Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5–3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.

中文翻译：

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在对 17 458 名受试者的全基因组研究中观察到的癫痫亚型特异性拷贝数负担。

大多数神经中心都常规应用细胞基因检测来治疗严重的小儿癫痫。然而，尚未在全基因组范围内探索拷贝数变异 (CNV) 的哪些特征赋予最大的癫痫风险以及哪些癫痫亚型携带最多的 CNV 负担。在这里，我们展示了迄今为止最大的癫痫 CNV 调查，涉及 10712 名欧洲癫痫病例和 6746 名血统匹配的对照。包括遗传性全身性癫痫、病灶性局灶性癫痫、非获得性局灶性癫痫以及发育性和癫痫性脑病的患者。所有样品均采用相同的技术和分析流程进行处理。所有研究的癫痫类型，包括病变局灶性癫痫患者，与对照组相比，至少在一个测试类别中显示出 CNV 负担增加。然而，我们观察到癫痫类型之间 CNV 负担的显着差异，并调查了 CNV 类别。在所有测试类别中，遗传性全身性癫痫患者的 CNV 负担最高，其次是发育性和癫痫性脑病患者。两种癫痫类型也显示出与覆盖不耐受截断变异的基因的缺失相关。全基因组 CNV 断点关联不仅显示出遗传性全身性、发育性和癫痫性脑病患者的显着位点，而且还显示了病灶性局灶性癫痫患者的显着位点。由于发展为遗传性全身性癫痫的风险为 34 倍，我们首次证明已建立的癫痫相关 15q13.3 缺失代表了整个基因组中遗传性全身性癫痫的最强风险 CNV。使用人类交互组，我们检查了在四种癫痫类型中与 CNV 重叠的基因的最大连接成分。我们观察到遗传性全身性癫痫和非获得性局灶性癫痫形成疾病模块。总之，我们发现在所有常见的癫痫类型中，1.5-3% 的患者携带与癫痫相关的 CNV。风险 CNV 的特征在癫痫类型之间和内部差异很大。因此，我们提倡全基因组基因组测试来识别所有与疾病相关的 CNV 类型。风险 CNV 的特征在癫痫类型之间和内部差异很大。因此，我们提倡全基因组基因组测试来识别所有与疾病相关的 CNV 类型。风险 CNV 的特征在癫痫类型之间和内部差异很大。因此，我们提倡全基因组基因组测试来识别所有与疾病相关的 CNV 类型。