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Genetics and Epigenetics of Autism Spectrum Disorders

  • Thomas Bourgeron
Chapter
Part of the Research and Perspectives in Neurosciences book series (NEUROSCIENCE)

Abstract

Autism spectrum disorders (ASD) are characterized by impairments in reciprocal social communication and stereotyped behaviors. Genetic and epigenetic studies have identified a relatively large number of genes and biological processes that constitute a comprehensive framework to better understand this heterogeneous syndrome. Based on the most robust findings, three observations can be made. First, genetic and epigenetic contributions to ASD are highly heterogeneous with most likely, at the genetic level, a combination of alleles with low and high penetrance. Second, the majority of the genetic mutations apparently affect a single allele, suggesting a key role for gene dosage in the susceptibility to ASD. Finally, the broad expression and function of the causative genes suggest that alteration of synaptic homeostasis could be a common biological process associated with ASD. The large spectrum of clinical heterogeneity might be due to the inter-individual difference in the capacity of “buffering” deleterious synaptic mutations. A better understanding of the interplay between genetic/epigenetic variations and synaptic homeostasis should shed new light on the causes of ASD and may provide means to modulate the severity of the symptoms.

Keywords

Autism Spectrum Disorder Autism Spectrum Disorder Intellectual Disability Intellectual Disability Angelman Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

I thank Isabelle Cloez-Tayarani for critical reading of the manuscript. This work was supported by the Institut Pasteur, Université Denis Diderot Paris 7, INSERM, CNRS, ANR, ERANET-NEURON, Fondation Orange, Tarifold, Fondation de France, Fondation FondaMentale.

References

  1. Abrahams BS, Geschwind DH (2008) Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9:341–355PubMedGoogle Scholar
  2. Alarcón M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV, Bomar JM, Sebat J, Wigler M, Martin CL, Ledbetter DH, Nelson SF, Cantor RM, Geschwind DH (2008) Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet 82:150–159PubMedGoogle Scholar
  3. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23:185–188PubMedGoogle Scholar
  4. Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Sykes N, Pagnamenta AT, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Carson AR, Casallo G, Casey J, Chu SH, Cochrane L, Corsello C, Crawford EL, Crossett A, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, LeCouteur A, Leventhal BL, Lionel AC, Liu XQ, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Melhem NM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Piven J, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, VanEngeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Wing K, Wittemeyer K, Wood S, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Gallagher L, Geschwind DH, Gill M, Haines JL, Miller J, Monaco AP, Nurnberger JI Jr, Paterson AD, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Devlin B, Ennis S, Hallmayer J (2010) A genome-wide scan for common alleles affecting risk for autism. Hum Mol Genet 19(20):4072–4082PubMedGoogle Scholar
  5. Arking DE, Cutler DJ, Brune CW, Teslovich TM, West K, Ikeda M, Rea A, Guy M, Lin S, Cook EH, Chakravarti A (2008) A common genetic variant in the neurex in superfamily member CNTNAP2 increases familial risk of autism. Am J Hum Genet 82:160–164PubMedGoogle Scholar
  6. Arndt TL, Stodgell CJ, Rodier PM (2005) The teratology of autism. Int J Dev Neurosci 23:189–199PubMedGoogle Scholar
  7. Bakkaloglu B, O'Roak BJ, Louvi A, Gupta AR, Abelson JF, Morgan TM, Chawarska K, Klin A, Ercan-Sencicek AG, Stillman AA, Tanriover G, Abrahams BS, Duvall JA, Robbins EM, Geschwind DH, Biederer T, Gunel M, Lifton RP, State MW (2008) Molecular cytogenetic analysis and resequencing of contact in associated protein-like 2 in autism spectrum disorders. Am J Hum Genet 82:165–173PubMedGoogle Scholar
  8. Bangash MA, Park JM, Melnikova T, Wang D, Jeon SK, Lee D, Syeda S, Kim J, Kouser M, Schwartz J, Cui Y, Zhao X, Speed HE, Kee SE, Tu JC, Hu JH, Petralia RS, Linden DJ, Powell CM, Savonenko A, Xiao B, Worley PF (2011) Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism. Cell 145:758–772PubMedGoogle Scholar
  9. Barnby G, Abbott A, Sykes N, Morris A, Weeks DE, Mott R, Lamb J, Bailey AJ, Monaco AP (2005) International Molecular Genetics Study of Autism Consortium. Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT. Am J Hum Genet 76:950–966PubMedGoogle Scholar
