NEW YORK – An international team led by investigators at the University of Leipzig Medical Center and the Max Planck Institute for Evolutionary Anthropology has uncovered an overrepresentation of rare genetic variants found in the general population in individuals with epilepsy, particularly those with a form known as non-acquired focal epilepsy (NAFE).
"Our results support the hypothesis that rare variants could be important in the NAFE pathomechanism," senior and co-corresponding author Diana Le Duc, a human genetics researcher at the University of Leipzig and the Max Planck Institute of Evolutionary Anthropology, and her colleagues wrote in the American Journal of Human Genetics on Monday, noting that the affected gene set suggests the brain extracellular matrix appears to play a central role in NAFE.
Using exome sequencing data for more than 8,400 unaffected control individuals and 9,170 individuals with epilepsy — including 3,597 NAFE cases, 1,021 individuals with severe developmental and epileptic encephalopathies (DEEs), and 3,108 cases of genetic generalized epilepsy (GGE) — Le Duc and members of the Epi25 Collaborative searched for rare, predicted deleterious variants that appeared to coincide with each of the epilepsy forms considered.
"Unlike common and de novo ultra-rare variants, rare variants in epilepsy have not been researched extensively," the authors explained, noting that "[w]hile the identification of such variants is paramount for understanding their role, their detection is statistically more challenging because they are present at low frequencies in the general population."
After applying an analytical approach that took rare variant enrichment and related risk burden across genes into account, the team saw an uptick in "qualifying rare variants" in 72 genes in individuals with NAFE. In the GGE subtype, the rare variants were overrepresented in 32 genes, while 21 genes were impacted by rare variants in those with a severe form of epilepsy, DEE.
"The present study confirms an involvement of rare variants for NAFE that occur also in the general population," the authors reported, "while in DEE and GGE, the contribution of such variants appears more limited."
The team's follow-up analyses on the rare variant-impacted genes provided some other clues about the epilepsy subtypes, as well, from enrichment for brain-expressed genes in NAFE-or DEE-affected individuals to genes from nervous system development pathways in the GGE cases.
One ion channel-related gene, HSPG2, had higher-than-usual rare variant rates across all of the epilepsy subtypes considered, the investigators reported. Genes coding for ion channel components or proteins interacting with them also had enhanced rare mutation rates within the NAFE subtype.
"For DEE, we retrieved genes that are highly expressed during development, which meets the expected pathomechanism; however, the number of identified genes is rather low," the authors reported. On the other hand, they noted that "we cannot infer which pathways play an important role in the pathomechanism" of the GGE subtype of the condition, based on the genes affected by rare variants in individuals with that disease subtype.