Abstract：
OBJECTIVE: To expand the clinical phenotype and mutation spectrum of familial mesial temporal lobe epilepsy (FMTLE) and provide a new perspective for exploring the pathological mechanisms of epilepsy caused by leucine-rich glioma inactivated 1 (LGI1) variants.
METHODS: We reported clinical data from two families with FMTLE and screened patients for variants in the LGI1 gene using Whole-exome sequencing and Sanger sequencing. The clinical features of FMTLE were analysed. The pathogenicity of the causative loci was assessed according to the American College of Medical Genetics and Genomics guidelines, and potential pathogenic mechanisms were predicted through multiple bioinformatics and molecular dynamics software.
RESULTS: We identified two novel LGI1 truncating variants within two large families with FMTLE: LGI1 (c.1174C>T, p.Q392X) and LGI1 (c.703C>T, p.Q235X). Compared to previous reports, we found that focal to bilateral tonic-clonic seizures are a common type of seizure in FMTLE. The clinical phenotypes of patients with FMTLE caused by LGI1 variants were relatively mild, and all patients responded well to valproic acid. Bioinformatics analyses and molecular dynamics simulations showed that protein structure and interactions were considerably weakened or damaged as a result of both variants.
CONCLUSIONS: This study presents the first report identifying LGI1 as a potential novel pathogenic gene within FMTLE families, thereby broadening the mutation spectrum associated with FMTLE. The findings of this study offer novel insights and avenues for understanding the intricate molecular mechanisms underlying LGI1 variants and their correlations with patient phenotypes. This study proposes the possibility of familial focal epilepsy syndromes overlapping.
METHODS: We reported clinical data from two families with FMTLE and screened patients for variants in the LGI1 gene using Whole-exome sequencing and Sanger sequencing. The clinical features of FMTLE were analysed. The pathogenicity of the causative loci was assessed according to the American College of Medical Genetics and Genomics guidelines, and potential pathogenic mechanisms were predicted through multiple bioinformatics and molecular dynamics software.
RESULTS: We identified two novel LGI1 truncating variants within two large families with FMTLE: LGI1 (c.1174C>T, p.Q392X) and LGI1 (c.703C>T, p.Q235X). Compared to previous reports, we found that focal to bilateral tonic-clonic seizures are a common type of seizure in FMTLE. The clinical phenotypes of patients with FMTLE caused by LGI1 variants were relatively mild, and all patients responded well to valproic acid. Bioinformatics analyses and molecular dynamics simulations showed that protein structure and interactions were considerably weakened or damaged as a result of both variants.
CONCLUSIONS: This study presents the first report identifying LGI1 as a potential novel pathogenic gene within FMTLE families, thereby broadening the mutation spectrum associated with FMTLE. The findings of this study offer novel insights and avenues for understanding the intricate molecular mechanisms underlying LGI1 variants and their correlations with patient phenotypes. This study proposes the possibility of familial focal epilepsy syndromes overlapping.
摘要：
目的：扩大家族性内侧颞叶癫痫(FMTLE)的临床表型和突变谱,为探索富亮氨酸胶质瘤灭活1(LGI1)变异体致癫痫的病理机制提供新的视角。
方法：我们报告了来自两个FMTLE家族的临床数据，并使用全外显子组测序和Sanger测序筛选了患者的LGI1基因变异。分析FMTLE的临床特点。根据美国医学遗传学和基因组学学会指南评估致病位点的致病性，并通过多种生物信息学和分子动力学软件预测潜在的致病机制。
结果：我们在两个大型FMTLE家族中鉴定了两个新的LGI1截短变体：LGI1（c.1174C>T，p.Q392X）和LGI1（c.703C>T，p.Q235X)。与以前的报告相比，我们发现,在FMTLE中,局灶性至双侧强直阵挛性癫痫发作是常见的癫痫发作类型.LGI1变异引起的FMTLE患者的临床表型相对较轻，所有患者对丙戊酸反应良好。生物信息学分析和分子动力学模拟表明，由于这两种变体，蛋白质结构和相互作用被大大削弱或破坏。
结论：本研究首次报告将LGI1鉴定为FMTLE家族中潜在的新型致病基因，从而拓宽与FMTLE相关的突变谱。这项研究的发现为理解LGI1变异的复杂分子机制及其与患者表型的相关性提供了新的见解和途径。这项研究提出了家族性局灶性癫痫综合征重叠的可能性。
方法：我们报告了来自两个FMTLE家族的临床数据，并使用全外显子组测序和Sanger测序筛选了患者的LGI1基因变异。分析FMTLE的临床特点。根据美国医学遗传学和基因组学学会指南评估致病位点的致病性，并通过多种生物信息学和分子动力学软件预测潜在的致病机制。
结果：我们在两个大型FMTLE家族中鉴定了两个新的LGI1截短变体：LGI1（c.1174C>T，p.Q392X）和LGI1（c.703C>T，p.Q235X)。与以前的报告相比，我们发现,在FMTLE中,局灶性至双侧强直阵挛性癫痫发作是常见的癫痫发作类型.LGI1变异引起的FMTLE患者的临床表型相对较轻，所有患者对丙戊酸反应良好。生物信息学分析和分子动力学模拟表明，由于这两种变体，蛋白质结构和相互作用被大大削弱或破坏。
结论：本研究首次报告将LGI1鉴定为FMTLE家族中潜在的新型致病基因，从而拓宽与FMTLE相关的突变谱。这项研究的发现为理解LGI1变异的复杂分子机制及其与患者表型的相关性提供了新的见解和途径。这项研究提出了家族性局灶性癫痫综合征重叠的可能性。
