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      Is Open Access

      AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 4 , 1 , 1 , 4 , 1 , 7 , 8 , 9 , 10 , 11 , 12 , 1 , 13 , 14 , 13 , 14 , 2 , 3 , 15 , 4 , 16 , 16 , 17 , 1 , 1 , 18 , 18 , 19 , 20 , 21 , 7 , 7 , 10 , 10 , 10 , 10 , 10 , 22 , 23 , 6 , 6 , 5 , 6 , 24 , 6 , 25 , 25 , 26 , 27 , 28 , 28 , 29 , 30 , 31 , 31 , 31 , 31 , 32 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 40 , 41 , 41 , 42 , 43 , 2 , 3 , 44 , 44 , SYNAPS Study Group 45 , 45 , 46 , 47 , 48 , 48 , 49 , 50 , 50 , 51 , 52 , 41 , 13 , 14 , 22 , 7 , 43 , 29 , 28 , 53 , 54 , 45 , 4 , 55 , 5 , 56 , 4 , , 1 ,
      Nature Communications
      Nature Publishing Group UK
      Next-generation sequencing, Synaptic development, Ion channels in the nervous system, Neurodevelopmental disorders

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca 2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.

          Abstract

          Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca 2+ transport and AMPAR currents.”

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          Most cited references41

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          • Abstract: found
          • Article: not found

          Rett syndrome: revised diagnostic criteria and nomenclature.

          Rett syndrome (RTT) is a severe neurodevelopmental disease that affects approximately 1 in 10,000 live female births and is often caused by mutations in Methyl-CpG-binding protein 2 (MECP2). Despite distinct clinical features, the accumulation of clinical and molecular information in recent years has generated considerable confusion regarding the diagnosis of RTT. The purpose of this work was to revise and clarify 2002 consensus criteria for the diagnosis of RTT in anticipation of treatment trials. RettSearch members, representing the majority of the international clinical RTT specialists, participated in an iterative process to come to a consensus on a revised and simplified clinical diagnostic criteria for RTT. The clinical criteria required for the diagnosis of classic and atypical RTT were clarified and simplified. Guidelines for the diagnosis and molecular evaluation of specific variant forms of RTT were developed. These revised criteria provide clarity regarding the key features required for the diagnosis of RTT and reinforce the concept that RTT is a clinical diagnosis based on distinct clinical criteria, independent of molecular findings. We recommend that these criteria and guidelines be utilized in any proposed clinical research.
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            • Record: found
            • Abstract: not found
            • Article: not found

            A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology.

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              • Record: found
              • Abstract: found
              • Article: not found

              The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity.

              The AMPA receptor (AMPAR) GluR2 subunit dictates the critical biophysical properties of the receptor, strongly influences receptor assembly and trafficking, and plays pivotal roles in a number of forms of long-term synaptic plasticity. Most neuronal AMPARs contain this critical subunit; however, in certain restricted neuronal populations and under certain physiological or pathological conditions, AMPARs that lack this subunit are expressed. There is a current surge of interest in such GluR2-lacking Ca2+-permeable AMPARs in how they affect the regulation of synaptic transmission. Here, we bring together recent data highlighting the novel and important roles of GluR2 in synaptic function and plasticity.
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                Author and article information

