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 SLC35A2, 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 SLC35A2 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 SLC35A2 variant allele fractions and the severity of epileptogenic phenotypes in different brain tissues obtained from a grid-based resection of clinically defined epileptogenic regions.

许多儿科患者顽固性癫痫的遗传学研究主要集中在患者血液中发现的遗传性、体质性遗传缺陷。最近，研究揭示了与癫痫相关的体细胞嵌合体，其中遗传变异仅存在于脑细胞的一个子集中。我们假设组织特异性体细胞嵌合体代表了癫痫的重要遗传病因，旨在发现受癫痫影响的脑组织中的体细胞改变。

我们进行了一项研究，以使用下一代测序 (NGS) 技术在接受手术切除受影响脑组织的难治性癫痫患者中识别脑体细胞嵌合体。

我们使用 NGS 技术和传统方法（放射学、组织病理学和电生理学）的综合组合来全面表征单个难治性癫痫患者的多个大脑区域。我们介绍了一名患有 West 综合征和顽固性强直性癫痫发作的 3 岁男性患者，我们在该患者中发现了SLC35A2中的致病性移码体细胞变异，在检测到的 12 个不同脑组织中存在一系列变异等位基因分数（4.2%–19.5%）通过靶向测序。SLC35A2变体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和位置相关。

我们的研究结果支持基于组织的测序的重要性，并强调了我们患者SLC35A2变异等位基因分数与从临床定义的致癫痫区域的基于网格的切除获得的不同脑组织中致癫痫表型的严重程度之间的相关性。