Genotype and phenotype distribution of 435 patients with Charcot–Marie–Tooth disease from central south China

Abstract

Background and purpose The purpose was to provide an overview of genotype and phenotype distribution in a cohort of patients with Charcot–Marie–Tooth disease (CMT) and related disorders from central south China. Methods In all, 435 patients were enrolled and detailed clinical data were collected. Multiplex ligation‐dependent probe amplification for PMP22 duplication/deletion and CMT multi‐gene panel sequencing were performed. Whole exome sequencing was further applied in the remaining patients who failed to achieve molecular diagnosis. Results Among the 435 patients, 216 had CMT1, 14 had hereditary neuropathy with pressure palsies (HNPP), 178 had CMT2, 24 had distal hereditary motor neuropathy (dHMN) and three had hereditary sensory and autonomic neuropathy (HSAN). The overall molecular diagnosis rate was 70%: 75.7% in CMT1, 100% in HNPP, 64.6% in CMT2, 41.7% in dHMN and 33.3% in HSAN. The most common four genotypes accounted for 68.9% of molecular diagnosed patients. Relatively frequent causes were missense changes in PMP22 (4.6%) and SH3TC2 (2.3%) in CMT1; and GDAP1 (5.1%), IGHMBP2 (4.5%) and MORC2 (3.9%) in CMT2. Twenty of 160 detected pathogenic variants and the associated phenotypes have not been previously reported. Broad phenotype spectra were observed in six genes, amongst which the pathogenic variants in BAG3 and SPTLC1 were detected in two sporadic patients presenting with the CMT2 phenotype. Conclusions Our results provided a unique genotypic and phenotypic landscape of patients with CMT and related disorders from central south China, including a relatively high proportion of CMT2 and lower occurrence of PMP22 duplication. The broad phenotype spectra in certain genes have advanced our understanding of CMT.

One PMP22/MPZ and Three MFN2/GDAP1 Concomitant Variants Occurred in a Cohort of 189 Chinese Charcot-Marie-Tooth Families

“…Heterozygous MFN2 variants were the primary mutations that could establish the diagnosis. The variant c.3G>T in GDAP1 changed the initiation codon, which has been reported in previous literature (21)(22)(23). The GDAP1 c.713G>T missense change occurred at the same position (p.W238) as another pathogenic variant observed (21,24).…”

Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients

“…The prevalence of CMT1E showed a difference according to the countries studied, but there appears to be no difference by continent. The prevalence of CMT1E in Korean CMT patients was similar to that of Chinese patients [ 38 , 39 ], but it was significantly higher than that of Japanese CMT patients without CMT1A [ 44 , 45 ]. When the prevalence was compared with European populations, it was clearly higher than those of Hungarians [ 42 ] and Spaniards [ 43 ].…”

“…The frequencies of CMT1E with PMP22 mutations was calculated as 1.69% in the total examined CMT probands (n = 1243) and 2.47% in the CMT probands (n = 850) excluding CMT1A (Table 2). When the prevalence of total CMT patients was compared with other countries, it was roughly similar with China at 0.94-2.38% [38,39], Italy at 1.36% [40], and Brazil at 2.10% [41] while it was higher than other examined populations, such as in Hungary at 0.37% [42] and Spain at 0.46% [43]. The prevalence of CMT1E in Japanese CMT patients excluding CMT1A ranged from 0.81-1.29%, which is a considerably low frequency compared with that of Korean CMT patients [44,45].…”

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

“…These top three genes are comparable to the findings of several other countries; however, GJB1, rather than MFN2, is the most common in their studies. This may be related to the predominance of axonal subtypes of IPNs in the current analysis, similar to Norway, but distinct from other countries, wherein demyelinating subtypes had predominance (1.1-3.18:1) [9,[14][15][16][17][18][19][20][21][22][23]27,29]. The reason for this phenomenon may be associated with the PMP22 CNV exclusion or as a regional characteristic.…”

“…To date, genetic spectrum studies of IPNs have been completed and updated in several countries [ 9 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. We have reviewed these reports and compared them with our findings in Table 2 .…”