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

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