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The landscape of epilepsy-related GATOR1 variants

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  • Sara Baldassari
  • Fabienne Picard
  • Nienke E Verbeek
  • Marjan van Kempen
  • Eva H Brilstra
  • Gaetan Lesca
  • Valerio Conti
  • Renzo Guerrini
  • Francesca Bisulli
  • Laura Licchetta
  • Tommaso Pippucci
  • Paolo Tinuper
  • Edouard Hirsch
  • Anne de Saint Martin
  • Jamel Chelly
  • Gabrielle Rudolf
  • Mathilde Chipaux
  • Sarah Ferrand-Sorbets
  • Georg Dorfmüller
  • Sanjay Sisodiya
  • Simona Balestrini
  • Natasha Schoeler
  • Laura Hernandez-Hernandez
  • S Krithika
  • Renske Oegema
  • Eveline Hagebeuk
  • Boudewijn Gunning
  • Charles Deckers
  • Bianca Berghuis
  • Ilse Wegner
  • Erik Niks
  • Floor E Jansen
  • Kees Braun
  • Daniëlle de Jong
  • Guido Rubboli
  • Inga Talvik
  • Valentin Sander
  • Peter Uldall
  • Marie-Line Jacquemont
  • Caroline Nava
  • Eric Leguern
  • Sophie Julia
  • Antonio Gambardella
  • Giuseppe d'Orsi
  • Giovanni Crichiutti
  • Laurence Faivre
  • Veronique Darmency
  • Barbora Benova
  • Christian Brandt
  • Rikke S Møller
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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.

Original languageEnglish
JournalGenetics in medicine : official journal of the American College of Medical Genetics
Volume21
Issue number2
Pages (from-to)398-408
Number of pages11
ISSN1098-3600
DOIs
Publication statusPublished - Feb 2019

ID: 56574265