                Contributors
                d.kullmann@ucl.ac.uk
                h.houlden@ucl.ac.uk
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                12 July 2019
                12 July 2019
                2019
                : 10
                : 3094
                Affiliations
                [1 ]ISNI 0000000121901201, GRID grid.83440.3b, Department of Neuromuscular Disorders, , UCL Queen Square Institute of Neurology, ; London, WC1N 3BG UK
                [2 ]ISNI 0000 0004 1760 0109, GRID grid.419504.d, Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto “Giannina Gaslini”, ; 16147 Genoa, Italy
                [3 ]ISNI 0000 0001 2151 3065, GRID grid.5606.5, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, , University of Genoa, ; 16132 Genoa, Italy
                [4 ]ISNI 0000000121901201, GRID grid.83440.3b, Department of Clinical and Experimental Epilepsy, , UCL Queen Square Institute of Neurology, ; London, WC1N 3BG UK
                [5 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Genome Sciences, , University of Washington School of Medicine, ; Seattle, Washington 98195 USA
                [6 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, , Central South University, ; Changsha, 410083 Hunan China
                [7 ]ISNI 0000 0004 1937 0546, GRID grid.12136.37, Pediatric Neurology Unit, Safra Children’s Hospital, Sheba Medical Center and Sackler Faculty of Medicine, , Tel Aviv University, ; Tel Aviv, 526121 Ramat Gan Israel
                [8 ]ISNI 0000 0004 1937 1098, GRID grid.413776.0, Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Département de Génétique et Embryologie Médicale, APHP, Hôpital Trousseau, ; 75012 Paris, France
                [9 ]ISNI 0000 0004 1937 1098, GRID grid.413776.0, Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Service de Neurologie Pédiatrique, APHP, Hôpital Trousseau, ; 75012 Paris, France
                [10 ]GRID grid.428467.b, GeneDx, ; Gaithersburg, MD 20877 USA
                [11 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, Biochemistry Center, , Heidelberg University, ; D-69120 Heidelberg, Germany
                [12 ]ISNI 0000 0004 0495 6261, GRID grid.419309.6, Royal Devon and Exeter NHS Foundation Trust, ; Exeter, EX1 2ED UK
                [13 ]ISNI 0000 0004 0472 0283, GRID grid.411147.6, Department of Biochemistry and Genetics, , University Hospital, ; 49933 Angers, France
                [14 ]ISNI 0000 0001 2248 3363, GRID grid.7252.2, MitoLab, UMR CNRS 6015-INSERM U1083, MitoVasc Institute, Angers University, ; 49100 Angers, France
                [15 ]GRID grid.420468.c, Great Ormond Street Hospital for Children, ; London, WC1N 3JH UK
                [16 ]ISNI 0000 0001 2284 9943, GRID grid.257060.6, Division of Medical Genetics, , Northwell Health/Hofstra University SOM, ; New York, 11020 USA
                [17 ]ISNI 0000000121901201, GRID grid.83440.3b, Department of Clinical and Movement Neurosciences and Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, ; London, WC1N 1PJ UK
                [18 ]ISNI 0000 0001 2336 6580, GRID grid.7605.4, Department of Medical Sciences, Medical Genetics Unit, , University of Torino, ; 10126 Torino, Italy
                [19 ]ISNI 0000 0001 2336 6580, GRID grid.7605.4, Department of Public Health and Pediatrics, , University of Torino, ; 10126 Torino, Italy
                [20 ]ISNI 0000 0001 0663 8628, GRID grid.411160.3, Unit of Medical and Molecular Genetics, , University Hospital Sant Joan de Deu Barcelona, ; 08950 Barcelona, Spain
                [21 ]Unit of Neuropediatrics, University Hospital, Angers Cedex, 49933 France
                [22 ]ISNI 0000 0004 0470 5905, GRID grid.31501.36, Department of Biomedical Sciences, , Seoul National University, ; Seoul, 03080 South Korea
