Epilepsy treatment is challenging due to heterogeneous syndromes, different seizure types and higher inter-individual variability. Identification of genetic variants predicting drug efficacy, tolerability and risk of adverse-effects for anti-seizure medications (ASMs) is essential. Here, we assessed the clinical actionability of known genetic variants, based on their functional and clinical significance and estimated their diagnostic predictability. We performed a systematic PubMed search to identify articles with pharmacogenomic (PGx) information for forty known ASMs. Functional annotation of the identified genetic variants was performed using different in silico tools, and their clinical significance was assessed using the American College of Medical Genetics (ACMG) guidelines for variant pathogenicity, level of evidence (LOE) from PharmGKB and the United States-Food and drug administration (US- FDA) drug labelling with PGx information. Diagnostic predictability of the replicated genetic variants was evaluated by calculating their accuracy. A total of 270 articles were retrieved with PGx evidence associated with 19 ASMs including 178 variants across 93 genes, classifying 26 genetic variants as benign/ likely benign, fourteen as drug response markers and three as risk factors for drug response. Only seventeen of these were replicated, with accuracy (up to 95%) in predicting PGx outcomes specific to six ASMs. Eight out of seventeen variants have FDA-approved PGx drug labelling for clinical implementation. Therefore, the remaining nine variants promise for potential clinical actionability and can be improvised with additional experimental evidence for clinical utility.

由于异质综合征、不同的癫痫类型和较高的个体差异，癫痫治疗具有挑战性。识别遗传变异以预测抗癫痫药物 (ASM) 的药物疗效、耐受性和不良反应风险至关重要。在这里，我们根据已知遗传变异的功能和临床意义评估其临床可操作性，并估计其诊断可预测性。我们进行了系统的 PubMed 搜索，以识别包含 40 种已知 ASM 的药物基因组 (PGx) 信息的文章。使用不同的计算机工具对已识别的遗传变异进行功能注释，并使用美国医学遗传学学会 (ACMG) 变异致病性指南、PharmGKB 和美国食品管理局的证据水平 (LOE) 评估其临床意义以及药物管理局 (US-FDA) 带有 PGx 信息的药物标签。通过计算复制的遗传变异的准确性来评估其诊断可预测性。总共检索到 270 篇文章，其中 PGx 证据与 19 个 ASM 相关，包括 93 个基因的 178 个变异，将 26 个遗传变异分类为良性/可能良性，14 个遗传变异作为药物反应标记，3 个作为药物反应的危险因素。其中只有 17 个被重复，在预测针对 6 个 ASM 的 PGx 结果时准确率高达 95%。十七种变体中有八种具有 FDA 批准的用于临床实施的 PGx 药物标签。因此，其余九种变体有望具有潜在的临床可操作性，并且可以通过额外的临床实用性实验证据即兴发挥。