Genetic spectrum and founder effect of non-dystrophic myotonia: a Japanese case series study
Genetic spectrum and founder effect of non-dystrophic myotonia: a Japanese case series study
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DOI：
10.1007/s00415-022-11305-6
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发表时间：
2022-07-30
影响因子：
6
通讯作者：
Takashima，Hiroshi
中科院分区：
文献类型：
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作者：
Yuan，Jun-Hui;Higuchi，Yujiro;Takashima，Hiroshi
非营养不良性肌强直（NDM）是一种罕见的骨骼肌通道病，主要与两个电压门控离子通道基因CLCN 1和SCN 4A有关。本研究的目的是确定日本NDM患者的临床和遗传特征。我们收集了日本全国范围内临床诊断为NDM患者的病例系列（1999-2021）。在88个家系中的71个中，使用桑格和新一代测序靶向CLCN 1和SCN 4A基因，从CLCN 1（31个先证者）、SCN 4A（36个先证者）或两个基因（4个先证者）检测到分类为致病/可能致病/未知意义的变异，其中11个是新的。CLCN 1单等位基因变异的家系比双等位基因/双变异的家系多见（24：7）。与携带CLCN 1变异的患者相比，携带SCN 4A变异的患者表现出更年轻的发病年龄（5.64 ± 4.70岁对9.23 ± 5.21岁），更少的热身现象，但更多的副肌强直，高CK血症，一过性肌无力和冷诱导的肌强直。单倍型分析证实了CLCN 1（p.T539A）和SCN 4A（p.T1313M）热点变异体的奠基者效应。本研究揭示了80.7%的病例中CLCN 1和SCN 4A的变异，扩展了NDM的遗传谱，并将进一步加深我们对CLCN 1和SCN 4A相关NDM的临床相似性/多样性以及遗传种族差异的理解。
Non-dystrophic myotonias (NDM) are rare skeletal muscle channelopathies, mainly linked to two voltage-gated ion channel genes,CLCN1andSCN4A. The aim of this study is to identify the clinical and genetic features of patients with NDM in Japan. We collected a Japanese nationwide case series of patients with clinical diagnosis of NDM (1999–2021). Among 71 out of 88 pedigrees, using Sanger and next-generation sequencing targeting bothCLCN1andSCN4Agenes, variants classified as pathogenic/likely pathogenic/unknown significance were detected fromCLCN1(31 probands),SCN4A(36 probands), or both genes (4 probands), and 11 of them were novel. Pedigrees carrying mono-allelicCLCN1variants were more commonly seen than that with bi-allelic/double variants (24:7). Compared to patients withCLCN1variants, patients harboringSCN4Avariants showed younger onset age (5.64 ± 4.70 years vs. 9.23 ± 5.21 years), fewer warm-up phenomenon, but more paramyotonia, hyperCKemia, transient muscle weakness, and cold-induced myotonia. Haplotype analysis verified founder effects of the hot spot variants in bothCLCN1(p.T539A) andSCN4A(p.T1313M). This study reveals variants inCLCN1andSCN4Afrom 80.7% of our case series, extending genetic spectrum of NDM, and would further our understanding of clinical similarity/diversity betweenCLCN1- andSCN4A-related NDM, as well as the genetic racial differences.