Diagnostic yield of genetic testing in epileptic encephalopathy in childhood
Diagnostic yield of genetic testing in epileptic encephalopathy in childhood
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DOI：
10.1111/epi.12954
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发表时间：
2015-05-01
期刊：
影响因子：
5.6
通讯作者：
Snead, O. Carter
中科院分区：
文献类型：
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作者：
Mercimek-Mahmutoglu, Saadet;Patel, Jaina;Snead, O. Carter
目的癫痫是儿童期常见的神经系统疾病。为了确定癫痫性脑病的遗传诊断率，我们在单个癫痫遗传学诊所进行了回顾性队列研究。方法我们纳入了 2012 年 1 月至 2014 年 6 月在癫痫遗传学诊所出现的所有顽固性癫痫、整体发育迟缓和认知功能障碍患者。我们对电子病历进行了临床特征、神经影像学、生化研究和分子遗传学研究，包括癫痫性脑病基因的下一代靶向测序。结果在 110 名患者中，有 28% 确定了遗传原因：7% 患有遗传性代谢性疾病，包括由 ALDH7A1 突变引起的吡哆醇依赖性癫痫、门克斯病、吡哆醇 5-磷酸氧化酶缺乏症、钴胺素 G 缺乏症、亚甲基四氢叶酸还原酶缺乏症、葡萄糖转运蛋白1缺乏症、甘氨酸脑病和丙酮酸脱氢酶复合物缺乏症； 21% 的人患有其他遗传原因，包括遗传综合征、阵列比较基因组杂交的致病性拷贝数变异，以及与 SCN1A、SCN2A、SCN8A、KCNQ2、STXBP1、PCDH19 和 SLC9A6 基因突变相关的癫痫性脑病。 45% 的患者通过靶向下一代测序癫痫性脑病小组获得了基因诊断。值得注意的是，4.5% 的患者患有可治疗的遗传性代谢性疾病。 意义 据我们所知，这是第一项将遗传性代谢性疾病与癫痫性脑病的其他遗传原因结合起来的研究。靶向下一代测序面板将癫痫性脑病患者的基因诊断率从 25% 提高了。
ObjectiveEpilepsy is a common neurologic disorder of childhood. To determine the genetic diagnostic yield in epileptic encephalopathy, we performed a retrospective cohort study in a single epilepsy genetics clinic.MethodsWe included all patients with intractable epilepsy, global developmental delay, and cognitive dysfunction seen between January 2012 and June 2014 in the Epilepsy Genetics Clinic. Electronic patient charts were reviewed for clinical features, neuroimaging, biochemical investigations, and molecular genetic investigations including targeted next-generation sequencing of epileptic encephalopathy genes.ResultsGenetic causes were identified in 28% of the 110 patients: 7% had inherited metabolic disorders including pyridoxine dependent epilepsy caused by ALDH7A1 mutation, Menkes disease, pyridox(am)ine-5-phosphate oxidase deficiency, cobalamin G deficiency, methylenetetrahydrofolate reductase deficiency, glucose transporter 1 deficiency, glycine encephalopathy, and pyruvate dehydrogenase complex deficiency; 21% had other genetic causes including genetic syndromes, pathogenic copy number variants on array comparative genomic hybridization, and epileptic encephalopathy related to mutations in the SCN1A, SCN2A, SCN8A, KCNQ2, STXBP1, PCDH19, and SLC9A6 genes. Forty-five percent of patients obtained a genetic diagnosis by targeted next-generation sequencing epileptic encephalopathy panels. It is notable that 4.5% of patients had a treatable inherited metabolic disease.SignificanceTo the best of our knowledge, this is the first study to combine inherited metabolic disorders and other genetic causes of epileptic encephalopathy. Targeted next-generation sequencing panels increased the genetic diagnostic yield from 25% in patients with epileptic encephalopathy.