The landscape of epilepsy-related GATOR1 variants

被引：198

作者：

Baldassari, Sara ^{[1
,2
,3
,4
,5
]}

Baulac, Stephanie ^{[1
,2
,3
,4
,5
,6
,7
]}

Picard, Fabienne ^{[8
]}

Verbeek, Nienke E. ^{[8
]}

van Kempen, Marjan ^{[8
]}

Brilstra, Eva H. ^{[9
,10
,11
]}

Lesca, Gaetan ^{[12
]}

Conti, Valerio ^{[12
]}

Guerrini, Renzo ^{[13
,14
]}

Bisulli, Francesca ^{[13
,14
]}

Licchetta, Laura ^{[15
]}

Pippucci, Tommaso ^{[13
,14
]}

Tinuper, Paolo ^{[13
,14
]}

Hirsch, Edouard ^{[16
]}

de Saint Martin, Anne ^{[17
]}

Chelly, Jamel ^{[18
]}

Rudolf, Gabrielle ^{[18
]}

Chipaux, Mathilde ^{[19
]}

Ferrand-Sorbets, Sarah ^{[19
]}

Dorfmueller, Georg ^{[19
]}

Sisodiya, Sanjay ^{[20
,21
]}

Balestrini, Simona ^{[20
,21
]}

Schoeler, Natasha ^{[20
,21
]}

Hernandez-Hernandez, Laura ^{[20
,21
]}

Krithika, S. ^{[20
,21
]}

Oegema, Renske ^{[8
]}

Hagebeuk, Eveline ^{[22
]}

Gunning, Boudewijn ^{[22
]}

Deckers, Charles ^{[22
]}

Berghuis, Bianca ^{[22
]}

Wegner, Ilse ^{[22
]}

Niks, Erik ^{[23
]}

Jansen, Floor E. ^{[24
]}

Braun, Kees ^{[24
]}

de Jong, Danielle ^{[25
]}

Rubboli, Guido ^{[26
]}

Talvik, Inga ^{[27
]}

Sander, Valentin ^{[27
]}

Uldall, Peter ^{[28
]}

Jacquemont, Marie-Line ^{[29
]}

Nava, Caroline ^{[1
,2
,3
,4
,5
]}

Leguern, Eric ^{[1
,2
,3
,4
,5
]}

Julia, Sophie ^{[30
]}

Gambardella, Antonio ^{[31
]}

d'Orsi, Giuseppe ^{[32
]}

Crichiutti, Giovanni ^{[33
]}

Faivre, Laurence ^{[34
]}

Darmency, Veronique ^{[35
]}

Benova, Barbora ^{[36
]}

Krsek, Pavel ^{[36
]}

机构：

[1] UPMC Univ Paris 06, Sorbonne Univ, UMR S 1127, F-75013 Paris, France

[2] INSERM, U1127, F-75013 Paris, France

[3] CNRS, UMR 7225, F-75013 Paris, France

[4] Hop La Pitie Salpetriere, Inst Cerveau & Moelle Epiniere ICM, F-75013 Paris, France

[5] Hop La Pitie Salpetriere, AP HP, Dept Genet, F-75013 Paris, France

[6] Univ Hosp Geneva, Dept Clin Neurosci, Geneva, Switzerland

[7] Med Sch Geneva, Geneva, Switzerland

[8] Univ Med Ctr Utrecht, Dept Genet, Utrecht, Netherlands

[9] Hosp Civils Lyon GHE, Serv Genet, Lyon, France

[10] INSERM U1028, CNRL, CNRS UMR 5292, Lyon, France

[11] Univ Claude Bernard Lyon 1, GHE, Lyon, France

[12] A Meyer Childrens Hosp, Pediatr Neurol Neurogenet & Neurobiol Unit & Labs, Florence, Italy

[13] Univ Bologna, IRCCS Ist Sci Neurol Bologna, Bologna, Italy

[14] Univ Bologna, Dept Biomed & Neuromotor Sci, Bologna, Italy

[15] Polyclin St Orsola Malpighi Univ Hosp, Med Genet Unit, Bologna, Italy

[16] Univ Hosp Strasbourg, Dept Neurol, Ctr Reference Epilepsies Rares, Strasbourg, France

[17] Univ Hosp Strasbourg, Dept Pediat, Ctr Reference Epilepsies Rares, Strasbourg, France

