Epilepsy Center and Neurology Department of Children's Hospital of Soochow University, Suzhou 215000, China.
Neurogenetic Group, Department of Neurology, Shenzhen Children's Hospital, Shenzhen 518000, China.
Seizure. 2024 Mar;116:113-118. doi: 10.1016/j.seizure.2023.10.008. Epub 2023 Oct 21.
The genetic causes of epilepsy with unknown etiology in most patients remain unknown. The aim of this study was to elucidate the phenotype of SCAF4-related epilepsy.
Trio-based whole-exome sequencing was performed in patients with epilepsy. Silico programs and protein modeling were employed to predict the damaging of variants. Previously reported SCAF4 variants were systematically reviewed to analyze the genotype-phenotype correlations.
Three heterozygous variants in the SCAF4 were detected in three cases, including one missense variant and two frameshift variants. All variants were de novo. None of these variants is present in gnomAD controls. The missense variant was predicted to be damaging in silico tools. Protein modeling showed that two frameshift variants resulted in loss of domains, and the missense variant may disrupt a nearby phosphorylation site and alter the hydrogen bonds around 54C and the stability of the SCAF4 protein. Intellectual development was mildly delayed for all patients except for one with whom contact was lost. All probands experienced epilepsy as infrequent seizures, responded well to antiseizure drugs, and had a median [IQR] seizure onset age of 4 [1.75, 7.5] years. The variants in the domain-encoding exons and upstream exons exhibited a strong association with epilepsy.
SCAF4 is a potential causative gene of epilepsy with neurodevelopmental disorders.
大多数病因不明的癫痫患者的遗传病因仍不清楚。本研究旨在阐明 SCAF4 相关癫痫的表型。
对癫痫患者进行基于三亲体的全外显子组测序。采用计算机程序和蛋白质建模来预测变异的破坏性。系统回顾了先前报道的 SCAF4 变异，以分析基因型-表型相关性。
在 3 例患者中检测到 SCAF4 中的 3 个杂合变异，包括 1 个错义变异和 2 个移码变异。所有变异均为新生。这些变异均不在 gnomAD 对照中。错义变异在计算机工具中被预测为具有破坏性。蛋白质建模表明，两个移码变异导致结构域丢失，而错义变异可能破坏附近的磷酸化位点，并改变 54C 周围的氢键和 SCAF4 蛋白的稳定性。除了一个失去联系的患者外，所有患者的智力发育都有轻度延迟。所有先证者均表现为偶发性癫痫发作，抗癫痫药物反应良好，发病中位年龄[IQR]为 4 [1.75, 7.5]岁。结构域编码外显子和上游外显子中的变异与癫痫有很强的相关性。
SCAF4 是一种潜在的伴神经发育障碍的癫痫致病基因。
