並列タイトル等Genetic Profile and Onset Features of 1,005 Patients with Charcot-Marie-Tooth disease in Japan
タイトル（掲載誌）Journal of Neurology, Neurosurgery & Psychiatry
学位博士(医学)
Doctor of Philosophy in Medical Science
一般注記博士論文本文, 最終試験結果の要旨, 論文審査の要旨, 博士論文要旨
Objective: To identify the genetic characteristics in a large-scale of patients with Charcot-Marie-Tooth disease (CMT) patients.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 analyzed 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 1 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.This article has been accepted for publication in Journal of Neurology, Neurosurgery & Psychiatry, 2019 following peer review, and the Version of Record can be accessed online at http://dx.doi.org/10.1136/jnnp-2018-318839.
DOIinfo:doi/10.1136/jnnp-2018-318839
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