Kontogeorgiou Zoi, Kartanou Chrisoula, Rentzos Michail, Kokotis Panagiotis, Anagnostou Evangelos, Zambelis Thomas, Chroni Elisabeth, Dinopoulos Argyris, Panas Marios, Koutsis Georgios, Karadima Georgia
Neurogenetics Unit, 1st Department of Neurology, Eginition Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
1st Department of Neurology, Eginition Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
J Peripher Nerv Syst. 2023 Dec;28(4):642-650. doi: 10.1111/jns.12598. Epub 2023 Oct 5.
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.
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.
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.
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.
夏科-马里-图斯病（CMT）的轴索性类型被归类为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多个基因的突变引起。我们目前旨在首次调查希腊人群中轴索性CMT的遗传情况。
对60例CMT2、dHMN或HSN的索引患者进行了筛查，采用桑格测序法（检测GJB1基因）与定制的二代测序基因panel相结合的方法，该基因panel涵盖了轴索性CMT中24个常见的突变基因。
总体而言，在20例索引病例中鉴定出20个杂合状态的变异，分类为致病性或可能致病性，占队列的33.3%。其中，14个是已知的致病性/可能致病性变异，另外6个根据ACMG分类，经电子评估、家族分离检测及进一步文献回顾后确定为致病性或可能致病性变异。最常涉及的基因是GJB1（11.7%）、MPZ（5%）和MFN2（5%），其次是DNM2（3.3%）和LRSAM1（3.3%）。还分别在1例患者中发现了BSCL2、HSPB1和GDAP1基因的突变。
在严重程度和发病年龄方面观察到广泛的表型变异性。鉴于所检测基因数量有限，本基因panel的诊断率与其他欧洲人群的研究相比具有优势。我们的研究描绘了希腊人群中遗传性轴索性神经病的遗传和表型变异性，并有助于对与轴索性神经病相关的更多变异进行致病性特征分析。