  10. Benayed R, Gharani N, Rossman I, Mancuso V, Lazar G, Kamdar S, Bruse SE, Tischfield S, Smith BJ, Zimmerman RA, Dicicco-Bloom E, Brzustowicz LM, Millonig JH (2005) Support for the homeobox transcription factor gene ENGRAILED 2 as an autism spectrum disorder susceptibility locus. Am J Hum Genet 77:851–868PubMedGoogle Scholar
  11. Ben-Shachar S, Lanpher B, German JR, Qasaymeh M, Potocki L, Nagamani SC, Franco LM, Malphrus A, Bottenfield GW, Spence JE, Amato S, Rousseau JA, Moghaddam B, Skinner C, Skinner SA, Bernes S, Armstrong N, Shinawi M, Stankiewicz P, Patel A, Cheung SW, Lupski JR, Beaudet AL, Sahoo T (2009) Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders. J Med Genet 46:382–388PubMedGoogle Scholar
  12. Biswas S, Reinhard J, Oakeshott J, Russell R, Srinivasan MV, Claudianos C (2010) Sensory regulation of neuroligins and neurexin I in the honeybee brain. PLoS One 5:e9133PubMedGoogle Scholar
  13. Bonora E, Lamb JA, Barnby G, Sykes N, Moberly T, Beyer KS, Klauck SM, Poustka F, Bacchelli E, Blasi F, Maestrini E, Battaglia A, Haracopos D, Pedersen L, Isager T, Eriksen G, Viskum B, Sorensen EU, Brondum-Nielsen K, Cotterill R, Engeland H, Jonge M, Kemner C, Steggehuis K, Scherpenisse M, Rutter M, Bolton PF, Parr JR, Poustka A, Bailey AJ, Monaco AP (2005) International Molecular Genetic Study of Austism Consortium. Mutation screening and association analysis of six candidate genes for autism on chromosome 7q. Eur J Hum Genet 13:198–207PubMedGoogle Scholar
  14. Bourgeron T (2007) The possible interplay of synaptic and clock genes in autism spectrum disorders. Cold Spring Harb Symp Quant Biol 72:645–654PubMedGoogle Scholar
  15. Bourgeron T (2009) A synaptic trek to autism. Curr Opin Neurobiol 19:231–234PubMedGoogle Scholar
  16. Bozdagi O, Sakurai T, Papapetrou D, Wang X, Dickstein DL, Takahashi N, Kajiwara Y, Yang M, Katz AM, Scattoni ML, Harris MJ, Saxena R, Silverman JL, Crawley JN, Zhou Q, Hof PR, Buxbaum JD (2010) Haplo insufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mol Autism 1:15PubMedGoogle Scholar
  17. Bromley RL, Mawer G, Clayton-Smith J, Baker GA (2008) Liverpool and Manchester Neurodevelopment Group. Autism spectrum disorders following in utero exposure to antiepileptic drugs. Neurology 71:1923–1924PubMedGoogle Scholar
  18. Bruder CE, Piotrowski A, Gijsbers AA, Andersson R, Erickson S, de StåhlT Diaz, Menzel U, Sandgren J, von Tell D, Poplawski A, Crowley M, Crasto C, Partridge EC, Tiwari H, Allison DB, Komorowski J, van Ommen GJ, Boomsma DI, Pedersen NL, den Dunnen JT, Wirdefeldt K, Dumanski JP (2008) Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am J Hum Genet 82:763–771PubMedGoogle Scholar
  19. Bucan M, Abrahams BS, Wang K, Glessner JT, Herman EI, Sonnenblick LI, Alvarez Retuerto AI, Imielinski M, Hadley D, Bradfield JP, Kim C, Gidaya NB, Lindquist I, Hutman T, Sigman M, Kustanovich V, Lajonchere CM, Singleton A, Kim J, Wassink TH, McMahon WM, Owley T, Sweeney JA, Coon H, Nurnberger JI, Li M, Cantor RM, Minshew NJ, Sutcliffe JS, Cook EH, Dawson G, Buxbaum JD, Grant SF, Schellenberg GD, Geschwind DH, Hakonarson H (2009) Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genet 5:e1000536PubMedGoogle Scholar
  20. Butler MG, Dasouki MJ, Zhou XP, Talebizadeh Z, Brown M, Takahashi TN, Miles JH, Wang CH, Stratton R, Pilarski R, Eng C (2005) Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet 42:318–321PubMedGoogle Scholar
  21. Cai G, Edelmann L, Goldsmith JE, Cohen N, Nakamine A, Reichert JG, Hoffman EJ, Zurawiecki DM, Silverman JM, Hollander E, Soorya L, Anagnostou E, Betancur C, Buxbaum JD (2008) Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: efficient identification of known microduplications and identification of a novel microduplication in ASMT. BMC Med Genomics 1:50PubMedGoogle Scholar
  22. Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C, Trillo S, Elia M, Schneider C, Melmed R, Sacco R, Persico AM, Levitt P (2006) A genetic variant that disrupts MET transcription is associated with autism. Proc Natl Acad Sci USA 103:16834–16839PubMedGoogle Scholar
  23. Castermans D, Wilquet V, Parthoens E, Huysmans C, Steyaert J, Swinnen L, Fryns JP, Van de Ven W, Devriendt K (2003) The neurobeachin gene is disrupted by a translocation in a patient with idiopathic autism. J Med Genet: 352–356Google Scholar
  24. Chadman KK, Gong S, Scattoni ML, Boltuck SE, Gandhy SU, Heintz N, Crawley JN (2008) Minimal aberrant behavioral phenotypes of neuroligin-3 R451C knockin mice. Autism Res 1:147–158PubMedGoogle Scholar
  25. Chahrour M, Jung SY, Shaw C, Zhou X, Wong ST, Qin J, Zoghbi HY (2008) MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320:1224–1229PubMedGoogle Scholar
  26. Chakrabarti S, Fombonne E (2001) Pervasive developmental disorders in preschool children. JAMA 285:3093–3099PubMedGoogle Scholar
