Identification of Genetic Causes of Inherited Peripheral Neuropathies by Targeted Gene Panel Sequencing

  • Nam, Soo Hyun (Department of Biological Sciences, Kongju National University) ;
  • Hong, Young Bin (Stem Cell & Regenerative Medicine Center and Neuroscience Center, Samsung Medical Center) ;
  • Hyun, Young Se (Department of Biological Sciences, Kongju National University) ;
  • Nam, Da Eun (Department of Biological Sciences, Kongju National University) ;
  • Kwak, Geon (Department of Neurology, Sungkyunkwan University School of Medicine) ;
  • Hwang, Sun Hee (Department of Neurology, Sungkyunkwan University School of Medicine) ;
  • Choi, Byung-Ok (Stem Cell & Regenerative Medicine Center and Neuroscience Center, Samsung Medical Center) ;
  • Chung, Ki Wha (Department of Biological Sciences, Kongju National University)
  • Received : 2015.10.20
  • Accepted : 2016.02.22
  • Published : 2016.05.31


Inherited peripheral neuropathies (IPN), which are a group of clinically and genetically heterogeneous peripheral nerve disorders including Charcot-Marie-Tooth disease (CMT), exhibit progressive degeneration of muscles in the extremities and loss of sensory function. Over 70 genes have been reported as genetic causatives and the number is still growing. We prepared a targeted gene panel for IPN diagnosis based on next generation sequencing (NGS). The gene panel was designed to detect mutations in 73 genes reported to be genetic causes of IPN or related peripheral neuropathies, and to detect duplication of the chromosome 17p12 region, the major genetic cause of CMT1A. We applied the gene panel to 115 samples from 63 non-CMT1A families, and isolated 15 pathogenic or likelypathogenic mutations in eight genes from 25 patients (17 families). Of them, eight mutations were unreported variants. Of particular interest, this study revealed several very rare mutations in the SPTLC2, DCTN1, and MARS genes. In addition, the effectiveness of the detection of CMT1A was confirmed by comparing five 17p12-nonduplicated controls and 15 CMT1A cases. In conclusion, we developed a gene panel for one step genetic diagnosis of IPN. It seems that its time- and cost-effectiveness are superior to previous tiered-genetic diagnosis algorithms, and it could be applied as a genetic diagnostic system for inherited peripheral neuropathies.


charcot-Marie-Tooth disease (CMT);DCTN1;gene panel;inherited peripheral neuropathy;MARS;SPTLC2


