非营养不良性肌痛(NDM)是罕见的骨骼肌信道病,主要与两个电压门控离子通道基因有关,CLCN1和SCN4A。这项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的患者(1999-2021)。88个家谱中有71个,使用Sanger和针对CLCN1和SCN4A基因的下一代测序,从CLCN1(31个先证者)中检测到分类为致病性/可能致病性/未知意义的变异,SCN4A(36个先证者),或两个基因(4个先证者),其中11个是小说。携带单等位基因CLCN1变体的谱系比具有双等位基因/双变体(24:7)的谱系更常见。与CLCN1变异的患者相比,携带SCN4A变异的患者发病年龄较小(5.64±4.70岁与9.23±5.21年),较少的热身现象,但更多的副肌强直,高CK血症,短暂性肌肉无力,和冷诱导的肌强直。单倍型分析验证了两个CLCN1中热点变体的创始人效应(p。T539A)和SCN4A(第T1313M)。这项研究揭示了我们病例系列中80.7%的CLCN1和SCN4A的变异,扩展NDM的遗传谱,并将进一步了解CLCN1-和SCN4A相关NDM之间的临床相似性/多样性,以及遗传种族差异。
Non-dystrophic myotonias (NDM) are rare skeletal muscle channelopathies, mainly linked to two voltage-gated ion channel genes, CLCN1 and SCN4A. 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 both CLCN1 and SCN4A genes, variants classified as pathogenic/likely pathogenic/unknown significance were detected from CLCN1 (31 probands), SCN4A (36 probands), or both genes (4 probands), and 11 of them were novel. Pedigrees carrying mono-allelic CLCN1 variants were more commonly seen than that with bi-allelic/double variants (24:7). Compared to patients with CLCN1 variants, patients harboring SCN4A variants 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 both CLCN1 (p.T539A) and SCN4A (p.T1313M). This
study reveals variants in CLCN1 and SCN4A from 80.7% of our case series, extending genetic spectrum of NDM, and would further our understanding of clinical similarity/diversity between CLCN1- and SCN4A-related NDM, as well as the genetic racial differences.