Beyond the identification of causal genetic variants in the diagnosis of Mendelian disorders, exome sequencing can detect numerous variants with potential relevance for clinical care. Clinical interventions can thus be conducted to improve future health outcomes for patients and their at-risk relatives, such as predicting late-onset genetic disorders accessible to prevention, treatment or identifying differential drug efficacy and safety. To evaluate the interest of such pharmacogenetic information, we designed an “in house” pipeline to determine the status of 122 PharmGKB (Pharmacogenomics Knowledgebase) variant-drug combinations in 31 genes. This pipeline was applied to a cohort of 90 epileptic patients who had previously an exome sequencing (ES) analysis, to determine the frequency of pharmacogenetic variants. We performed a retrospective analysis of drug plasma concentrations and treatment efficacy in patients bearing at least one relevant PharmGKB variant. For PharmGKB level 1A variants, CYP2C9 status for phenytoin prescription was the only relevant information. Nineteen patients were treated with phenytoin, among phenytoin-treated patients, none were poor metabolizers and four were intermediate metabolizers. While being treated with a standard protocol (10–23 mg/kg/30 min loading dose followed by 5 mg/kg/8 h maintenance dose), all identified intermediate metabolizers had toxic plasma concentrations (20 mg/L). In epileptic patients, pangenomic sequencing can provide information about common pharmacogenetic variants likely to be useful to guide therapeutic drug monitoring, and in the case of phenytoin, to prevent clinical toxicity caused by high plasma levels.

除了在孟德尔疾病的诊断中识别致病基因变异外，外显子组测序还可以检测出许多与临床护理具有潜在相关性的变异。因此，可以进行临床干预以改善患者及其处于危险中的亲属未来的健康结果，例如预测可预防、治疗的迟发性遗传病或确定不同的药物疗效和安全性。为了评估此类药物遗传学信息的重要性，我们设计了一个“内部”管道来确定 31 个基因中 122 个 PharmGKB（药物基因组学知识库）变异药物组合的状态。该管道应用于一组 90 名先前进行过外显子组测序 (ES) 分析的癫痫患者，以确定药物遗传学变异的频率。我们对携带至少一种相关 PharmGKB 变体的患者的药物血浆浓度和治疗效果进行了回顾性分析。对于 PharmGKB 1A 级变体，苯妥英处方的CYP2C9状态是唯一的相关信息。19 名患者接受了苯妥英钠治疗，在接受苯妥英钠治疗的患者中，没有一名是弱代谢者，四名是中间代谢者。在接受标准方案（10–23 mg/kg/30 分钟负荷剂量，然后是 5 mg/kg/8 小时维持剂量）治疗时，所有已识别的中间代谢者都具有毒性血浆浓度 (20 mg/L)。在癫痫患者中，泛基因组测序可以提供有关常见药物遗传学变异的信息，这些变异可能有助于指导治疗药物监测，并且在苯妥英的情况下，可以防止高血浆水平引起的临床毒性。