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Research paper
Genetic profile and onset features of 1005 patients with Charcot-Marie-Tooth disease in Japan
  1. Akiko Yoshimura1,
  2. Jun-Hui Yuan1,
  3. Akihiro Hashiguchi1,
  4. Masahiro Ando1,
  5. Yujiro Higuchi1,
  6. Tomonori Nakamura1,
  7. Yuji Okamoto1,
  8. Masanori Nakagawa2,
  9. Hiroshi Takashima1
  1. 1 Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
  2. 2 North Medical Center, Kyoto Prefectural University of Medicine, Kyoto, Japan
  1. Correspondence to Dr Hiroshi Takashima, Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan; thiroshi{at}


Objective To identify the genetic characteristics in a large-scale of patients with Charcot-Marie-Tooth disease (CMT).

Methods From May 2012 to August 2016, we collected 1005 cases with suspected CMT throughout Japan, whereas PMP22 duplication/deletion were excluded in advance for demyelinating CMT cases. We performed next-generation sequencing targeting CMT-related gene panels using Illumina MiSeq or Ion Proton, then analysed the gene-specific onset age of the identified cases and geographical differences in terms of their genetic spectrum.

Results From 40 genes, we identified pathogenic or likely pathogenic variants in 301 cases (30.0%). The most common causative genes were GJB1 (n=66, 21.9%), MFN2 (n=66, 21.9%) and MPZ (n=51, 16.9%). In demyelinating CMT, variants were detected in 45.7% cases, and the most common reasons were GJB1 (40.3%), MPZ (27.1%), PMP22 point mutations (6.2%) and NEFL (4.7%). Axonal CMT yielded a relatively lower detection rate (22.9%), and the leading causes, occupying 72.4%, were MFN2 (37.2%), MPZ (9.0%), HSPB1 (8.3%), GJB1 (7.7%), GDAP1 (5.1%) and MME (5.1%). First decade of life was found as the most common disease onset period, and early-onset CMT cases were most likely to receive a molecular diagnosis. Geographical distribution analysis indicated distinctive genetic spectrums in different regions of Japan.

Conclusions Our results updated the genetic profile within a large-scale of Japanese CMT cases. Subsequent analyses regarding onset age and geographical distribution advanced our understanding of CMT, which would be beneficial for clinicians.

  • charcot-marie-tooth disease
  • molecular epidemiology
  • next generation sequencing
  • gene panel

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  • Contributors AY, J-HY, and MA contributed to laboratory data acquisition, analysis or interpretation of data. AY, J-HY and HT contributed to drafting or revising of the manuscript. AH, YH and YO contributed to clinical data analysis or interpretation. TN contributed to nerve conduction study analysis. MN and HT contributed to study conception and supervision.

  • Funding This study is supported by grants from the research on the Nervous and Mental Disorders and Research Committee for Charcot–Marie–Tooth Disease, Neuropathy, and Applying Health and Technology of Ministry of Health, Welfare and Labour, Japan (201331010B, 201610002B). This research is also supported by the Research program for conquering intractable disease from Japan Agency for Medical Research and development (AMED) (201442014A, 201442071A and 17929553) and Japan Society for the Promotion of Science (26461275, 18H02742).

  • Competing interests None declared.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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