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, 362 (13), 1181-91

Whole-genome Sequencing in a Patient With Charcot-Marie-Tooth Neuropathy


Whole-genome Sequencing in a Patient With Charcot-Marie-Tooth Neuropathy

James R Lupski et al. N Engl J Med.


Background: Whole-genome sequencing may revolutionize medical diagnostics through rapid identification of alleles that cause disease. However, even in cases with simple patterns of inheritance and unambiguous diagnoses, the relationship between disease phenotypes and their corresponding genetic changes can be complicated. Comprehensive diagnostic assays must therefore identify all possible DNA changes in each haplotype and determine which are responsible for the underlying disorder. The high number of rare, heterogeneous mutations present in all humans and the paucity of known functional variants in more than 90% of annotated genes make this challenge particularly difficult. Thus, the identification of the molecular basis of a genetic disease by means of whole-genome sequencing has remained elusive. We therefore aimed to assess the usefulness of human whole-genome sequencing for genetic diagnosis in a patient with Charcot-Marie-Tooth disease.

Methods: We identified a family with a recessive form of Charcot-Marie-Tooth disease for which the genetic basis had not been identified. We sequenced the whole genome of the proband, identified all potential functional variants in genes likely to be related to the disease, and genotyped these variants in the affected family members.

Results: We identified and validated compound, heterozygous, causative alleles in SH3TC2 (the SH3 domain and tetratricopeptide repeats 2 gene), involving two mutations, in the proband and in family members affected by Charcot-Marie-Tooth disease. Separate subclinical phenotypes segregated independently with each of the two mutations; heterozygous mutations confer susceptibility to neuropathy, including the carpal tunnel syndrome.

Conclusions: As shown in this study of a family with Charcot-Marie-Tooth disease, whole-genome sequencing can identify clinically relevant variants and provide diagnostic information to inform the care of patients.

Conflict of interest statement

Disclosure forms provided by the authors are available with the full text of this article at


Figure 1
Figure 1. Charcot–Marie–Tooth (CMT) Disease Phenotypes, Their Genetic Forms of Inheritance, and Their Mapped Genes and Loci
CMT is divided in two major phenotypic types — glial myelinopathy (CMT type 1) and neuronal axonopathy (CMT type 2) — according to electrophysiological, clinical, and nerve-biopsy evaluations. Each type can be inherited in a dominant, recessive, or X-linked fashion. There are also autosomal dominant intermediate forms of CMT that can have features of both axonal and demyelinating neuropathies. Several genes have been associated with CMT disease to date, and other loci have been associated and mapped but their genes not yet identified. MPZ, GDAP1, and GJB1 are known to be associated with CMT type 1, but select mutations in these genes can also cause CMT type 2; NEFL is known to be associated with CMT type 2, but select mutations convey a CMT type 1 phenotype. Dominant intermediate forms of CMT have been reported to be associated with MPZ mutations. Specific recessive alleles related to CMT have also been reported for EGR2 and PMP22. Of the 31 genes in 39 known CMT loci, only 15 genes are currently available for clinical testing. Current evidence-based clinical guidelines for distal symmetric polyneuropathy recommend genetic testing consisting of screening for common mutations, including the CMT1A duplication copynumber variant and point mutations of the X-linked GJB1 gene.
Figure 2
Figure 2. Pedigree of the Study Family and Segregation and Conservation of SH3TC2 Mutations
Panel A shows the pedigree of the proband (arrow) and his family and their SH3TC2 genotypes: plus signs indicate the wild-type allele; Y169H indicates the A→G mutation on chromosome 5 at nucleotide 148,402,474 and corresponding to the amino acid missense mutation Tyr169His, and R954X indicates the G→A mutation in the genomic DNA in exon 11 of SH3TC2 on chromosome 5 at nucleotide 148,386,628, leading to the amino acid nonsense mutation Arg954ter. (Genomic coordinates for the mutations in the proband are based on the human genome reference sequence, build 36.2.) Squares indicate male subjects, and circles female subjects slashes indicate deceased subjects. Subjects in generations I and II had three phenotypes. The paternal grandfather (Subject I-1) was studied 20 years ago, at 80 years of age, and had normal results, with the sole exception of a median-nerve mononeuropathy at the wrist, thought to be caused by his occupation as a carpenter. The paternal grandmother (Subject I-2, 77 years of age at the time of evaluation) and the father (Subject II-2) had evidence of a patchy axonal polyneuropathy, with definite median-nerve mononeuropathy at the wrist. The maternal grandmother (evaluated at 90 years of age; data not shown) and the mother (Subject II-1) had normal findings except for very mild median-nerve mononeuropathy at the wrist. Two of the proband’s sisters (Subjects III-3 and III-7) had this same phenotype. Two members of this generation had completely normal findings (Subjects III-1 and III-5). The other four siblings had diffuse, disproportionate conduction slowing in the distal median nerve, without evidence of conduction block, findings that are suggestive of a superimposed median mononeuropathy at the wrist. Subjects III-2, III-4, III-6, and III-8 had Charcot–Marie–Tooth type 1 (CMT1) disease. Panel B shows the results of TaqI restriction digestion of the SH3TC2 exon 11 polymerase-chain-reaction product on which the G→A mutation, corresponding to the R954X allele, occurs. This mutation was present in the proband’s mother and six of the eight siblings, as well as in the maternal grandmother (not shown). The mutation destroys the restriction site for TaqI; the wild type yields two small bands and the heterozygous mutant yields three bands, the upper of which is the uncut DNA. Panel C shows sequence alignment of the SH3TC2 protein among various species. The downward arrowhead indicates the location of the highly conserved Tyr169 amino acid that, in persons with the novel missense mutation Y169H, is changed to His. Sequences were obtained from the National Center for Biotechnology Information.

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