Journal of Neurology

, Volume 261, Issue 5, pp 970–982

Whole-exome sequencing in patients with inherited neuropathies: outcome and challenges

Authors

  • Maria Schabhüttl
    • Department of OrthopaedicsMedical University Vienna
  • Thomas Wieland
    • Institute of Human GeneticsHelmholtz Zentrum München-German Research Center for Environmental Health
  • Jan Senderek
    • Department of Neurology, Friedrich-Baur InstituteLudwig-Maximilians University Munich
  • Jonathan Baets
    • VIB Department of Molecular Genetics, Neurogenetics GroupUniversity of Antwerp
    • Laboratory of Neurogenetics, Institute Born-BungeUniversity of Antwerp
    • Division of NeurologyUniversity Hospital Antwerp (UZA)
  • Vincent Timmerman
    • Laboratory of Neurogenetics, Institute Born-BungeUniversity of Antwerp
    • VIB-Department of Molecular Genetics, Peripheral Neuropathy GroupUniversity of Antwerp-CDE
  • Peter De Jonghe
    • VIB Department of Molecular Genetics, Neurogenetics GroupUniversity of Antwerp
    • Laboratory of Neurogenetics, Institute Born-BungeUniversity of Antwerp
    • Division of NeurologyUniversity Hospital Antwerp (UZA)
  • Mary M. Reilly
    • MRC Centre for Neuromuscular DiseasesUCL Institute of Neurology
  • Karl Stieglbauer
    • Neurologist in Private Practice
  • Eva Laich
    • Department of NeurologyHospital Steyr
  • Reinhard Windhager
    • Department of OrthopaedicsMedical University Vienna
  • Wolfgang Erwa
    • Clinical Institute of Medical and Chemical Laboratory DiagnosticsMedical University of Graz
  • Slave Trajanoski
    • Center of Medical ResearchMedical University of Graz
  • Tim M. Strom
    • Institute of Human GeneticsHelmholtz Zentrum München-German Research Center for Environmental Health
    • Institute for Human GeneticsTechnical University Munich
    • Department of OrthopaedicsMedical University Vienna
Original Communication

DOI: 10.1007/s00415-014-7289-8

Cite this article as:
Schabhüttl, M., Wieland, T., Senderek, J. et al. J Neurol (2014) 261: 970. doi:10.1007/s00415-014-7289-8

Abstract

Inherited peripheral neuropathies (IPN) are one of the most frequent inherited causes of neurological disability characterized by considerable phenotypic and genetic heterogeneity. Based on clinical and electrophysiological properties, they can be subdivided into three main groups: HMSN, dHMN, and HSN. At present, more than 50 IPN genes have been identified. Still, many patients and families with IPN have not yet received a molecular genetic diagnosis because clinical genetic testing usually only covers a subset of IPN genes. Moreover, a considerable proportion of IPN genes has to be identified. Here we present results of WES in 27 IPN patients excluded for mutations in many known IPN genes. Eight of the patients received a definite diagnosis. While six of these patients carried bona fide pathogenic mutations in known IPN genes, two patients had mutations in genes known to be involved in other types of neuromuscular disorders. A further group of eight patients carried sequence variations in IPN genes that could not unequivocally be classified as pathogenic. In addition, combining data of WES and linkage analysis identified SH3BP4, ITPR3, and KLHL13 as novel IPN candidate genes. Moreover, there was evidence that particular mutations in PEX12, a gene known to cause Zellweger syndrome, could also lead to an IPN phenotype. We show that WES is a useful tool for diagnosing IPN and we suggest an expanded phenotypic spectrum of some genes involved in other neuromuscular and neurodegenerative disorders. Nevertheless, interpretation of variants in known and potential novel disease genes has remained challenging.

Keywords

IPNCMTdHMNHMSNWES

Supplementary material

415_2014_7289_MOESM1_ESM.pdf (979 kb)
Supplementary material 1 (PDF 979 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2014