The landscape of epilepsy-related GATOR1 variants
- Creators
- Baldassari S.
- Picard F.
- Verbeek N. E.
- van Kempen M.
- Brilstra E. H.
- Lesca G.
- Conti V.
- Guerrini R.
- Bisulli F.
- Licchetta L.
- Pippucci T.
- Tinuper P.
- Hirsch E.
- de Saint Martin A.
- Chelly J.
- Rudolf G.
- Chipaux M.
- Ferrand-Sorbets S.
- Dorfmuller G.
- Sisodiya S.
- Balestrini S.
- Schoeler N.
- Hernandez-Hernandez L.
- Krithika S.
- Oegema R.
- Hagebeuk E.
- Gunning B.
- Deckers C.
- Berghuis B.
- Wegner I.
- Niks E.
- Jansen F. E.
- Braun K.
- de Jong D.
- Rubboli G.
- Talvik I.
- Sander V.
- Uldall P.
- Jacquemont M. -L.
- Nava C.
- Leguern E.
- Julia S.
- Gambardella A.
- d'Orsi G.
- Crichiutti G.
- Faivre L.
- Darmency V.
- Benova B.
- Krsek P.
- Biraben A.
- Lebre A. -S.
- Jennesson M.
- Sattar S.
- Marchal C.
- Nordli D. R.
- Lindstrom K.
- Striano P.
- Lomax L. B.
- Kiss C.
- Bartolomei F.
- Lepine A. F.
- Schoonjans A. -S.
- Stouffs K.
- Jansen A.
- Panagiotakaki E.
- Ricard-Mousnier B.
- Thevenon J.
- de Bellescize J.
- Catenoix H.
- Dorn T.
- Zenker M.
- Muller-Schluter K.
- Brandt C.
- Krey I.
- Polster T.
- Wolff M.
- Balci M.
- Rostasy K.
- Achaz G.
- Zacher P.
- Becher T.
- Cloppenborg T.
- Yuskaitis C. J.
- Weckhuysen S.
- Poduri A.
- Lemke J. R.
- Moller R. S.
- Baulac S.
- Others:
- Baldassari, S.
- Picard, F.
- Verbeek, N. E.
- van Kempen, M.
- Brilstra, E. H.
- Lesca, G.
- Conti, V.
- Guerrini, R.
- Bisulli, F.
- Licchetta, L.
- Pippucci, T.
- Tinuper, P.
- Hirsch, E.
- de Saint Martin, A.
- Chelly, J.
- Rudolf, G.
- Chipaux, M.
- Ferrand-Sorbets, S.
- Dorfmuller, G.
- Sisodiya, S.
- Balestrini, S.
- Schoeler, N.
- Hernandez-Hernandez, L.
- Krithika, S.
- Oegema, R.
- Hagebeuk, E.
- Gunning, B.
- Deckers, C.
- Berghuis, B.
- Wegner, I.
- Niks, E.
- Jansen, F. E.
- Braun, K.
- de Jong, D.
- Rubboli, G.
- Talvik, I.
- Sander, V.
- Uldall, P.
- Jacquemont, M. -L.
- Nava, C.
- Leguern, E.
- Julia, S.
- Gambardella, A.
- D'Orsi, G.
- Crichiutti, G.
- Faivre, L.
- Darmency, V.
- Benova, B.
- Krsek, P.
- Biraben, A.
- Lebre, A. -S.
- Jennesson, M.
- Sattar, S.
- Marchal, C.
- Nordli, D. R.
- Lindstrom, K.
- Striano, P.
- Lomax, L. B.
- Kiss, C.
- Bartolomei, F.
- Lepine, A. F.
- Schoonjans, A. -S.
- Stouffs, K.
- Jansen, A.
- Panagiotakaki, E.
- Ricard-Mousnier, B.
- Thevenon, J.
- de Bellescize, J.
- Catenoix, H.
- Dorn, T.
- Zenker, M.
- Muller-Schluter, K.
- Brandt, C.
- Krey, I.
- Polster, T.
- Wolff, M.
- Balci, M.
- Rostasy, K.
- Achaz, G.
- Zacher, P.
- Becher, T.
- Cloppenborg, T.
- Yuskaitis, C. J.
- Weckhuysen, S.
- Poduri, A.
- Lemke, J. R.
- Moller, R. S.
- Baulac, S.
Description
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.
Additional details
- URL
- http://hdl.handle.net/11567/1021985
- URN
- urn:oai:iris.unige.it:11567/1021985
- Origin repository
- UNIGE