Novel mutations and phenotypes of epilepsy-associated genes in epileptic encephalopathies
Novel mutations and phenotypes of epilepsy-associated genes in epileptic encephalopathies
复制标题
癫痫性脑病中癫痫相关基因的新突变和表型
DOI：
10.1111/gbb.12456
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发表时间：
2018-11-01
影响因子：
2.5
通讯作者：
Liao, W. -P.
中科院分区：
文献类型：
--
作者：
Zhou, P.;He, N.;Liao, W. -P.
癫痫脑病是一种严重的癫痫疾病，具有很强的遗传基础。我们对70例癫痫脑病患者进行了靶向下一代测序。通过美国医学遗传学和基因组学学会(ACMG)评分结合接受的临床表现来评估候选基因变异的可能致病性。经过群体过滤和计算预测后，检测到33个候选变异。根据ACMG，21个候选变异，包括18个从头开始的变异，被评估为致病/可能致病，与临床一致。ACMG初步评估了12个变异为不确定意义，其中3个被认为是原因，另外3个在临床一致性分析后被认为可能是原因。总共有24个变异被确定为推定原因，其中19个是新发现。在50%的Drave氏综合征患者中发现了SCN1A突变。66.7%的结节性硬化症患者存在TSC1/TSC2突变。STXBP1突变是West综合征的主要表现。在伴有迁移性局灶性癫痫发作的癫痫患儿中发现了SCN2A、KCNT1、KCNQ2和CLCN4基因突变，其中KCNQ2和CLCN4基因首次被确定为潜在的致病基因。在Lennox-Gastaut综合征患者中仅检测到一个CHD2突变。这项研究强调了靶向NGS在癫痫脑病基因诊断中的应用，并基于ACMG评分和临床一致性评估对变异的致病性进行了综合评估。癫痫脑病有不同的遗传原因，而基因-表型的相关性将提供对潜在致病机制的洞察。
Epileptic encephalopathies are severe epilepsy disorders with strong genetic bases. We performed targeted next-generation sequencing (NGS) in 70 patients with epileptic encephalopathies. The likely pathogenicity of variants in candidate genes was evaluated by American College of Medical Genetics and Genomics (ACMG) scoring taken together with the accepted clinical presentation. Thirty-three candidate variants were detected after population filtration and computational prediction. According to ACMG, 21 candidate variants, including 18 de novo variants, were assessed to be pathogenic/likely pathogenic with clinical concordance. Twelve variants were initially assessed as uncertain significance by ACMG, among which 3 were considered causative and 3 others were considered possibly causative after analysis of clinical concordance. In total, 24 variants were identified as putatively causative, among which 19 were novel findings. SCN1A mutations were identified in 50% of patients with Dravet syndrome. TSC1/TSC2 mutations were detected in 66.7% of patients with tuberous sclerosis. STXBP1 mutations were the main findings in patients with West syndrome. Mutations in SCN2A, KCNT1, KCNQ2 and CLCN4 were identified in patients with epileptic infantile with migrating focal seizures; among them, KCNQ2 and CLCN4 were first identified as potential causative genes. Only one CHD2 mutation was detected in patients with Lennox-Gastaut syndrome. This study highlighted the utility of targeted NGS in genetic diagnoses of epileptic encephalopathies and a comprehensive evaluation of the pathogenicity of variants based on ACMG scoring and assessment of clinical concordance. Epileptic encephalopathies differ in genetic causes, and the genotype-phenotype correlations would provide insights into the underlying pathogenic mechanisms.