Unveiling the hidden genetics and pathomechanisms of rare pediatric epileptogenic malformations of brain development (MOGHE) – EPIGAL

Genetic mosaicism is increasingly recognized as an important cause of developmental brain disorders. Recently, somatic loss-of-function variants in the SLC35A2 gene have been identified in the brain tissue of patients with MOGHE (mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy), a new rare developmental brain malformation clinically characterized by drug-resistant pediatric epilepsy, neurodevelopmental comorbidities, and white matter abnormalities. Surgical resection of the epileptogenic zone can be applied to control seizures, providing access to pathologically-relevant human tissue for diagnostic and research purposes. Yet, ~50% of patients with MOGHE do not carry SLC35A2 variants, and ~40% of patients do not achieve seizure control after surgery, emphasizing the urge for a better understanding of the disease. Combining genetic, transcriptomic, and functional investigations on postoperative human brain tissues and in vitro models, the EPIGAL project aims at unveiling the hidden genetic causes of MOGHE, and elucidating the cellular and molecular components of the disease.