Neuro Disorders Involving Epilepsy Include Distinct De Novo Variants

Epilepsy is a central nervous system (neurological) disorder in which brain activity becomes abnormal, causing seizures or periods of unusual behavior, sensations, and sometimes loss of awareness.

Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. Anyone can develop epilepsy as epilepsy affects both males and females of all races, ethnic backgrounds and ages.


Scientists at the University of Leipzig Hospitals (Leipzig, Germany) and their international colleagues analyzed de novo variants (DNVs) in 6,753 parent–offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, 529 of who had epilepsy syndromes termed epileptic encephalopathies (EE), while the remaining 1,413 of whom were classified as NDD with unspecified epilepsy.

The team used Illumina instruments to sequence protein-coding and searched for DNVs that corresponded to NDD with or without these types of epilepsy. The team noted that epilepsy was more common within groups of patients who had more severe forms of NDD. Likewise, DNVs in a set of 50 genes previously implicated in EE appeared more common in individuals with NDD who either had EE or unspecified epilepsy than in the epilepsy-free NDD cases.

Across the wider exomes, meanwhile, they saw an uptick in missense DNVs in the cases with both forms of epilepsy compared with those without, while highlighting 33 genes that were particularly prone to such alterations in the epilepsy-affected groups. That set included genes such KCNQ2, SCN2A, and SCN1A. When analyzing the full collection of NDD cases together, they flagged 101 DNV-prone genes, including 62 gene sets that had more missense DNVs in the NDD cases with epilepsy compared with the other NDDs.

In a series of follow-up analyses, the team took a closer look at the 33 genes with excess DNVs in the epilepsy-NDD cases, as well as the genes impacted by DNVs within the broader NDD cohorts. They identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1E as a novel disease-associated gene.

The authors concluded that that a little more than half of the DNVs in those genes would be picked up using two dozen available diagnostic sequencing panels for EE or other forms of epilepsy. Such data provided grounds for replacing genes with limited evidence with genes with higher evidence in the design of gene panels for NDDs with epilepsy. The study was published on June 25, 2018, in the journal Nature Genetics.

Related Links:
University of Leipzig Hospitals