Gallagher Declan, Pérez-Palma Eduardo, Bruenger Tobias, Ghanty Ismael, Brilstra Eva, Ceulemans Berten, Chemaly Nicole, de Lange Iris, Depienne Christel, Guerrini Renzo, Mei Davide, Møller Rikke S, Nabbout Rima, Regan Brigid M, Schneider Amy L, Scheffer Ingrid E, Schoonjans An-Sofie, Symonds Joseph D, Weckhuysen Sarah, Zuberi Sameer M, Lal Dennis, Brunklaus Andreas
School of Health and Wellbeing, University of Glasgow, Glasgow, UK.
Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK.
Epilepsia. 2024 Apr;65(4):1046-1059. doi: 10.1111/epi.17882. Epub 2024 Feb 27.
SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype-phenotype associations remain poorly understood.
We assessed data from a retrospective cohort of 1018 individuals with SCN1A-related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), SCN1A genetic score), seizure characteristics, and epilepsy phenotype.
DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0 months, p < .001). In silico variant scores were higher in DS versus GEFS+ (p < .001). Patients with missense variants in functionally important regions (conserved N-terminus, S4-S6) exhibited earlier seizure onset (6.0 vs. 7.0 months, p = .003) and were more likely to have DS (280/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0 months, p = .036) and were more likely to have GEFS+ (15/29, χ = 19.16, p < .001). A minority of protein-truncating variants were associated with GEFS+ (10/393) and more likely to be located in the proximal first and last exon coding regions than elsewhere in the gene (9.7% vs. 1.0%, p < .001). Carriers of the same missense variant exhibited less variability in age at seizure onset compared with carriers of different missense variants for both DS (1.9 vs. 2.9 months, p = .001) and GEFS+ (8.0 vs. 11.0 months, p = .043). Status epilepticus as presenting seizure type is a highly specific (95.2%) but nonsensitive (32.7%) feature of DS.
Understanding genotype-phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS.
SCN1A基因变异与多种癫痫综合征相关，范围从轻度伴热性惊厥附加症的遗传性癫痫（GEFS+）到严重的德雷维特综合征（DS）。许多变异是新发的，这使得早期表型预测困难，并且基因型与表型的关联仍知之甚少。
我们评估了来自1018例与SCN1A相关癫痫患者的回顾性队列数据。我们探究了变异特征（位置、计算机预测分数：综合注释依赖损耗（CADD）、罕见外显子变异集成学习器（REVEL）、SCN1A基因分数）、癫痫发作特征和癫痫表型之间的关系。
DS的癫痫发作起始比其他GEFS+表型更早（5.3个月对12.0个月，p < 0.001）。与GEFS+相比，DS的计算机变异分数更高（p < 0.001）。在功能重要区域（保守的N端、S4 - S6）有错义变异的患者癫痫发作起始更早（6.0个月对7.0个月，p = 0.003），并且更有可能患DS（280/340）；在非保守区域有错义变异的患者发作起始较晚（10.0个月对7.0个月，p = 0.036），并且更有可能患GEFS+（15/29，χ = 19.16，p < 0.001）。少数蛋白质截短变异与GEFS+相关（10/393），并且比基因中其他位置更有可能位于近端的第一个和最后一个外显子编码区域（9.7%对1.0%，p < 0.001）。与不同错义变异携带者相比，相同错义变异携带者在癫痫发作起始年龄上的变异性更小，DS患者中分别为1.9个月对2.9个月（p = 0.001），GEFS+患者中分别为8.0个月对11.0个月（p = 0.043）。癫痫持续状态作为首发癫痫发作类型是DS的一个高度特异性（95.2%）但不敏感（32.7%）的特征。
了解SCN1A相关癫痫中的基因型 - 表型关联对于早期诊断和管理至关重要。我们证明了在重要功能区域有错义变异的患者疾病起始更早、GEFS+截短变异的发生情况以及计算机预测分数的价值。癫痫持续状态作为初始癫痫发作类型是DS的一个高度特异性但不敏感的早期特征。