[18] Strasbourg Univ, CNRS, INSERM, IGBMC, Strasbourg, France

[19] Fdn Adolphe De Rothschild, Dept Pediat Neurosurg, F-75019 Paris, France

[20] UCL Inst Neurol, Dept Clin & Expt Epilepsy, London WC1N 3BG, England

[21] Chalfont Ctr Epilepsy, Gerrards Cross, Bucks, England

[22] Stichting Epilepsie Instellingen Nederland, Zwolle Heemstede, Netherlands

[23] Leiden Univ, Med Ctr, Leiden, Netherlands

[24] Univ Med Ctr, Brain Ctr Rudolf Magnus, Dept Child Neurol, Utrecht, Netherlands

[25] Acad Ctr Epileptol Kempenhaeghe, Dept Neurol, Heeze, Netherlands

[26] Univ Copenhagen, Danish Epilepsy Ctr, Copenhagen, Denmark

[27] Tallinn Childrens Hosp, Dept Neurol & Rehabil, Tallinn, Estonia

[28] Danish Epilepsy Ctr, Dianalund, Denmark

[29] CHU La Reunion, Unit Med Genet, F-97448 St Pierre, France

[30] Hop Purpan CHU Toulouse, Pavillon Lefebvre, Serv Genet Med, Toulouse, France

[31] Magna Graecia Univ Catanzaro, Dept Med & Surg Sci, Inst Neurol, Catanzaro, Italy

[32] Univ Foggia, Riuniti Hosp, Clin Nervous Syst Dis, Epilepsy Ctr, Foggia, Italy

[33] Univ Hosp Udine, Inst Med, Dept Pediat, Udine, Italy

[34] Univ Bourgogne, CHU Dijon, Ctr Reference Anomalies Dev & Syndromes Malformat, Dijon, France

[35] CHU Dijon, Serv Neurophysiol & Pediat 1, Dijon, France

[36] Charles Univ Prague, Fac Med 2, Motol Univ Hosp, Dept Paediat Neurol, Prague, Czech Republic

[37] Ctr Hosp Univ Rennes, F-35000 Rennes, France

[38] CHU Reims, Hop Maison Blanche, Pole Biol, Serv Genet, F-51092 Reims, France

[39] CHU Reims, Amer Mem Hosp, Serv Pediat, REIMS, F-51092 Reims, France

[40] Univ Calif San Diego, Rady Childrens Hosp, Dept Pediat Neurol, San Diego, CA USA

[41] CHU Bordeaux, Serv Epileptol Clin, Bordeaux, France

[42] Univ Southern Calif, Keck Sch Med, Childrens Hosp Los Angeles, Los Angeles, CA 90033 USA

[43] Phoenix Childrens Hosp, Div Genet & Metab, Phoenix, AZ USA

[44] Univ Genoa, G Gaslini Inst, Pediat Neurol & Muscular Dis Unit, Dept Neurosci Rehabil Ophthalmol Genet Maternal &, Genoa, Italy

[45] Queens Univ, Div Neurol & Respirol, Dept Med, Kingston, ON, Canada

[46] Kingston Hlth Sci Ctr, Kingston, ON K7L 2V7, Canada

[47] Timone Hosp, APHM, Pediat Neurol Dept, Marseille, France

[48] Antwerp Univ Hosp, Dept Pediat Neurol, Edegem, Belgium

[49] VUB, UZ Brussel, Neurogenet Res Grp, Laarbeeklaan 101, B-1090 Brussels, Belgium

[50] Univ Hosp Lyon HCL, Paediat Clin Epileptol Sleep disorders & Funct Ne, Lyon, France

来源：

GENETICS IN MEDICINE | 2019年 / 21卷 / 02期

基金：

欧洲研究理事会;

关键词：

DEPDC5; mTORC1; pathway; Genetic focal epilepsy; Focal cortical dysplasia; SUDEP; SUDDEN UNEXPECTED DEATH; FAMILIAL FOCAL EPILEPSY; MAMMALIAN TARGET; CORTICAL DYSPLASIA; DEPDC5; MUTATIONS; GENES; GENETICS; COMPLEX; GTPASES; MODEL;

D O I：

10.1038/s41436-018-0060-2

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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.

引用

页码：398 / 408

页数：11

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