Genetic profile and onset features of 1005 patients with Charcot-Marie-Tooth disease in Japan.
Genetic profile and onset features of 1005 patients with Charcot-Marie-Tooth disease in Japan.
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DOI：
10.1136/jnnp-2018-318839
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Takashima H
中科院分区：
文献类型：
--
作者：
Yoshimura A;Yuan JH;Hashiguchi A;Ando M;Higuchi Y;Nakamura T;Okamoto Y;Nakagawa M;Takashima H
目的探讨大规模腓骨肌萎缩症（CMT）患者的遗传学特征。从2012年5月至2016年8月，我们在日本各地收集了1005例疑似CMT病例，而对于脱髓鞘CMT病例，提前排除了PMP 22重复/缺失。我们使用Illumina MiSeq或Ion Proton对CMT相关基因组进行了下一代测序，然后分析了已确定病例的基因特异性发病年龄及其遗传谱的地理差异。从40个基因中，我们在301例（30.0%）中鉴定出致病性或可能致病的变异体。最常见的致病基因是GJB 1（n=66，21.9%）、MFN 2（n=66，21.9%）和MPZ（n=51，16.9%）。脱髓鞘型CMT中变异检出率为45.7%，其中GJB 1（40.3%）、MPZ（27.1%）、PMP 22点突变（6.2%）和NEFL（4.7%）是最常见的变异原因。轴索型CMT检出率较低（22.9%），占72.4%的前5位病因依次为MFN 2（37.2%）、MPZ（9.0%）、HSPB 1（8.3%）、GJB 1（7.7%）、GDAP 1（5.1%）和MME（5.1%）。发现生命的前十年是最常见的疾病发作期，并且早发性CMT病例最有可能接受分子诊断。地理分布分析表明，在日本不同地区的独特的遗传谱。我们的研究结果更新了大规模日本CMT病例的遗传特征。随后对发病年龄和地理分布的分析促进了我们对CMT的理解，这将对临床医生有益。
To identify the genetic characteristics in a large-scale of patients with Charcot-Marie-Tooth disease (CMT). From May 2012 to August 2016, we collected 1005 cases with suspected CMT throughout Japan, whereas PMP22 duplication/deletion were excluded in advance for demyelinating CMT cases. We performed next-generation sequencing targeting CMT-related gene panels using Illumina MiSeq or Ion Proton, then analysed the gene-specific onset age of the identified cases and geographical differences in terms of their genetic spectrum. From 40 genes, we identified pathogenic or likely pathogenic variants in 301 cases (30.0%). The most common causative genes were GJB1 (n=66, 21.9%), MFN2 (n=66, 21.9%) and MPZ (n=51, 16.9%). In demyelinating CMT, variants were detected in 45.7% cases, and the most common reasons were GJB1 (40.3%), MPZ (27.1%), PMP22 point mutations (6.2%) and NEFL (4.7%). Axonal CMT yielded a relatively lower detection rate (22.9%), and the leading causes, occupying 72.4%, were MFN2 (37.2%), MPZ (9.0%), HSPB1 (8.3%), GJB1 (7.7%), GDAP1 (5.1%) and MME (5.1%). First decade of life was found as the most common disease onset period, and early-onset CMT cases were most likely to receive a molecular diagnosis. Geographical distribution analysis indicated distinctive genetic spectrums in different regions of Japan. Our results updated the genetic profile within a large-scale of Japanese CMT cases. Subsequent analyses regarding onset age and geographical distribution advanced our understanding of CMT, which would be beneficial for clinicians.
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影响因子：
3.8
作者：
Manganelli, Fiore;Tozza, Stefano;Santoro, Lucio
通讯作者：
Santoro, Lucio
影响因子：
11.2
作者：
Higuchi, Yujiro;Hashiguchi, Akihiro;Yuan, Junhui;Yoshimura, Akiko;Mitsui, Jun;Ishiura, Hiroyuki;Tanaka, Masaki;Ishihara, Satoshi;Tanabe, Hajime;Nozuma, Satoshi;Okamoto, Yuji;Matsuura, Eiji;Ohkubo, Ryuichi;Inamizu, Saeko;Shiraishi, Wataru;Yamasaki, Ryo;Ohyagi, Yasumasa;Kira, Jun-ichi;Oya, Yasushi;Yabe, Hayato;Nishikawa, Noriko;Tobisawa, Shinsuke;Matsuda, Nozomu;Masuda, Masayuki;Kugimoto, Chiharu;Fukushima, Kazuhiro;Yano, Satoshi;Yoshimura, Jun;Doi, Koichiro;Nakagawa, Masanori;Morishita, Shinichi;Tsuji, Shoji;Takashima, Hiroshi
通讯作者：
Takashima, Hiroshi
影响因子：
1.2
作者：
Maeda, Kengo;Idehara, Ryo;Takashima, Hiroshi
通讯作者：
Takashima, Hiroshi
影响因子：
14.5
作者：
Sevilla, Teresa;Lupo, Vincenzo;Espinos, Carmen
通讯作者：
Espinos, Carmen
影响因子：
9.8
作者：
Antonellis, A;Ellsworth, RE;Green, ED
通讯作者：
Green, ED