  27. Cheng HY, Papp JW, Varlamova O, Dziema H, Russell B, Curfman JP, Nakazawa T, Shimizu K, Okamura H, Impey S, Obrietan K (2007) microRNA modulation of circadian-clock period and entrainment. Neuron 54:813–829PubMedGoogle Scholar
  28. Chih B, Afridi SK, Clark L, Scheiffele P (2004) Disorder-associated mutations lead to functional inactivation of neuroligins. Hum Mol Genet 13:1471–1477PubMedGoogle Scholar
  29. Cook EH, Leventhal BL (1996) The serotonin system in autism. Curr Opin Pediatr 8:348–354PubMedGoogle Scholar
  30. Dahlhaus R, El-Husseini A (2010) Altered neuroligin expression is involved in social deficits in a mouse model of the fragile X syndrome. Behav Brain Res 208:96–105PubMedGoogle Scholar
  31. de Kovel CG, Trucks H, Helbig I, Mefford HC, Baker C, Leu C, Kluck C, Muhle H, von Spiczak S, Ostertag P, Obermeier T, Kleefuss-Lie AA, Hallmann K, Steffens M, Gaus V, Klein KM, Hamer HM, Rosenow F, Brilstra EH, Trenité DK, Swinkels ME, Weber YG, Unterberger I, Zimprich F, Urak L, Feucht M, Fuchs K, Møller RS, Hjalgrim H, De Jonghe P, Suls A, Rückert IM, Wichmann HE, Franke A, Schreiber S, Nürnberg P, Elger CE, Lerche H, Stephani U, Koeleman BP, Lindhout D, Eichler EE, Sander T (2010) Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 133(Pt 1):23–32PubMedGoogle Scholar
  32. De Rubeis S, Bagni C (2011) Regulation of molecular pathways in the fragile XSyndrome: insights into autism spectrum disorders. J Neurodev Disord 3:257–269PubMedGoogle Scholar
  33. Delahanty RJ, Kang JQ, Brune CW, Kistner EO, Courchesne E, Cox NJ, Cook EH Jr, Macdonald RL, Sutcliffe JS (2011) Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism. Mol Psychiat 16:86–96Google Scholar
  34. Depienne C, Moreno-De-Luca D, Heron D, Bouteiller D, Gennetier A, Delorme R, Chaste P, Siffroi JP, Chantot-Bastaraud S, Benyahia B, Trouillard O, Nygren G, Kopp S, Johansson M, Rastam M, Burglen L, Leguern E, Verloes A, Leboyer M, Brice A, Gillberg C, Betancur C (2009) Screening for genomic rearrangements and methylation abnormalities of the 15q11-q13 region in autism spectrum disorders. Biol Psychiat 66:349–359PubMedGoogle Scholar
  35. Devlin B, Cook EH Jr, Coon H, Dawson G, Grigorenko EL, McMahon W, Minshew N, Pauls D, Smith M, Spence MA, Rodier PM, Stodgell C, Schellenberg GD (2005) Autism and the serotonin transporter: the long and short of it. Mol Psychiat 10:1110–1116Google Scholar
  36. Dindot SV, Antalffy BA, Bhattacharjee MB, Beaudet AL (2008) The Angelman syndromeubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology. Hum Mol Genet 17:111–118PubMedGoogle Scholar
  37. Doornbos M, Sikkema-Raddatz B, Ruijvenkamp CA, Dijkhuizen T, Bijlsma EK, Gijsbers AC, Hilhorst-Hofstee Y, Hordijk R, Verbruggen KT, Kerstjens-Frederikse WS, van Essen T, Kok K, van Silfhout AT, Breuning M, van Ravenswaaij-Arts CM (2009) Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioural disturbances. Eur J Med Genet 52:108–115PubMedGoogle Scholar
  38. Dufour-Rainfray D, Vourc'h P, Le Guisquet AM, Garreau L, Ternant D, Bodard S, Jaumain E, Gulhan Z, Belzung C, Andres CR, Chalon S, Guilloteau D (2010) Behavior and serotonergic disorders in rats exposed prenatally to valproate: a model forautism. Neurosci Lett 470:55–59PubMedGoogle Scholar
  39. Dufour-Rainfray D, Vourc'h P, Tourlet S, Guilloteau D, Chalon S, Andres CR (2011) Fetal exposure to teratogens: evidence of genes involved in autism. Neurosci Biobehav Rev 35:1254–1265PubMedGoogle Scholar
  40. Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, Nygren G, Rastam M, Gillberg IC, Anckarsäter H, Sponheim E, Goubran-Botros H, Delorme R, Chabane N, Mouren-Simeoni MC, de Mas P, Bieth E, Rogé B, Héron D, Burglen L, Gillberg C, Leboyer M, Bourgeron T (2007) Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 39:25–27PubMedGoogle Scholar
  41. Ehlers MD (2003) Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nat Neurosci 6(3):231–242PubMedGoogle Scholar
  42. Feng J, Schroer R, Yan J, Song W, Yang C, Bockholt A, Cook EH Jr, Skinner C, Schwartz CE, Sommer SS (2006) High frequency of neurexin 1beta signal peptide structural variants in patients with autism. Neurosci Lett 409:10–13PubMedGoogle Scholar
  43. Fernandez T, Morgan T, Davis N, Klin A, Morris A, Farhi A, Lifton RP, State MW (2008) Disruption of Contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome. Am J Hum Genet 82:1385PubMedGoogle Scholar
  44. Fernell E, Gillberg C (2010) Autism spectrum disorder diagnoses in Stockholm preschoolers. Res Dev Disabil 31:680–685PubMedGoogle Scholar
  45. Freitag CM (2007) The genetics of autistic disorders and its clinical relevance: a review of the literature. Mol Psychiat 12:2–22Google Scholar
