Table1_A novel mutation in ryanodine receptor 2 (RYR2) genes at c.12670G>T associated with focal epilepsy in a 3-year-old child.xlsx

BackgroundRyanodine receptor 2 (RYR2) encodes a component of a calcium channel. RYR2 variants were well-reported to be associated with catecholaminergic polymorphic ventricular tachycardia (CPVT), but rarely reported in epilepsy cases. Here, we present a novel heterozygous mutation of RYR2 in a child with focal epilepsy.MethodsAt the age of 2 years and 7 months, the patient experienced seizures, such as eye closure, tooth clenching, clonic jerking and hemifacial spasm, as well as abnormal electroencephalogram (EEG). Then, he was analyzed by whole-exome sequencing (WES). The mutations of both the proband and his parents were further confirmed by Sanger sequencing. The pathogenicity of the variant was further assessed by population-based variant frequency screening, evolutionary conservation comparison, and American Association for Medical Genetics and Genomics (ACMG) scoring.ResultsWES sequencing revealed a novel heterozygous truncating mutation [c.12670G > T, p.(Glu4224*), NM_001035.3] in RYR2 gene of the proband. Sanger sequencing confirmed that this mutation was inherited from his mother. This novel variant was predicted to be damaging by different bioinformatics methods. Cardiac investigation showed that the proband had no structural abnormalities, but sinus tachycardia.ConclusionWe proposed that RYR2 is a potential candidate gene for focal epilepsy, and epilepsy patients carried with RYR2 variants should be given more attention, even if they do not show cardiac abnormalities

背景：ryanodine受体2（RYR2）编码钙通道的一个组分。RYR2变异体已被广泛报道与儿茶酚胺能多形性室性心动过速（CPVT）相关联，但在癫痫病例中报道较少。在本研究中，我们提出了一例具有局灶性癫痫的儿童中发现的RYR2新型杂合突变。方法：患者在2岁7个月大时出现癫痫发作，表现为眼睑闭合、牙齿紧咬、阵挛性抽搐和半侧面肌痉挛，以及异常脑电图（EEG）。随后，对患者进行了全外显子测序（WES）。通过Sanger测序进一步确认了受试者及其父母的突变。通过基于人群的变异频率筛查、进化保守性比较以及美国医学遗传学和基因组学协会（ACMG）评分等方法，对变异体的致病性进行了进一步评估。结果：WES测序在受试者RYR2基因中揭示了一个新型杂合截断突变[c.12670G>T, p.(Glu4224*)，NM_001035.3]。Sanger测序证实该突变来自其母亲。不同的生物信息学方法预测该新型变异体具有破坏性。心脏检查显示受试者无结构性异常，但存在窦性心动过速。结论：我们认为RYR2是局灶性癫痫的潜在候选基因，携带RYR2变异的癫痫患者应受到更多关注，即使他们没有表现出心脏异常。