Journal of Neurology

, Volume 261, Issue 5, pp 970–982 | Cite as

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

  • Maria Schabhüttl
  • Thomas Wieland
  • Jan Senderek
  • Jonathan Baets
  • Vincent Timmerman
  • Peter De Jonghe
  • Mary M. Reilly
  • Karl Stieglbauer
  • Eva Laich
  • Reinhard Windhager
  • Wolfgang Erwa
  • Slave Trajanoski
  • Tim M. Strom
  • Michaela Auer-Grumbach
Original Communication


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.





We are grateful for the participation of the patients and families in this study. This work was supported by the Austrian Science Fund (FWF, P23223-B19), the University of Antwerp (UA), the Association Belge contre les Maladies Neuromusculaires (ABMM), the Medical Foundation Queen Elisabeth (GSKE), the agency for Innovation by Science and Technology (IWT), the Fund for Scientific Research Flanders (FWO-Flanders) and the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 2012-305121 “Integrated European–omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEUROMICS)”.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Supplementary material

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Supplementary material 1 (PDF 979 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Maria Schabhüttl
    • 1
  • Thomas Wieland
    • 2
  • Jan Senderek
    • 3
  • Jonathan Baets
    • 4
    • 5
    • 6
  • Vincent Timmerman
    • 5
    • 7
  • Peter De Jonghe
    • 4
    • 5
    • 6
  • Mary M. Reilly
    • 8
  • Karl Stieglbauer
    • 9
  • Eva Laich
    • 10
  • Reinhard Windhager
    • 1
  • Wolfgang Erwa
    • 11
  • Slave Trajanoski
    • 12
  • Tim M. Strom
    • 2
    • 13
  • Michaela Auer-Grumbach
    • 1
  1. 1.Department of OrthopaedicsMedical University ViennaViennaAustria
  2. 2.Institute of Human GeneticsHelmholtz Zentrum München-German Research Center for Environmental HealthNeuherbergGermany
  3. 3.Department of Neurology, Friedrich-Baur InstituteLudwig-Maximilians University MunichMunichGermany
  4. 4.VIB Department of Molecular Genetics, Neurogenetics GroupUniversity of AntwerpAntwerpBelgium
  5. 5.Laboratory of Neurogenetics, Institute Born-BungeUniversity of AntwerpAntwerpBelgium
  6. 6.Division of NeurologyUniversity Hospital Antwerp (UZA)AntwerpBelgium
  7. 7.VIB-Department of Molecular Genetics, Peripheral Neuropathy GroupUniversity of Antwerp-CDEAntwerpBelgium
  8. 8.MRC Centre for Neuromuscular DiseasesUCL Institute of NeurologyLondonUK
  9. 9.Neurologist in Private PracticeLinzAustria
  10. 10.Department of NeurologyHospital SteyrSteyrAustria
  11. 11.Clinical Institute of Medical and Chemical Laboratory DiagnosticsMedical University of GrazGrazAustria
  12. 12.Center of Medical ResearchMedical University of GrazGrazAustria
  13. 13.Institute for Human GeneticsTechnical University MunichMunichGermany

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