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Molecular characterization of Turkish patients with demyelinating Charcot-Marie-Tooth disease

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Abstract

Charcot-Marie-Tooth (CMT) disease represents a distinct subgroup of inherited peripheral neuropathies with a significant prevalence throughout the world and manifests both phenotypic and genetic heterogeneity. Electrophysiological studies subclassify CMT mainly as demyelinating or axonal types. In this study, we investigated the molecular characteristics of a Turkish cohort of 23 probands out of 34 symptomatic demyelinating CMT individuals from January 2019 to December 2021. In order to identify the underlying genetic cause, we applied a rational algorithm: PMP22 gene was initially analyzed for duplication, if PMP22-duplication testing was negative, other most causative genes (GJB1, MPZ) and PMP22 were then sequenced and if no variant was detected at aforementioned tests, whole exome sequencing (WES) test was finally performed. A total of 17 patients (≅ 74%; n = 23) were found to harbor a disease-causing variant in demyelinating CMT-related genes and among the variants, PMP22-duplication was the most frequent (≅ 41%). CMT1, CMTX, and CMT4 subtypes were manifested in ten, five, and two individuals respectively. GJB1 and SBF2 genes were the only detected genes associated with the CMTs other than CMT1. We also reported totally five novel variants: c.379A > C (p.Ile127Leu) and c.548G > T (p.Arg183Leu) variants in GJB1, c.988G > T (p.Glu330Ter) variant in NEFL, c.765_770delCCCTAT (p.Pro256_Ile257del) and c.2552A > C (p.His851Pro) variants in SBF2. As the understanding of pathophysiology and molecular mechanisms of CMT continues to evolve rapidly, many therapeutic strategy options including promising small-molecular compounds, gene replacement therapy, or disease-modifying therapies will soon be implemented in the clinical setting.

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Authors and Affiliations

  1. Department of Medical Genetics, Isparta City Hospital, Isparta, Turkey

    Taner Karakaya

  2. Department of Medical Genetics, Karadeniz Technical University Faculty of Medicine , Trabzon, Turkey

    Ayberk Turkyilmaz & Alper Han Cebi

  3. Department of Pediatric Neurology, Kartal Dr. Lutfi Kirdar City Hospital, Istanbul, Turkey

    Gunes Sager

  4. Department of Neurology, Kartal Dr. Lutfi Kirdar City Hospital, Istanbul, Turkey

    Rahsan Inan

  5. Department of Medical Genetics, Erzurum Regional Education and Research Hospital, Erzurum, Turkey

    Oguzhan Yarali

  6. Department of Pediatrics, Kartal Dr. Lutfi Kirdar City Hospital, Istanbul, Turkey

    Yasemin Akin

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Contributions

Taner KARAKAYA: conceptualization, methodology, ınvestigation, resources, visualization, writing—original draft preparation, writing—review and editing. Ayberk TURKYILMAZ: data curation, ınvestigation, supervision, resources, writing—review and editing. Gunes SAGER: conceptualization, visualization, ınvestigation, resources. Rahsan INAN: resources. Oguzhan YARALI: data curation, resources. Alper Han CEBI: data curation, resources. Yasemin AKIN: resources, supervision.

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Karakaya, T., Turkyilmaz, A., Sager, G. et al. Molecular characterization of Turkish patients with demyelinating Charcot-Marie-Tooth disease. Neurogenetics 23, 213–221 (2022). https://doi.org/10.1007/s10048-022-00693-6

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