The contribution of next generation sequencing to epilepsy genetics

Abstract

During the last decade, next generation sequencing technologies such as targeted gene panels, whole exome sequencing and whole genome sequencing have led to an explosion of gene identifications in monogenic epilepsies including both familial epilepsies and severe epilepsies, often referred to as epileptic encephalopathies. The increased knowledge about causative genetic variants has had a major impact on diagnosis of genetic epilepsies and has already been translated into treatment recommendations for a few genes. This article provides an overview of how next generation sequencing has advanced our understanding of epilepsy genetics and discusses some of the recently discovered genes in monogenic epilepsies.

The spectrum of intermediate SCN8A‐related epilepsy

“…We systematically screened all exons and exon‐intron boundaries of SCN8A in a cohort of 1095 unselected patients with various forms of epilepsy using different next generation sequencing (NGS) panels . The panels included from 45 to 500+ genes related to epilepsy, intellectual disability, or autism.…”

Novel treatment perspectives from advances in understanding of genetic epilepsy syndromes

“…In particular, the use of highthroughput approaches to sequence DNA is revealing a landscape of mutations in genetic epilepsies, affecting a variety of genes involved in neuronal excitability, synaptic transmission, neuronal metabolism, or network development. [6,7] Thus, mutations of protocadherin delta-2 subclass of the cadherin super family (PCDH19), Aristalessrelated homeobox, cyclin-dependent, kinase-like 5, and syntaxin-binding protein 1 genes have been identified in monogenic epilepsies without brain malformations that often manifest as severe forms, with features of epileptic encephalopathy, often having early seizure onset and developmental delay, even if with diverse and distinctive phenotypes. [6,7] Other examples are mutations of the LGI1 gene (leucine-rich, glioma-inactivated 1) that have been associated to autosomal dominant temporal lobe epilepsy, a form of focal epilepsy associated to auditory symptoms and audiogenic seizures.…”

“…[6,7] Thus, mutations of protocadherin delta-2 subclass of the cadherin super family (PCDH19), Aristalessrelated homeobox, cyclin-dependent, kinase-like 5, and syntaxin-binding protein 1 genes have been identified in monogenic epilepsies without brain malformations that often manifest as severe forms, with features of epileptic encephalopathy, often having early seizure onset and developmental delay, even if with diverse and distinctive phenotypes. [6,7] Other examples are mutations of the LGI1 gene (leucine-rich, glioma-inactivated 1) that have been associated to autosomal dominant temporal lobe epilepsy, a form of focal epilepsy associated to auditory symptoms and audiogenic seizures. [9] In addition, recent studies have identified some families presenting with familial focal epilepsy with variable foci mutations in Dishevelled, Egl-10, and Pleckstrin domain-containing (DEPDC5) protein, whose function is still unclear but might be involved in membrane trafficking, G protein signaling, and/or modulation of the mTOR complex 1.…”

“…[5,6] Thus, it is increasingly clear that epilepsy is genetically heterogeneous, and novel gene discoveries have moved the field beyond the known contribution of ion channels to implicate chromatin remodeling, transcriptional regulation, and regulation of cortical development in the etiology of epilepsy. [6,7] Although such discoveries pave the way for new therapeutics, [8] relatively little has been written on the potential implications for treatment. In this review, we discuss the most recent advances in the field of epilepsy genetics, as facilitated by genomic technologies, and highlight several novel molecular targets and the potential novel therapeutic strategies.…”

A novel homozygous KCNQ3 loss‐of‐function variant causes non‐syndromic intellectual disability and neonatal‐onset pharmacodependent epilepsy

“…1 Early genetic diagnosis is critical for prognostic assessment, genetic counseling, and, in some cases, personalized treatment attempts. 1 Early genetic diagnosis is critical for prognostic assessment, genetic counseling, and, in some cases, personalized treatment attempts.…”