Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
Key Laboratory of Tropical Diseases Control (SYSU), Sun Yat-sen University, Guangzhou, 510080, China.
BMC Neurol. 2021 Mar 2;21(1):96. doi: 10.1186/s12883-021-02093-z.
Due to large genetic and phenotypic heterogeneity, the conventional workup for Charcot-Marie-Tooth (CMT) diagnosis is often underpowered, leading to diagnostic delay or even lack of diagnosis. In the present study, we explored how bioinformatics analysis on whole-exome sequencing (WES) data can be used to diagnose patients with CMT disease efficiently.
The proband is a 29-year-old female presented with a severe amyotrophy and distal skeletal deformity that plagued her family for over 20 years since she was 5-year-old. No other aberrant symptoms were detected in her speaking, hearing, vision, and intelligence. Similar symptoms manifested in her younger brother, while her parents and her older brother showed normal. To uncover the genetic causes of this disease, we performed exome sequencing for the proband and her parents. Subsequent bioinformatics analysis on the KGGSeq platform and further Sanger sequencing identified a novel homozygous GDAP1 nonsense mutation (c.218C > G, p.Ser73*) that responsible for the family. This genetic finding then led to a quick diagnosis of CMT type 4A (CMT4A), confirmed by nerve conduction velocity and electromyography examination of the patients.
The patients with severe muscle atrophy and distal skeletal deformity were caused by a novel homozygous nonsense mutation in GDAP1 (c.218C > G, p.Ser73*), and were diagnosed as CMT4A finally. This study expanded the mutation spectrum of CMT disease and demonstrated how affordable WES could be effectively employed for the clinical diagnosis of unexplained phenotypes.
由于遗传和表型的巨大异质性，传统的 Ch arcot-Marie-Tooth (CMT) 诊断方法往往效果不佳，导致诊断延迟甚至无法诊断。在本研究中，我们探讨了如何通过全外显子组测序 (WES) 数据分析有效地诊断 CMT 疾病患者。
先证者为一名 29 岁女性，自 5 岁起，其四肢严重萎缩和远端骨骼畸形，困扰其家庭超过 20 年。其言语、听力、视力和智力均无其他异常症状。她的弟弟也有类似症状，而她的父母和哥哥则表现正常。为了揭示这种疾病的遗传原因，我们对先证者及其父母进行了外显子组测序。随后，我们在 KGGSeq 平台上进行了生物信息学分析，并通过 Sanger 测序进一步鉴定出一种新的 GDAP1 无义突变（c.218C > G，p.Ser73*），该突变导致了家族中该病的发生。这一遗传学发现迅速确定了患者为 CMT 4A（CMT4A），通过对患者的神经传导速度和肌电图检查得到了证实。
该患者表现为严重的肌肉萎缩和远端骨骼畸形，是由于 GDAP1 中一个新的纯合无义突变（c.218C > G，p.Ser73*）引起的，最终被诊断为 CMT4A。本研究扩展了 CMT 疾病的突变谱，并展示了如何有效地利用负担得起的 WES 进行不明表型的临床诊断。