Supported by : National Research Foundation


  1. Antoniadi, T., Buxton, C., Dennis, G., Forrester, N., Smith, D., Lunt, P., and Burton-Jones, S. (2015). Application of targeted multigene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability. BMC Med. Genet. 16, 84.
  2. Bone, L.J., Deschenes, S.M., Balice-Gordon, R.J., Fischbeck, K.H., and Scherer, S.S. (1997). Connexin32 and X-linked Charcot-Marie-Tooth disease. Neurobiol. Dis. 4, 221-230.
  3. Choi, B.O., Kim, J., Lee, K.L., Yu, J.S., Hwang, J.H., and Chung, K.W. (2007). Rapid diagnosis of CMT1A duplications and HNPP deletions by multiplex microsatellite PCR. Mol. Cells 23, 39-48.
  4. Choi, B.O., Koo, S.K., Park, M.H., Rhee, H., Yang, S.J., Choi, K.G., Jung, S.C., Kim, H.S., Hyun, Y.S., Nakhro, K., et al. (2012). Exome sequencing is an efficient tool for genetic screening of Charcot-Marie-Tooth disease. Hum. Mutat. 33, 1610-1615.
  5. Choi, B.O., Nakhro, K., Park, H.J., Hyun, Y.S., Lee, J.H., Kanwal, S., Jung, S.C., and Chung, K.W. (2015). A cohort study of MFN2 mutations and phenotypic spectrums in Charcot-Marie-Tooth disease 2A patients. Clin. Genet. 87, 594-598.
  6. Chung, K.W., Kim, S.B., Park, K.D., Choi, K.G., Lee, J.H., Eun, H.W., Suh, J.S., Hwang, J.H., Kim, W.K., Seo, B.C., et al. (2006). Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. Brain 129, 2103-2118.
  7. Drew, A.P., Zhu, D., Kidambi, A., Ly, C., Tey, S., Brewer, M.H., Ahmad-Annuar, A., Nicholson, G.A., and Kennerson, M.L. (2015). Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing. Mol. Genet. Genomic Med. 3, 143-154.
  8. Ernst, D., Murphy, S.M., Sathiyanadan, K., Wei, Y., Othman, A., Laura, M., Liu, Y.T., Penno, A., Blake, J., Donaghy, M., et al. (2015). Novel HSAN1 mutation in serine palmitoyltransferase resides at a putative phosphorylation site that is involved in regulating substrate specificity. Neuromolecular Med. 17, 47-57.
  9. Gonzaga-Jauregui, C., Harel, T., Gambin, T., Kousi, M., Griffin, L.B., Francescatto, L., Ozes, B., Karaca, E., Jhangiani, S.N., Bainbridge, M.N., et al. (2015). Exome sequence analysis suggests that genetic burden contributes to phenotypic variability and complex neuropathy. Cell Rep. 12, 1169-1183
  10. Gonzalez, M., McLaughlin, H., Houlden, H. Guo, M., Yo-Tsen, L., Hadjivassilious, M., Speziani, F., Yang, X.L., Antonellis, A., Reilly, M.M., et al. (2013). Exome sequencing identifies a significant variant in methionyl-tRNA synthetase (MARS) in a family with late-onset CMT2. J. Neurol. Neurosurg. Psychiatry 84, 1247-1249.
  11. Hyun, Y.S., Park, H.J., Heo, S.H., Yoon, B.R., Nam, S.H., Kim, S.B., Park, C.I., Choi, B.O., and Chung, K.W. (2014). Rare variants in methionyl- and tyrosyl-tRNA synthetase genes in late-onset autosomal dominant Charcot-Marie-Tooth neuropathy. Clin. Genet. 86, 592-594.
  12. Lupski, J.R., and Garcia, C.A. (2000). Charcot-Marie-Tooth peripheral neuropathies and related disorders. In the metabolic and molecular bases of inherited disease. Vol. 4. 8th, C.R. Scriver, ed. (New York, Mc Graw Hill), pp. 5759-5788.
  13. Montenegro, G., Powell, E., Huang, J. Speziani, F., Edwards, Y.J., Beecham, G., Hulme, W., Siskind, C., Vance, J., Shy, M., et al. (2011). Exome sequencing allows for rapid gene identification in a Charcot-Marie-Tooth family. Ann. Neurol. 69, 464-470.
  14. Murphy, S.M., Laura, M., and Reilly, M.M. (2013). DNA testing in hereditary neuropathies. Handb. Clin. Neurol. 115, 213-232.
  15. Nakhro, K., Park, J.M., Choi, B.O., and Chung, K.W. (2013). Missense mutations of mitofusin 2 in axonal Charcot-Marie-Tooth neuropathy: polymorphic or incomplete penetration?. Anim. Cells Syst. 17, 228-236.
  16. Nelis, E., Van Broeckhoven, C., De Jonghe, P., Lofgren, A., Vandenberghe, A., Latour, P., Le Guern, E., Brice, A., Mostacciuolo, M.L., Schiavon, F., et al. (1996). Estimation of the mutation frequencies in Charcot-Marie-Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies: a European collaborative study. Eur. J. Hum. Genet. 4, 25-33.
  17. Oterino, A., Monton, F.I., Cabrera, V.M., Pinto, F., Gonzalez, A., and Lavilla, N.R. (1996). Arginine-164-tryptophan substitution in connexin32 associated with X linked dominant Charcot-Marie-Tooth disease. J. Med. Genet. 33, 413-415.
  18. Patzko, A., and Shy, M.E. (2011). Update on Charcot-Marie-Tooth disease. Curr. Neurol. Neurosci. Rep. 11, 78-88.
  19. Puls, I., Jonnakuty, C., LaMonte, B.H., Holzbaur, E.L., Tokito, M., Mann, E., Floeter, M.K., Bidus, K., Drayna, D., Oh, S.J., et al. (2003). Mutant dynactin in motor neuron disease. Nat. Genet. 33, 455-456.
  20. Rossor, A.M., Polke, J.M., Houlden, H., and Reilly, M.M. (2013). Clinical implications of genetic advances in Charcot-Marie-Tooth disease. Nat. Rev. Neurol. 9, 562-571.
  21. Rotthier, A., Auer-Grumbach, M., Janssens, K., Baets, J., Penno, A., Almeida-Souza, L., Van Hoof, K., Jacobs, A., De Vriendt, E., Schlotter-Weigel, B., et al. (2010). Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. Am. J. Hum. Genet. 87, 513-522.
  22. Rudnik-Schoneborn, S., Tolle, D., Senderek, J., Eggermann, K., Elbracht, M., Kornak, U., von der Hagen, M., Kirschner, J., Leube, B., Muller-Felber, W., et al. (2016). Diagnostic algorithms in Charcot-Marie-Tooth neuropathies: experiences from a German genetic laboratory on the basis of 1206 index patients. Clin. Genet. 89, 34-43.
  23. Saporta, A.S., Sottile, S.L., Miller, L.J., Feely, S.M., Siskind, C.E., and Shy, M.E. (2011). Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann. Neurol. 69, 22-33.
  24. Schiavon, F., Fracasso, C., and Mostacciuolo, M.L. (1996). Novel missense mutation of the connexin32 (GJB1) gene in X-linked dominant Charcot-Marie-Tooth neuropathy. Hum. Mutat. 8, 83-84.<83::AID-HUMU14>3.0.CO;2-N
  25. Sinkiewicz-Darol, E., Lacerda, A.F., Kostera-Pruszczyk, A., Potulska-Chromik, A., Sokolowska, B., Kabzinska, D., Brunetti, C.R., Hausmanowa-Petrusewicz, I., and Kochanski, A. (2015). The LITAF/SIMPLE I92V sequence variant results in an earlier age of onset of CMT1A/HNPP diseases. Neurogenetics 16, 27-32.
  26. Ylikallio, E., Johari, M., Konovalova, S., Moilanen, J.S., Kiuru-Enari, S., Auranen, M., Pajunen, L., and Tyynismaa, H. (2014). Targeted next-generation sequencing reveals further genetic heterogeneity in axonal Charcot-Marie-Tooth neuropathy and a mutation in HSPB1. Eur. J. Hum. Genet. 22, 522-527.

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