Genetic Variants Identified from Epilepsy of Unknown Etiology in Chinese Children by Targeted Exome Sequencing

Abstract

Genetic factors play a major role in the etiology of epilepsy disorders. Recent genomics studies using next generation sequencing (NGS) technique have identified a large number of genetic variants including copy number (CNV) and single nucleotide variant (SNV) in a small set of genes from individuals with epilepsy. These discoveries have contributed significantly to evaluate the etiology of epilepsy in clinic and lay the foundation to develop molecular specific treatment. However, the molecular basis for a majority of epilepsy patients remains elusive, and furthermore, most of these studies have been conducted in Caucasian children. Here we conducted a targeted exome-sequencing of 63 trios of Chinese epilepsy families using a custom-designed NGS panel that covers 412 known and candidate genes for epilepsy. We identified pathogenic and likely pathogenic variants in 15 of 63 (23.8%) families in known epilepsy genes including SCN1A, CDKL5, STXBP1, CHD2, SCN3A, SCN9A, TSC2, MBD5, POLG and EFHC1. More importantly, we identified likely pathologic variants in several novel candidate genes such as GABRE, MYH1, and CLCN6. Our results provide the evidence supporting the application of custom-designed NGS panel in clinic and indicate a conserved genetic susceptibility for epilepsy between Chinese and Caucasian children.

Mutations in SCN3A cause early infantile epileptic encephalopathy

“…However, it has been consistently noted that Nav1.3 current includes a relatively prominent slowly inactivating/"persistent" current component (I NaP ) of between 0.5 and 10.3% of peak transient sodium current (I NaT ). [20][21][22] Previous studies have reported heterozygous variants in SCN3A in association with less severe forms of epilepsy; [21][22][23][24][25] however, de novo mutation in SCN3A as a cause of early infantile epileptic encephalopathy has yet to be described. Prior reports include cases of focal epilepsy, with onset after infancy, and not consistently associated with developmental delay/intellectual disability; variants were in most instances not shown definitively to be de novo mutations.…”

“…Previous studies have reported heterozygous variants in SCN3A in association with less severe forms of epilepsy; 21–25 however, de novo mutation in SCN3A as a cause of early infantile epileptic encephalopathy has yet to be described. Prior reports include cases of focal epilepsy, with onset after infancy, and not consistently associated with developmental delay/intellectual disability; variants were in most instances not shown definitively to be de novo mutations.…”

Diagnostic Testing in Epilepsy Genetics Clinical Practice

“…However, due to a huge phenotypic and genetic heterogeneity characteristic of disorders involving epilepsy or seizures, as illustrated by EpiGene database (http://www.kimg.eu/en/tools/epigene-database), gene panels may lead to smaller diagnostic yields due to their restrictiveness. Testing of 500 epileptic encephalopathy patients with a gene panel containing 65 genes gave a diagnostic yield of 10% [43], 30 gene or 90 gene panels in 349 patients with treatment-resistant epilepsies gave a diagnostic yield of 20.3% [44], a gene panel of 46 genes in 216 patients with various epilepsies gave 23% diagnostic yield [45], a gene panel trio-testing of 412 genes in 63 probands with variable epilepsies gave 23.8% diagnostic yield [46], and a combined approach of 46 gene panel and targeted exon-level aCGH in 400 patients with early onset epilepsy and developmental delay gave 18% diagnostic yield [27]. Comparisons of gene panel testing studies are hindered by a huge phenotypic and gene panel variability in all these studies.…”

Rare variants in the GABAA receptor subunit ε identified in patients with a wide spectrum of epileptic phenotypes

“…At the age of 18 years he had a first tonic-clonic seizure, without clearly provoking factors. He was treated Wang, Du, et al (2017). Sequence variants were annotated using reference sequence NM_004961.3/NP_004952.2.…”

“…exome sequencing, GABA receptor type A subunit epsilon, GABRE, genetic epilepsy, novel sequence variants | 3 of 13 MARKUS et Al. significance in the GABA A receptor subunit ε gene (GABRE, OMIM: 300093) have been reported in single epilepsy-cases (Butler et al, 2018;Hernandez et al, 2016b;Wang, Du, et al, 2017).…”