Department of Neurology and Geriatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima.
Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo.
Eur J Neurol. 2017 Oct;24(10):1274-1282. doi: 10.1111/ene.13360. Epub 2017 Aug 3.
The microrchidia family CW-type zinc finger 2 gene (MORC2) was newly identified as a causative gene of Charcot-Marie-Tooth disease (CMT) type 2Z in 2016. We aimed to describe the clinical and mutational spectrum of patients with CMT harboring MORC2 mutations in Japan.
We analyzed samples from 781 unrelated patients clinically diagnosed with CMT using deoxyribonucleic acid microarray or targeted resequencing by next-generation sequencing, and samples from 434 mutation-negative patients were subjected to whole-exome sequencing. We extracted MORC2 variants from these whole-exome sequencing data and classified them according to American College of Medical Genetics standards and guidelines.
We identified MORC2 variants in 13 patients. As the second most common causative gene of CMT type 2 after MFN2, MORC2 variants were detected in 2.7% of patients with CMT type 2. The mean age of onset was 10.3 ± 8.7 years, and the inheritance pattern was mostly sporadic (11/13 patients, 84.6%). The clinical phenotype was typically length-dependent polyneuropathy, and electrophysiological studies revealed sensory-dominant axonal neuropathy. Mental retardation was identified in 4/13 patients (30.8%). p.Arg190Trp, as a mutational hotspot, was observed in eight unrelated families. We also identified two novel probably pathogenic variants, p.Cys345Tyr and p.Ala369Val, and one novel uncertain significance variant, p.Tyr332Cys.
Our study is the largest report of patients harboring MORC2 variants. We revealed a clinical and mutational spectrum of Japanese patients with MORC2 variants. More attention should be paid to cognitive impairment, and the responsible mechanism requires further research for elucidation.
2016 年，微线体相关卷曲螺旋结构域蛋白 2 基因（MORC2）被新确定为 2Z 型腓骨肌萎缩症（CMT）的致病基因。本研究旨在描述日本携带 MORC2 突变的 CMT 患者的临床和突变谱。
我们分析了通过脱氧核糖核酸微阵列或靶向下一代测序进行的 781 例临床诊断为 CMT 的无关联患者的样本，以及 434 例无突变患者的样本进行了外显子组测序。我们从这些外显子组测序数据中提取 MORC2 变体，并根据美国医学遗传学学院的标准和指南对其进行分类。
我们在 13 例患者中发现了 MORC2 变体。作为继 MFN2 之后第二常见的 CMT 2 型致病基因，MORC2 变体在 2.7%的 CMT 2 型患者中被检测到。发病年龄的平均值为 10.3±8.7 岁，遗传模式主要为散发性（13 例患者中的 11 例，84.6%）。临床表型通常为长度依赖性多发性神经病，电生理学研究显示感觉神经为主的轴索性神经病。4/13 例（30.8%）患者存在智力障碍。p.Arg190Trp 作为突变热点，在 8 个无关联的家系中被观察到。我们还鉴定了两个新的可能致病性变异体 p.Cys345Tyr 和 p.Ala369Val，以及一个新的不确定意义的变异体 p.Tyr332Cys。
本研究是最大规模的关于携带 MORC2 变体患者的报告。我们揭示了日本患者携带 MORC2 变体的临床和突变谱。应更加关注认知障碍，其致病机制需要进一步研究阐明。
