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

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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.

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Acknowledgments

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.

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Authors and Affiliations

  1. Department of Orthopaedics, Medical University Vienna, Währingergürtel 18-20, 1090, Vienna, Austria

    Maria Schabhüttl, Reinhard Windhager & Michaela Auer-Grumbach

  2. Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764, Neuherberg, Germany

    Thomas Wieland & Tim M. Strom

  3. Department of Neurology, Friedrich-Baur Institute, Ludwig-Maximilians University Munich, 80336, Munich, Germany

    Jan Senderek

  4. VIB Department of Molecular Genetics, Neurogenetics Group, University of Antwerp, 2610, Antwerp, Belgium

    Jonathan Baets & Peter De Jonghe

  5. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2610, Antwerp, Belgium

    Jonathan Baets, Vincent Timmerman & Peter De Jonghe

  6. Division of Neurology, University Hospital Antwerp (UZA), 2650, Antwerp, Belgium

    Jonathan Baets & Peter De Jonghe

  7. VIB-Department of Molecular Genetics, Peripheral Neuropathy Group, University of Antwerp-CDE, 2610, Antwerp, Belgium

    Vincent Timmerman

  8. MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, WC1N 3BG, UK

    Mary M. Reilly

  9. Neurologist in Private Practice, 4020, Linz, Austria

    Karl Stieglbauer

  10. Department of Neurology, Hospital Steyr, 4400, Steyr, Austria

    Eva Laich

  11. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036, Graz, Austria

    Wolfgang Erwa

  12. Center of Medical Research, Medical University of Graz, 8010, Graz, Austria

    Slave Trajanoski

  13. Institute for Human Genetics, Technical University Munich, 81675, Munich, Germany

    Tim M. Strom

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  1. Maria Schabhüttl
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  2. Thomas Wieland
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Correspondence to Michaela Auer-Grumbach.

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Schabhüttl, M., Wieland, T., Senderek, J. et al. Whole-exome sequencing in patients with inherited neuropathies: outcome and challenges. J Neurol 261, 970–982 (2014). https://doi.org/10.1007/s00415-014-7289-8

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