Whole-exome sequencing is a valuable diagnostic tool for inherited peripheral neuropathies: Outcomes from a cohort of 50 families

Clin Genet. 2018 Feb;93(2):301-309. doi: 10.1111/cge.13101. Epub 2017 Dec 12.


The inherited peripheral neuropathies (IPNs) are characterized by marked clinical and genetic heterogeneity and include relatively frequent presentations such as Charcot-Marie-Tooth disease and hereditary motor neuropathy, as well as more rare conditions where peripheral neuropathy is associated with additional features. There are over 250 genes known to cause IPN-related disorders but it is estimated that in approximately 50% of affected individuals a molecular diagnosis is not achieved. In this study, we examine the diagnostic utility of whole-exome sequencing (WES) in a cohort of 50 families with 1 or more affected individuals with a molecularly undiagnosed IPN with or without additional features. Pathogenic or likely pathogenic variants in genes known to cause IPN were identified in 24% (12/50) of the families. A further 22% (11/50) of families carried sequence variants in IPN genes in which the significance remains unclear. An additional 12% (6/50) of families had variants in novel IPN candidate genes, 3 of which have been published thus far as novel discoveries (KIF1A, TBCK, and MCM3AP). This study highlights the use of WES in the molecular diagnostic approach of highly heterogeneous disorders, such as IPNs, places it in context of other published neuropathy cohorts, while further highlighting associated benefits for discovery.

Keywords: diagnostic utility; hereditary motor and sensory neuropathy; inherited peripheral neuropathy; next-generation sequencing; whole-exome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / genetics
  • Charcot-Marie-Tooth Disease / diagnosis
  • Charcot-Marie-Tooth Disease / genetics*
  • Charcot-Marie-Tooth Disease / pathology
  • Exome / genetics
  • Exome Sequencing*
  • Female
  • High-Throughput Nucleotide Sequencing*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Kinesins / genetics
  • Male
  • Mutation
  • Peripheral Nervous System Diseases / diagnosis
  • Peripheral Nervous System Diseases / genetics*
  • Peripheral Nervous System Diseases / pathology
  • Protein Serine-Threonine Kinases / genetics


  • Intracellular Signaling Peptides and Proteins
  • KIF1A protein, human
  • Acetyltransferases
  • MCM3AP protein, human
  • Protein Serine-Threonine Kinases
  • TBCK protein, human
  • Kinesins

Supplementary concepts

  • Inherited Peripheral Neuropathy

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