Yoshimura A, Yuan J-H, Hashiguchi A, Hiramatsu Y, Ando M, Higuchi Y, Nakamura T, Okamoto Y, Matsumura K, Hamano T, Sawaura N, Shimatani Y, Kumada S, Okumura Y, Miyahara J, Yamaguchi Y, Kitamura S, Haginoya K, Mitsui J, Ishiura H, Tsuji S, Takashima H
Department of Neurology and Geriatrics, Kagoshima University, Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Department of Neurology, Teikyo University, Tokyo, Japan.
Clin Genet. 2017 Sep;92(3):274-280. doi: 10.1111/cge.13002. Epub 2017 Apr 19.
Mutations in GDAP1 are responsible for heterogeneous clinical and electrophysiological phenotypes of Charcot-Marie-Tooth disease (CMT), with autosomal dominant or recessive inheritance pattern. The aim of this study is to identify the clinical and mutational spectrum of CMT patients with GDAP1 variants in Japan.
From April 2007 to October 2014, using three state-of-art technologies, we conducted gene panel sequencing in a cohort of 1,030 patients with inherited peripheral neuropathies (IPNs), and 398 mutation-negative cases were further analyzed with whole-exome sequencing.
We identified GDAP1 variants from 10 patients clinically diagnosed with CMT. The most frequent recessive variant in our cohort (5/10), c.740C>T (p.A247V), was verified to be associated with a founder event. We also detected three novel likely pathogenic variants: c.928C>T (p.R310W) and c.546delA (p.E183Kfs*23) in Case 2 and c.376G>A (p.E126K) in Case 8. Nerve conduction study or sural nerve biopsy of all 10 patients indicated axonal type peripheral neuropathy.
We identified GDAP1 variants in approximately 1% of our cohort with IPNs, and established a founder mutation in half of these patients. Our study originally described the mutational spectrum and clinical features of GDAP1-related CMT patients in Japan.
GDAP1基因突变与夏科-马里-图斯病（CMT）的临床和电生理表型异质性有关，其遗传方式为常染色体显性或隐性遗传。本研究旨在确定日本携带GDAP1变异的CMT患者的临床和突变谱。
2007年4月至2014年10月，我们采用三种先进技术，对1030例遗传性周围神经病（IPN）患者进行了基因panel测序，并对398例突变阴性病例进行了全外显子组测序。
我们从10例临床诊断为CMT的患者中鉴定出GDAP1变异。在我们的队列中最常见的隐性变异（5/10），即c.740C>T（p.A247V），经证实与一个奠基者事件相关。我们还检测到三个新的可能致病变异：病例2中的c.928C>T（p.R310W）和c.546delA（p.E183Kfs*23）以及病例8中的c.376G>A（p.E126K）。对所有10例患者进行的神经传导研究或腓肠神经活检均显示为轴索性周围神经病。
我们在约1%的IPN队列患者中鉴定出GDAP1变异，并在其中一半患者中确定了一个奠基者突变。我们的研究首次描述了日本GDAP1相关CMT患者的突变谱和临床特征。