  46. Friedman JI, Vrijenhoek T, Markx S, Janssen IM, van der Vliet WA, Faas BH, Knoers NV, Cahn W, Kahn RS, Edelmann L, Davis KL, Silverman JM, Brunner HG, vanKessel AG, Wijmenga C, Ophoff RA, Veltman JA (2008) CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. Mol Psych 13:261–266Google Scholar
  47. Fukuchi M, Nii T, Ishimaru N, Minamino A, Hara D, Takasaki I, Tabuchi A, Tsuda M (2009) Valproic acid induces up- or down-regulation of gene expression responsible for the neuronal excitation and inhibition in rat cortical neurons through its epigenetic actions. Neurosci Res 65:35–43PubMedGoogle Scholar
  48. Garber KB, Visootsak J, Warren ST (2008) Fragile X syndrome. Eur J Hum Genet 16:666–672PubMedGoogle Scholar
  49. Gauthier J, Spiegelman D, Piton A, Lafrenière RG, Laurent S, St-Onge J, Lapointe L, Hamdan FF, Cossette P, Mottron L, Fombonne E, Joober R, Marineau C, Drapeau P, Rouleau GA (2009) Novel de novo SHANK3 mutation in autistic patients. Am J Med Genet B Neuropsychiatr Genet 150B:421–424PubMedGoogle Scholar
  50. Gillberg C, Coleman M (2000) The biology of the autistic syndromes. Oxford University Press, OxfordGoogle Scholar
  51. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, Zhang H, Estes A, Brune CW, Bradfield JP, Imielinski M, Frackelton EC, Reichert J, Crawford EL, Munson J, Sleiman PM, Chiavacci R, Annaiah K, Thomas K, Hou C, Glaberson W, Flory J, Otieno F, Garris M, Soorya L, Klei L, Piven J, Meyer KJ, Anagnostou E, Sakurai T, Game RM, Rudd DS, Zurawiecki D, McDougle CJ, Davis LK, Miller J, Posey DJ, Michaels S, Kolevzon A, Silverman JM, Bernier R, Levy SE, Schultz RT, Dawson G, Owley T, McMahon WM, Wassink TH, Sweeney JA, Nurnberger JI, Coon H, Sutcliffe JS, Minshew NJ, Grant SF, Bucan M, Cook EH, Buxbaum JD, Devlin B, Schellenberg GD, Hakonarson H (2009) Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459:569–573PubMedGoogle Scholar
  52. Greer PL, Hanayama R, Bloodgood BL, Mardinly AR, Lipton DM, Flavell SW, Kim TK, Griffith EC, Waldon Z, Maehr R, Ploegh HL, Chowdhury S, Worley PF, Steen J, Greenberg ME (2010) The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 140:704–716PubMedGoogle Scholar
  53. Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miller J, Fedele A, Collins J, Smith K, Lotspeich L, Croen LA, Ozonoff S, Lajonchere C, Grether JK, Risch N (2011) Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiat 68:1095–1102PubMedGoogle Scholar
  54. Helbig I, Mefford HC, Sharp AJ, Guipponi M, Fichera M, Franke A, Muhle H, deKovel C, Baker C, von Spiczak S, Kron KL, Steinich I, Kleefuss-Lie AA, Leu C, Gaus V, Schmitz B, Klein KM, Reif PS, Rosenow F, Weber Y, Lerche H, Zimprich F, Urak L, Fuchs K, Feucht M, Genton P, Thomas P, Visscher F, de Haan GJ, Møller RS, Hjalgrim H, Luciano D, Wittig M, Nothnagel M, Elger CE, Nürnberg P, Romano C, Malafosse A, Koeleman BP, Lindhout D, Stephani U, Schreiber S, Eichler EE, Sander T (2009) 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet 41:160–162PubMedGoogle Scholar
  55. Hogart A, Leung KN, Wang NJ, Wu DJ, Driscoll J, Vallero RO, Schanen NC, LaSalle JM (2009) Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number. J Med Genet 46:86–93PubMedGoogle Scholar
  56. Hu VW, Frank BC, Heine S, Lee NH, Quackenbush J (2006) Gene expression profiling of lymphoblastoid cell lines from monozygotic twins discordant in severity of autism reveals differential regulation of neurologically relevant genes. BMC Genomics 7:118PubMedGoogle Scholar
  57. International Schizophrenia Consortium (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455:237–241Google Scholar
  58. Jacquemont ML, Sanlaville D, Redon R, Raoul O, Cormier-Daire V, Lyonnet S, Amiel J, Le Merrer M, Heron D, de Blois MC, Prieur M, Vekemans M, Carter NP, Munnich A, Colleaux L, Philippe A (2006) Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. J Med Genet 43:843–849PubMedGoogle Scholar
  59. Jamain S, Betancur C, Quach H, Philippe A, Fellous M, Giros B, Gillberg C, Leboyer M, Bourgeron T (2002) Paris Autism Research International Sibpair (PARIS) Study. Linkage and association of the glutamate receptor 6 gene with autism. Mol Psychiat 7:302–310Google Scholar
  60. Jamain S, Quach H, Betancur C, Råstam M, Colineaux C, Gillberg IC, Soderstrom H, Giros B, Leboyer M, Gillberg C, Bourgeron T (2003) Paris Autism Research International Sibpair Study. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 34:27–29PubMedGoogle Scholar
  61. Jamain S, Radyushkin K, Hammerschmidt K, Granon S, Boretius S, Varoqueaux F, Ramanantsoa N, Gallego J, Ronnenberg A, Winter D, Frahm J, Fischer J, Bourgeron T, Ehrenreich H, Brose N (2008) Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc Natl Acad Sci USA 105:1710–1715PubMedGoogle Scholar
  62. Kelleher RJ, 3rd, Bear MF (2008) The autistic neuron: troubled translation? Cell 135(3): 401–406PubMedGoogle Scholar
