Abstract

The terms developmental epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS) and epileptic encephalopathy with spike-and-wave activation in sleep (EE-SWAS) designate a spectrum of conditions that are typified by different combinations of motor, cognitive, language, and behavioral regression linked to robust spike-and-wave activity during sleep. In this study, we aimed at describing the clinical and molecular findings in “(developmental) epileptic encephalopathy with spike-and-wave activation in sleep” (D)EE-SWAS) patients as well as at contributing to the genetic etiologic spectrum of (D)EE-SWAS. Single nucleotide polymorphism (SNP) array and whole-exome sequencing (WES) techniques were used to determine the underlying genetic etiologies. Of the 24 patients included in the study, 8 (33%) were female and 16 (67%) were male. The median age at onset of the first seizure was 4 years and the median age at diagnosis of (D)EE-SWAS was 5 years. Of the 24 cases included in the study, 13 were compatible with the clinical diagnosis of DEE-SWAS and 11 were compatible with the clinical diagnosis of EE-SWAS. Abnormal perinatal history was present in four cases (17%), and two cases (8%) had a family history of epilepsy. Approximately two-thirds (63%) of all patients had abnormalities detected on brain computerized tomography/magnetic resonance (CT/MR) imaging. After SNP array and WES analysis, the genetic etiology was revealed in 7 out of 24 (29%) cases. Three of the variants detected were novel (SLC12A5, DLG4, SLC9A6). This study revealed for the first time that Smith-Magenis syndrome, SCN8A-related DEE type 13 and SLC12A5 gene variation are involved in the genetic etiology of (D)EE-SWAS. (D)EE-SWAS is a genetically diverse disorder with underlying copy number variations and single-gene abnormalities. In the current investigation, rare novel variations in genes known to be related to (D)EE-SWAS and not previously reported genes to be related to (D)EE-SWAS were discovered, adding to the molecular genetic spectrum. Molecular etiology enables the patient and family to receive thorough and accurate genetic counseling as well as a personalized medicine approach.

中文翻译：

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通过睡眠中的棘波激活扩大（发育性）癫痫性脑病的临床和遗传景观：土耳其队列研究的结果

摘要

术语“睡眠中伴有棘波激活的发育性癫痫性脑病”(DEE-SWAS) 和“睡眠中伴有棘波激活的癫痫性脑病”(EE-SWAS) 指的是一系列以运动、认知、语言和行为退化与睡眠期间强烈的尖波活动有关。在这项研究中，我们旨在描述“睡眠中伴有棘波激活的（发育性）癫痫性脑病”（D）EE-SWAS）患者的临床和分子发现，以及对（ D）EE-SWAS 。使用单核苷酸多态性（SNP）阵列和全外显子组测序（WES）技术来确定潜在的遗传病因。在该研究纳入的 24 名患者中，8 名 (33%) 为女性，16 名 (67%) 为男性。首次癫痫发作时的中位年龄为 4 岁，诊断 (D)EE-SWAS 时的中位年龄为 5 岁。研究纳入的24例病例中，13例符合DEE-SWAS的临床诊断，11例符合EE-SWAS的临床诊断。4例（17%）有异常围产史，2例（8%）有癫痫家族史。大约三分之二 (63%) 的患者在大脑计算机断层扫描/磁共振 (CT/MR) 成像中检测到异常。经过 SNP 阵列和 WES 分析，24 例中有 7 例 (29%) 揭示了遗传病因。检测到的三个变体是新的（SLC12A5、DLG4、SLC9A6）。该研究首次揭示了Smith-Magenis综合征、SCN8A相关的DEE 13型和SLC12A5基因变异与(D)EE-SWAS的遗传病因有关。(D)EE-SWAS 是一种遗传多样性疾病，具有潜在的拷贝数变异和单基因异常。在当前的研究中，发现了已知与 (D)EE-SWAS 相关的基因以及之前未报道的与 (D)EE-SWAS 相关的基因的罕见新变异，从而增加了分子遗传谱。分子病因学使患者和家人能够接受彻底、准确的遗传咨询以及个性化的医疗方法。