                [23 ]ISNI 0000 0004 0470 5905, GRID grid.31501.36, Department of Pediatrics, , Seoul National University, ; Seoul, 03080 South Korea
                [24 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Psychiatry, , University of Washington, ; Seattle, WA 98195 USA
                [25 ]ISNI 0000 0004 0427 667X, GRID grid.240023.7, Center for Autism and Related Disorders, Kennedy Krieger Institute, ; Baltimore, Maryland 21211 USA
                [26 ]ISNI 0000000084992262, GRID grid.7177.6, Department of Clinical Genetics, , University of Amsterdam, ; Meibergdreef 9, 1105 Amsterdam, Netherlands
                [27 ]Department of Pediatric Neurology, Amsterdam UMC, 1105 Amsterdam, Netherlands
                [28 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Epilepsy Research Centre, Department of Medicine, , University of Melbourne, Austin Health, Melbourne, ; Victoria, 3084 Australia
                [29 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Pediatrics, , University of Washington, ; Seattle, WA 98195 USA
                [30 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Pediatrics, Division of Genetic Medicine, , University of Washington, ; Seattle, WA 98195 USA
                [31 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Department of Clinical Genomics, , Mayo Clinic, ; Rochester, 55902 MN USA
                [32 ]ISNI 0000 0001 2182 2255, GRID grid.28046.38, Children’s Hospital of Eastern Ontario Research Institute, , University of Ottawa, ; Ottawa, K1H 8L1 Canada
                [33 ]ISNI 0000 0000 9064 4811, GRID grid.63984.30, Department of Human Genetics, , McGill University Health Centre, ; Montréal, QC H4A 3J1 Canada
                [34 ]Genome Québec Innovation Center, Montréal, QC H3A 0G1 Canada
                [35 ]Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, CIBERSAM, 28007 Madrid, Spain
                [36 ]Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Maranon, Universidad Complutense, CIBERSAM, 28007 Madrid, Spain
                [37 ]ISNI 0000 0001 0277 7938, GRID grid.410526.4, Hospital Gregorio Maranon, IiSGM, School of Medicine, Calle Dr Esquerdo, 46, ; 28007 Madrid, Spain
                [38 ]ISNI 0000000109410645, GRID grid.11794.3a, Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), CIMUS, Universidade de Santiago de Compostela, ; 15782 Santiago de Compostela, Spain
                [39 ]ISNI 0000 0004 4688 8850, GRID grid.443929.1, Fundación Pública Galega de Medicina Xenómica- IDIS- Servicio Galego de Saúde (SERGAS), 15706, ; 15782 Santiago de Compostela, Spain
                [40 ]ISNI 0000000089452978, GRID grid.10419.3d, Department of Clinical Genetics, , Leiden University Medical Center, ; 2333 ZA Leiden, Netherlands
                [41 ]ISNI 0000 0001 2150 9058, GRID grid.411439.a, Department of Genetics, Assistance Publique - Hôpitaux de Paris, , University Hôpital Pitié-Salpêtrière, ; 75013 Paris, France
                [42 ]ISNI 0000 0004 1762 5517, GRID grid.10776.37, Department of Health Promotion,Mother and Child Care, Internal Medicine and Medical Specialities “G. D’Alessandro”, , University of Palermo, ; 90133 Palermo, Italy
                [43 ]ISNI 0000 0004 1760 0109, GRID grid.419504.d, Laboratory of Neurogenetics and Neuroscience, IRCCS Istituto “Giannina Gaslini”, ; 16147 Genova, Italy
                [44 ]ISNI 0000 0001 1941 4308, GRID grid.5133.4, Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, , University of Trieste, ; 34134 Trieste, Italy
                [45 ]Department of Pediatric Neurology, University Hospital Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
