Montreal Researchers Identify Gene Linked to Rare, Severe Form of Epilepsy
A team at the Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM) has identified a gene that appears to be responsible for a rare and serious type of epilepsy. The discovery, published March 23, 2026, could lead to improved diagnosis for patients who currently have no clear explanation for their condition. Identifying the genetic causes of epilepsy is a crucial step toward personalized treatment and improved quality of life for those affected.
“We are talking about particularly severe cases of epilepsy that are often resistant to available anti-epileptic treatments,” said Professor Eric Samarut of the CRCHUM, who led the research. “These epilepsies often begin in childhood and persist into adulthood, significantly impacting patients’ quality of life.”
Surprisingly, he added, the cause of the disease remains unknown in as many as 50% of cases. “If we don’t recognize the cause, it puts us in a really difficult situation… given that we don’t know what mechanism we need to address.”
The breakthrough came through a collaboration with the mother of two young sisters diagnosed with a severe epilepsy syndrome, Lennox-Gastaut syndrome. Researchers determined that the THAP12 gene appears to be responsible for what is known as an “autosomal recessive” form of epilepsy – a hereditary disease that occurs when both copies of the gene, one inherited from each parent, are defective.
“No genetic cause had been identified previously, but the fact that it involved two sisters strongly suggested a genetic basis,” explained Professor Samarut.
The parents’ decision to have a second child, despite the first daughter’s illness since three months of age – driven by the lack of evidence suggesting a genetic component – ultimately proved pivotal. Comparing the genomes of the two sisters and their parents, researchers identified two genetic variants.
To confirm their findings, the team replicated the genetic anomalies in both mice and zebrafish (a species that shares up to 80% of its genes with humans). They found that these mutations significantly reduced the production of a protein whose function was previously unknown.
The results, shared via email, were described as “striking: early lethality, major alterations in brain development, abnormal neuronal activity and increased susceptibility to seizures.”
Prior to this research, the function of the THAP12 gene was unknown and had never been linked to neurological disorders. Researchers now understand that it plays a key role “very early in embryonic development and in the survival of progenitor cells that will become future nerve cells.”
When the gene doesn’t function properly, brain development is disrupted, leading to abnormal brain activity and a higher risk of epileptic seizures.
“This was a very long and even somewhat ‘perilous’ project,” Professor Samarut admitted. “How could we prove there was a problem with the function of something whose function we didn’t know? It was a bit of a vicious cycle. But now, we have converging evidence showing that these mutations cause a loss of function in this gene.”
The discovery could eventually lead to the development of new treatments, particularly given recent advances in gene therapy. However, Professor Samarut emphasized that, for now, the findings primarily offer new diagnostic avenues and provide answers to affected families.
“A genetic diagnosis is a really essential first step in their therapeutic journey,” he said. “And often it’s reassuring for them to have a name, to have a cause, even if it doesn’t immediately change their daily lives, it validates their illness and really helps them move forward.”
He added, “To use an analogy, it could allow us to identify mechanisms on which we could apply a little oil to improve the clinical presentation of these patients and therefore improve their daily lives.”
Professor Samarut noted that the THAP12 gene has eleven “brothers and sisters,” suggesting that this discovery could open the door to understanding the functions of the entire gene family, particularly within the central nervous system.
The research findings have been posted on Medrxiv while awaiting publication in a scientific journal – a process that can seize up to two years – “so that it can benefit other patients who have not yet been diagnosed,” Professor Samarut explained. You can learn more about research at the CRCHUM here and the Centre de recherche du Centre hospitalier de l’Université de Montréal here.
