, Web Resources 1000 Genomes

E. Browser, gov/genbank/ GeneMatcher, https://genematcher.org/ Genic Intolerance, http://genic-intolerance.org/ gnomAD Browser, GTEx Portal

. Jvarkit, http://mtr-viewer.mdhs. unimelb.edu.au/ MutationTaster, http://www.mutationtaster.org/ National Database for Autism Research, https://ndar.nih.gov NHLBI Exome Sequencing Project (ESP) Exome Variant Server, pymol.org RCSB Protein Data Banksamtools.sourceforge.net/ SIFT Human Protein, 2017.

, Accepted, 2017.

R. 1. Grant, S. G. Silva, and A. J. , Targeting learning, Trends in Neurosciences, vol.17, issue.2, pp.71-75, 1994.
DOI : 10.1016/0166-2236(94)90077-9

J. Lisman, R. Yasuda, R. , and S. , Mechanisms of CaMKII action in long-term potentiation, Nature Reviews Neuroscience, vol.2006, issue.3, pp.169-182, 2012.
DOI : 10.1126/stke.3562006re11

X. Fan, W. Y. Jin, W. , and Y. T. , The NMDA receptor complex: a multifunctional machine at the glutamatergic synapse, Frontiers in Cellular Neuroscience, vol.27, p.160, 2014.
DOI : 10.1523/jneurosci.4486-07.2007

R. C. Malenka and M. F. Bear, LTP and LTD, Neuron, vol.44, issue.1, pp.5-21, 2004.
DOI : 10.1016/j.neuron.2004.09.012

S. A. Buffington, W. Huang, C. , and M. , Translational Control in Synaptic Plasticity and Cognitive Dysfunction, Annual Review of Neuroscience, vol.37, issue.1, pp.17-38, 2014.
DOI : 10.1146/annurev-neuro-071013-014100

T. V. Bliss, G. L. Collingridge, M. , and R. G. , Synaptic plasticity in health and disease: introduction and overview, Philosophical Transactions of the Royal Society B: Biological Sciences, vol.369, issue.1432, 2013.
DOI : 10.1098/rstb.2003.1282

C. G. Lau and R. S. Zukin, NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders, Nature Reviews Neuroscience, vol.29, issue.6, pp.413-426, 2007.
DOI : 10.1038/nrn2153

L. Mony, J. N. Kew, M. J. Gunthorpe, and P. Paoletti, , 2009.

, Allosteric modulators of NR2B-containing NMDA receptors: molecular mechanisms and therapeutic potential, Br. J. Pharmacol, vol.157, pp.1301-1317

S. F. Traynelis, L. P. Wollmuth, C. J. Mcbain, F. S. Menniti, K. M. Vance et al., Glutamate Receptor Ion Channels: Structure, Regulation, and Function, Pharmacological Reviews, vol.62, issue.3, pp.405-496, 2010.
DOI : 10.1124/pr.109.002451

C. Barkus, D. J. Sanderson, J. N. Rawlins, M. E. Walton, P. J. Harrison et al., What causes aberrant salience in schizophrenia? A role for impaired short-term habituation and the GRIA1 (GluA1) AMPA receptor subunit, Molecular Psychiatry, vol.13, issue.10, pp.1060-1070, 2014.
DOI : 10.1038/nn.2647

J. Zhang, A. , and J. M. , The role of GluA1 in central nervous system disorders, Reviews in the Neurosciences, vol.24, issue.5, pp.499-505, 2013.
DOI : 10.1515/revneuro-2013-0021

Y. Wu, A. C. Arai, G. Rumbaugh, A. K. Srivastava, G. Turner et al., Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans, Proc. Natl. Acad. Sci. USA, pp.18163-18168, 2007.
DOI : 10.1086/513609

A. K. Philips, A. Sirén, K. Avela, M. Somer, M. Peippo et al., X-exome sequencing in Finnish families with Intellectual Disability - four novel mutations and two novel syndromic phenotypes, Orphanet Journal of Rare Diseases, vol.9, issue.1, p.49, 2014.
DOI : 10.1093/hmg/8.10.1913

