Research from the Costain Lab Improves Genetic Diagnosis for Infantile Epilepsy

Revisiting sequencing data provides answers for unresolved epilepsy cases

Epilepsy is the most common neurologic disorder with a typical onset in infancy and is associated with poor neurodevelopment and high mortality. Current clinical tests use genome sequencing technologies to identify genetic variants associated with epilepsy, yet many infants remain genetically undiagnosed after initial testing.

Research led by PhD candidate Jimmy Nguyen in the lab of Dr. Gregory Costain, published in the journal Neurology, showed that reanalysis of infantile epilepsy sequencing data can increase positive diagnosis results by identifying clinically relevant variants that were missed or uninterpretable at the time of the original test.

By revisiting unresolved cases using updated analytical approaches, the researchers focused on challenging variant types that are not routinely assessed in standard clinical workflows. Through collaboration with clinical and research teams, the study identified new genetic diagnoses in approximately 5% of previously unsolved cases, ultimately informing patient care and clinical decision-making.

The findings reinforce that a negative or nondiagnostic genetic test does not necessarily exclude an underlying genetic cause. As genomic technologies and interpretation methods continue to evolve, reanalysis offers an opportunity to identify diagnoses that may not have been possible during the initial assessment.

“This work reinforces that a negative genomic result is not the end of the diagnostic journey,” says Nguyen. “By revisiting genomic data with new tools and knowledge, we can continue to improve patient care and deliver answers that matter for patients and families.”

The study supports broader implementation of genome sequencing reanalysis in routine clinical care, where it is currently used infrequently despite its potential to improve diagnostic outcomes.

Looking ahead, the team is working to develop scalable and systematic approaches for genomic reanalysis while incorporating emerging technologies such as long-read genome sequencing to further improve diagnostic yield. Their ongoing work also focuses on increasing access to genomic testing and supporting equitable implementation across clinical care settings.

This study was supported by the Canadian Institutes of Health Research (CIHR), Epilepsy Canada, the University of Toronto McLaughlin Centre, and SickKids Foundation donors.