Abstract
Various genomic variants were linked to inherited peripheral neuropathies (IPNs), including large duplication/deletion and repeat expansion, making genetic diagnosis challenging. This large case series aimed to identify the genetic characteristics of Japanese patients with IPNs. We collected data on 2695 IPN cases throughout Japan, in which PMP22 copy number variation (CNV) was pre-excluded. Genetic analyses were performed using DNA microarrays, next-generation sequencing-based gene panel sequencing, whole-exome sequencing, CNV analysis, and RFC1 repeat expansion analysis. The overall diagnostic rate and the genetic spectrum of patients were summarized. We identified 909 cases with suspected IPNs, pathogenic or likely pathogenic variants. The most common causative genes were MFN2, GJB1, MPZ, and MME. MFN2 was the most common cause for early-onset patients, whereas GJB1 and MPZ were the leading causes of middle-onset and late-onset patients, respectively. Meanwhile, GJB1 and MFN2 were leading causes for demyelinating and axonal subtypes, respectively. Additionally, we identified CNVs in MPZ and GJB1 genes and RFC1 repeat expansions. Comprehensive genetic analyses explicitly demonstrated the genetic basis of our IPN case series. A further understanding of the clinical characteristics of IPN and genetic spectrum would assist in developing efficient genetic testing strategies and facilitate early diagnosis.