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

Feng Zhu,Cheng Wang,Dan Sun,Jiehui Ma,Kun Ni,Yan Liu,Ming Chen,Zhisheng Liu,Wei Cai,Yuanyuan Zhu,Yongchu Liu

doi:10.3389/fped.2021.635703

Abstract

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.

Highlights

Epileptic encephalopathies (EEs) are characterized by frequent severe seizures, severe electroencephalography (EEG) abnormalities, and intellectual/developmental disabilities [1,2,3]
We evaluated the clinical application of profiling both SNPs/Indels and copy number variations (CNVs) in a cohort of 73 infants with EEs who underwent Whole exome sequencing (WES) as a diagnostic test
Thirty-two (43.84%) infants had been diagnosed with epilepsy syndrome

Summary

Introduction

Epileptic encephalopathies (EEs) are characterized by frequent severe seizures, severe electroencephalography (EEG) abnormalities, and intellectual/developmental disabilities [1,2,3]. EEs commonly occur during infancy and early childhood, with poor clinical outcome. They are highly heterogeneous in clinical features, including West syndrome (WS), Dravet syndrome (DS), Ohtahara syndrome (OS), migrating partial epilepsy of infancy (MPEI), and other related epilepsy syndromes [4,5,6]. 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. The possibility of profiling both disease-causing SNVs/Indels and CNVs in a single test based on WES in EEs was evaluated

Methods

Results

Conclusion