Clinical Neurophysiology, IRCCS Stella Maris Foundation, Pisa, Italy.
Molecular Medicine and Neurogenetics, Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Via dei Giacinti 2, 56028, Pisa, Italy.
Neurogenetics. 2020 Jan;21(1):1-18. doi: 10.1007/s10048-019-00598-x. Epub 2019 Dec 13.
Over the past 10 years, the increasingly important role played by next-generation sequencing panels in the genetic diagnosis of epilepsy has led to a growing list of gene variants and a plethora of new scientific data. To date, however, there is still no consensus on what constitutes the "ideal panel design," or on the most rational criteria for selecting the best candidates for gene-panel analysis, even though both might optimize the cost-benefit ratio and the diagnostic efficiency of customized gene panels. Even though more and more laboratories are adopting whole-exome sequencing as a first-tier diagnostic approach, interpreting, "in silico," a set of epilepsy-related genes remains difficult. In the light of these considerations, we performed a systematic review of the targeted gene panels for epilepsy already reported in the available scientific literature, with a view to identifying the best criteria for selecting patients for gene-panel analysis, and the best way to design an "ideal," gold-standard panel that includes all genes with an established role in epilepsy pathogenesis, as well as those that might help to guide decisions regarding specific medical interventions and treatments. Our analyses suggest that the usefulness and diagnostic power of customized gene panels for epilepsy may be greatest when these panels are confined to rationally selected, relatively small, pools of genes, and applied in more carefully selected epilepsy patients (those with complex forms of epilepsy). A panel containing 64 genes, which includes the 45 genes harboring a significant number of pathogenic variants identified in previous literature, the 32 clinically actionable genes, and the 21 ILAE (International League Against Epilepsy) recommended genes, may represent an "ideal" core set likely able to provide the highest diagnostic efficiency and cost-effectiveness and facilitate gene prioritization when testing patients with whole-exome/whole-genome sequencing.
在过去的 10 年中，下一代测序在癫痫的遗传诊断中的作用越来越重要，这导致了越来越多的基因变异和大量新的科学数据。然而，迄今为止，对于什么构成“理想的面板设计”，或者对于选择基因面板分析的最佳候选者的最合理标准，仍然没有共识，尽管这两者都可能优化定制基因面板的成本效益比和诊断效率。尽管越来越多的实验室正在将全外显子组测序作为一线诊断方法，但对一组与癫痫相关的基因进行“计算机模拟”解读仍然很困难。有鉴于此，我们对已在现有科学文献中报道的针对癫痫的靶向基因面板进行了系统评价，以期确定选择患者进行基因面板分析的最佳标准，以及设计一个包含所有具有既定癫痫发病机制作用的基因的“理想”黄金标准面板的最佳方法，以及那些可能有助于指导特定医疗干预和治疗决策的基因。我们的分析表明，当这些面板仅限于合理选择的、相对较小的基因池，并应用于更仔细选择的癫痫患者（那些具有复杂形式的癫痫患者）时，用于癫痫的定制基因面板的有用性和诊断能力可能最大。一个包含 64 个基因的面板，其中包括在以前的文献中发现的大量致病性变异的 45 个基因、32 个临床可操作的基因和 21 个 ILAE（国际抗癫痫联盟）推荐的基因，可能代表一个“理想”的核心集，能够提供最高的诊断效率和成本效益，并在对进行全外显子/全基因组测序的患者进行测试时有助于基因优先级排序。
