Klein Christopher J, Foroud Tatiana M
Department of Neurology and Department of Medical Genetics, Mayo Clinic, Rochester, MN.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN.
Mayo Clin Proc. 2017 Feb;92(2):292-305. doi: 10.1016/j.mayocp.2016.09.008.
Next-generation sequencing (NGS) is increasingly being applied to clinical testing. This practice is predicted to grow especially in neurology clinics because many of their patients have monogenetic causes for their "diagnostic odyssey." The cost of sequencing has been steadily decreasing, but the cost of DNA sequencing is a minor part of the total cost. Downstream data analysis, storage, and interpretation account for most of the total expense. In patients with nonspecific neurologic disorders in which an extensive number of genetic differential diagnoses exist, whole-genome sequencing (WGS) or whole-exome sequencing (WES) has shown promise in the identification of genetic causes. However, both WGS and WES have incomplete coverage and produce a large number of rare variants of unknown importance. In addition, ethical dilemmas are often created by unexpected findings in genes unrelated to the initial sequencing indication. Targeted-panel NGS starts with the capture of a set of disease-focused genes, followed by massive parallel sequencing. For many genetically heterogeneous neurologic disorders, a genetic panel that is disease focused yet inclusive of a large genetic differential diagnosis can be defined to reduce cost, increase turnaround time, and optimize performance. Targeted-panel NGS is currently the preferred first-tier approach because it provides a reliable clinical application while eliminating unexpected ethical dilemmas. Targeted-panel NGS is leading to a paradigm shift in the diagnosis of many neurologic disorders, enabling individualized precision medicine. In this review, we provide an overview of WGS, WES, and targeted-panel NGS in consideration of their utility in clinical testing for neurologic diseases.
下一代测序（NGS）正越来越多地应用于临床检测。预计这种做法在神经科诊所尤其会有所增长，因为许多患者的“诊断之旅”存在单基因病因。测序成本一直在稳步下降，但DNA测序成本只是总成本的一小部分。下游数据分析、存储和解读占了总费用的大部分。在存在大量基因鉴别诊断的非特异性神经系统疾病患者中，全基因组测序（WGS）或全外显子组测序（WES）在确定遗传病因方面已显示出前景。然而，WGS和WES都存在覆盖不完整的问题，并且会产生大量重要性未知的罕见变异。此外，与初始测序指征无关的基因中出现的意外发现常常会引发伦理困境。靶向基因panel NGS首先捕获一组针对疾病的基因，然后进行大规模平行测序。对于许多基因异质性神经系统疾病，可以定义一个既针对疾病又包含大量基因鉴别诊断的基因panel，以降低成本、缩短周转时间并优化性能。靶向基因panel NGS目前是首选的一线方法，因为它提供了可靠的临床应用，同时消除了意外的伦理困境。靶向基因panel NGS正在导致许多神经系统疾病诊断的范式转变，实现个性化精准医学。在本综述中，我们考虑了WGS、WES和靶向基因panel NGS在神经系统疾病临床检测中的效用，对它们进行了概述。