F. F. Hamdan, J. Gauthier, Y. Araki, D. T. Lin, Y. Yoshizawa et al., Excess of De Novo Deleterious Mutations in Genes Associated with Glutamatergic Systems in Nonsyndromic Intellectual Disability, The American Journal of Human Genetics, vol.88, issue.3, pp.306-316, 2011.
DOI : 10.1016/j.ajhg.2011.02.001

D. Li, H. Yuan, X. R. Ortiz-gonzalez, E. D. Marsh, L. Tian et al., GRIN2D Recurrent De Novo Dominant Mutation Causes a Severe Epileptic Encephalopathy Treatable with NMDA Receptor Channel Blockers, The American Journal of Human Genetics, vol.99, issue.4, pp.802-816, 2016.
DOI : 10.1016/j.ajhg.2016.07.013

G. L. Carvill, B. M. Regan, S. C. Yendle, B. J. O-'roak, N. Lozovaya et al., GRIN2A mutations cause epilepsy-aphasia spectrum disorders, Nature Genetics, vol.45, issue.9, pp.1073-1076, 2013.
DOI : 10.1038/nature10989
URL : http://europepmc.org/articles/pmc3868952?pdf=render

S. Endele, G. Rosenberger, K. Geider, B. Popp, C. Tamer et al., Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes, Nature Genetics, vol.3, issue.11, pp.1021-1026, 2010.
DOI : 10.1038/nsmb.1721

, The American Journal of Human Genetics, vol.101, pp.768-788, 2017.

J. R. Lemke, R. Hendrickx, K. Geider, B. Laube, M. Schwake et al., mutations in west syndrome and intellectual disability with focal epilepsy, Annals of Neurology, vol.22, issue.1, pp.147-154, 2014.
DOI : 10.1016/j.yebeh.2011.07.024

J. R. Lemke, D. Lal, E. M. Reinthaler, I. Steiner, M. Nothnagel et al., Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes, Nature Genetics, vol.49, issue.9, pp.1067-1072, 2013.
DOI : 10.1073/pnas.81.11.3443

G. Lesca, G. Rudolf, N. Bruneau, N. Lozovaya, A. Labalme et al., GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction, Nature Genetics, vol.45, issue.9, pp.1061-1066, 2013.
DOI : 10.1113/jphysiol.2006.112193

J. Lisman, H. Schulman, and H. Cline, The molecular basis of CaMKII function in synaptic and behavioural memory, Nature Reviews Neuroscience, vol.20, issue.3, pp.175-190, 2002.
DOI : 10.1016/0896-6273(93)90337-Q

N. E. Erondu and M. B. Kennedy, Regional distribution of type II Ca2+/calmodulin-dependent protein kinase in rat brain, The Journal of Neuroscience, vol.5, issue.12, pp.3270-3277, 1985.
DOI : 10.1523/JNEUROSCI.05-12-03270.1985

R. J. Colbran, Targeting of calcium/calmodulin-dependent protein kinase II, Biochemical Journal, vol.378, issue.1, pp.1-16, 2004.
DOI : 10.1042/bj20031547

K. Kim, T. Saneyoshi, T. Hosokawa, K. Okamoto, and Y. Hayashi, Interplay of enzymatic and structural functions of CaMKII in long-term potentiation, Journal of Neurochemistry, vol.110, issue.6, pp.959-972, 2016.
DOI : 10.1016/S0092-8674(02)00897-8

P. Paoletti, C. Bellone, and Q. Zhou, NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease, Nature Reviews Neuroscience, vol.135, issue.6, pp.383-400, 2013.
DOI : 10.1093/brain/aws092

L. Hoffman, M. M. Farley, and M. N. Waxham, Calcium-Calmodulin-Dependent Protein Kinase II Isoforms Differentially Impact the Dynamics and Structure of the Actin Cytoskeleton, Biochemistry, vol.52, issue.7, pp.1198-1207, 2013.
DOI : 10.1021/bi3016586

