The implementation of whole exome sequencing (WES) has had a major impact on the diagnostic yield of genetic testing in individuals with epilepsy. The identification of a genetic etiology paves the way to precision medicine: an individualized treatment approach, based on the disease pathophysiology. The aim of this retrospective cohort study was to: (1) determine the diagnostic yield of WES in a heterogeneous cohort of individuals with epilepsy referred for genetic testing in a real-world clinical setting, (2) investigate the influence of epilepsy characteristics on the diagnostic yield, (3) determine the theoretical yield of treatment changes based on genetic diagnosis and (4) explore the barriers to implementation of precision medicine. WES was performed in 247 individuals with epilepsy, aged between 7 months and 68 years. In 34/247 (14 %) a (likely) pathogenic variant was identified. In 7/34 (21 %) of these individuals the variant was found using a HPO-based filtering. Diagnostic yield was highest for individuals with an early onset of epilepsy (39 %) or in those with a developmental and epileptic encephalopathy (34 %). Precision medicine was a theoretical possibility in 20/34 (59 %) of the individuals with a (likely) pathogenic variant but implemented in only 11/34 (32 %). The major barrier to implementation of precision treatment was the limited availability or reimbursement of a given drug. These results confirm the potential impact of genetic analysis on treatment choices, but also highlight the hurdles to the implementation of precision medicine. To optimize precision medicine in real-world practice, additional endeavors are needed: unifying definitions of precision medicine, establishment of publicly accessible databases that include data on the functional effect of gene variants, increasing availability and reimbursement of precision therapeutics, and broadening access to innovative clinical trials.

中文翻译：

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遗传性癫痫从诊断到治疗：精准医疗在现实临床实践中的实施

全外显子组测序（WES）的实施对癫痫患者基因检测的诊断率产生了重大影响。遗传病因的识别为精准医学铺平了道路：基于疾病病理生理学的个体化治疗方法。这项回顾性队列研究的目的是：(1) 确定 WES 在现实临床环境中进行基因检测的异质癫痫患者队列中的诊断率，(2) 调查癫痫特征对癫痫特征的影响诊断产量，（3）确定基于基因诊断的治疗改变的理论产量，（4）探索实施精准医疗的障碍。对 247 名年龄在 7 个月至 68 岁之间的癫痫患者进行了 WES。在 34/247 (14%) 中，鉴定出了（可能的）致病变异。使用基于 HPO 的过滤在 7/34 (21%) 的个体中发现了该变异。对于早期癫痫发作的个体（39%）或患有发育性癫痫性脑病的个体（34%），诊断率最高。理论上，精准医疗对于 20/34 (59%) 具有（可能）致病变异的个体是可能的，但只有 11/34 (32%) 的个体得以实施。实施精准治疗的主要障碍是特定药物的可用性或报销有限。这些结果证实了遗传分析对治疗选择的潜在影响，但也凸显了实施精准医疗的障碍。为了优化现实世界实践中的精准医疗，需要做出更多努力：统一精准医疗的定义，建立可公开访问的数据库，其中包括基因变异功能影响的数据，提高精准治疗的可用性和报销，以及扩大创新的获取途径临床试验。