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.

Keywords:

• Epilepsy
• familial epilepsies
• epileptic encephalopathies
• next generation sequencing
• gene panels
• whole exome sequencing
• genetics
• de novo mutations

Key issues

• Unraveling the genetics of a complex disorder; epilepsy is genetically heterogeneous and comprises a genetic spectrum ranging from monogenic to complex genetics.

• New discoveries in epilepsy genetics are technology facilitated, driven by next generation sequencing (NGS).

• For some epilepsy genes, broad phenotypic heterogeneities have been observed, a phenomenon referred to as variable expressivity. In addition, there is also genetic heterogeneity for distinct epilepsy syndromes.

• A wide genetic spectrum even in monogenic familial conditions have been observed: from low risk genetic variants to de novo mutations with high effect size.

• The diagnostic yield of NGS in epileptic encephalopathies is within the range of 20–30%.

• Common epilepsies including idiopathic generalized epilepsies are likely to have a polygenic inheritance, and for these conditions, the genetic etiology is still unsolved.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.