Genetic profile and onset features of 1005 patients with Charcot-Marie-Tooth disease in Japan.

Abstract

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 <i>PMP22</i> 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 <i>GJB1</i> (n=66, 21.9%), <i>MFN2</i> (n=66, 21.9%) and <i>MPZ</i> (n=51, 16.9%). In demyelinating CMT, variants were detected in 45.7% cases, and the most common reasons were <i>GJB1</i> (40.3%), <i>MPZ</i> (27.1%), <i>PMP22</i> point mutations (6.2%) and <i>NEFL</i> (4.7%). Axonal CMT yielded a relatively lower detection rate (22.9%), and the leading causes, occupying 72.4%, were <i>MFN2</i> (37.2%), <i>MPZ</i> (9.0%), <i>HSPB1</i> (8.3%), <i>GJB1</i> (7.7%), <i>GDAP1</i> (5.1%) and <i>MME</i> (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.