Sun Dan, Liu Yan, Cai Wei, Ma Jiehui, Ni Kun, Chen Ming, Wang Cheng, Liu Yongchu, Zhu Yuanyuan, Liu Zhisheng, Zhu Feng
Department of Neurology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Pediatr. 2021 May 13;9:635703. doi: 10.3389/fped.2021.635703. eCollection 2021.
Epileptic encephalopathies (EEs) are a pediatric entity with highly phenotypic and genetic heterogeneity. Both single nucleotide variants (SNVs)/Indels and copy number variations (CNVs) could be the causes. Whole exome sequencing (WES) is widely applied to detect SNVs/Indels, but the bioinformatics approach for detecting CNVs is still limited and weak. In the current study, the possibility of profiling both disease-causing SNVs/Indels and CNVs in a single test based on WES in EEs was evaluated. The infants diagnosed with EEs were enrolled from a single pediatric epilepsy center between January 2018 and February 2020. Demographic and clinical data were collected. In WES data, the pathogenic SNVs were identified through an in-house pipeline, and pathogenic CNVs were identified by CNVkit. The diagnostic rate was evaluated, and the molecular findings were characterized. A total of 73 infants were included; 36 (49.32%) of them were males. The median age was 7 months. Thirty-two (43.84%) infants had been diagnosed with epilepsy syndrome. The most common type of syndrome was West syndrome (22/73, 30.1%), followed by Dravet syndrome (20/77, 27.4%). Fifty-four (73.97%) had intellectual development delay. The genetic cause of EEs, pathogenic or likely pathogenic variants, were successfully discovered in 46.6% (34/73) of the infants, and 29 (39.7%) infants carried SNVs/Indels, while 5 (6.8%) carried CNVs. The majority of the disease-causing variants were inherited in pattern (25, 71.4%). In addition to showing that the variants in the ion channel encoding genes accounted for the main etiology, we discovered and confirmed two new disease-causing genes, and . Five discovered CNVs were deletions of 2q24.3, 1p36, 15q11-q13, 16p11.2, and 17p13.3, and all were confirmed by array comparative genomic hybridization. The application of both SNVs/Indels and CNVs detection in a single test based on WES yielded a high diagnosis rate in EEs. WES may serve as a first-tier test with cost-effective benefit in EEs.
癫痫性脑病（EEs）是一种具有高度表型和遗传异质性的儿科疾病。单核苷酸变异（SNVs）/插入缺失（Indels）和拷贝数变异（CNVs）都可能是其病因。全外显子组测序（WES）被广泛应用于检测SNVs/Indels，但检测CNVs的生物信息学方法仍然有限且薄弱。在本研究中，评估了基于WES在单次检测中对EEs致病SNVs/Indels和CNVs进行分析的可能性。2018年1月至2020年2月期间，从一家儿科癫痫中心招募了被诊断为EEs的婴儿。收集了人口统计学和临床数据。在WES数据中，通过内部流程鉴定致病SNVs，通过CNVkit鉴定致病CNVs。评估诊断率并对分子结果进行特征分析。共纳入73名婴儿；其中36名（49.32%）为男性。中位年龄为7个月。32名（43.84%）婴儿被诊断为癫痫综合征。最常见的综合征类型是韦斯特综合征（22/73，30.1%），其次是德雷维特综合征（20/77，27.4%）。54名（73.97%）有智力发育迟缓。在46.6%（34/73）的婴儿中成功发现了EEs的遗传病因，即致病或可能致病的变异，29名（39.7%）婴儿携带SNVs/Indels，而5名（6.8%）携带CNVs。大多数致病变异呈遗传模式（25名，71.4%）。除了表明离子通道编码基因中的变异是主要病因外，我们还发现并证实了两个新的致病基因，即 和 。发现的5个CNVs分别是2q24.3、1p36、15q11-q13、16p11.2和17p13.3的缺失，所有这些均通过阵列比较基因组杂交得到证实。基于WES在单次检测中同时检测SNVs/Indels和CNVs在EEs中产生了较高的诊断率。WES在EEs中可能作为一种具有成本效益的一线检测方法。
