title: Clinical and mutational spectrum of Japanese patients with Charcot-Marie-Tooth disease caused by GDAP1 variants.
abstract: BACKGROUND
  Mutations in GDAP1 are responsible for heterogeneous clinical and electrophysiological phenotypes of Charcot-Marie-Tooth disease (CMT), with autosomal dominant or recessive inheritance pattern. The aim of this study is to identify the clinical and mutational spectrum of CMT patients with GDAP1 variants in Japan.
  
  
  METHODS
  From April 2007 to October 2014, using three state-of-art technologies, we conducted gene panel sequencing in a cohort of 1,030 patients with inherited peripheral neuropathies (IPNs), and 398 mutation-negative cases were further analyzed with whole-exome sequencing.
  
  
  RESULTS
  We identified GDAP1 variants from 10 patients clinically diagnosed with CMT. The most frequent recessive variant in our cohort (5/10), c.740C>T (p.A247V), was verified to be associated with a founder event. We also detected three novel likely pathogenic variants: c.928C>T (p.R310W) and c.546delA (p.E183Kfs*23) in Case 2 and c.376G>A (p.E126K) in Case 8. Nerve conduction study or sural nerve biopsy of all 10 patients indicated axonal type peripheral neuropathy.
  
  
  CONCLUSIONS
  We identified GDAP1 variants in approximately 1% of our cohort with IPNs, and established a founder mutation in half of these patients. Our study originally described the mutational spectrum and clinical features of GDAP1-related CMT patients in Japan.
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University, Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Yoshimura
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University, Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: J-H
authors.initials: JH
authors.lastname: Yuan
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University, Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Hashiguchi
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University, Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hiramatsu
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University, Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ando
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University, Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Higuchi
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University, Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University, Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: Department of Neurology, Teikyo University, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Matsumura
authors.affiliation: Department of Neurology, Kansai Electric Power Hospital, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Hamano
authors.affiliation: Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Sawaura
authors.affiliation: Department of Clinical Neuroscience, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Shimatani
authors.affiliation: Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kumada
authors.affiliation: Department of Pediatric Neurology, Shizuoka Children's Hospital, Shizuoka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Okumura
authors.affiliation: Department of Neurology, Tominaga Hospital, Osaka, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Miyahara
authors.affiliation: Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Department of Neurology, Konan Hospital, Hyogo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kitamura
authors.affiliation: Department of Pediatric Neurology, Miyagi Children's Hospital, Miyagi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Haginoya
authors.affiliation: Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Mitsui
authors.affiliation: Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ishiura
authors.affiliation: Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Department of Neurology and Geriatrics, Kagoshima University, Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Takashima
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009185:Myelin Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D015203:Reproducibility of Results; D000073359:Exome Sequencing; D055815:Young Adult
chemical_list: C118663:GDAP protein; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; C073687:PMP22 protein, human
keywords: 
  GDAP1
  ; Charcot-Marie-Tooth disease; founder mutation; gene-panel sequencing; inherited peripheral neuropathy; whole-exome sequencing