                [46 ]Neuroscience Medical Group, 1625 Stockton Boulevard, Suite 104, Sacramento, CA 95816 USA
                [47 ]ISNI 0000 0001 0690 7621, GRID grid.413957.d, Department of Genetics and Inherited Metabolic diseases, , Children’s Hospital Colorado, ; Aurora, CO 80045 USA
                [48 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Department of Pediatrics, , Washington University School of Medicine, ; St. Louis, MO 63110 USA
                [49 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, William Greenleaf Eliot Division of Child & Adolescent Psychiatry, Department of Psychiatry, , Washington University School of Medicine, ; St. Louis, MO 63110 USA
                [50 ]ISNI 0000 0001 1941 4308, GRID grid.5133.4, Department of Chemical and Pharmaceutical Sciences, , University of Trieste, ; 34134 Trieste, Italy
                [51 ]ISNI 0000 0004 1937 0722, GRID grid.11899.38, Neurogenetics Unit, Department of Neurology, , University of Sao Paulo, ; Sao Paulo, 01308-000 Brazil
                [52 ]Mendelics Genomic Analysis, Sao Paulo, SP 04013-000 Brazil
                [53 ]GRID grid.498924.a, Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, , Central Manchester University Hospitals NHS Foundation Trust, ; Lancashire, M13 9WL UK
                [54 ]ISNI 0000000121662407, GRID grid.5379.8, Division of Evolution and Genomic Sciences, School of Biological Sciences, , University of Manchester, ; Manchester, M13 9WL UK
                [55 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Cell Biology, , Yale University School of Medicine, ; New Haven, CT 06520 USA
                [56 ]ISNI 0000000122986657, GRID grid.34477.33, Howard Hughes Medical Institute, , University of Washington, ; Seattle, WA 98195 USA
                [57 ]Children’s Hospital of Rabat, University of Rabat, 6527 Rabat, Morocco
                [58 ]ISNI 0000 0004 0621 0092, GRID grid.410563.5, Department of Paediatrics, , Medical University of Sofia, ; Sofia, 1431 Bulgaria
                [59 ]ISNI 0000 0000 8607 6858, GRID grid.411374.4, Centre of Human Genetics, , University Hospital Liege, ; 4000 Liege, Belgium
                [60 ]ISNI 0000 0000 8853 2677, GRID grid.5361.1, Department of Neurology, , Medical University Innsbruck, ; Anichstrasse 35, 6020 Innsbruck, Austria
                [61 ]ISNI 0000 0004 1755 3242, GRID grid.7763.5, Ospedale Pediatrico “A. Cao”, Department of Biomedical Sciences, , University of Cagliari, ; 09121 Cagliari, Italy
                [62 ]ISNI 0000 0001 2200 8888, GRID grid.9841.4, Child and Adolescent Neuropsychiatry, , University of Campania “Luigi Vanvitelli”, ; 81100 Caserta, Italy
                [63 ]ISNI 0000 0004 1767 3121, GRID grid.413495.e, Division of Paediatric Neurology, Dayanand Medical College & Hospital, ; Ludhiana, Punjab 141001 India
                [64 ]Department of Paediatric Neurology, Children’s Hospital of Lahore, Lahore, 381-D/2 Pakistan
                [65 ]ISNI 0000 0004 0606 972X, GRID grid.411190.c, Department of Medical Genetics, , Aga Khan University Hospital, Karachi, ; Karachi City, Sindh 74800 Pakistan
                [66 ]ISNI 0000 0004 0606 972X, GRID grid.411190.c, Department of Paediatric Neurology, , Aga Khan University Hospital, Karachi, ; Karachi City, Sindh 74800 Pakistan
                [67 ]ISNI 0000 0000 8661 1590, GRID grid.411621.1, Department of Pediatrics, , Shimane University School of Medicine, ; 89-1 Enya, Izumo, Shimane 6938501 Japan
                [68 ]Institute of Child Health and Shishu Shastho Foundation Hospital, Mirpur, Dhaka 1216 Bangladesh
                [69 ]ISNI 0000 0004 1772 7935, GRID grid.414189.1, Vittore Buzzi Children’s Hospital, ; Via Castelvetro 32, 20154 Milan, Italy