  63. Kilpinen H, Ylisaukko-oja T, Rehnström K, Gaál E, Turunen JA, Kempas E, von Wendt L, Varilo T, Peltonen L (2009) Linkage and linkage disequilibrium scan for autism loci in an extended pedigree from Finland. Hum Mol Genet 18:2912–2921PubMedGoogle Scholar
  64. Kirov G, Grozeva D, Norton N, Ivanov D, Mantripragada KK, Holmans P, International Schizophrenia Consortium, Wellcome Trust Case Control Consortium, Craddock N, Owen MJ, O'Donovan MC (2009) Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Hum Mol Genet 18:1497–1503PubMedGoogle Scholar
  65. Kocerha J, Faghihi MA, Lopez-Toledano MA, Huang J, Ramsey AJ, Caron MG, Sales N, Willoughby D, Elmen J, Hansen HF, Orum H, Kauppinen S, Kenny PJ, Wahlestedt C (2009) MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. ProcNatl Acad Sci U S A 106:3507–3512Google Scholar
  66. Laumonnier F, Bonnet-Brilhault F, Gomot M, Blanc R, David A, Moizard MP, Raynaud M, Ronce N, Lemonnier E, Calvas P, Laudier B, Chelly J, Fryns JP, Ropers HH, Hamel BC, Andres C, Barthélémy C, Moraine C, Briault S (2004) X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am J Hum Genet 74:552–557PubMedGoogle Scholar
  67. Lawson-Yuen A, Saldivar JS, Sommer S, Picker J (2008) Familial deletion within NLGN4 associated with autism and Tourette syndrome. Eur J Hum Genet 16:614–618PubMedGoogle Scholar
  68. Le Meur N, Holder-Espinasse M, Jaillard S, Goldenberg A, Joriot S, Amati-Bonneau P, Guichet A, Barth M, Charollais A, Journel H, Auvin S, Boucher C, Kerckaert JP, David V, Manouvrier-Hanu S, Saugier-Veber P, Frébourg T, Dubourg C, Andrieux J, Bonneau D (2010) MEF2C haploin sufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations. J Med Genet 47:22–29PubMedGoogle Scholar
  69. Lichtenstein P, Carlström E, Råstam M, Gillberg C, Anckarsäter H (2010) The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am J Psychiat 167:1357–1363PubMedGoogle Scholar
  70. Macarov M, Zeigler M, Newman JP, Strich D, Sury V, Tennenbaum A, Meiner V (2007) Deletions of VCX-A and NLGN4: a variable phenotype including normal intellect. J Intellect Disabil Res 51(Pt 5):329–333PubMedGoogle Scholar
  71. Macleod GT, Zinsmaier KE (2006) Synaptic homeostasis on the fast track. Neuron 52:569–571PubMedGoogle Scholar
  72. Markram K, Rinaldi T, La Mendola D, Sandi C, Markram H (2008) Abnormal fearconditioning and amygdala processing in an animal model of autism. Neuropsychopharmacol 33:901–912Google Scholar
  73. Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, Shago M, Moessner R, Pinto D, Ren Y, Thiruvahindrapduram B, Fiebig A, Schreiber S, Friedman J, Ketelaars CE, Vos YJ, Ficicioglu C, Kirkpatrick S, Nicolson R, Sloman L, Summers A, Gibbons CA, Teebi A, Chitayat D, Weksberg R, Thompson A, Vardy C, Crosbie V, Luscombe S, Baatjes R, Zwaigenbaum L, Roberts W, Fernandez B, Szatmari P, Scherer SW (2008) Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82:477–488PubMedGoogle Scholar
  74. Masurel-Paulet A, Andrieux J, Callier P, Cuisset JM, Le Caignec C, Holder M, Thauvin-Robinet C, Doray B, Flori E, Alex-Cordier MP, Beri M, Boute O, Delobel B, Dieux A, Vallee L, Jaillard S, Odent S, Isidor B, Beneteau C, Vigneron J, Bilan F, Gilbert-Dussardier B, Dubourg C, Labalme A, Bidon C, Gautier A, Pernes P, Pinoit JM, Huet F, Mugneret F, Aral B, Jonveaux P, Sanlaville D, Faivre L (2010) Delineation of 15q13.3 microdeletions. Clin Genet 78:149–161PubMedGoogle Scholar
  75. Meguro-Horike M, Yasui DH, Powell W, Schroeder DI, Oshimura M, Lasalle JM, Horike S (2011) Neuron-specific impairment of inter-chromosomal pairing and transcription in a novel model of human 15q-duplication syndrome. Hum Mol Genet 20:3798–3810PubMedGoogle Scholar
  76. Melin M, Carlsson B, Anckarsater H, Rastam M, Betancur C, Isaksson A, Gillberg C, Dahl N (2006) Constitutional down regulation of SEMA5A expression in autism. Neuropsychobiology 54:64–69PubMedGoogle Scholar
  77. Melke J, Goubran Botros H, Chaste P, Betancur C, Nygren G, Anckarsäter H, Rastam M, Ståhlberg O, Gillberg IC, Delorme R, Chabane N, Mouren-Simeoni MC, Fauchereau F, Durand CM, Chevalier F, Drouot X, Collet C, Launay JM, Leboyer M, Gillberg C, Bourgeron T (2008) Abnormal melatonin synthesis in autism spectrum disorders. Mol Psychiat 13:90–98Google Scholar
  78. Miller G (2009) Neuroscience. Sleeping to reset overstimulated synapses. Science 324:322Google Scholar
  79. Miller DT, Shen Y, Weiss LA, Korn J, Anselm I, Bridgemohan C, Cox GF, Dickinson H, Gentile J, Harris DJ, Hegde V, Hundley R, Khwaja O, Kothare S, Luedke C, Nasir R, Poduri A, Prasad K, Raffalli P, Reinhard A, Smith SE, Sobeih MM, Soul JS, Stoler J, Takeoka M, Tan WH, Thakuria J, Wolff R, Yusupov R, Gusella JF, Daly MJ, Wu BL (2009) Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet 46:242–248PubMedGoogle Scholar
