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

Xie, Yuanyang; Lin, Zhi Xiu; Liu, Lei; Li, Xiaobo; Huang, Shunxiang; Zhao, Huadong; Wang, Binghao; Zeng, Sen; Cao, Wanqian; Li, Lü; Zhu, Xiying; Huang, S.W.; Yang, Hao; Hu, Zhengmao; Wang, Junling; Guo, Jifeng; Shen, Lu; Jiang, Hong; Züchner, Stephan; Tang, Beisha; Zhang, Ruxu

doi:10.1111/ene.15024

Cited by 24 publications

(29 citation statements)

References 37 publications

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“…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).…”

Section: Discussionsupporting

confidence: 68%

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

Xie

Lin

et al. 2022

Front. Neurol.

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Background and AimsCharcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited peripheral neuropathies. The wide phenotypic variability may not be completely explained by a single mutation.Aims and MethodsTo explore the existence of concomitant variants in CMT, we enrolled 189 patients and performed molecular diagnosis by application of next-generation sequencing combined with multiplex ligation-dependent probe amplification. We conducted a retrospective analysis of patients harboring coinherited variants in different genes.ResultsFour families were confirmed to possess variants in two genes, accounting for 2.1% (4/189) of the total in our cohort. One CMT1 patient with PMP22 duplication and MPZ variant (c.286A>C, p.K96Q) exhibited moderate neuropathy with infantile onset, while her father possessing MPZ variant was mildly affected with adolescence onset. A CMT2 patient with heterozygous variants in MFN2 (c.613_622delGTCACCACAG, p.V205Sfs*26) and GDAP1 (c.713G>T, p.W238L) exhibited childhood onset mild phenotype, while his mother with MFN2 variant developed bilateral pes cavus only. A CMT2 patient with heterozygous variants in MFN2 (c.839G>A, p.R280H) and GDAP1 (c.3G>T, p.M1?) presented infantile onset and rapid progression, while her father with MFN2 variant presented with absence of deep tendon reflexes. One sporadic CMT2 patient with early onset was confirmed harboring de novo MFN2 variant (c.1835C>T, p.S612F) and heterozygous GDAP1 variant (c.767A>G, p.H256R).ConclusionOur results suggest that the possibility of concomitant variants was not uncommon and should be considered when significant intrafamilial clinical heterogeneity is observed.

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Section: Discussionsupporting

confidence: 68%

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

Xie

Lin

et al. 2022

Front. Neurol.

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“…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 ].…”

Section: Discussionmentioning

confidence: 87%

“…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].…”

Section: Prevalence Of Cmt1e In Cmt Patientsmentioning

confidence: 84%

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

Jung

Kwon

Nam

et al. 2022

Genes

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Duplication and deletion of the peripheral myelin protein 22 (PMP22) gene cause Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), respectively, while point mutations or small insertions and deletions (indels) usually cause CMT type 1E (CMT1E) or HNPP. This study was performed to identify PMP22 mutations and to analyze the genotype–phenotype correlation in Korean CMT families. By the application of whole-exome sequencing (WES) and targeted gene panel sequencing (TS), we identified 14 pathogenic or likely pathogenic PMP22 mutations in 21 families out of 850 CMT families who were negative for 17p12 (PMP22) duplication. Most mutations were located in the well-conserved transmembrane domains. Of these, eight mutations were not reported in other populations. High frequencies of de novo mutations were observed, and the mutation sites of c.68C>G and c.215C>T were suggested as the mutational hotspots. Affected individuals showed an early onset-severe phenotype and late onset-mild phenotype, and more than 40% of the CMT1E patients showed hearing loss. Physical and electrophysiological symptoms of the CMT1E patients were more severely damaged than those of CMT1A while similar to CMT1B caused by MPZ mutations. Our results will be useful for the reference data of Korean CMT1E and the molecular diagnosis of CMT1 with or without hearing loss.

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“…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.…”

Section: Discussionmentioning

confidence: 73%

“…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 .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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.

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

Cited by 24 publications

References 37 publications

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

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

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

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

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