Y. Elgersma, N. B. Fedorov, S. Ikonen, E. S. Choi, M. Elgersma et al., Inhibitory Autophosphorylation of CaMKII Controls PSD Association, Plasticity, and Learning, Neuron, vol.36, issue.3, pp.493-505, 2002.
DOI : 10.1016/S0896-6273(02)01007-3

K. P. Giese, N. B. Fedorov, R. K. Filipkowski, and A. J. Silva, Autophosphorylation at Thr286 of the  Calcium-Calmodulin Kinase II in LTP and Learning, Science, vol.279, issue.5352, pp.870-873, 1998.
DOI : 10.1126/science.279.5352.870

Y. Yamagata, S. Kobayashi, T. Umeda, A. Inoue, H. Sakagami et al., Kinase-Dead Knock-In Mouse Reveals an Essential Role of Kinase Activity of Ca2+/Calmodulin-Dependent Protein Kinase II?? in Dendritic Spine Enlargement, Long-Term Potentiation, and Learning, Journal of Neuroscience, vol.29, issue.23, pp.7607-7618, 2009.
DOI : 10.1523/JNEUROSCI.0707-09.2009

A. J. Silva, C. F. Stevens, S. Tonegawa, W. , and Y. , Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice, Science, vol.257, issue.5067, pp.201-206, 1992.
DOI : 10.1126/science.1378648

A. J. Silva, R. Paylor, J. M. Wehner, and S. Tonegawa, Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice, Science, vol.257, issue.5067, pp.206-211, 1992.
DOI : 10.1126/science.1321493

G. M. Van-woerden, F. E. Hoebeek, Z. Gao, R. Y. Nagaraja, C. C. Hoogenraad et al., ??CaMKII controls the direction of plasticity at parallel fiber???Purkinje cell synapses, Nature Neuroscience, vol.5, issue.7, pp.823-825, 2009.
DOI : 10.1126/science.284.5411.162

N. Z. Borgesius, G. M. Van-woerden, G. H. Buitendijk, N. Keijzer, D. Jaarsma et al., bCaMKII plays a nonenzymatic role in hippocampal synaptic plasticity and learning by targeting aCaMKII to synapses, 2011.

, J. Neurosci, vol.31, pp.10141-10148

N. Sobreira, F. Schiettecatte, D. Valle, and A. Hamosh, GeneMatcher: A Matching Tool for Connecting Investigators with an Interest in the Same Gene, Human Mutation, vol.312, issue.Database issue, pp.928-930, 2015.
DOI : 10.1001/jama.2014.14601

H. V. Firth, S. M. Richards, A. P. Bevan, S. Clayton, M. Corpas et al., DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources, The American Journal of Human Genetics, vol.84, issue.4, pp.524-533, 2009.
DOI : 10.1016/j.ajhg.2009.03.010
URL : https://doi.org/10.1016/j.ajhg.2009.03.010

B. Isidor, S. Küry, J. A. Rosenfeld, T. Besnard, S. Schmitt et al., Cause Syndromic Intellectual Disability, Human Mutation, vol.142, issue.Database issue, pp.354-358, 2016.
DOI : 10.1016/j.cell.2010.08.020
URL : https://hal.archives-ouvertes.fr/hal-01259225

, Prevalence and architecture of de novo mutations in developmental disorders, Deciphering Developmental Disorders, S.; and Deciphering Developmental Disorders Study Nature, vol.542, pp.433-438, 2017.

