Comprehensive Genetic Analyses of Inherited Peripheral Neuropathies in Japan: Making Early Diagnosis Possible

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.

INF2 mutations in patients with a broad phenotypic spectrum of Charcot‐Marie‐Tooth disease and focal segmental glomerulosclerosis

“…In this study on Korean families, the frequencies of patients with INF2 mutations were calculated to be 0.26% of the total patients and 0.40% of the patients negative for PMP22 duplication. Except for 1.61% of a small number of patients excluding CMT1A in a Lebanese study, 17 this prevalence was similar to or slightly higher than 0.33% of Japanese patients, 28 and 0.20% of Danish patients. 29 In particular, no CMT patient with INF2 mutation was found in the studies of the South Chinese, 30 Turkish, 1 and Brazilian populations.…”

Clinical phenotypic diversity ofNOTCH2NLC-related disease in the largest case series of inherited peripheral neuropathy in Japan

“…Moreover, comprehensive genetic analyses of IPN/CMT have been performed in several countries worldwide; however, a large proportion of patients remain genetically undiagnosed. For example, 66.7% of patients with IPN/CMT who have been screened for duplication/deletion of PMP22 remained undiagnosed in our previous report 5…”

“…Among patients who were negative at initial screening, 758 were further evaluated via whole-exome sequencing using the Illumina Hiseq platform (Illumina, San Diego, California, USA) or Ion Proton sequencing (ThermoFisher Scientific, Waltham, Massachusetts, USA). Subsequently, the remaining undiagnosed 1475 patients without autosomal dominant family history were screened for RFC1 repeat expansions using the previously described methodology 4 5 Figure 1A. shows the study flowchart.…”

“…Notably, IPN phenotypes, apart from CMT, include distal hereditary motor neuropathy (dHMN), hereditary sensory neuropathy, hereditary sensory autonomic neuropathy and hereditary neuropathy with liability to pressure palsy (HNPP). In the studies in the relevant literature, >140 genes have been associated with IPN/CMT to date 4 5. Moreover, comprehensive genetic analyses of IPN/CMT have been performed in several countries worldwide; however, a large proportion of patients remain genetically undiagnosed.…”

Genetic research of inherited peripheral neuropathies

“…We have received genetic testing requests from medical institutions nationwide and reported comprehensive genetic diagnosis results for >2500 cases of CMT/inherited peripheral neuropathies (IPN) (Figure 2). 1,5,6 In contrast, non‐coding repeat expansions within the RFC1 and NOTCH2NLC genes have lately been linked to multisystem neurodegenerative diseases, namely neuronal intranuclear inclusion disease 7,8 and cerebellar ataxia, neuropathy, vestibular areflexia syndrome, and are also beginning to attract attention as a cause of IPNs. Moreover, recently, we have reported the frequency of the repeat expansions of the RFC1 and NOTCH2NLC genes in patients with IPN, highlighting the necessity of genetic screening, particularly for genetically undiagnosed patients with IPN 6,9 .…”