The landscape of epilepsy-related GATOR1 variants

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

doi:10.1038/s41436-018-0060-2

The landscape of epilepsy-related GATOR1 variants

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 SisodiyaSimona 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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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.

Originalsprog	Engelsk
Tidsskrift	Genetics in medicine : official journal of the American College of Medical Genetics
Vol/bind	21
Udgave nummer	2
Sider (fra-til)	398-408
Antal sider	11
ISSN	1098-3600
DOI	https://doi.org/10.1038/s41436-018-0060-2
Status	Udgivet - feb. 2019

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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., Dorfmüller, G., ... Møller, R. S. (2019). The landscape of epilepsy-related GATOR1 variants. Genetics in medicine : official journal of the American College of Medical Genetics, 21(2), 398-408. https://doi.org/10.1038/s41436-018-0060-2

Baldassari, S, Picard, F, Verbeek, NE, van Kempen, M, Brilstra, EH, 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, Dorfmüller, 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, FE, 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, Brandt, C & Møller, RS 2019, 'The landscape of epilepsy-related GATOR1 variants', Genetics in medicine : official journal of the American College of Medical Genetics, bind 21, nr. 2, s. 398-408. https://doi.org/10.1038/s41436-018-0060-2

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title = "The landscape of epilepsy-related GATOR1 variants",

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.",

keywords = "DEPDC5, Focal cortical dysplasia, Genetic focal epilepsy, mTORC1 pathway, SUDEP",

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

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language = "English",

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journal = "Genetics in medicine : official journal of the American College of Medical Genetics",

issn = "1098-3600",

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T1 - The landscape of epilepsy-related GATOR1 variants

AU - Baldassari, Sara

AU - Picard, Fabienne

AU - Verbeek, Nienke E

AU - van Kempen, Marjan

AU - Brilstra, Eva H

AU - Lesca, Gaetan

AU - Conti, Valerio

AU - Guerrini, Renzo

AU - Bisulli, Francesca

AU - Licchetta, Laura

AU - Pippucci, Tommaso

AU - Tinuper, Paolo

AU - Hirsch, Edouard

AU - de Saint Martin, Anne

AU - Chelly, Jamel

AU - Rudolf, Gabrielle

AU - Chipaux, Mathilde

AU - Ferrand-Sorbets, Sarah

AU - Dorfmüller, Georg

AU - Sisodiya, Sanjay

AU - Balestrini, Simona

AU - Schoeler, Natasha

AU - Hernandez-Hernandez, Laura

AU - Krithika, S

AU - Oegema, Renske

AU - Hagebeuk, Eveline

AU - Gunning, Boudewijn

AU - Deckers, Charles

AU - Berghuis, Bianca

AU - Wegner, Ilse

AU - Niks, Erik

AU - Jansen, Floor E

AU - Braun, Kees

AU - de Jong, Daniëlle

AU - Rubboli, Guido

AU - Talvik, Inga

AU - Sander, Valentin

AU - Uldall, Peter

AU - Jacquemont, Marie-Line

AU - Nava, Caroline

AU - Leguern, Eric

AU - Julia, Sophie

AU - Gambardella, Antonio

AU - d'Orsi, Giuseppe

AU - Crichiutti, Giovanni

AU - Faivre, Laurence

AU - Darmency, Veronique

AU - Benova, Barbora

AU - Brandt, Christian

AU - Møller, Rikke S

PY - 2019/2

Y1 - 2019/2

N2 - 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.

AB - 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.

KW - DEPDC5

KW - Focal cortical dysplasia

KW - Genetic focal epilepsy

KW - mTORC1 pathway

KW - SUDEP

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U2 - 10.1038/s41436-018-0060-2

DO - 10.1038/s41436-018-0060-2

M3 - Journal article

C2 - 30093711

SN - 1098-3600

VL - 21

SP - 398

EP - 408

JO - Genetics in medicine : official journal of the American College of Medical Genetics

JF - Genetics in medicine : official journal of the American College of Medical Genetics

IS - 2

ER -

The landscape of epilepsy-related GATOR1 variants

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