I. Iossifov, B. J. O-'roak, S. J. Sanders, M. Ronemus, N. Krumm et al., The contribution of de novo coding mutations to autism spectrum disorder, Nature, vol.43, issue.7526, pp.216-221, 2014.
DOI : 10.1038/ng.902

K. Retterer, J. Juusola, M. T. Cho, P. Vitazka, F. Millan et al., Clinical application of whole-exome sequencing across clinical indications, Genetics in Medicine, vol.11, issue.7, pp.696-704, 2016.
DOI : 10.1007/s10048-015-0454-0

C. A. Brownstein, A. H. Beggs, L. Rodan, J. Shi, M. C. Towne et al., Clinical heterogeneity associated with KCNA1 mutations include cataplexy and nonataxic presentations, neurogenetics, vol.137, issue.5, pp.11-16, 2016.
DOI : 10.1085/jgp.201010573

A. Nesbitt, E. J. Bhoj, K. Mcdonald-gibson, Z. Yu, E. Denenberg et al., Exome sequencing expands the mechanism of SOX5-associated intellectual disability: A case presentation with review of sox-related disorders, American Journal of Medical Genetics Part A, vol.76, issue.11, pp.2548-2554, 2015.
DOI : 10.1086/430134

K. D. Farwell, L. Shahmirzadi, D. El-khechen, Z. Powis, E. C. Chao et al., Enhanced utility of family-centered diagnostic exome sequencing with inheritance model???based analysis: results from 500 unselected families with undiagnosed genetic conditions, Genetics in Medicine, vol.17, issue.7, pp.578-586, 2015.
DOI : 10.1016/j.ajhg.2014.05.003

M. Hempel, K. Cremer, C. W. Ockeloen, K. D. Lichtenbelt, J. C. Herkert et al., De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment, The American Journal of Human Genetics, vol.97, issue.3, pp.493-500, 2015.
DOI : 10.1016/j.ajhg.2015.08.003

O. L. Holla, O. L. Busk, K. Tveten, H. T. Hilmarsen, L. Strand et al., Diagnostisk eksomsekvensering ??? norske erfaringer, Tidsskrift for Den norske legeforening, vol.135, issue.20, pp.1833-1837, 2015.
DOI : 10.4045/tidsskr.14.1442

G. W. Santen, E. Aten, Y. Sun, R. Almomani, C. Gilissen et al., Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome, Nature Genetics, vol.132, issue.4, pp.379-380, 2012.
DOI : 10.1146/annurev-genet-110410-132512

M. N. Bainbridge, M. Wang, Y. Wu, I. Newsham, D. M. Muzny et al., Targeted enrichment beyond the consensus coding DNA sequence exome reveals exons with higher variant densities, Genome Biology, vol.12, issue.7, p.68, 2011.
DOI : 10.1093/bioinformatics/btp324

Y. Yang, D. M. Muzny, J. G. Reid, M. N. Bainbridge, A. Willis et al., Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian Disorders, New England Journal of Medicine, vol.369, issue.16, pp.1502-1511, 2013.
DOI : 10.1056/NEJMoa1306555

C. Evers, C. Staufner, M. Granzow, N. Paramasivam, K. Hinderhofer et al., Impact of clinical exomes in neurodevelopmental and neurometabolic disorders, Molecular Genetics and Metabolism, vol.121, issue.4, pp.297-307, 2017.
DOI : 10.1016/j.ymgme.2017.06.014

G. M. Van-woerden, K. D. Harris, M. R. Hojjati, R. M. Gustin, S. Qiu et al., Rescue of neurological deficits in a mouse model for Angelman syndrome by reduction of ??CaMKII inhibitory phosphorylation, Nature Neuroscience, vol.36, issue.3, pp.280-282, 2007.
DOI : 10.1016/j.neuron.2006.08.013

G. Banker and K. Goslin, Culturing Nerve Cells, 1991.

Y. Zhang, I-TASSER server for protein 3D structure prediction, BMC Bioinformatics, vol.9, issue.1, p.40, 2008.
DOI : 10.1186/1471-2105-9-40

, Largescale discovery of novel genetic causes of developmental disorders, Deciphering Developmental Disorders Study Nature, vol.519, pp.223-228, 2015.

J. S. Ware, K. E. Samocha, J. Homsy, and M. J. Daly, Interpreting de novo variation in human disease using denovolyzeR, Current Prot. Human Genet, vol.87, pp.21-36, 2015.

