Analysis of rare copy number variation in absence epilepsies.
Analysis of rare copy number variation in absence epilepsies.
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DOI：
10.1212/nxg.0000000000000056
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发表时间：
2016-04
期刊：
影响因子：
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通讯作者：
Pal DK
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作者：
Addis L;Rosch RE;Valentin A;Makoff A;Robinson R;Everett KV;Nashef L;Pal DK
确定常见缺失癫痫（AE）亚型（儿童缺失癫痫[CAE]，青少年缺失癫痫[JAE]和未分类缺失癫痫[UAE]）之间的共享基因和通路，这些基因和通路可能表明缺失发作产生的共同机制和潜在的诊断连续性。我们使用高密度单核苷酸多态性阵列分析了144例ae患儿（95例CAE， 26例UAE， 23例JAE）的全基因组罕见拷贝数变异（CNV）。我们在4例患者中发现了已知的AE危险因素CNVs，包括3x 15q11.2缺失。我们还扩展了在其他神经发育障碍中更常见的4个区域的表型：1p36.33重复，1q21.1缺失，22q11.2重复和Xp22.31缺失和重复。15例患者（10.5%）被发现携带罕见的CNVs，破坏与神经元发育和功能相关的基因（8例CAE， 2例JAE， 5例UAE）。四类蛋白质分别被几个CNVs破坏：(1)突触囊泡膜或囊泡内吞作用，(2)突触细胞粘附，(3)通过肌动蛋白的突触组织和运动，以及(4)间隙连接。这些类别中的CNVs在AE亚型中是共享的。我们的研究结果加强了ae的复杂性和异质性及其潜在的共同遗传机制，并强调了几种可能在癫痫发作的癫痫发生中很重要的途径。
To identify shared genes and pathways between common absence epilepsy (AE) subtypes (childhood absence epilepsy [CAE], juvenile absence epilepsy [JAE], and unclassified absence epilepsy [UAE]) that may indicate common mechanisms for absence seizure generation and potentially a diagnostic continuum. We used high-density single-nucleotide polymorphism arrays to analyze genome-wide rare copy number variation (CNV) in a cohort of 144 children with AEs (95 CAE, 26 UAE, and 23 JAE). We identified CNVs that are known risk factors for AE in 4 patients, including 3x 15q11.2 deletion. We also expanded the phenotype at 4 regions more commonly identified in other neurodevelopmental disorders: 1p36.33 duplication, 1q21.1 deletion, 22q11.2 duplication, and Xp22.31 deletion and duplication. Fifteen patients (10.5%) were found to carry rare CNVs that disrupt genes associated with neuronal development and function (8 CAE, 2 JAE, and 5 UAE). Four categories of protein are each disrupted by several CNVs: (1) synaptic vesicle membrane or vesicle endocytosis, (2) synaptic cell adhesion, (3) synapse organization and motility via actin, and (4) gap junctions. CNVs within these categories are shared across the AE subtypes. Our results have reinforced the complex and heterogeneous nature of the AEs and their potential for shared genetic mechanisms and have highlighted several pathways that may be important in epileptogenesis of absence seizures.