Frequent genes in rare diseases: panel-based next generation sequencing to disclose causal mutations in hereditary neuropathies.

Dohrn MF1,2, Glöckle N1, Mulahasanovic L1, Heller C1, Mohr J1, Bauer C1, Riesch E1, Becker A1, Battke F1, Hörtnagel K1, Hornemann T3, Suriyanarayanan S3, Blankenburg M4,5, Schulz JB2,6, Claeys KG7, Gess B2, Katona I8, Ferbert A9, Vittore D10, Grimm A10, Wolking S10, Schöls L10, Lerche H10, Korenke GC11, Fischer D12, Schrank B13, Kotzaeridou U14, Kurlemann G15, Dräger B16, Schirmacher A16, Young P16, Schlotter-Weigel B17, Biskup S1.
  1. CeGaT GmbH and Praxis für Humangenetik Tübingen, Tuebingen, Germany.
  2. Department of Neurology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
  3. Institute for Clinical Chemistry, University Hospital Zürich, Zurich, Switzerland.
  4. Department of Pediatric Neurology Klinikum Stuttgart, Olgahospital, Stuttgart, Germany.
  5. Faculty of Health, Witten/Herdecke University, Witten, Germany.
  6. JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, Germany.
  7. Department of Neurology, University Hospitals Leuven and University of Leuven (KU Leuven), Leuven, Belgium.
  8. Institute of Neuropathology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
  9. Department of Neurology, Klinikum Kassel, Kassel, Germany.
  10. Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tuebingen, Germany.
  11. Department of Neuropediatrics, Children’s Hospital Oldenburg, Oldenburg, Germany.
  12. Department of Neurology, University of Basel Hospital, Basel, Switzerland.
  13. Department of Neurology, Deutsche Klinik für Diagnostik, Wiesbaden, Germany.
  14. Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children’s Hospital, Heidelberg, Germany.
  15. Department of Neuropediatrics, University Hospital Münster, Muenster, Germany.
  16. Department of Sleep Medicine and Neuromuscular Disorders, University Hospital Münster, Muenster, Germany.
  17. Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University of Munich, Munich, Germany.


Hereditary neuropathies comprise a wide variety of chronic diseases associated to more than 80 genes identified to date. We herein examined 612 index patients with either a Charcot-Marie-Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a customized multigene panel based on the next generation sequencing technique. In 121 cases (19.8%), we identified at least one putative pathogenic mutation. Of these, 54.4% showed an autosomal dominant, 33.9% an autosomal recessive, and 11.6% an X-linked inheritance. The most frequently affected genes were PMP22 (16.4%), GJB1 (10.7%), MPZ, and SH3TC2 (both 9.9%), and MFN2 (8.3%). We further detected likely or known pathogenic variants in HINT1, HSPB1, NEFL, PRX, IGHMBP2, NDRG1, TTR, EGR2, FIG4, GDAP1, LMNA, LRSAM1, POLG, TRPV4, AARS, BIC2, DHTKD1, FGD4, HK1, INF2, KIF5A, PDK3, REEP1, SBF1, SBF2, SCN9A, and SPTLC2 with a declining frequency. Thirty-four novel variants were considered likely pathogenic not having previously been described in association with any disorder in the literature. In one patient, two homozygous mutations in HK1 were detected in the multigene panel, but not by whole exome sequencing. A novel missense mutation in KIF5A was considered pathogenic because of the highly compatible phenotype. In one patient, the plasma sphingolipid profile could functionally prove the pathogenicity of a mutation in SPTLC2. One pathogenic mutation in MPZ was identified after being previously missed by Sanger sequencing. We conclude that panel based next generation sequencing is a useful, time- and cost-effective approach to assist clinicians in identifying the correct diagnosis and enable causative treatment considerations.