J. Traynelis, M. Silk, Q. Wang, S. F. Berkovic, L. Liu et al., Optimizing genomic medicine in epilepsy through a gene-customized approach to missense variant interpretation, Genome Research, vol.7, issue.10, pp.1715-1729, 2017.
DOI : 10.1038/ncomms13293
URL : http://genome.cshlp.org/content/27/10/1715.full.pdf

J. R. Stephenson, X. Wang, T. L. Perfitt, W. P. Parrish, B. C. Shonesy et al., Mutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors, The Journal of Neuroscience, vol.37, issue.8, pp.2216-2233, 2017.
DOI : 10.1523/JNEUROSCI.2068-16.2017

H. Tabata and K. Nakajima, Efficient in utero gene transfer system to the developing mouse brain using electroporation: visualization of neuronal migration in the developing cortex, Neuroscience, vol.103, issue.4, pp.865-872, 2001.
DOI : 10.1016/S0306-4522(01)00016-1

T. Saito and N. Nakatsuji, Efficient Gene Transfer into the Embryonic Mouse Brain Using in Vivo Electroporation, Developmental Biology, vol.240, issue.1, pp.237-246, 2001.
DOI : 10.1006/dbio.2001.0439
URL : https://doi.org/10.1006/dbio.2001.0439

Y. Taniguchi, T. Young-pearse, A. Sawa, and A. Kamiya, In Utero Electroporation as a Tool For Genetic Manipulation In Vivo to Study Psychiatric Disorders, The Neuroscientist, vol.15, issue.2, pp.169-179, 2012.
DOI : 10.1038/nprot.2009.226

K. Shen, M. N. Teruel, K. Subramanian, M. , and T. , CaMKII?? Functions As an F-Actin Targeting Module that Localizes CaMKII??/?? Heterooligomers to Dendritic Spines, Neuron, vol.21, issue.3, pp.593-606, 1998.
DOI : 10.1016/S0896-6273(00)80569-3
URL : https://doi.org/10.1016/s0896-6273(00)80569-3

K. U. Bayer, J. Löhler, H. Schulman, and K. Harbers, Developmental expression of the CaM kinase II isoforms: ubiquitous ??- and ??-CaM kinase II are the early isoforms and most abundant in the developing nervous system, Molecular Brain Research, vol.70, issue.1, pp.147-154, 1999.
DOI : 10.1016/S0169-328X(99)00131-X

M. Mayford, M. E. Bach, Y. Y. Huang, L. Wang, R. D. Hawkins et al., Control of Memory Formation Through Regulated Expression of a CaMKII Transgene, Science, vol.274, issue.5293, pp.1678-1683, 1996.
DOI : 10.1126/science.274.5293.1678

M. Mayford, J. Wang, E. R. Kandel, O. Dell, and T. J. , CaMKII regulates the frequency-response function of hippocampal synapses for the production of both LTD and LTP, Cell, vol.81, issue.6, pp.891-904, 1995.
DOI : 10.1016/0092-8674(95)90009-8

J. W. Hell, CaMKII: Claiming Center Stage in Postsynaptic Function and Organization, Neuron, vol.81, issue.2, pp.249-265, 2014.
DOI : 10.1016/j.neuron.2013.12.024
URL : https://doi.org/10.1016/j.neuron.2013.12.024

K. G. Achterberg, G. H. Buitendijk, M. J. Kool, S. M. Goorden, L. Post et al., Temporal and region-specific requirements of aCaMKII in spatial and contextual learning, 2014.
DOI : 10.1523/jneurosci.0640-14.2014
URL : http://www.jneurosci.org/content/jneuro/34/34/11180.full.pdf

, J. Neurosci, vol.34, pp.11180-11187

A. D. Bachstetter, S. J. Webster, T. Tu, D. S. Goulding, J. Haiech et al., Generation and behavior characterization of CaMKIIb knockout mice, PLoS ONE, vol.9, 2014.

