Marie–Tooth disease (CMT), next-generation sequencing (NGS) technologies are applied in the form of specific CMT-associated gene panels, whole-exome sequencing, whole-genome sequencing (WGS), mitochondrial sequencing and high-throughput transcriptome sequencing. Interpretation of NGS-derived variants is challenging owing to the high volume of returned variants and the phenotypic and genetic heterogeneity of CMT. Setting a maximum credible population allele frequency for pathogenic variants in dominant and recessive CMT-associated genes is crucial for efficiently filtering NGS-derived variants. A genome-first approach utilizing WGS has multiple advantages over other genetic tests for the diagnosis of C