Novel GATOR1 variants in focal epilepsy

Introduction Variants in GATOR1 genes are well established in focal epilepsy syndromes. A strong association of GATOR1 variants with drug-resistant epilepsy as well as an increased risk of sudden unexplained death in epilepsy warrants developing strategies to facilitate the identification of patients who could potentially benefit from genetic testing and precision medicine. We aimed to determine the yield of GATOR1 gene sequencing in patients with focal epilepsy typically referred for genetic testing, establish novel GATOR1 variants and determine clinical, electroencephalographic, and radiological characteristics of variant carriers. Patients and Methods Ninety-six patients with clinical suspicion of genetic focal epilepsy with previous comprehensive diagnostic epilepsy evaluation in The Neurology Clinic, University Clinical Center of Serbia, were included in the study. Sequencing was performed using a custom gene panel encompassing DEPDC5, NPRL2, and NPRL3. Variants of interest (VOI) were classified according to criteria proposed by the American College of Medical Genetics and the Association for Molecular Pathology. Results Four previously unreported VOI in 4/96 (4.2%) patients were found in our cohort. Three likely pathogenic variants were determined in 3/96 (3.1%) patients, one frameshift variant in DEPDC5 in a patient with nonlesional frontal lobe epilepsy, one splicogenic DEPDC5 variant in a patient with nonlesional posterior quadrant epilepsy, and one frameshift variant in NPRL2 in a patient with temporal lobe epilepsy associated with hippocampal sclerosis. Only one VOI, a missense variant in NPRL3, found in 1/96 (1.1%) patients, was classified as a variant of unknown significance. Conclusion GATOR1 gene sequencing was diagnostic in 3.1% of our cohort and revealed three novel likely pathogenic variants, including a previously unreported association of temporal lobe epilepsy with hippocampal sclerosis with an NPRL2 variant. Further research is essential for a better understanding of the clinical scope of GATOR1 gene-associated epilepsy.