Am J Hum Genet. 2019 Aug 1;105(2):267-282. doi: 10.1016/j.ajhg.2019.05.020. Epub 2019 Jul 18.
Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.
基于测序的研究已经确定了与严重癫痫相关的新风险基因，并揭示了在较轻形式的癫痫中存在过多罕见的有害变异。为了确定不同类型癫痫的共同和独特的超罕见遗传风险因素，我们对 9170 名癫痫患者和 8436 名欧洲血统对照者进行了全外显子组测序 (WES) 分析。我们专注于三个表型组：严重发育性和癫痫性脑病 (DEEs)、遗传性全面性癫痫 (GGE) 和非获得性局灶性癫痫 (NAFE)。我们观察到，与对照组相比，任何类型的癫痫患者携带过多的超罕见、有害约束基因和先前与癫痫相关的基因变异；我们在 DEEs 患者中观察到最强的富集，在 NAFE 患者中观察到最弱的富集。此外，我们发现抑制性 GABA 受体基因在所有三种类型的癫痫中都富含错义变异，而兴奋性受体基因则没有富集。GABA 能途径或阳离子通道的较大基因组在 DEEs 和 GGE 中也显示出显著的突变负担。虽然在 GGE 或 NAFE 患者中没有单个基因超过外显子组范围的显著意义，但高度约束的基因和编码离子通道的基因是主要关联之一；这些基因包括 GGE 中的 CACNA1G、EEF1A2 和 GABRG2 以及 NAFE 中的 LGI1、TRIM3 和 GABRG2。我们的研究是迄今为止最大的癫痫 WES 研究，证实了严重和较轻癫痫的遗传学在超罕见编码变异方面的趋同，并强调了 GABA 能抑制在癫痫发病机制中的普遍作用。