  80. Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J, Zwaigenbaum L, Fernandez B, Roberts W, Szatmari P, Scherer SW (2007) Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet 81:1289–1297PubMedGoogle Scholar
  81. Moore SJ, Turnpenny P, Quinn A, Glover S, Lloyd DJ, Montgomery T, Dean JC (2000) A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet 37:489–497PubMedGoogle Scholar
  82. Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS, Mukaddes NM, Balkhy S, Gascon G, Hashmi A, Al-Saad S, Ware J, Joseph RM, Greenblatt R, Gleason D, Ertelt JA, Apse KA, Bodell A, Partlow JN, Barry B, Yao H, Markianos K, Ferland RJ, Greenberg ME, Walsh CA (2008) Identifying autism loci and genes by tracing recent shared ancestry. Science 321:218–223PubMedGoogle Scholar
  83. Murthy SK, Nygren AO, El Shakankiry HM, Schouten JP, Al Khayat AI, Ridha A, Al Ali MT (2007) Detection of a novel familial deletion of four genes between BP1 and BP2 of the Prader-Willi/Angelman syndrome critical region by oligo-array CGH in a child with neurological disorder and speech impairment. Cytogenet Genome Res 116:135–140PubMedGoogle Scholar
  84. Nakatani J, Tamada K, Hatanaka F, Ise S, Ohta H, Inoue K, Tomonaga S, Watanabe Y, Chung YJ, Banerjee R, Iwamoto K, Kato T, Okazawa M, Yamauchi K, Tanda K, Takao K, Miyakawa T, Bradley A, Takumi T (2009) Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism. Cell 137:1235–1246PubMedGoogle Scholar
  85. Napoli I, Mercaldo V, Boyl PP, Eleuteri B, Zalfa F, De Rubeis S, Di Marino D, Mohr E, Massimi M, Falconi M, Witke W, Costa-Mattioli M, Sonenberg N, Achsel T, Bagni C (2008) The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 134:1042–1054PubMedGoogle Scholar
  86. Neves-Pereira M, Müller B, Massie D, Williams JH, O'Brien PC, Hughes A, Shen SB, Clair DS, Miedzybrodzka Z (2009) Deregulation of EIF4E: a novel mechanism for autism. J Med Genet 46:759–765PubMedGoogle Scholar
  87. Nguyen A, Rauch TA, Pfeifer GP, Hu VW (2010) Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brain. FASEB J 24:3036–3051PubMedGoogle Scholar
  88. Pagnamenta AT, Wing K, Sadighi Akha E, Knight SJ, Bölte S, Schmötzer G, Duketis E, Poustka F, Klauck SM, Poustka A, Ragoussis J, Bailey AJ, Monaco AP (2009) International Molecular Genetic Study of Autism Consortium. A 15q13.3 microdeletion segregating with autism. Eur J Hum Genet 17:687–692PubMedGoogle Scholar
  89. Peça J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, Lascola CD, Fu Z, Feng G (2011) Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472:437–442PubMedGoogle Scholar
  90. Persico AM, Bourgeron T (2006) Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci 29:349–358PubMedGoogle Scholar
  91. Petek E, Schwarzbraun T, Noor A, Patel M, Nakabayashi K, Choufani S, Windpassinger C, Stamenkovic M, Robertson MM, Aschauer HN, Gurling HM, Kroisel PM, Wagner K, Scherer SW, Vincent JB (2007) Molecular and genomic studies of IMMP2L and mutation screening in autism and Tourette syndrome. Mol Genet Genomics 277:71–81PubMedGoogle Scholar
  92. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276:36734–36741PubMedGoogle Scholar
  93. Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Almeida J, Bacchelli E, Bader GD, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Bryson SE, Carson AR, Casallo G, Casey J, Chung BH, Cochrane L, Corsello C, Crawford EL, Crossett A, Cytrynbaum C, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green A, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu XQ, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Pilorge M, Piven J, Ponting CP, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Sequeira AF, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stein O, Sykes N, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Webber C, Weksberg R, Wing K, Wittemeyer K, Wood S, Wu J, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Devlin B, Ennis S, Gallagher L, Geschwind DH, Gill M, Haines JL, Hallmayer J, Miller J, Monaco AP, Nurnberger JI Jr, Paterson AD, Pericak-Vance MA, Schellenberg GD, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Scherer SW, Sutcliffe JS, Betancur C (2010) Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466:368–372PubMedGoogle Scholar
  94. Piton A, Michaud JL, Peng H, Aradhya S, Gauthier J, Mottron L, Champagne N, Lafrenière RG, Hamdan FF, S2D team, Joober R, Fombonne E, Marineau C, Cossette P, Dubé MP, Haghighi P, Drapeau P, Barker PA, Carbonetto S, Rouleau GA (2008) Mutations in the calcium-related gene IL1RAPL1 are associated with autism. Hum Mol Genet 17:3965–3974PubMedGoogle Scholar
  95. Ramocki MB, Zoghbi HY (2008) Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. Nature 455:912–918PubMedGoogle Scholar
