A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations

Trio exome sequencing has been successful in identifying genes with de novo mutations (DNMs) causing epileptic encephalopathy (EE) and other neurodevelopmental disorders. Here, we evaluate how well a case-control collapsing analysis recovers genes causing dominant forms of EE originally implicated by DNM analysis. We performed a genome-wide search for an enrichment of "qualifying variants" in protein-coding genes in 488 unrelated cases compared to 12,151 unrelated controls. These "qualifying variants" were selected to be extremely rare variants predicted to functionally impact the protein to enrich for likely pathogenic variants. Despite modest sample size, three known EE genes (KCNT1, SCN2A, and STXBP1) achieved genome-wide significance (p−6). In addition, six of the 10 most significantly associated genes are known EE genes, and the majority of the known EE genes (17 out of 25) originally implicated in trio sequencing are nominally significant (p−17). Our results indicate that a case-control collapsing analysis can identify several of the EE genes originally implicated in trio sequencing studies, and clearly show that additional genes would be implicated with larger sample sizes. The case-control analysis not only makes discovery easier and more economical in early onset disorders, particularly when large cohorts are available, but also supports the use of this approach to identify genes in diseases that present later in life when parents are not readily available.三人组外显子组测序（Trio exome sequencing）已成功用于鉴定携带新发突变（de novo mutations, DNMs）的基因，此类突变可导致癫痫性脑病（epileptic encephalopathy, EE）及其他神经发育障碍。本研究旨在评估病例对照合并分析（case-control collapsing analysis）对恢复由新发突变分析最初鉴定的显性遗传性癫痫性脑病致病基因的效果。我们对488名无关病例与12151名无关对照的蛋白编码基因中“合格变异体”的富集情况开展了全基因组搜索。此处的“合格变异体”经筛选为极罕见变异，且经预测可对蛋白质产生功能影响，以富集潜在致病变异。尽管样本量中等，仍有3个已知癫痫性脑病基因（KCNT1、SCN2A及STXBP1）达到全基因组显著性水平（p < 10^−6）。此外，显著性排名前10的基因中有6个为已知癫痫性脑病基因；且最初通过三人组测序鉴定的已知癫痫性脑病基因（共25个）中，大多数（17个）达到名义显著性水平（p < 10^−17）。本研究结果表明，病例对照合并分析可鉴定出最初通过三人组测序研究发现的多个癫痫性脑病致病基因，且明确显示，扩大样本量后可鉴定出更多致病基因。病例对照分析不仅使早发性疾病的基因发现工作更简便、更经济（尤其在可获得大型队列的情况下），还支持将该方法用于父母样本不易获取的晚发性疾病的基因鉴定。