Detection of Disease-Causing SNVs/Indels and CNVs in Single Test Based on Whole Exome Sequencing: A Retrospective Case Study in Epileptic Encephalopathies

Frontiers in Pediatrics

article

Dan Sun¹  Zhisheng Liu¹  Feng Zhu²  Yan Liu⁴  Wei Cai⁵  Jiehui Ma¹  Kun Ni¹  Ming Chen⁶  Cheng Wang²  Yongchu Liu⁷  Yuanyuan Zhu⁷ 

[1] Department of Neurology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology;Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology;Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology;Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology;Department of Hematology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology;Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science;Ltd.

关键词: epileptic encephalopathies;    whole exome sequencing;    genetics;    copy number variation;    variant;   

DOI  :  10.3389/fped.2021.635703

学科分类：社会科学、人文和艺术（综合）

来源: Frontiers

【 摘 要 】

Background: 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. Methods: 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. Results: 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 de novo 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, CACNA1E and WDR26 . 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. Conclusion: 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.

【 授权许可】

CC BY