  96. Ramocki MB, Peters SU, Tavyev YJ, Zhang F, Carvalho CM, Schaaf CP, Richman R, Fang P, Glaze DG, Lupski JR, Zoghbi HY (2009) Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome. Ann Neurol 66:771–782PubMedGoogle Scholar
  97. Ramoz N, Reichert JG, Smith CJ, Silverman JM, Bespalova IN, Davis KL, Buxbaum JD (2004) Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. Am J Psychiat 161:662–669PubMedGoogle Scholar
  98. Rasalam AD, Hailey H, Williams JH, Moore SJ, Turnpenny PD, Lloyd DJ, Dean JC (2005) Characteristics of fetal anticonvulsant syndrome associated autistic disorder. Dev Med Child Neurol 47:551–555PubMedGoogle Scholar
  99. Rodier PM, Ingram JL, Tisdale B, Croog VJ (1997) Linking etiologies in humans andanimal models: studies of autism. Reprod Toxicol 11:417–422PubMedGoogle Scholar
  100. Ronald A, Larsson H, Anckarsäter H, Lichtenstein P (2011) A twin study of autism symptoms in Sweden. Mol Psychiat 16:1039–1047Google Scholar
  101. Roohi J, Montagna C, Tegay DH, Palmer LE, DeVincent C, Pomeroy JC, Christian SL, Nowak N, Hatchwell E (2009) Disruption of contactin 4 in three subjects with autism spectrum disorder. J Med Genet 46:176–182PubMedGoogle Scholar
  102. Rosser TL, Packer RJ (2003) Neurocognitive dysfunction in children with neurofibromatosis type 1. Curr Neurol Neurosci Rept 3:129–136Google Scholar
  103. Roussignol G, Ango F, Romorini S, Tu JC, Sala C, Worley PF, Bockaert J, Fagni L (2005) Shank expression is sufficient to induce functional dendritic spine synapses in aspiny neurons. J Neurosci 25:3560–3570PubMedGoogle Scholar
  104. Sarachana T, Zhou R, Chen G, Manji HK, Hu VW (2010) Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines. Genome Med 2:23PubMedGoogle Scholar
  105. Schanen NC (2006) Epigenetics of autism spectrum disorders. Hum Mol Genet 15(Spec No 2):R138–150PubMedGoogle Scholar
  106. Schneider T, Przewlocki R (2005) Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacol 30:80–89Google Scholar
  107. Schneider T, Turczak J, Przewłocki R (2006) Environmental enrichment reversesbehavioral alterations in rats prenatally exposed to valproic acid: issues for a therapeutic approach in autism. Neuropsychopharmacol 31:36–46Google Scholar
  108. Sharp AJ, Mefford HC, Li K, Baker C, Skinner C, Stevenson RE, Schroer RJ, Novara F, De Gregori M, Ciccone R, Broomer A, Casuga I, Wang Y, Xiao C, Barbacioru C, Gimelli G, Bernardina BD, Torniero C, Giorda R, Regan R, Murday V, Mansour S, Fichera M, Castiglia L, Failla P, Ventura M, Jiang Z, Cooper GM, Knight SJ, Romano C, Zuffardi O, Chen C, Schwartz CE, Eichler EE (2008) A recurrent15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet 40:322–328PubMedGoogle Scholar
  109. Shen Y, Dies KA, Holm IA, Bridgemohan C, Sobeih MM, Caronna EB, Miller KJ, Frazier JA, Silverstein I, Picker J, Weissman L, Raffalli P, Jeste S, Demmer LA, Peters HK, Brewster SJ, Kowalczyk SJ, Rosen-Sheidley B, McGowan C, Duda AW 3rd, Lincoln SA, Lowe KR, Schonwald A, Robbins M, Hisama F, Wolff R, Becker R, Nasir R, Urion DK, Milunsky JM, Rappaport L, Gusella JF, Walsh CA, Wu BL, Miller DT (2010) Autism Consortium Clinical Genetics/DNA Diagnostics Collaboration. Clinical genetic testing for patients with autism spectrum disorders. Pediatrics 125:727–735Google Scholar
  110. Shinawi M, Schaaf CP, Bhatt SS, Xia Z, Patel A, Cheung SW, Lanpher B, Nagl S, Herding HS, Nevinny-Stickel C, Immken LL, Patel GS, German JR, Beaudet AL, Stankiewicz P (2009) A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes. Nat Genet 41:1269–1271PubMedGoogle Scholar
  111. Skaar DA, Shao Y, Haines JL, Stenger JE, Jaworski J, Martin ER, DeLong GR, Moore JH, McCauley JL, Sutcliffe JS, Ashley-Koch AE, Cuccaro ML, Folstein SE, Gilbert JR, Pericak-Vance MA (2005) Analysis of the RELN gene as a genetic risk factor for autism. Mol Psychiat 10:563–571Google Scholar
  112. Skuse DH (2007) Rethinking the nature of genetic vulnerability to autistic spectrum disorders. Trends Genet 23:387–395PubMedGoogle Scholar
  113. Splawski I, Yoo DS, Stotz SC, Cherry A, Clapham DE, Keating MT (2006) CACNA1H mutations in autism spectrum disorders. J Biol Chem 281:22085–22091PubMedGoogle Scholar
  114. Stefansson H, Rujescu D, Cichon S, Pietiläinen OP, Ingason A, Steinberg S, Fossdal R, Sigurdsson E, Sigmundsson T, Buizer-Voskamp JE, Hansen T, Jakobsen KD, Muglia P, Francks C, Matthews PM, Gylfason A, Halldorsson BV, Gudbjartsson D, Thorgeirsson TE, Sigurdsson A, Jonasdottir A, Jonasdottir A, Bjornsson A, Mattiasdottir S, Blondal T, Haraldsson M, Magnusdottir BB, Giegling I, Möller HJ, Hartmann A, Shianna KV, Ge D, Need AC, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Paunio T, Toulopoulou T, Bramon E, Di Forti M, Murray R, Ruggeri M, Vassos E, Tosato S, Walshe M, Li T, Vasilescu C, Mühleisen TW, Wang AG, Ullum H, Djurovic S, Melle I, Olesen J, Kiemeney LA, Franke B; GROUP, Sabatti C, Freimer NB, Gulcher JR, Thorsteinsdottir U, Kong A, Andreassen OA, Ophoff RA, Georgi A, Rietschel M, Werge T, Petursson H, Goldstein DB, Nöthen M, Peltonen L, Collier DA, St Clair D, Stefansson K (2008) Large recurrent microdeletions associated with schizophrenia. Nature 455:232–236Google Scholar
