Researchers and patients from Austin Health and the University of Melbourne have taken part in the largest ever study looking at the genetic sequences of people with epilepsy. The findings (“Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals”), published in the American Journal of Human Genetics, involved almost 18,000 people worldwide and identified rare genetic variations that are associated with a higher risk of epilepsy.
“Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry,” the investigators wrote.
“We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes.
“The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.
Sam Berkovic, MD, director of epilepsy with Austin Health and laureate professor with the University of Melbourne, said the study found there were genetic links shared by both severe forms of epilepsy and less severe forms of the disease.
“There are approximately 50 million people across the world with epilepsy, a condition that causes repeated seizures due to excessive electrical activity in the brain,” he noted. “Epilepsy comes in a number of different forms ranging from less common variations such as developmental and epileptic encephalopathies that cause severe symptoms, to other, less severe forms such as genetic generalized epilepsy and non-acquired focal epilepsy that account for up to 40% of cases.
“This research is important because the more we understand the genes that are linked to epilepsy, the better we can tailor treatments to reduce the symptoms and let patients live more active lives.”
The study brought together more than 200 researchers from across the world to better understand the genetics of the disease. Researchers used sequencing to look at the genes of 17,606 people from across 37 sites in Europe, North America, Australasia, and Asia and found rare genetic variations that are associated with both severe and less severe forms of epilepsy.
The coordination of the clinical data occurred in Melbourne with the gene sequencing performed at the Broad Institute in Boston, led by Benjamin Neale, PhD.
The study included 1,370 patients from Austin Health and the University of Melbourne, and was five times larger than any previous research looking at the gene sequencing of epilepsy patients.
“Genetic sequencing has significantly improved our understanding of the risk factors association with epilepsy in recent years,” according to Berkovic. “This study shows that more and less severe forms of the disease share similar genetic features, and the more we understand these features the better chance we have to personalize the care we give to patients.
“There are already plans in place to double the size of the study in the next year to further explore the significance of the genetic variations that are linked with epilepsy.”