Genetic Discovery Could Improve Diagnosis of Drug-Resistant Epilepsy

Many patients lack a definitive genetic diagnosis, making clinical management and family counseling more difficult. Understanding how disruptions in cortical development occur could help improve diagnostic testing in neurology. New research has now identified genetic mutations that can disrupt key cellular signaling processes involved in brain development, revealing a molecular mechanism that may drive the formation of FCD.

Investigators at National Yang Ming Chiao Tung University (NYCU; Hsinchu, Taiwan), working with University College London and collaborators in Belgium, identified the transcription factor FOXJ3 as a regulator of cortical development associated with focal epilepsy. The researchers found that FOXJ3 acts as a transcriptional regulator controlling expression of PTEN, a gene that suppresses activity in the mTOR signaling pathway. When FOXJ3 function is impaired, PTEN activation is reduced, leading to increased mTOR signaling and abnormal neuronal growth characteristic of focal cortical dysplasia.

The study combined human genetics with developmental neuroscience. The work began after clinicians at Taipei Veterans General Hospital identified a Taiwanese family with inherited drug-resistant epilepsy and focal cortical dysplasia. Whole-genome sequencing revealed a FOXJ3 variant that segregated with the epilepsy phenotype in affected family members. Additional analyses, including studies in mouse models and single-cell datasets, showed that FOXJ3 is highly expressed in neural progenitor cells during early corticogenesis and declines as cortical layers begin to form.

Further experiments demonstrated that restoring PTEN activity could correct developmental abnormalities in experimental models, highlighting the importance of the FOXJ3–PTEN regulatory axis in cortical development. The findings identify FOXJ3 as a new genetic contributor within disorders affecting the mTOR pathway (mTORpathies) and provide insight into mechanisms underlying cortical malformations associated with epilepsy. According to the researchers, the work could improve genetic diagnosis for patients with focal epilepsy, including individuals whose MRI results appear normal, and may inform future therapeutic strategies targeting mTOR signaling. The study was published in Nature Communications on March 9, 2026.