Characteristics of Clinical and Electrophysiological Pattern in a Large Cohort of Chinese Patients With Charcot-Marie-Tooth 4C.

Xiaohui Duan,Xiaoxuan Liu,Yan Ma,Dongsheng Fan

doi:10.3389/fneur.2021.598168

Abstract

The “Src homology 3 (SH3) domain and tetratricopeptide repeats 2” (SH3TC2) gene is mutated in individuals with Charcot-Marie-Tooth disease (CMT) and considered relevant to a demyelinating or intermediate subtype of CMT disease, CMT4C. In this study, we screened a cohort of 465 unrelated Chinese CMT patients alongside 650 controls. We used Sanger, next-generation, or whole-exome sequencing to analyze SH3TC2 and other CMT-related genes and identified 12 SH3TC2 variants (eight novel) in seven families. Of the eight novel variants, seven were likely pathogenic (c.280–2 A > G, c.732–1 G > A, c.1177+6 T > C, c.3328–1 G > A, G299S, R548W, L1048P), and 1 had uncertain significance (S221P). The CMT4C frequency was calculated to be 4.24% in demyelinating or intermediate CMT patients without PMP22 duplication. Additionally, we detected variant R954* in the Chinese cohort in our study, indicating that this variant may be present among Asians, albeit with a relatively low frequency. The onset age varied among the eight patients, three of whom presented scoliosis. We summarized phenotypes in the Chinese CMT cohort and concluded that the absence of scoliosis, cranial nerve involvement, or late-onset symptoms does not necessarily preclude SH3TC2 involvement in a given case.

Highlights

Charcot-Marie-Tooth disease (CMT) 4C is one of the most common forms of autosomal recessive (AR) demyelinating neuropathies caused by a mutation in the “Src homology 3 (SH3) domain and tetratricopeptide repeats 2” (SH3TC2) gene (1)
SH3TC2 mutations were detected in 7 of these 165 index patients (4.24%); 2 of these patients were included in the 42 AR families (4.76%), and five were included in the 123 (4%) isolated patients
Ten patients from seven families were included in genetic testing, but the clinical features were only obtained from eight patients with SH3TC2 mutations (Table 1)

Summary

Introduction

Charcot-Marie-Tooth disease (CMT) 4C is one of the most common forms of autosomal recessive (AR) demyelinating neuropathies caused by a mutation in the “Src homology 3 (SH3) domain and tetratricopeptide repeats 2” (SH3TC2) gene (1). The typical clinical features of CMT4C include early-onset distal motor and sensory neuropathy, scoliosis, and cranial nerve involvement. More than 70 SH3TC2 mutations have been identified in CMT4C patients (hihg.med.miami.edu/code/http/ cmt/public_html/index.html#/). The frequency of CMT4C among AR demyelinating CMT patients without PMP22 duplication is >20% in the Czech Republic (3) and Italy (4) but is relatively low in Germany (5.2%) (5), Japan (1.76%) (6) and Korea (2.02%) (7). A previous study screened for SH3TC2 mutations in 84 Chinese probands with AR or sporadic CMT and identified only three novel heterozygous variants of undetermined significance (VUSs) (8). We describe the SH3TC2 variants in a large cohort of Chinese patients. We aimed to investigate the phenotypic diversity in clinical or electrophysiological features, and the genotype-phenotype correlations among the patients, thereby providing new insight into the phenotypic spectrum of each genetic subgroup

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Conclusion