Next Generation Sequencing Methods for Diagnosis of Epilepsy Syndromes

Abstract

Epilepsy is a neurological disorder characterized by an increased predisposition for seizures. Although this definition suggests that it is a single disorder, epilepsy encompasses a group of disorders with diverse aetiologies and outcomes. A genetic basis for epilepsy syndromes has been postulated for several decades, with several mutations in specific genes identified that have increased our understanding of the genetic influence on epilepsies. With 70-80% of epilepsy cases identified to have a genetic cause, there are now hundreds of genes identified to be associated with epilepsy syndromes which can be analyzed using next generation sequencing (NGS) techniques such as targeted gene panels, whole exome sequencing (WES) and whole genome sequencing (WGS). For effective use of these methodologies, diagnostic laboratories and clinicians require information on the relevant workflows including analysis and sequencing depth to understand the specific clinical application and diagnostic capabilities of these gene sequencing techniques. As epilepsy is a complex disorder, the differences associated with each technique influence the ability to form a diagnosis along with an accurate detection of the genetic etiology of the disorder. In addition, for diagnostic testing, an important parameter is the cost-effectiveness and the specific diagnostic outcome of each technique. Here, we review these commonly used NGS techniques to determine their suitability for application to epilepsy genetic diagnostic testing.

Keywords: bioinformatics; d‘iagnostics; epilepsy; gene panels; neurology; next generation sequencing; whole exome sequencing; whole genome sequencing.

Figure 1

A suggested clinical workflow for identifying the genetic cause of epilepsy. This figure was adapted based off Xue et al. (2015). The use of genetic testing for epilepsy diagnosis needs to be determined based on how specific certain symptoms are. Karyotypes, single gene testing and FISH can be successfully utilized when a certain well-characterized disorder with epilepsy is considered. Gene panels can be used when specific phenotype—genotype correlation is proposed or for non-specific causes when a large number of genes can be included on the panel. Chromosomal microarray testing allows non-specific analysis of CNVs as well as uniparental disomy which may be associated with non-specific symptoms. Non-specific genetic testing is where WES and WGS can be best utilized as they can provide a non-phenotype derived approach to epilepsy diagnosis using little to no prior clinical information to provide a diagnosis. ^*All times for diagnosis are conservative guides based off the turn around times stated from commercial genetic testing companies sourced from the Genetic Testing Registry https://www.ncbi.nlm.nih.gov/gtr/. The turn-around times for diagnosis may differ depending on the laboratory performing the test.