Structural variations causing inherited peripheral neuropathies: A paradigm for understanding genomic organization, chromatin interactions, and gene dysregulation

Mol Genet Genomic Med. 2018 May;6(3):422-433. doi: 10.1002/mgg3.390. Epub 2018 Mar 23.


Inherited peripheral neuropathies (IPNs) are a clinically and genetically heterogeneous group of diseases affecting the motor and sensory peripheral nerves. IPNs have benefited from gene discovery and genetic diagnosis using next-generation sequencing with over 80 causative genes available for testing. Despite this success, up to 50% of cases remain genetically unsolved. In the absence of protein coding mutations, noncoding DNA or structural variation (SV) mutations are a possible explanation. The most common IPN, Charcot-Marie-Tooth neuropathy type 1A (CMT1A), is caused by a 1.5 Mb duplication causing trisomy of the dosage sensitive gene PMP22. Using genome sequencing, we recently identified two large genomic rearrangements causing IPN subtypes X-linked CMT (CMTX3) and distal hereditary motor neuropathy (DHMN1), thereby expanding the spectrum of SV mutations causing IPN. Understanding how newly discovered SVs can cause IPN may serve as a useful paradigm to examine the role of topologically associated domains (TADs), chromatin interactions, and gene dysregulation in disease. This review will describe the growing role of SV in the pathogenesis of IPN and the importance of considering this type of mutation in Mendelian diseases where protein coding mutations cannot be identified.

Keywords: gene dysregulation; inherited peripheral neuropathies; structural variation; topological associated domains.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Charcot-Marie-Tooth Disease / genetics
  • Chromatin
  • Chromosome Mapping
  • Gene Dosage / genetics
  • Genome
  • Genomic Structural Variation / genetics
  • Genomics
  • Hereditary Sensory and Motor Neuropathy / genetics
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Peripheral Nervous System Diseases / genetics*
  • Peripheral Nervous System Diseases / physiopathology*
  • Point Mutation


  • Chromatin

Supplementary concepts

  • Charcot-Marie-Tooth disease, X-linked recessive, 3
  • Inherited Peripheral Neuropathy