Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe-University Frankfurt, Frankfurt am Main, Germany.
Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, Frankfurt am Main, Germany.
Epilepsia Open. 2023 Jun;8(2):497-508. doi: 10.1002/epi4.12719. Epub 2023 Mar 17.
The phenotypic and genotypic spectrum of adult patients with epilepsy and intellectual disability (ID) is less clear than in children. We investigated an adult patient cohort to further elucidate this and inform the genetic testing approach.
Fifty-two adult patients (30 male, 22 female) with epilepsy, at least mild ID and no known genetic or acquired cause were included and phenotyped. Variants identified through exome sequencing were evaluated using ACMG criteria. Identified variants were compared with commercially available gene panels. Cluster analysis of two features, age at seizure onset and age at ascertainment of cognitive deficits, was performed.
Median age was 27 years (range 20-57 years) with median seizure onset at 3 years and median ascertainment of cognitive deficits at 1 year. Likely pathogenic/pathogenic variants were identified in 16/52 patients (31%) including 14 (27%) single nucleotide variants and 2 (4%) copy number variants. Simulated yield of commercial gene panels varied between 13% in small (≤144 genes) and 27% in large panels (≥1478 genes). Cluster analysis (optimal number 3 clusters) identified a cluster with early seizure onset and early developmental delay (developmental and epileptic encephalopathy, n = 26), a cluster with early developmental delay but late seizure onset (ID with epilepsy, n = 16) and a third cluster with late ascertainment of cognitive deficits and variable seizure onset (n = 7). The smaller gene panels particularly missed the genes identified in the cluster with early ascertainment of cognitive deficits and later onset of epilepsy (0/4) as opposed to the cluster with developmental and epileptic encephalopathy (7/10).
Our data indicates that adult patients with epilepsy and ID represent a heterogeneous cohort that includes grown-up patients with DEE but also patients with primary ID and later onset of epilepsy. To maximize diagnostic yield in this cohort either large gene panels or exome sequencing should be used.
与儿童相比，患有癫痫和智力障碍（ID）的成年患者的表型和基因型谱不太明确。我们调查了一组成年患者，以进一步阐明这一点，并为基因检测方法提供信息。
纳入 52 名患有癫痫、至少轻度 ID 且无已知遗传或获得性病因的成年患者进行表型分析。通过外显子组测序鉴定的变异体使用 ACMG 标准进行评估。将鉴定出的变异体与商业上可用的基因组合进行比较。对两个特征（癫痫发作年龄和认知缺陷确诊年龄）进行聚类分析。
中位年龄为 27 岁（范围 20-57 岁），中位癫痫发作年龄为 3 岁，中位认知缺陷确诊年龄为 1 岁。在 52 名患者中发现了 16 名（31%）可能具有致病性/致病性的变异体，包括 14 名（27%）单核苷酸变异体和 2 名（4%）拷贝数变异体。商业基因组合的模拟检出率在小（≤144 个基因）和大（≥1478 个基因）面板之间分别为 13%和 27%。聚类分析（最佳聚类数为 3 个聚类）确定了一个具有早期癫痫发作和早期发育迟缓的聚类（发育性和癫痫性脑病，n=26）、一个具有早期发育迟缓但晚期癫痫发作的聚类（癫痫伴 ID，n=16）和第三个聚类认知缺陷和可变癫痫发作的确诊时间较晚（n=7）。较小的基因组合特别错过了在认知缺陷和癫痫发作较晚确诊的聚类中发现的基因（0/4），而不是在发育性和癫痫性脑病的聚类中发现的基因（7/10）。
我们的数据表明，患有癫痫和 ID 的成年患者代表一个异质性队列，其中包括患有 DEE 的成年患者，但也包括患有原发性 ID 和癫痫发作较晚的患者。为了最大限度地提高该队列的诊断效果，应使用大基因组合或外显子组测序。