K. Barcomb, J. W. Hell, T. A. Benke, and K. U. Bayer, , 2016.

, The CaMKII/GluN2B protein interaction maintains synaptic strength, J. Biol. Chem, vol.291, pp.16082-16089

M. K. Smith, R. J. Colbran, D. A. Brickey, and T. R. Soderling, Functional determinants in the autoinhibitory domain of calcium/calmodulin-dependent protein kinase II. Role of His282 and multiple basic residues, J. Biol. Chem, vol.267, pp.1761-1768, 1992.

K. Shen, M. , and T. , Dynamic Control of CaMKII Translocation and Localization in Hippocampal Neurons by NMDA Receptor Stimulation, Science, vol.284, issue.5411, pp.162-166, 1999.
DOI : 10.1126/science.284.5411.162

M. J. Kool, J. E. Van-de-bree, H. E. Bodde, Y. Elgersma, and G. M. Van-woerden, The molecular, temporal and region-specific requirements of the beta isoform of Calcium/Calmodulin-dependent protein kinase type 2 (CAMK2B) in mouse locomotion, Scientific Reports, vol.211, issue.1, p.26989, 2016.
DOI : 10.1016/j.expneurol.2007.12.012

M. Vincent, C. Collet, A. Verloes, L. Lambert, C. Herlin et al., Large deletions encompassing the TCOF1 and CAMK2A genes are responsible for Treacher Collins syndrome with intellectual disability, European Journal of Human Genetics, vol.48, issue.1, pp.52-56, 2014.
DOI : 10.1016/j.gene.2005.12.023

C. Chen, D. G. Rainnie, R. W. Greene, and S. Tonegawa, Abnormal fear response and aggressive behavior in mutant mice deficient for alpha-calcium-calmodulin kinase II, Science, vol.266, issue.5183, pp.291-294, 1994.
DOI : 10.1126/science.7939668

S. Takemoto-kimura, K. Suzuki, S. I. Horigane, S. Kamijo, M. Inoue et al., Calmodulin kinases: essential regulators in health and disease, Journal of Neurochemistry, vol.1338, issue.6, 2017.
DOI : 10.1016/S0167-4838(97)00004-6
URL : http://onlinelibrary.wiley.com/doi/10.1111/jnc.14020/pdf

, J. Neurochem, vol.141, pp.808-818

S. A. Ament, S. Szelinger, G. Glusman, J. Ashworth, L. Hou et al., Bipolar Genome Study, 2015.

, Rare variants in neuronal excitability genes influence risk for bipolar disorder, Proc. Natl. Acad. Sci. USA, pp.3576-3581

O. 'roak, B. J. Vives, L. Fu, W. Egertson, J. D. Stanaway et al., Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders, Science, vol.11, issue.5, pp.1619-1622, 2012.
DOI : 10.1038/ncb1864

, The American Journal of Human Genetics, vol.101, pp.768-788, 2017.

J. De-ligt, M. H. Willemsen, B. W. Van-bon, T. Kleefstra, H. G. Yntema et al., Diagnostic Exome Sequencing in Persons with Severe Intellectual Disability, New England Journal of Medicine, vol.367, issue.20, pp.1921-1929, 2012.
DOI : 10.1056/NEJMoa1206524

F. Che, Y. Zhang, G. Wang, X. Heng, S. Liu et al., The role of GRIN2B in Tourette syndrome: Results from a transmission disequilibrium study, Journal of Affective Disorders, vol.187, pp.62-65, 2015.
DOI : 10.1016/j.jad.2015.07.036

Y. Yang, W. Li, H. Zhang, G. Yang, X. Wang et al., Association Study of N-Methyl-D-Aspartate Receptor Subunit 2B (GRIN2B) Polymorphisms and Schizophrenia Symptoms in the Han Chinese Population, PLOS ONE, vol.44, issue.5, 2015.
DOI : 10.1371/journal.pone.0125925.s004

Y. Pan, J. Chen, H. Guo, J. Ou, Y. Peng et al., Association of genetic variants of GRIN2B, p.8296, 2015.