IFIH1 variants are associated with generalised epilepsy preceded by febrile seizures.

IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Journal of Medical Genetics Pub Date : 2024-08-29 DOI:10.1136/jmg-2024-109950
Wang Song, Wen-Jun Bian, Hua Li, Qing-Hui Guo, Jie Wang, Bin Tang, Jia-Yuan Zhang, Wei Wei, Xiao-Rong Liu, Wei-Ping Liao, Bin Li, Na He
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Abstract

Background: IFIH1 variants have been reported to be associated with immune-related disorders with/without seizures. It is unknown whether IFIH1 variants are associated with common epilepsy without acquired causes and the mechanism underlying phenotypic variation remains elusive.

Methods: Trio-based whole-exome sequencing was performed on patients with febrile seizures or epilepsy with antecedent febrile seizures. Previously reported variants were systematically reviewed to investigate genotype-phenotype associations.

Results: Two de novo heterozygous and three biallelic missense variants were identified in five patients with generalised epilepsy with antecedent febrile seizures. The variants were predicted to be damaging by in silico tools and were associated with hydrogen bonding changes to neighbouring amino acids or decreased protein stability. Patients exhibited an early onset age and became seizure-free with favourable outcome. Further analysis revealed that de novo missense variants located in the Hel region resulted in seizures with multiple neurological abnormalities, while those in the pincer domain or C-terminal domain led to seizures with normal neurodevelopment, suggesting a sub-molecular effect. Biallelic missense variants, which were inherited from unaffected parents and presented low allele frequencies in general populations, were associated with seizures without neurological abnormalities. Truncation variants were related to refractory epilepsy and severe developmental delay, suggesting a genotype-phenotype correlation. IFIH1 is predominantly expressed in the neonatal stage and decreases dramatically in the adulthood, which is consistent with the early onset age and favourable outcome of the patients.

Conclusions: IFIH1 variants are potentially associated with generalised epilepsy with antecedent febrile seizures. The sub-molecular implication and genotype-phenotype association help explain phenotype variations of IFIH1 variants.

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IFIH1 变异与发热性癫痫发作前的全身性癫痫有关。
背景:据报道,IFIH1变异与伴有/不伴有癫痫发作的免疫相关疾病有关。目前尚不清楚IFIH1变异是否与无后天原因的常见癫痫有关,表型变异的机制也仍未确定:方法:对发热性癫痫发作患者或有先兆发热性癫痫发作的癫痫患者进行了基于三重全外显子组测序。方法:对发热性癫痫发作患者或先兆发热性癫痫发作的癫痫患者进行了基于三重全外显子组测序,并系统回顾了之前报道的变异,以研究基因型与表型的关联:结果:在五名先有发热性癫痫发作的全身性癫痫患者中发现了两个新发杂合变异和三个双叶错义变异。硅学工具预测这些变异具有损伤性,并与邻近氨基酸的氢键变化或蛋白质稳定性降低有关。患者的发病年龄较早,且无癫痫发作,预后良好。进一步的分析表明,位于Hel区域的从头错义变异会导致癫痫发作和多种神经系统异常,而位于钳状结构域或C-末端结构域的错义变异则会导致癫痫发作和正常的神经发育,这表明存在亚分子效应。双拷贝错义变体是从未受影响的父母那里遗传来的,在一般人群中等位基因频率较低,与无神经系统异常的癫痫发作有关。截断变异与难治性癫痫和严重发育迟缓有关,这表明基因型与表型之间存在相关性。IFIH1主要在新生儿期表达,成年后急剧下降,这与患者的早期发病年龄和良好的预后是一致的:结论:IFIH1变体可能与先兆发热性癫痫发作的全身性癫痫有关。IFIH1变体的亚分子影响和基因型-表型关联有助于解释IFIH1变体的表型变化。
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来源期刊
Journal of Medical Genetics
Journal of Medical Genetics 医学-遗传学
CiteScore
7.60
自引率
2.50%
发文量
92
审稿时长
4-8 weeks
期刊介绍: Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.
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