                [70 ]ISNI 0000000089452978, GRID grid.10419.3d, Leiden University Medical Center, ; Albinusdreef 2, 2333 Leiden, Netherlands
                [71 ]ISNI 0000 0004 1757 2611, GRID grid.158820.6, Paediatric Department, , San Salvatore Hospital, University of L’Aquila, ; L’Aquila, Italy
                [72 ]Department of Pediatrics, University of Pavia, IRCCS Policlinico “San Matteo”, 27100 Pavia, Italy
                [73 ]ISNI 0000 0004 1764 2907, GRID grid.25786.3e, Computational Modelling of Nanoscale and Biophysical systems Laboratory, Italian Institute of Technology, ; Genoa, Italy
                [74 ]Laboratorio di Neuropatologia Clinica, U.O.S. Malattie, Neuromuscolari Associazione OASI Maria SS. ONLUS – IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy
                [75 ]ISNI 0000 0001 2178 8421, GRID grid.10438.3e, Department of Pediatrics, , University Hospital “Gaetano Martino”, University of Messina, ; 98123 Messina, Italy
                [76 ]ISNI 0000 0004 1757 1969, GRID grid.8158.4, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, , University of Catania, ; 95124 Catania, Italy
                [77 ]ISNI 0000 0004 1760 0109, GRID grid.419504.d, Department of Neurosurgery, , IRCCS Istituto Giannina Gaslini, ; Genoa, Italy
                [78 ]ISNI 0000 0001 2299 3507, GRID grid.16753.36, Department of Neurology, , Northwestern University Feinberg School of Medicine, ; Chicago, IL 60611 USA
                [79 ]GRID grid.428337.9, Courtagen Life Sciences, ; 12 Gill Street Suite 3700, Woburn, MA 01801 USA
                [80 ]ISNI 0000 0004 1767 6103, GRID grid.413618.9, Division of Genetics, Department of Pediatrics, , All India Institute of Medical Sciences (AIIMS), ; New Delhi, India
                [81 ]ISNI 0000 0004 0609 0940, GRID grid.417705.0, The Cyprus Institute of Neurology and Genetics, ; 1683 Nicosia, Cyprus
                [82 ]GRID grid.411299.6, University Hospital of Larissa, Department of Neurology, ; Larissa, 413 34 Greece
                [83 ]Department of Developmental and Behavioral Pediatrics, Children Hospital Complex and Institute of Child Health, Lahore, 381-D/2 Pakistan
                [84 ]Department of Pediatric Neurology, Children Hospital Complex and Institute of Child Health, Multan, 60000 Pakistan
                [85 ]Hilal Pediatric Hospital Hebron, Hebron, West Bank, Hebron, 90403 Palestine
                [86 ]ISNI 0000 0001 2308 5949, GRID grid.10347.31, Department of Biomedical Science, Faculty of Medicine, , University of Malaysia, ; Selangor, 50603 Malaysia
                [87 ]GRID grid.440425.3, Jeffrey Cheah School of Medicine and Health Sciences, , Monash University Malaysia, ; Selangor, 47500 Malaysia
                [88 ]GRID grid.414406.3, Neurogenetics Unit, Neurology Department, , Eginition Hospital, National and Kapodistrian University, ; Athens, 16121 Greece
                [89 ]ISNI 0000 0004 1760 0109, GRID grid.419504.d, Laboratorio di Genetica Umana, IRCCS Istituto Giannina Gaslini, ; Genoa, 16147 Italy
                [90 ]ISNI 0000 0000 9961 060X, GRID grid.157868.5, University Hospital Montpellier, ; Montpellier, 34080 France
                [91 ]Albashir University Hospital, Amman, 11180 Jordan
                [92 ]GRID grid.415773.3, Prince Hamzah Hospital, Ministry of Health, ; Amman, 11181 Jordan
                [93 ]ISNI 0000 0004 1773 5396, GRID grid.56302.32, King Saud University, ; Riyadh, 11362 Saudi Arabia
                [94 ]ISNI 0000 0001 2150 9058, GRID grid.411439.a, Institute of Myology, Hôpital La Pitié Salpêtrière, ; Paris, 75651 France
                [95 ]ISNI 0000 0001 0790 385X, GRID grid.4691.a, CEINGE, Biotecnologie Avanzate S.c.a.rl., ; Naples, 80145 Italy
