Original Communication

Journal of Neurology

, Volume 261, Issue 5, pp 970-982

First online:

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

  • Maria SchabhüttlAffiliated withDepartment of Orthopaedics, Medical University Vienna
  • , Thomas WielandAffiliated withInstitute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health
  • , Jan SenderekAffiliated withDepartment of Neurology, Friedrich-Baur Institute, Ludwig-Maximilians University Munich
  • , Jonathan BaetsAffiliated withVIB Department of Molecular Genetics, Neurogenetics Group, University of AntwerpLaboratory of Neurogenetics, Institute Born-Bunge, University of AntwerpDivision of Neurology, University Hospital Antwerp (UZA)
  • , Vincent TimmermanAffiliated withLaboratory of Neurogenetics, Institute Born-Bunge, University of AntwerpVIB-Department of Molecular Genetics, Peripheral Neuropathy Group, University of Antwerp-CDE
  • , Peter De JongheAffiliated withVIB Department of Molecular Genetics, Neurogenetics Group, University of AntwerpLaboratory of Neurogenetics, Institute Born-Bunge, University of AntwerpDivision of Neurology, University Hospital Antwerp (UZA)
  • , Mary M. ReillyAffiliated withMRC Centre for Neuromuscular Diseases, UCL Institute of Neurology
  • , Karl StieglbauerAffiliated withNeurologist in Private Practice
  • , Eva LaichAffiliated withDepartment of Neurology, Hospital Steyr
    • , Reinhard WindhagerAffiliated withDepartment of Orthopaedics, Medical University Vienna
    • , Wolfgang ErwaAffiliated withClinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz
    • , Slave TrajanoskiAffiliated withCenter of Medical Research, Medical University of Graz
    • , Tim M. StromAffiliated withInstitute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental HealthInstitute for Human Genetics, Technical University Munich
    • , Michaela Auer-GrumbachAffiliated withDepartment of Orthopaedics, Medical University Vienna Email author 

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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.

Keywords

IPN CMT dHMN HMSN WES