Wang Ting, Ouyang Shijia, Niu Xueyang, Cheng Miaomiao, Yang Ying, Yang Yonghua, Tan Quanzhen, Liu Wenwei, Yang Xiaoling, Zhang Yuehua
Children's Medical Center of Peking University First Hospital, Beijing, China.
Department of Respiratory, Beijing Children's Hospital, Capital Medical University, Beijing, China.
Front Neurosci. 2025 Jun 6;19:1570997. doi: 10.3389/fnins.2025.1570997. eCollection 2025.
To explore the genotypic spectrum and refine the genotype-phenotype correlation of -related developmental and epileptic encephalopathy (DEE).
whole-exome sequencing or whole-genome sequencing was performed to all patients. Clinical data of 15 epilepsy patients in current study and 21 epilepsy patients from published studies were collected and analyzed.
In this study, 15 patients were identified with 13 variants. Among these, seven frameshift variants and one gene inversion between intron 11 and intron 13 (including exons 12 and 13) were novel. 80% of patients experiencing seizure onset before the age of one. The seizure types observed included epileptic spasms (93.3%), tonic seizures (46.7%), myoclonic seizures (46.7%), focal seizures (40.0%), atypical absence seizures (13.3%), generalized tonic-clonic seizures (6.7%) and myoclonic atonic seizures (6.7%). All patients exhibited global developmental delay. MRI abnormalities were noticed in 9 patients, including widened subarachnoid space, bilateral ventricular width, poor myelination of white matter, and dysplasia of the corpus callosum. 80% specifically diagnosed with infantile epileptic spasms syndrome (IESS). When combining data from this study and published studies, 66.7% of patients experienced seizure onset before the age of one, and 77.8% were diagnosed with IESS. In patients with variants located in the catalytic domain (CD), 45.4% patients exhibited multiple seizure types, while 45.4% patients presented only with epileptic spasms. In contrast, among patients with variants in regulatory domain (RD), 87% had multiple seizure types and only 8.7% had epileptic spasms alone. Additionally, 45.5% of patients with CD variants had comorbid autism spectrum disorders, compared to 13% patients with RD variants. Recurrent variants included p.His92Arg, p.Asp234Glu, p.Glu282Lys, and p.Ser419Asnfs*31.
This study is the first to report a gene inversion in -related DEE. Patients with only epileptic spasms were more prevalent in those with CD variants, compared to those with RD variants. Conversely, patients with multiple seizure types were more common among those with RD variants. The most frequently diagnosed epileptic syndrome was IESS. Additionally, comorbid ASD were more commonly observed in patients with CD variants than in those with RD variants.
探索与发育性和癫痫性脑病（DEE）相关的基因型谱，并完善基因型与表型的相关性。
对所有患者进行全外显子组测序或全基因组测序。收集并分析了本研究中15例癫痫患者以及已发表研究中的21例癫痫患者的临床数据。
在本研究中，15例患者鉴定出13种变异。其中，7种移码变异以及内含子11和内含子13（包括外显子12和13）之间的1种基因倒位是新发现的。80%的患者在1岁前出现癫痫发作。观察到的癫痫发作类型包括婴儿痉挛症（93.3%）、强直发作（46.7%）、肌阵挛发作（46.7%）、局灶性发作（40.0%）、非典型失神发作（13.3%）、全身强直阵挛发作（6.7%）和肌阵挛失张力发作（6.7%）。所有患者均表现出全面发育迟缓。9例患者存在MRI异常，包括蛛网膜下腔增宽、双侧脑室增宽、白质髓鞘化不良以及胼胝体发育异常。80%的患者被明确诊断为婴儿痉挛症综合征（IESS）。将本研究数据与已发表研究数据相结合时，66.7%的患者在1岁前出现癫痫发作，77.8%的患者被诊断为IESS。在位于催化结构域（CD）的变异患者中，45.4%的患者表现出多种癫痫发作类型，而45.4%的患者仅表现为婴儿痉挛症。相比之下，在位于调节结构域（RD）的变异患者中，87%有多种癫痫发作类型，仅8.7%的患者仅有婴儿痉挛症。此外，45.5%的CD变异患者合并自闭症谱系障碍，而RD变异患者中这一比例为13%。反复出现的变异包括p.His92Arg、p.Asp234Glu、p.Glu282Lys和p.Ser419Asnfs*31。
本研究首次报道了与DEE相关的基因倒位。与RD变异患者相比，仅表现为婴儿痉挛症的患者在CD变异患者中更为普遍。相反，多种癫痫发作类型的患者在RD变异患者中更为常见。最常诊断的癫痫综合征是IESS。此外，CD变异患者比RD变异患者更常观察到合并自闭症谱系障碍。
