The importance of multiple gene analysis for diagnosis and differential diagnosis in charcot marie tooth disease

Yalçıntepe, Sinem; Gürkan, Hakan; Doğan, İbrahim; Demır, Selma; Sağ, Şebnem Özemri; Kabayegit, Zehra Manav; Atlı, Emine İkbal; Atli, Engin; Eker, Damla; Temel, Şehime Gülsün

doi:10.5137/1019-5149.jtn.33661-21.3

Cited by 6 publications

(4 citation statements)

References 16 publications

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“…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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Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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“…Patients were offered an annual follow-up evaluation for VUS. In different CMT-NGS studies, various results were reported for VUS according to population diversities [16][17][18] . Larger population-based studies could reduce the prevalence of VUS.…”

Section: Gnb4 Litaf Mfn2mentioning

confidence: 99%

High diagnostic yield with algorithmic molecular approach on hereditary neuropathies

Ceylan

Habiloğlu

Çavdarlı

et al. 2023

Rev. Assoc. Med. Bras.

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OBJECTIVE: Charcot-Marie-Tooth disease covers a group of inherited peripheral neuropathies. The aim of this study was to investigate the effect of targeted next-generation sequencing panels on the molecular diagnosis of Charcot-Marie-Tooth disease and its subtypes in routine clinical practice, and also to show the limitations and importance of next-generation sequencing in the diagnosis of Charcot-Marie-Tooth diseases. METHODS: This is a retrospective study. Three different molecular methods (multiplex ligation probe amplification, next-generation sequencing, and whole-exome sequencing) were used to detect the mutations related to Charcot-Marie-Tooth disease. RESULTS: In total, 64 patients (33 males and 31 females) with suspected Charcot-Marie-Tooth disease were analyzed for molecular etiology. In all, 25 (39%) patients were diagnosed by multiplex ligation probe amplification. With an extra 11 patients with normal PMP22 multiplex ligation probe amplification results that were consulted to our laboratory for further genetic analysis, a total of 50 patients underwent next-generation sequencing for targeted gene panels associated with Charcot-Marie-Tooth disease. Notably, 18 (36%) patients had pathogenic/likely pathogenic variants. Wholeexome sequencing was performed on five patients with normal next-generation sequencing results; the diagnostic yield by whole-exome sequencing was 80% and it was higher in the childhood group. CONCLUSION: The molecular etiology in Charcot-Marie-Tooth disease patients can be determined according to pre-test evaluation, deciding the inheritance type with pedigree analysis, the clinical phenotype, and an algorithm for the genetic analysis. The presence of patients without a molecular diagnosis in all the literature suggests that there are new genes or mechanisms waiting to be discovered in the etiology of Charcot-Marie-Tooth disease.

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“…This results in the loss of regulatory activity on HSPB2, which eventually causes aberrant nuclear foci formation (Morelli et al, 2017b). Finally, from the analysis of a small cohort of CMT/dHMN patients, a novel variant of unknown significance, the HSPB3 L6F, has been recently identified in a patient affected by dHMNII (Yalcintepe et al, 2021). To our knowledge, animal models of HSPB3 mutants have not been developed.…”

Section: Hspb3mentioning

confidence: 99%

Insights on Human Small Heat Shock Proteins and Their Alterations in Diseases

Tedesco

Cristofani

Ferrari

et al. 2022

Front. Mol. Biosci.

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The family of the human small Heat Shock Proteins (HSPBs) consists of ten members of chaperones (HSPB1-HSPB10), characterized by a low molecular weight and capable of dimerization and oligomerization forming large homo- or hetero-complexes. All HSPBs possess a highly conserved centrally located α-crystallin domain and poorly conserved N- and C-terminal domains. The main feature of HSPBs is to exert cytoprotective functions by preserving proteostasis, assuring the structural maintenance of the cytoskeleton and acting in response to cellular stresses and apoptosis. HSPBs take part in cell homeostasis by acting as holdases, which is the ability to interact with a substrate preventing its aggregation. In addition, HSPBs cooperate in substrates refolding driven by other chaperones or, alternatively, promote substrate routing to degradation. Notably, while some HSPBs are ubiquitously expressed, others show peculiar tissue-specific expression. Cardiac muscle, skeletal muscle and neurons show high expression levels for a wide variety of HSPBs. Indeed, most of the mutations identified in HSPBs are associated to cardiomyopathies, myopathies, and motor neuropathies. Instead, mutations in HSPB4 and HSPB5, which are also expressed in lens, have been associated with cataract. Mutations of HSPBs family members encompass base substitutions, insertions, and deletions, resulting in single amino acid substitutions or in the generation of truncated or elongated proteins. This review will provide an updated overview of disease-related mutations in HSPBs focusing on the structural and biochemical effects of mutations and their functional consequences.

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The importance of multiple gene analysis for diagnosis and differential diagnosis in charcot marie tooth disease

Cited by 6 publications

References 16 publications

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

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

High diagnostic yield with algorithmic molecular approach on hereditary neuropathies

Insights on Human Small Heat Shock Proteins and Their Alterations in Diseases

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