Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures.
Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures.
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DOI：
10.1038/s41390-021-01509-3
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发表时间：
2022-03
影响因子：
3.6
通讯作者：
Glass, Hannah C.
中科院分区：
文献类型：
--
作者：
Numis, Adam L.;da Gente, Gilberto;Sherr, Elliott H.;Glass, Hannah C.
致病基因变异对新生儿急性症状性癫痫发作后癫痫发展的影响尚不清楚。对 20 名有急性症状性新生儿癫痫病史的儿童进行病例对照研究：10 名患有新生儿后癫痫，10 名不患有新生儿后癫痫。我们进行了全外显子组测序（WES），并从已确定的和候选的癫痫相关基因中鉴定了致病性从头、传播和非传播变异，并将这些变异的患病率与癫痫结果相关联。我们对与冠状动脉疾病 (CAD) 相关的基因进行了敏感性分析。我们分析了整个外显子组的变异，以使用探索性 KEGG 搜索来评估功能特性的差异富集。通过查询 200 个已确定的和候选的癫痫基因，在 5 名患有新生儿后癫痫的儿童中鉴定出了致病性变异，而只有 1 名儿童随后没有癫痫。癫痫或 CAD 基因中具有非传播性致病变异的三重奏的数量没有差异。探索性 KEGG 分析表明，随后未患癫痫的儿童的细胞死亡途径相对丰富。在这项试点研究中，通过靶向癫痫基因测序分析，与随后没有癫痫发作的患者相比，急性症状性新生儿癫痫发作后患有癫痫的儿童的编码变异患病率更高。我们对 20 名三人组进行了全外显子组测序 (WES)，其中 10 名患有癫痫症的儿童和 10 名没有癫痫症的儿童，均是在新生儿急性症状性癫痫发作后进行的。与没有新生儿后癫痫的儿童相比，患有新生儿后癫痫的儿童癫痫相关基因的致病性变异负担更高。评估这种关联的未来研究可能会更好地了解急性症状性新生儿癫痫发作后癫痫的风险，并阐明脑损伤后失调并与癫痫发生有关的分子途径。
The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.
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