Journal Article

The landscape of epilepsy-related GATOR1 variants

Sander, Valentin, Krsek, Pavel, Cloppenborg, Thomas, de Saint Martin, Anne, Jacquemont, Marie-Line, Nordli, Douglas R, Dorn, Thomas, Dorfmüller, Georg, Schoeler, Natasha, Braun, Kees, d’Orsi, Giuseppe, Lebre, Anne-Sophie, Wolff, Markus, Verbeek, Nienke E., Chipaux, Mathilde, Weckhuysen, Sarah, Niks, Erik, Nava, Caroline, Gambardella, Antonio, Panagiotakaki, Eleni, Bisulli, Francesca, Jansen, Floor E., Stouffs, Katrien, Møller, Rikke S., Balci, Meral, Bartolomei, Fabrice, Brandt, Christian, Pippucci, Tommaso, Brilstra, Eva H., Crichiutti, Giovanni, Rubboli, Guido, Achaz, Guillaume, Berghuis, Bianca, Lindstrom, Kristin, de Bellescize, Julitta, Baulac, Stéphanie, Baldassari, Sara, Sattar, Shifteh, Thevenon, Julien, Hagebeuk, Eveline, Uldall, Peter, Julia, Sophie, Hirsch, Edouard, Oegema, Renske, de Jong, Daniëlle, Yuskaitis, Christopher J., Picard, Fabienne, Lepine, Anne Fabienne, Polster, Tilman, Rostasy, Kevin, Biraben, Arnaud, Gunning, Boudewijn, Talvik, Inga, Darmency, Veronique, Ricard-Mousnier, Brigitte, Sisodiya, Sanjay, Rudolf, Gabrielle, Ferrand-Sorbets, Sarah, van Kempen, Marjan, Jennesson, Mél

2019

Overview

Purpose To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5 , NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway Methods We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants. Results The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign. Conclusion Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.

• Publisher: Nature Publishing Group US,Elsevier Limited,Nature Publishing Group
• Subject: Adolescent / Biomedical and Life Sciences / Biomedicine / Brugada Syndrome - genetics / Brugada Syndrome - mortality / Brugada Syndrome - physiopathology / Child / Child, Preschool / Convulsions & seizures / DNA Copy Number Variations - genetics / Epilepsy / Epilepsy - complications / Epilepsy - epidemiology / Epilepsy - genetics / Epilepsy - physiopathology / Female / Genetic Predisposition to Disease / Genetics / GTPase-Activating Proteins - genetics / Human Genetics / Humans / INDEL Mutation - genetics / Infant / Infant, Newborn / Laboratory Medicine / Life Sciences / Loss of Function Mutation - genetics / Male / Mechanistic Target of Rapamycin Complex 1 - genetics / Multiprotein Complexes - genetics / Pedigree / Repressor Proteins - genetics / Seizures - complications / Seizures - epidemiology / Seizures - genetics / Seizures - physiopathology / SIDS / Signal Transduction - genetics / Sudden infant death syndrome / Tumor Suppressor Proteins - genetics