Mohsenpour Neda, Roknizadeh Hassan, Maghbooli Mehdi, Changi-Ashtiani Majid, Shahrooei Mohammad, Salehi Mansoor, Behnam Mahdiyeh, Shahani Tina, Biglari Alireza
Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences (ZUMS), Zanjan, Iran.
Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences (ZUMS), Zanjan, Iran.
Int J Mol Cell Med. 2019 Summer;8(3):169-178. doi: 10.22088/IJMCM.BUMS.8.3.169.
Charcot-Marie-Tooth disease (CMT) is the most common hereditary neuropathy of the peripheral nervous system with a wide range of severity and age of onset. CMT patients share similar phenotypes which make it often impossible to identify the disease types based on clinical presentation and electrophysiological studies alone. In recent years, novel genetic diagnostic approaches such as whole exome sequencing (WES) has provided a ground for accurate diagnosis of CMT through identification of the disease-causing mutation(s). In the present study, that approach was effectively employed. Two unrelated large pedigrees with multiple affected cases of various pattern of inheritance (one autosomal dominant and one X-linked) were included. Clinical and electrophysiological data were obtained. DNA sample from each pedigree's proband was subjected to WES. Data analysis was performed using an in-house developed pipeline, adopted from GATK and ANNOVAR. Candidate variant segregation was evaluated by PCR-based Sanger sequencing. A known but extremely rare (unreported in the Middle Easterners) mutation in (c.C269T:p.S90L) as well as a novel hemizygous variant in (c.G224C:p.R75P) were identified and segregations were confirmed by Sanger sequencing. This study supports effectiveness of WES for genetic diagnosis of CMT in undiagnosed families.
夏科-马里-图斯病（CMT）是周围神经系统最常见的遗传性神经病变，严重程度和发病年龄范围广泛。CMT患者具有相似的表型，这使得仅根据临床表现和电生理研究往往无法确定疾病类型。近年来，诸如全外显子组测序（WES）等新型基因诊断方法通过识别致病突变，为CMT的准确诊断提供了依据。在本研究中，有效采用了该方法。纳入了两个无关的大家系，其中有多个不同遗传模式（一个常染色体显性遗传和一个X连锁遗传）的受累病例。获取了临床和电生理数据。对每个家系先证者的DNA样本进行全外显子组测序。使用从GATK和ANNOVAR采用的内部开发流程进行数据分析。通过基于聚合酶链反应（PCR）的桑格测序评估候选变异的分离情况。在（c.C269T:p.S90L）中鉴定出一个已知但极其罕见（中东人群中未报道）的突变以及在（c.G224C:p.R75P）中的一个新的半合子变异，并通过桑格测序证实了其分离情况。本研究支持全外显子组测序在未确诊家庭中对CMT进行基因诊断的有效性。
