Whole exome sequencing and the clinician: we need clinical skills and functional validation in variant filtering.
Whole exome sequencing and the clinician: we need clinical skills and functional validation in variant filtering.
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DOI：
10.1007/s00415-015-7755-y
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发表时间：
2015-07
影响因子：
6
通讯作者：
Horvath R
中科院分区：
文献类型：
--
作者：
Daud D;Griffin H;Douroudis K;Kleinle S;Eglon G;Pyle A;Chinnery PF;Horvath R
全外显子组测序（WES）是遗传学研究中最近开发的一项技术，试图在复杂的、未诊断的遗传疾病中鉴定致病突变。致病突变通常在从由表型选择的个体DNA中过滤WES上的数百个变体后被鉴定。我们研究了一个缓慢进行性慢性轴索远端运动神经病变和锥体外系综合征患者使用WES，其中常见的基因突变已被排除。变异过滤在三种已知的疾病基因中鉴定出潜在有害的突变：DCTN 1、KIF 5A和NEFH，它们都与肌萎缩侧索硬化症、帕金森综合征和/或遗传性痉挛性截瘫的相似临床表现相关。预测突变的功能效应与详细的临床研究并行分析。这个案例突出了在复杂神经系统疾病患者中应用WES的困难和陷阱，并作为一个有启发性的故事。
Whole exome sequencing (WES) is a recently developed technique in genetics research that attempts to identify causative mutations in complex, undiagnosed genetic conditions. Causative mutations are usually identified after filtering the hundreds of variants on WES from an individual’s DNA selected by the phenotype. We investigated a patient with a slowly progressive chronic axonal distal motor neuropathy and extrapyramidal syndrome using WES, in whom common genetic mutations had been excluded. Variant filtering identified potentially deleterious mutations in three known disease genes: DCTN1, KIF5A and NEFH, which have been all associated with similar clinical presentations of amyotrophic lateral sclerosis, Parkinsonism and/or hereditary spastic paraplegia. Predicting the functional effect of the mutations were analysed in parallel with detailed clinical investigations. This case highlights the difficulties and pitfalls of applying WES in patients with complex neurological diseases and serves as an instructive tale.