Scientists identify genetic markers that may predict fatal epilepsy outcomes
A new study examining the genetic architecture of Sudden Unexpected Death in Epilepsy (SUDEP) reveals that common DNA variants may encode a hidden layer of risk for this devastating condition.
For the millions of people living with epilepsy, and for their families, the condition is often more than a matter of managing seizures. It carries the weight of a quiet, persistent fear of other serious risks like Sudden Unexpected Death in Epilepsy, or SUDEP. This tragic outcome, which can occur without a clear medical trigger, is poorly understood and agonizingly difficult to predict. SUDEP can occur after a first seizure or following years of managed epilepsy, leaving families and clinicians grappling with profound uncertainty.
While past research has often focused on rare, high-impact genes directly linked to epilepsy, a new study published in eBiomedicine has turned its attention to the vast landscape of common genetic variants—the millions of small, widespread DNA differences between individuals. The researchers hypothesized that in aggregate, the subtle effects of these DNA variations might add up to influence a person's risk of SUDEP.
Piecing together the genetic mosaic of SUDEP
The international research team, led by scientists at University College London, analyzed the DNA of 161 people who had died from SUDEP and compared it to nearly 2,000 controls—both healthy individuals and people with epilepsy who had not experienced SUDEP. Using Polygenic Risk Scores (PRS), they tallied the tiny, cumulative effects of thousands of common genetic variations.
They focused on two unexpected targets: Polygenic risk score statistics for longevity and for intelligence. The scores don’t measure cognitive ability or lifespan directly. Instead, they serve as proxies for what the researchers termed "genomically mediated resilience to health challenges", i.e. the body's innate genetic capacity to weather major physiological storms. The idea being that people with lower baseline genetic resilience might be more vulnerable to SUDEP, regardless of epilepsy severity.
Uncovering genetic vulnerability
The researchers found that individuals with SUDEP had lower polygenic scores for both longevity and intelligence when compared to people living with epilepsy. Notably, the score for epilepsy itself showed no difference, suggesting that SUDEP risk isn't simply about a more severe genetic risk of epilepsy but represents a distinct vulnerability.
"Common genetic variants can potentially contribute to better prediction of SUDEP, which is a rare and tragic phenomenon that we desperately need to improve outcomes for," says Sarah Weckhuysen.
These scores showed that the effect of common genetic variations was small but detectable, accounting for only 1-4% of risk. However, its value became clear when combined with clinical data. SUDEP-3, a well-established clinical risk score, while helpful, has limited ability in identifying at-risk individuals. When researchers created a new predictive model that integrated the SUDEP-3 with the genetic resilience scores, its accuracy rose sharply, exceeding 90% compared with about 70% for SUDEP-3 alone.
The study has limitations: it focused on European ancestry, included limited SUDEP cases, and the biological mechanisms remain unclear. The polygenic scores for “intelligence” are statistical measures for genetic variants that affect brain function and long-term health, rather than a comment on an individual's cognitive function. Larger, more diverse cohorts and real-world validation are needed to improve the model.
Towards a hopeful future with earlier prediction
At the same time, the study opens up promising directions for future research, suggesting that genetic information could assist clinicians in identifying high-risk patients earlier. Genetic risk factors have a unique advantage over clinical risk factors because they are present from birth and can be determined at the time of diagnosis, while most clinical risk factors for SUDEP, like frequent seizures, can only be assessed years into the disease.
“For families living with that persistent fear of SUDEP," Weckhuysen concludes, "this could mean identifying risk and providing support much earlier in their journey."