Miller Katherine E, Koboldt Daniel C, Schieffer Kathleen M, Bedrosian Tracy A, Crist Erin, Sheline Adrienne, Leraas Kristen, Magrini Vincent, Zhong Huachun, Brennan Patrick, Bush Jocelyn, Fitch James, Bir Natalie, Miller Anthony R, Cottrell Catherine E, Leonard Jeffrey, Pindrik Jonathan A, Rusin Jerome A, Shah Summit H, White Peter, Wilson Richard K, Mardis Elaine R, Pierson Christopher R, Ostendorf Adam P
The Steve and Cindy Rasmussen Institute for Genomic Medicine (K.E.M., D.C.K., K.M.S., T.A.B., E.C., K.L., V.M., H.Z., P.B., J.B., J.F., N.B., A.R.M., C.E.C., P.W., R.K.W., E.R.M.), Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH; Division of Genetic and Genomic Medicine (E.C.), Nationwide Children's Hospital, Columbus, OH; Department of Neurosurgery (A.S., J.L., J.A.P.), Nationwide Children's Hospital, Columbus, OH; Department of Pathology and Laboratory Medicine (C.R.P.), Nationwide Children's Hospital, Columbus, OH; Division of Child Neurology (A.P.O.), Nationwide Children's Hospital, Columbus, OH; Department of Radiology (J.A.R., S.H.S), Nationwide Children's Hospital, Columbus, OH; Department of Pediatrics (D.C.K., V.M., C.E.C., J.L., P.W., R.K.W, E.R.M., A.P.O.), The Ohio State University College of Medicine, Columbus, OH; Department of Neurosurgery (J.L., J.A.P., A.P.O.), The Ohio State University College of Medicine, Columbus, OH; Department of Pathology (C.E.C., C.R.P.), The Ohio State University College of Medicine, Columbus, OH; and Department of Biomedical Education & Anatomy (C.R.P.), Division of Anatomy, The Ohio State University College of Medicine, Columbus, OH.
Neurol Genet. 2020 Jun 17;6(4):e460. doi: 10.1212/NXG.0000000000000460. eCollection 2020 Aug.
Many genetic studies of intractable epilepsy in pediatric patients primarily focus on inherited, constitutional genetic deficiencies identified in patient blood. Recently, studies have revealed somatic mosaicism associated with epilepsy in which genetic variants are present only in a subset of brain cells. We hypothesize that tissue-specific, somatic mosaicism represents an important genetic etiology in epilepsy and aim to discover somatic alterations in epilepsy-affected brain tissue.
We have pursued a research study to identify brain somatic mosaicism, using next-generation sequencing (NGS) technologies, in patients with treatment refractory epilepsy who have undergone surgical resection of affected brain tissue.
We used an integrated combination of NGS techniques and conventional approaches (radiology, histopathology, and electrophysiology) to comprehensively characterize multiple brain regions from a single patient with intractable epilepsy. We present a 3-year-old male patient with West syndrome and intractable tonic seizures in whom we identified a pathogenic frameshift somatic variant in , present at a range of variant allele fractions (4.2%-19.5%) in 12 different brain tissues detected by targeted sequencing. The proportion of the variant correlated with severity and location of neurophysiology and neuroimaging abnormalities for each tissue.
Our findings support the importance of tissue-based sequencing and highlight a correlation in our patient between variant allele fractions and the severity of epileptogenic phenotypes in different brain tissues obtained from a grid-based resection of clinically defined epileptogenic regions.
许多针对小儿难治性癫痫的基因研究主要集中在患者血液中发现的遗传性、先天性基因缺陷。最近，研究揭示了与癫痫相关的体细胞镶嵌现象，其中基因变异仅存在于一部分脑细胞中。我们假设组织特异性体细胞镶嵌现象是癫痫的一种重要遗传病因，并旨在发现癫痫受累脑组织中的体细胞改变。
我们开展了一项研究，利用下一代测序（NGS）技术，在接受了受累脑组织手术切除的难治性癫痫患者中识别脑体细胞镶嵌现象。
我们使用了NGS技术与传统方法（放射学、组织病理学和电生理学）的综合组合，以全面表征一名难治性癫痫患者的多个脑区。我们报告了一名患有韦斯特综合征和难治性强直发作的3岁男性患者，在该患者中，我们通过靶向测序在检测的12种不同脑组织中，于[具体基因]中鉴定出一个致病性移码体细胞变异，变异等位基因分数范围为4.2% - 19.5%。该变异的比例与每个组织的神经生理学和神经影像学异常的严重程度及位置相关。
我们的研究结果支持基于组织的测序的重要性，并突出了在我们的患者中，变异等位基因分数与从临床定义的致痫区域基于网格的切除所获得的不同脑组织中癫痫发作表型的严重程度之间的相关性。
