Abstract：
BACKGROUND: Developmental and epileptic encephalopathy (DEE) exhibits phenotypic and genetic heterogeneity. Biallelic variants of the SZT2 gene can lead to DEE18, of which few cases have been reported. This study aimed to analyze the potential pathogenic factors in three cases of DEE18.
METHODS: Trio-whole exome sequencing and crystal structure simulation analysis were performed, along with a literature review of DEE18 cases.
RESULTS: All three patients had compound heterozygous variants in the SZT2 gene (patient 1, c.2887A > G/c.7970G > A; patient 2, c.3508A > G/c.7936C > T; and patient 3, c.2489G > T/c.8640_8641insC). The variants were predicted to have structural effects on the protein. Particularly, c.3508A > G/p.Ser1170Gly may lead to impaired binding of SZT2 to GATOR1, potentially resulting in the overactivation of the mTORC1 signaling pathway, causing seizures. Through the literature review, we observed that 27 patients with DEE had different degrees of intellectual and developmental disorders (DDs), and the variants leading to protein truncation cause severe DD and refractory epilepsy. Therefore, the phenotypic severity of patients may be related to the residual activity of variant SZT2 protein.
CONCLUSIONS: We provide recently developed knowledge on the DEE18 genotype-phenotype spectrum and suggest that gene detection is of great value for the accurate diagnosis of patients with early-onset epilepsy. Further research is required for the development of individualized interventions for patients with DEE.
METHODS: Trio-whole exome sequencing and crystal structure simulation analysis were performed, along with a literature review of DEE18 cases.
RESULTS: All three patients had compound heterozygous variants in the SZT2 gene (patient 1, c.2887A > G/c.7970G > A; patient 2, c.3508A > G/c.7936C > T; and patient 3, c.2489G > T/c.8640_8641insC). The variants were predicted to have structural effects on the protein. Particularly, c.3508A > G/p.Ser1170Gly may lead to impaired binding of SZT2 to GATOR1, potentially resulting in the overactivation of the mTORC1 signaling pathway, causing seizures. Through the literature review, we observed that 27 patients with DEE had different degrees of intellectual and developmental disorders (DDs), and the variants leading to protein truncation cause severe DD and refractory epilepsy. Therefore, the phenotypic severity of patients may be related to the residual activity of variant SZT2 protein.
CONCLUSIONS: We provide recently developed knowledge on the DEE18 genotype-phenotype spectrum and suggest that gene detection is of great value for the accurate diagnosis of patients with early-onset epilepsy. Further research is required for the development of individualized interventions for patients with DEE.
摘要：
背景：发育性和癫痫性脑病（DEE）表现出表型和遗传异质性。SZT2基因的双等位基因变体可导致DEE18，其中很少有病例报道。本研究旨在分析3例DEE18的潜在致病因素。
方法：进行三全外显子组测序和晶体结构模拟分析，并对DEE18例进行文献复习。
结果：所有三名患者均在SZT2基因中具有复合杂合变体（患者1，c.2887A>G/c.7970G>A；患者2，c.350A>G/c.7936C>T；和患者3，c.2489G>T/c.8640_8641insC）。预测变体对蛋白质具有结构效应。特别是,c.3508A>G/p。Ser1170Gly可能导致SZT2与GATOR1的结合受损，可能导致mTORC1信号通路的过度激活，导致癫痫发作。通过文献综述,我们观察到27例DEE患者有不同程度的智力和发育障碍（DDs），导致蛋白质截短的变异会导致严重的DD和难治性癫痫。因此,患者的表型严重程度可能与变异SZT2蛋白的残留活性有关。
结论：我们提供了有关DEE18基因型-表型谱的最新发展的知识，并表明基因检测对于准确诊断早发性癫痫患者具有重要价值。需要进一步的研究来开发针对DEE患者的个性化干预措施。
方法：进行三全外显子组测序和晶体结构模拟分析，并对DEE18例进行文献复习。
结果：所有三名患者均在SZT2基因中具有复合杂合变体（患者1，c.2887A>G/c.7970G>A；患者2，c.350A>G/c.7936C>T；和患者3，c.2489G>T/c.8640_8641insC）。预测变体对蛋白质具有结构效应。特别是,c.3508A>G/p。Ser1170Gly可能导致SZT2与GATOR1的结合受损，可能导致mTORC1信号通路的过度激活，导致癫痫发作。通过文献综述,我们观察到27例DEE患者有不同程度的智力和发育障碍（DDs），导致蛋白质截短的变异会导致严重的DD和难治性癫痫。因此,患者的表型严重程度可能与变异SZT2蛋白的残留活性有关。
结论：我们提供了有关DEE18基因型-表型谱的最新发展的知识，并表明基因检测对于准确诊断早发性癫痫患者具有重要价值。需要进一步的研究来开发针对DEE患者的个性化干预措施。