                [96 ]ISNI 0000 0001 2191 4301, GRID grid.415310.2, King Faisal Specialist Hospital and Research Center, ; Riyadh, 43518 Saudi Arabia
                [97 ]GRID grid.439444.a, The Portland Hospital, ; 205-209 Great Portland Street, London, W1W 5AH UK
                [98 ]ISNI 0000 0004 0621 6144, GRID grid.411437.4, Assiut University Hospital, ; Assiut, 71515 Egypt
                [99 ]Research Unit UR12 SP24, Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, Tunisi, 22252 Tunisia
                [100 ]Laboratoire de Recherche en Neurosciences, Service de Neurologie, Algeri, 19785 Tunisia
                [101 ]ISNI 0000 0004 0581 3406, GRID grid.411654.3, Department of Anatomy, , Cell Biology and Physiology, American University of Beirut Medical Center, ; Beirut, 1107 2020 Lebanon
                [102 ]ISNI 0000 0004 0428 8304, GRID grid.412274.6, Department of Child Neurology, , Tbilisi State Medical University, ; Tbilisi, 380077 Georgia
                [103 ]Baghdad College of Medicine, Children Welfare Teaching Hospital, Baghdad, 10007 Iraq
                [104 ]ISNI 0000 0001 2151 8157, GRID grid.419725.c, Human Genetics and Genome Research Division, National Research Centre, ; Cairo, 12622 Egypt
                [105 ]Child Neurology Department, Hedi Chaker hospital- Sfax Tunisia, Sfax, 3000 Tunisia
                [106 ]ISNI 0000 0004 1764 2907, GRID grid.25786.3e, Istituto Italiano di Tecnologia, ; Genoa, 16132 Italy
                [107 ]ISNI 0000 0000 8728 1538, GRID grid.411306.1, Paediatric Neurology Unit, Department of Pediatrics, , University of Tripoli, ; Tripoli, Libya
                [108 ]ISNI 0000 0000 8897 2840, GRID grid.416317.6, Neurology Unit, S. Anna Hospital, ; Como, 22042 Italy
                [109 ]ISNI 0000 0001 0727 6809, GRID grid.414125.7, Child Neurology Unit, “Bambino Gesù” Pediatric Hospital, ; Rome, 00165 Italy
                [110 ]ISNI 0000 0004 0493 6690, GRID grid.413174.4, Child Neuropsychiatry Department, , Epilepsy Center, C. Poma Hospital, ; Mantova, 46100 Italy
                [111 ]ISNI 0000000121901201, GRID grid.83440.3b, Genetics Research Centre, Molecular and Clinical Sciences Institute, , St George’s, University of London, Cranmer Terrace, ; London, SW17 0RE UK
                [112 ]ISNI 0000 0001 1895 1777, GRID grid.413095.a, Medical University of Duhok, ; Duhok, Kurdistan region 1006 AJ Iraq
                [113 ]ISNI 0000 0000 8668 7085, GRID grid.411283.d, College of Medicine, , University of Lagos (CMUL) & Lagos University Teaching Hospital, ; Idi Araba, Lagos State Nigeria
                [114 ]ISNI 0000 0000 8878 5287, GRID grid.412975.c, University of Ilorin Teaching Hospital (UITH), ; Ilorin, Kwara State Nigeria
                [115 ]ISNI 0000 0004 1937 1493, GRID grid.411225.1, Ahmadu Bello University, ; Zaria, Kaduna State Nigeria
                [116 ]GRID grid.449066.9, Delta State University Teaching Hospital, ; Oghara, Delta State Nigeria
                [117 ]GRID grid.414823.8, Federal Medical Centre, ; Owerri, Imo State Nigeria
                [118 ]ISNI 0000 0000 9161 1296, GRID grid.413131.5, University of Nigeria Teaching Hospital, ; Ituku-Ozalla, Enugu State Nigeria
                [119 ]ISNI 0000 0001 0291 6387, GRID grid.413097.8, University of Calabar Teaching Hospital, ; Calabar, Cross Rivers State Nigeria
                [120 ]GRID grid.412738.b, University of Port Harcourt Teaching Hospital, ; Port Harcourt, Rivers State Nigeria
                [121 ]GRID grid.442581.e, Babcock University, Ilishan, Remo & Federal Medical Centre, ; Abeokuta, 4003 Ogun State Nigeria
                [122 ]ISNI 0000 0000 9364 4761, GRID grid.459853.6, Obafemi Awolowo University Teaching Hospital (OAUTH), ; Ile-Ife, Osun State Nigeria
