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EnglishPurpose: 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.
| Titolo: | The landscape of epilepsy-related GATOR1 variants | |
| Autore/i: | Baldassari S.; Picard F.; Verbeek N. E.; van Kempen M.; Brilstra E. H.; Lesca G.; Conti V.; Guerrini R.; Bisulli F.; Licchetta L.; 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.; Pippucci, Tommaso | |
| Autore/i Unibo: | ||
| Anno: | 2019 | |
| Rivista: | ||
| Digital Object Identifier (DOI): | http://dx.doi.org/10.1038/s41436-018-0060-2 | |
| Abstract: | 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. | |
| Data stato definitivo: | 2020-01-08T11:04:32Z | |
| Appare nelle tipologie: | 1.01 Articolo in rivista |
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