Mutational screening of Greek patients with axonal Charcot-Marie-Tooth disease using targeted next-generation sequencing: Clinical and molecular spectrum delineation

IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Journal of the Peripheral Nervous System Pub Date : 2023-09-25 DOI:10.1111/jns.12598
Zoi Kontogeorgiou, Chrisoula Kartanou, Michail Rentzos, Panagiotis Kokotis, Evangelos Anagnostou, Thomas Zambelis, Elisabeth Chroni, Argyris Dinopoulos, Marios Panas, Georgios Koutsis, Georgia Karadima
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Abstract

Background and Aims

Axonal forms of Charcot-Marie-Tooth disease (CMT) are classified as CMT2, distal hereditary motor neuropathy (dHMN) or hereditary sensory neuropathy (HSN) and can be caused by mutations in over 100 genes. We presently aimed to investigate for the first time the genetic landscape of axonal CMT in the Greek population.

Methods

Sixty index patients with CMT2, dHMN or HSN were screened by a combination of Sanger sequencing (GJB1) and next-generation sequencing custom-made gene panel covering 24 commonly mutated genes in axonal CMT.

Results

Overall, 20 variants classified as pathogenic or likely pathogenic were identified in heterozygous state in 20 index cases, representing 33.3% of the cohort. Of these, 14 were known pathogenic/likely pathogenic and six were designated as such according to ACMG classification, after in silico evaluation, testing for familial segregation and further literature review. The most frequently involved genes were GJB1 (11.7%), MPZ (5%) and MFN2 (5%), followed by DNM2 (3.3%) and LRSAM1 (3.3%). Single cases were identified with mutations in BSCL2, HSPB1 and GDAP1.

Interpretation

A wide phenotypic variability in terms of severity and age of onset was noted. Given the limited number of genes tested, the diagnostic yield of the present panel compares favourably with studies in other European populations. Our study delineates the genetic and phenotypic variability of inherited axonal neuropathies in the Greek population and contributes to the pathogenicity characterization of further variants linked to axonal neuropathies.

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使用靶向下一代测序对希腊轴索性Charcot-Marie Tooth病患者进行突变筛查:临床和分子谱描绘。
背景和目的:Charcot-Marie Tooth病(CMT)的轴索型分为CMT2、远端遗传性运动神经病(dHMN)或遗传性感觉神经病(HSN),可由100多个基因突变引起。我们目前的目标是首次调查希腊人群中轴突CMT的遗传景观。方法:采用Sanger测序(GJB1)和下一代测序定制基因组相结合的方法对60例CMT2、dHMN或HSN指数患者进行筛选,该基因组涵盖了轴突CMT中24个常见突变基因。其中,14例为已知致病性/可能致病性,6例根据ACMG分类,经过计算机评估、家族分离测试和进一步的文献综述后被指定为已知致病/可能致病。最常见的相关基因是GJB1(11.7%)、MPZ(5%)和MFN2(5%),其次是DNM2(3.3%)和LRSAM1(3.3%)。单个病例被鉴定为BSCL2、HSPB1和GDAP1突变。解释:在严重程度和发病年龄方面存在广泛的表型变异。鉴于测试的基因数量有限,本小组的诊断结果与其他欧洲人群的研究相比是有利的。我们的研究描述了希腊人群中遗传性轴索神经病的遗传和表型变异性,并有助于与轴索神经病相关的进一步变异的致病性表征。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.10
自引率
7.90%
发文量
45
审稿时长
>12 weeks
期刊介绍: The Journal of the Peripheral Nervous System is the official journal of the Peripheral Nerve Society. Founded in 1996, it is the scientific journal of choice for clinicians, clinical scientists and basic neuroscientists interested in all aspects of biology and clinical research of peripheral nervous system disorders. The Journal of the Peripheral Nervous System is a peer-reviewed journal that publishes high quality articles on cell and molecular biology, genomics, neuropathic pain, clinical research, trials, and unique case reports on inherited and acquired peripheral neuropathies. Original articles are organized according to the topic in one of four specific areas: Mechanisms of Disease, Genetics, Clinical Research, and Clinical Trials. The journal also publishes regular review papers on hot topics and Special Issues on basic, clinical, or assembled research in the field of peripheral nervous system disorders. Authors interested in contributing a review-type article or a Special Issue should contact the Editorial Office to discuss the scope of the proposed article with the Editor-in-Chief.
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