Largest-ever Genetic Study of Epilepsy Finds Possible Therapeutic Targets
November 13, 2024
Article Published by Medical Xpress
A new study from the Epi25 Collaborative, a group of over 200 researchers around the world working to uncover the genetic basis of epilepsy, has revealed new potential targets for treatment, both shared by and unique to different subtypes of epilepsy. The researchers used an approach called whole exome sequencing to look at every gene in the protein-coding region of the genome. Since 2014, Epi25 has collected information from patients with multiple types of epilepsy, including a severe group of epilepsies known as developmental and epileptic encephalopathies, as well as more common and milder forms called genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). To find genes that strongly contribute to these epilepsies, the authors searched the participants’ exomes for “ultra-rare” variants, or URVs—mutations found less than once per 10,000 participants. If these variants are found more often in people with epilepsy than in those without, or in one type of epilepsy than another, they are more likely to play a role in the disease. The study’s 54,000 participants included about 21,000 patients with epilepsy and 33,000 controls. To improve their ability to focus on specific cellular pathways, the researchers aggregated data from genes with similar functions or that encode parts of the same protein complex. For example, they found that data from patients with NAFE showed a strong signal for the gene DEPDC5, which encodes a part of a protein complex called GATOR1 that is critical to brain cell function. When combining it in their analysis with the two genes that encode the rest of the GATOR1 complex, the signal became even stronger, indicating that GATOR1 may be highly involved in a mechanism that contributes to NAFE. The researchers say the findings could improve genetic testing for epilepsy and provide a clearer sense of how genetic variation leads to disease. “These genetic insights provide data-driven starting points for unraveling the biology of epilepsies,” said Benjamin Neale, co-director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, “which in turn should help spur future, subtype-tailored advances in diagnosis and treatment.”