The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy

Genet Med. 2016 May;18(5):443-51. doi: 10.1038/gim.2015.124. Epub 2015 Sep 17.


Purpose: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders of the peripheral nervous system. Copy-number variants (CNVs) contribute significantly to CMT, as duplication of PMP22 underlies the majority of CMT1 cases. We hypothesized that CNVs and/or single-nucleotide variants (SNVs) might exist in patients with CMT with an unknown molecular genetic etiology.

Methods: Two hundred patients with CMT, negative for both SNV mutations in several CMT genes and for CNVs involving PMP22, were screened for CNVs by high-resolution oligonucleotide array comparative genomic hybridization. Whole-exome sequencing was conducted on individuals with rare, potentially pathogenic CNVs.

Results: Putatively causative CNVs were identified in five subjects (~2.5%); four of the five map to known neuropathy genes. Breakpoint sequencing revealed Alu-Alu-mediated junctions as a predominant contributor. Exome sequencing identified MFN2 SNVs in two of the individuals.

Conclusion: Neuropathy-associated CNV outside of the PMP22 locus is rare in CMT. Nevertheless, there is potential clinical utility in testing for CNVs and exome sequencing in CMT cases negative for the CMT1A duplication. These findings suggest that complex phenotypes including neuropathy can potentially be caused by a combination of SNVs and CNVs affecting more than one disease-associated locus and contributing to a mutational burden.Genet Med 18 5, 443-451.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Age of Onset
  • Charcot-Marie-Tooth Disease / genetics*
  • Charcot-Marie-Tooth Disease / physiopathology
  • Child, Preschool
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations / genetics
  • Exome / genetics
  • Female
  • GTP Phosphohydrolases / genetics*
  • Genetic Predisposition to Disease
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Male
  • Mitochondrial Proteins / genetics*
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Myelin P0 Protein / genetics
  • Myelin Proteins / genetics*
  • Neural Conduction / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Polyneuropathies / genetics*
  • Polyneuropathies / physiopathology


  • MPZ protein, human
  • Mitochondrial Proteins
  • Myelin P0 Protein
  • Myelin Proteins
  • PMP22 protein, human
  • GTP Phosphohydrolases
  • MFN2 protein, human