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

Abstract

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 (WES), wholegenome 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 2 structural variants and the opportunity to perform genome-wide dense homozygosity mapping. We propose an algorithm for incorporating WGS into the CMT diagnostic pathway.

Neuronal substrates alter the migratory responses of nonmyelinating Schwann cells to controlled brain‐derived neurotrophic factor gradients

“…Mobile impairment occurs in millions of aging and mature adults, worldwide, as a result of neuromuscular and neurodegenerative disease (Cowling & Thielemans, ; Pipis, Rossor, Laura, & Reilly, ) as well as chronic and traumatic injury to the brain and/or spinal cord (Alizadeh, Dyck, & Karimi‐Abdolrezaee, ; New & Biering‐Sorensen, ). Traditional therapies have sought to restore mobility through direct action on neuronal cells (Silva, Sousa, Reis, & Salgado, ; Venkatesh, Ghosh, Mullick, Manivasagam, & Sen, ), but have reported modest recovery with considerable disparity in mobility outcomes (Filipp et al, ; Gupta, Jaiswal, Norman, & Depaul, ).…”

Long term AAV2/9-mediated silencing of PMP22 prevents CMT1A disease in rats and validates skin biomarkers as treatment outcome measure

“…The large majority of patients suffering from hereditary diseases of peripheral nerves, namely Charcot-Marie-Tooth diseases (CMT), have defects in the myelin sheath formation, function or maintenance [10]. The most common of these myelin-related CMT diseases is CMT1A (prevalence 5-10/10000) [47]. This disease, resulting from the duplication of the PMP22 gene, is characterized by a large heterogeneity of symptoms, the most serious being feet and hands deformation and walking problems [44].…”

Association of small-fiber polyneuropathy with three previously unassociated rare missense SCN9A variants

“…45,47 In addition, mitochondrial mutations, which are not captured, can be salient for small fiber and other polyneuropathies, including those associated with multiple lipomas. [48][49][50][51][52] Whole genome sequencing will eventually replace gene panels and whole exome sequencing as prices continue to drop and evidence of its value increases. 53 The current greatest limitation may be the lack of detailed phenotyping of the kind performed here.…”