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.
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 CMT and should be combined with virtual gene panels to achieve the optimum balance between improved diagnostic yield and burden of variant analysis.
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M.P. is funded by the NIH, the Office of Rare Diseases Research and the Inherited Neuropathy Consortium (INC; grant U54NS065712). A.M.R. is funded by a Wellcome Trust Postdoctoral Fellowship for Clinicians (grant 110043/Z/15/Z). M.M.R. is grateful to the National Institutes of Neurological Diseases and Stroke, the Office of Rare Diseases (grant U54NS065712) and the Muscular Dystrophy Association (grant MDA510281) for their support. The INC is a part of the National Center for Advancing Translational Services (NCATS) Rare Diseases Clinical Research Network (RDCRN). Work undertaken at University College London Hospitals and University College London was partly funded by the Department of Health’s National Institute for Health Research Biomedical Research Centres.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Bottlenecked populations
Populations that at some point suffered a steep decline in size and subsequently recovered from a smaller pool of individuals.
Marriage within a community or restricted population.
- Founder mutations
Mutations that occurred spontaneously in an ancestral allele at some point in the past and have been inherited by individuals in subsequent generations. In ethnically or geographically restricted populations that do not outbreed, the founder mutation will be observed at an increased frequency and might even occur only in that population.
Mating of closely blood-related individuals such as first or second cousins.
The frequency of individuals with an expressed phenotype among carriers of a genetic mutation. If some individuals with the genetic mutation never express a phenotype, the disease is described as having incomplete or reduced penetrance.
- Sanger sequencing
Also referred to as first-generation sequencing, Sanger sequencing is the standard sequencing biochemistry described by Frederick Sanger’s group in 1977 and was used to sequence the reference human genome. The technique uses fluorescently labelled DNA chain terminators in the form of dideoxynucleotide triphosphates, which are randomly incorporated into chains of sequenced DNA during the polymerase chain reaction and arrest the elongation of the DNA sequence chain. These chains of DNA are subsequently aligned according to length and the fluorescent signal is read one nucleotide at a time, thus yielding a sequence read.
- Multiple ligation-dependent probe amplification
A molecular genetic technique in which multiple pairs of oligonucleotide probes are used to hybridize to specific genomic sites. Each pair of probes is designed to hybridize to immediately adjacent sites and, once this is done, each pair of probes is ligated into a single fragment that is unique in length. Successfully ligated fragments are amplified by a polymerase chain reaction, separated according to size, detected and quantitatively analysed by comparison to reference values. Genomic sites with single nucleotide polymorphisms, point mutations and copy number variants would interfere with the ligation and/or proportional amplification of fragments and, therefore, will be highlighted during the fragment detection and analysis step.
- Read depths
The number of times a specific nucleotide or base pair has been sequenced and read in a single sequencing experiment or series of experiments.
The position of two variants in a set of alleles in relation to one another. If the variants are on the same allele, they are in ‘cis phase’ and if they are on opposite alleles they are in ‘trans phase’.
- Variant calling
The step in next-generation sequencing data analysis during which the sequenced data are reviewed or ‘queried’ for genetic variation compared with the reference genome, and variations at the nucleotide base level or over longer DNA sequences are identified and marked (or called).
A genetic principle describing the variety of phenotypic features in affected individuals with a specific gene mutation. A genetic modifier (which is different to the causal genetic mutation) can influence which phenotypic features manifest in the affected individual.
A phenomenon that occurs when the functional loss of one of two alleles of a specific gene causes a reduction in the amount of gene product, usually by 50%. Depending on the gene product and its function in the cell or tissue in which it is expressed, haploinsufficiency can lead to a disease state. If no disease ensues, the cell, tissue or organism harbouring the heterozygous allele loss is said to tolerate haploinsufficiency.
- Coding synonymous variants
Single nucleotide changes in the protein-coding DNA that do not alter the amino acid in the translated protein.
- Sequencing trace
The colour-coded peak chart, also known as the electropherogram, that is produced as a consequence of the readout of the fluorescent signal in a Sanger sequencing reaction.
- Microsatellite array
An array-based molecular genetic technique that uses specific oligonucleotide probes to genotype specific short repetitive DNA sequences (referred to as microsatellites) that are present at particular loci across the genome. The number of repeats in these microsatellites varies between individuals, so the unique combination of a set of repeat sequences can be used as a genetic tracker.
- Runs of homozygosity
Contiguous genomic regions that are homozygous across all base pairs in an individual. This phenomenon occurs when the transmitted maternal and paternal alleles are identical and would have been inherited from a common ancestor at some point in the past.
- Uniparental disomy
A phenomenon that occurs when offspring inherit two copies of a chromosome or part of a chromosome from one parent and no copies from the other parent. Uniparental disomy usually occurs as a random event during the stage of meiosis in gametogenesis.
- Microarray comparative genomic hybridization
An array-based molecular genetic technique that compares the genome of interest to the reference genome for duplications or deletions of genetic material, also known as copy number variants (CNVs). This technique can detect CNVs as small as 50 kb.
- Secondary findings
Genetic variants which may be of significance, that are identified in a patient but are unrelated to the primary diagnostic question or the reason for which the sequencing data were generated. They may be discovered additionally (if there was intentional opportunistic screening, e.g. for variants in cancer genes) or incidentally (if they were not sought).