Mutation spectrum of Charcot‐Marie‐Tooth disease among the Han Chinese in Taiwan

Abstract

Objective Charcot‐Marie‐Tooth disease (CMT) is a clinically and genetically heterogeneous group of inherited neuropathies. Mutations in more than 90 genes have been implicated in CMT; however, the mutational spectrum of CMT in Chinese population remains obscure. This study aims to provide a comprehensive overview of the frequency of mutations in Taiwanese patients with CMT and look for genotype‐phenotype correlations. Methods Mutational analyses were performed on 427 unrelated Taiwanese patients with CMT by polymorphic microsatellite markers analysis or real‐time fluorescent PCR for PMP22 duplication, Sanger sequencing for GJB1 mutations, and targeted sequencing covering 124 genes causing or relevant to inherited neuropathies. We also correlated the genotypes with the phenotypic features, such as age at disease onset and ulnar motor nerve conduction velocity. Results Pathogenic mutations were identified in 312 patients (73.1%; 312/427), including 208 patients with a PMP22 duplication, 40 patients with a GJB1 mutation, and 64 patients with a mutation in one of other 18 CMT genes. A confirmed molecular diagnosis was achieved in 84.4% (266/315) of the patients with demyelinating CMT and 41.1% (46/112) of the patients with axonal CMT. Mutations in MPZ, MFN2, or NEFL are the most frequent disease causes in patients with infantile‐onset CMT (≤2 years), while PMP22 duplications and mutations in GJB1, MFN2, or MPZ are the frequent causes among patients with childhood‐ or adolescence‐onset CMT (3–9 years). Interpretation This study provides a genotype‐phenotype landscape of CMT in Taiwan and highlights the unique spectrum of CMT genes frequencies among patients of Chinese origin.

Clinical and Genetic Diversity of PMP22 Mutations in a Large Cohort of Chinese Patients With Charcot-Marie-Tooth Disease

“…These patients showed a milder disease course than patients with an early onset. These data are consistent with a Japanese study (50%) ( 8 ) and a study from Taipei (55.2%) ( 18 ), but the values higher than some Western countries (18–26%) ( 17 , 19 ), suggesting that Mongolian populations may have a mild phenotype due to genetic modifying factors ( 20 ) and or environmental factors and may be unaware of being affected. Some patients only had pes cavus, which did not warrant a detailed examination at hospitals, and hence, the prevalence may be underestimated.…”

Genetic and clinical spectrums in Korean Charcot‐Marie‐Tooth disease patients with myelin protein zero mutations

“…The frequency of CMT patients with the MPZ mutations was determined to be 3.2% in the total independent patients and 4.7% in the patients negative for PMP22 duplication (Table 3). These frequencies were similar with those of the China (3.3% and 6.4%) (Hsu et al, 2019) and Britain (3.1% and 5.1%) (Murphy et al, 2012), but were relatively lower than those of most other examined countries.…”

“…The frequencies of CMT patients with MPZ mutations are different depending on the ethnic groups. The frequency of CMT patients with the MPZ mutations from the total Korean cases was similar with Chinese (3.3%), British (3.1%), and Russian patients (3.5%) (Hsu et al, 2019; Mersiyanova et al, 2000; Murphy et al, 2012). However, the Korean frequency was somewhat lower than those in most of the other examined countries: from 4.0% in Austrians to 6.0% in Norwegians (Fridman et al, 2015; Gess et al, 2013; Manganelli et al, 2014; Milley et al, 2018; Miltenberger‐Miltenyi et al, 2009; Østern et al, 2013; Silander et al, 1998; Sivera et al, 2013; Yoshimura et al, 2019).…”

Cohort Analysis of 67 Charcot-Marie-Tooth Italian Patients: Identification of New Mutations and Broadening of Phenotype Expression Produced by Rare Variants

“…De novo MFN2 mutations are regularly found in patients with a classical CMT2 phenotype ( Østern et al, 2013 ), and some MFN2 mutations have also been reported as de novo in several patients ( Züchner et al, 2004 ; Chung et al, 2006 ; Verhoeven et al, 2006 ; Cho et al, 2007 ). The early onset of the proband, at 7 years old, is in line with data reporting that mutations in MPZ , MFN2 , or NEFL are the most frequent disease causes of patients with infantile-onset CMT ( Hsu et al, 2019 ).…”