                [123 ]Almazov Medical Research Centre and Pavlov First Saint Petersburg State Medical University, Saint-Petersburg, 197341 Russia
                [124 ]Kazakh National State University, Almaty, 050040 Kazakhstan
                [125 ]Shymkent Medical Academy, Almaty, 122002 Kazakhstan
                [126 ]Kazakh National State University, Almaty, 050040 Kazakhstan
                [127 ]ISNI 0000 0004 0472 6634, GRID grid.443571.0, Avicenna Tajik State Medical University, ; Dushanbe, D61/8 Tajikistan
                [128 ]Mediclub clinic, Baku, Azerbaijan
                [129 ]Azerbaijan State Medical University, Baku, 15080 Azerbaijan
                [130 ]“Somnus” Neurology Clinic Sleep and Movement Disorders Center, Yerevan, 0087 Armenia
                [131 ]ISNI 0000 0001 0941 3192, GRID grid.8142.f, Department of Neurology, , Università Cattolica del Sacro Cuore, ; Rome, 00168 Italy
                [132 ]ISNI 0000 0004 0621 6144, GRID grid.411437.4, Department of Neurology and Psychiatry, , Assuit University Hospital, ; Assiut, 71515 Egypt
                [133 ]ISNI 0000 0004 1760 0109, GRID grid.419504.d, Neonatal Intensive Care Unit, Istituto Giannina Gaslini, ; 16147 Genova, Italy
                [134 ]ISNI 0000 0001 0035 6670, GRID grid.410558.d, Department of Neurology, Medical School, University of Thessaly, ; Volos, 38221 Greece
                [135 ]GRID grid.417150.6, Radiology Unit, Papardo Hospital, Viale Ferdinando Stagno d’Alcontres, Contrada Papardo, ; Messina, 98158 Italy
                [136 ]ISNI 0000 0001 2178 8421, GRID grid.10438.3e, Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, , University of Messina, ; 98124 Messina, Italy
                [137 ]ISNI 0000000109457005, GRID grid.4793.9, Department of Biology, Medical School, , Aristotle University, ; Thessaloniki, 54124 Greece
                [138 ]ISNI 0000 0004 0576 3437, GRID grid.8127.c, Department of Neurology, Medical School, , University of Crete, ; Heraklion, 74100 Greece
                [139 ]ISNI 0000 0001 2171 1133, GRID grid.4868.2, William Harvey Research Institute, The NIHR Biomedical Research Centre at Barts, Queen Mary University London, ; London, E1 4NS UK
                Author information
                http://orcid.org/0000-0001-5701-8365
                http://orcid.org/0000-0003-4900-9877
                http://orcid.org/0000-0002-1119-6809
                http://orcid.org/0000-0003-4530-4537
                http://orcid.org/0000-0001-5790-1051
                http://orcid.org/0000-0001-9567-649X
                http://orcid.org/0000-0001-9090-7690
                http://orcid.org/0000-0002-8727-9184
                http://orcid.org/0000-0002-8318-7231
                http://orcid.org/0000-0001-5260-7187
                http://orcid.org/0000-0002-9420-085X
                http://orcid.org/0000-0002-7222-9985
                http://orcid.org/0000-0002-8059-6064
                http://orcid.org/0000-0002-9195-1455
                http://orcid.org/0000-0002-8246-4014
                http://orcid.org/0000-0001-6696-3545
                http://orcid.org/0000-0002-2866-7777
                Article
                10910
                10.1038/s41467-019-10910-w
                6626132
                31300657
                bd95a327-0f7c-4f2d-b92d-64e51007f0ad
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 30 July 2018
                : 22 May 2019
                Funding
                Funded by: Wellcome Trust (WT093205MA, WT104033AIA)
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                next-generation sequencing,synaptic development,ion channels in the nervous system,neurodevelopmental disorders

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