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. 2019 Feb;21(2):398-408.
doi: 10.1038/s41436-018-0060-2. Epub 2018 Aug 10.

The landscape of epilepsy-related GATOR1 variants

Sara Baldassari  1   2   3   4   5 , Fabienne Picard  6 , Nienke E Verbeek  7 , Marjan van Kempen  7 , Eva H Brilstra  7 , Gaetan Lesca  8 , Valerio Conti  9 , Renzo Guerrini  9 , Francesca Bisulli  10 , Laura Licchetta  10 , Tommaso Pippucci  11 , Paolo Tinuper  10 , Edouard Hirsch  12 , Anne de Saint Martin  13 , Jamel Chelly  14 , Gabrielle Rudolf  14 , Mathilde Chipaux  15 , Sarah Ferrand-Sorbets  15 , Georg Dorfmüller  15 , Sanjay Sisodiya  16 , Simona Balestrini  16 , Natasha Schoeler  16 , Laura Hernandez-Hernandez  16 , S Krithika  16 , Renske Oegema  7 , Eveline Hagebeuk  17 , Boudewijn Gunning  17 , Charles Deckers  17 , Bianca Berghuis  17 , Ilse Wegner  17 , Erik Niks  18 , Floor E Jansen  19 , Kees Braun  19 , Daniëlle de Jong  20 , Guido Rubboli  21 , Inga Talvik  22 , Valentin Sander  22 , Peter Uldall  23 , Marie-Line Jacquemont  24 , Caroline Nava  1   2   3   4   5 , Eric Leguern  1   2   3   4   5 , Sophie Julia  25 , Antonio Gambardella  26 , Giuseppe d'Orsi  27 , Giovanni Crichiutti  28 , Laurence Faivre  29 , Veronique Darmency  30 , Barbora Benova  31 , Pavel Krsek  31 , Arnaud Biraben  32 , Anne-Sophie Lebre  33 , Mélanie Jennesson  34 , Shifteh Sattar  35 , Cécile Marchal  36 , Douglas R Nordli Jr  37 , Kristin Lindstrom  38 , Pasquale Striano  39 , Lysa Boissé Lomax  40   41 , Courtney Kiss  41 , Fabrice Bartolomei  42 , Anne Fabienne Lepine  42 , An-Sofie Schoonjans  43 , Katrien Stouffs  44 , Anna Jansen  44 , Eleni Panagiotakaki  45 , Brigitte Ricard-Mousnier  46 , Julien Thevenon  47 , Julitta de Bellescize  45 , Hélène Catenoix  45 , Thomas Dorn  48 , Martin Zenker  49 , Karen Müller-Schlüter  50 , Christian Brandt  51 , Ilona Krey  52 , Tilman Polster  51 , Markus Wolff  53 , Meral Balci  54 , Kevin Rostasy  54 , Guillaume Achaz  55 , Pia Zacher  56 , Thomas Becher  57 , Thomas Cloppenborg  51 , Christopher J Yuskaitis  58   59   60 , Sarah Weckhuysen  61 , Annapurna Poduri  58   59   60 , Johannes R Lemke  52 , Rikke S Møller  62 , Stéphanie Baulac  63   64   65   66   67
Affiliations

The landscape of epilepsy-related GATOR1 variants

Sara Baldassari et al. Genet Med. 2019 Feb.

Erratum in

  • Correction to: The landscape of epilepsy-related GATOR1 variants.
    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, Martin AS, 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 F, Braun K, Jong D, Rubboli G, Talvik I, Sander V, Uldall P, Jacquemont ML, Nava C, Leguern E, Julia S, Gambardella A, d'Orsi G, Crichiutti G, Faivre L, Darmency V, Benova B, Krsek P, Biraben A, Lebre AS, Jennesson M, Sattar S, Marchal C, NordliJr DR, Lindstrom K, Striano P, Lomax LB, Kiss C, Bartolomei F, Lepine AF, Schoonjans AS, Stouffs K, Jansen A, Panagiotakaki E, Ricard-Mousnier B, Thevenon J, Bellescize J, Catenoix H, Dorn T, Zenker M, Müller-Schlüter K, Brandt C, Krey I, Polster T, Wolff M, Balci M, Rostasy K, Achaz G, Zacher P, Becher T, Cloppenborg T, Yuskaitis CJ, Weckhuysen S, Poduri A, Lemke JR, Møller RS, Baulac S. Baldassari S, et al. Genet Med. 2019 Jul;21(7):1671. doi: 10.1038/s41436-018-0284-1. Genet Med. 2019. PMID: 30158694 Free PMC article.
  • Correction: The landscape of epilepsy-related GATOR1 variants.
    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 EH, Jansen FE, Braun K, de Jong D, Rubboli G, Talvik I, Sander V, Uldall P, Jacquemont ML, Nava C, Leguern E, Julia S, Gambardella A, d'Orsi G, Crichiutti G, Faivre L, Darmency V, Benova B, Krsek P, Biraben A, Lebre AS, Jennesson M, Sattar S, Marchal C, NordliJr DR, Lindstrom K, Striano P, Lomax LB, Kiss C, Bartolomei F, Lepine AF, Schoonjans AS, Stouffs K, Jansen A, Panagiotakaki E, Ricard-Mousnier B, Thevenon J, de Bellescize J, Catenoix H, Dorn T, Zenker M, Müller-Schlüter K, Brandt C, Krey I, Polster T, Wolff M, Balci M, Rostasy K, Achaz G, Zacher P, Becher T, Cloppenborg T, Yuskaitis CJ, Weckhuysen S, Poduri A, Lemke JR, Møller RS, Baulac S. Baldassari S, et al. Genet Med. 2019 Aug;21(8):1896. doi: 10.1038/s41436-018-0325-9. Genet Med. 2019. PMID: 30262923 Free PMC article.

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; SUDEP; mTORC1 pathway.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1. Schematic diagram showing the domain/structural organization of DEPDC5, NPRL2, and NPRL3 proteins and the positions of the 140 distinct epilepsy-related variants reported so far according to the 3D-structure of the GATOR1 protein complex.
In the upper panels of each protein are indicated loss-of-function (LoF) variants, while missense and splice-region variants are shown in the bottom part and classified according to our novel proposed framework. Recurrent variants are indicated in blue. VUS variant of uncertain significance
Fig. 2
Fig. 2. All 63 distinct GATOR1 variants identified in the new patient cohort.
For missense variants, Mendelian Clinically Applicable Pathogenicity (M-CAP) was used to predict possible pathogenic (D) or possible benign (B) variants. Human Splice Finder (HSF) v3.0 was used to discriminate splice-region variants with a possible impact on the splicing (D) and those not predicted to impact the splicing of mRNA (B). cDNA complementary DNA, VUS variant of uncertain significance, LoF loss of function, N/A not available. Recurrent variants are indicated in blue
Fig. 3
Fig. 3. Classification framework for epilepsy-related GATOR1 variants.
Pathogenic range: 6 alleles for DEPDC5, 3 alleles for NPRL2, and 4 alleles for NPRL3
Fig. 4
Fig. 4. Distribution of the 140 distinct epilepsy-related GATOR1 variants among the 183 probands reported so far.
Percentages and number of probands are indicated for each gene
See this image and copyright information in PMC

References

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