  115. Stickgold R, Walker MP (2005) Memory consolidation and reconsolidation: what is the role of sleep? Trends Neurosci 28:408–415PubMedGoogle Scholar
  116. Sudhof TC (2008) Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455:903–911PubMedGoogle Scholar
  117. Sutcliffe JS, Delahanty RJ, Prasad HC, McCauley JL, Han Q, Jiang L, Li C, Folstein SE, Blakely RD (2005) Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. Am J Hum Genet 77:265–279PubMedGoogle Scholar
  118. Szafranski P, Schaaf CP, Person RE, Gibson IB, Xia Z, Mahadevan S, Wiszniewska Bacino CA, Lalani S, Potocki L, Kang SH, Patel A, Cheung SW, Probst FJ, Graham BH, Shinawi M, Beaudet AL, Stankiewicz P (2010) Structures and molecular mechanisms forcommon 15q13.3 microduplications involving CHRNA7: benign or pathological? Hum Mutat 31:840–850PubMedGoogle Scholar
  119. Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ, Vincent JB, Skaug JL, Thompson AP, Senman L, Feuk L, Qian C, Bryson SE, Jones MB, Marshall CR, Scherer SW, Vieland VJ, Bartlett C, Mangin LV, Goedken R, Segre A, Pericak-Vance MA, Cuccaro ML, Gilbert JR, Wright HH, Abramson RK, Betancur C, Bourgeron T, Gillberg C, Leboyer M, Buxbaum JD, Davis KL, Hollander E, Silverman JM, Hallmayer J, Lotspeich L, Sutcliffe JS, Haines JL, Folstein SE, Piven J, Wassink TH, Sheffield V, Geschwind DH, Bucan M, Brown WT, Cantor RM, Constantino JN, Gilliam TC, Herbert M, Lajonchere C, Ledbetter DH, Lese-Martin C, Miller J, Nelson S, Samango-Sprouse CA, Spence S, State M, Tanzi RE, Coon H, Dawson G, Devlin B, Estes A, Flodman P, Klei L, McMahon WM, Minshew N, Munson J, Korvatska E, Rodier PM, Schellenberg GD, Smith M, Spence MA, Stodgell C, Tepper PG, Wijsman EM, Yu CE, Rogé B, Mantoulan C, Wittemeyer K, Poustka A, Felder B, Klauck SM, Schuster C, Poustka F, Bölte S, Feineis-Matthews S, Herbrecht E, Schmötzer G, Tsiantis J, Papanikolaou K, Maestrini E, Bacchelli E, Blasi F, Carone S, Toma C, Van Engeland H, de Jonge M, Kemner C, Koop F, Langemeijer M, Hijmans C, Staal WG, Baird G, Bolton PF, Rutter ML, Weisblatt E, Green J, Aldred C, Wilkinson JA, Pickles A, Le Couteur A, Berney T, McConachie H, Bailey AJ, Francis K, Honeyman G, Hutchinson A, Parr JR, Wallace S, Monaco AP, Barnby G, Kobayashi K, Lamb JA, Sousa I, Sykes N, Cook EH, Guter SJ, Leventhal BL, Salt J, Lord C, Corsello C, Hus V, Weeks DE, Volkmar F, Tauber M, Fombonne E, Shih A, Meyer KJ (2007) Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 39:319–328PubMedGoogle Scholar
  120. Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X, Powell CM, Südhof TC (2007) A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318:71–76PubMedGoogle Scholar
  121. Tam GW, van de Lagemaat LN, Redon R, Strathdee KE, Croning MD, Malloy MP, Muir WJ, Pickard BS, Deary IJ, Blackwood DH, Carter NP, Grant SG (2010) Confirmed rare copy number variants implicate novel genes in schizophrenia. Biochem Soc Trans 38:445–451PubMedGoogle Scholar
  122. Tavazoie SF, Alvarez VA, Ridenour DA, Kwiatkowski DJ, Sabatini BL (2005) Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat Neurosci 8:1727–1734PubMedGoogle Scholar
  123. Toma C, Rossi M, Sousa I, Blasi F, Bacchelli E, Alen R, Vanhala R, Monaco AP, Järvelä I, Maestrini E (2007) International Molecular Genetic Study of Autism Consortium. Is ASMT a susceptibility gene for autism spectrum disorders? A replication study in European populations. Mol Psychiat 12:977–979Google Scholar
  124. Tononi G, Cirelli C (2003) Sleep and synaptic homeostasis: a hypothesis. Brain Res Bull 62:143–150PubMedGoogle Scholar
  125. Toro R, Konyukh M, Delorme R, Leblond C, Chaste P, Fauchereau F, Coleman M, Leboyer M, Gillberg C, Bourgeron T (2010) Key role for gene dosage and synaptic homeostasis in autism spectrum disorders. Trends Genet 26:363–372PubMedGoogle Scholar
  126. Tsujino N, Nakatani Y, Seki Y, Nakasato A, Nakamura M, Sugawara M, Arita H (2007) Abnormality of circadian rhythm accompanied by an increase in frontal cortex serotonin in animal model of autism. Neurosci Res 57:289–295PubMedGoogle Scholar
  127. Turrigiano GG (1999) Homeostatic plasticity in neuronal networks: the more things change, the more they stay the same. Trends Neurosci 22:221–227PubMedGoogle Scholar
  128. Turrigiano GG, Nelson SB (2004) Homeostatic plasticity in the developing nervous system. Nat Rev Neurosci 5:97–107PubMedGoogle Scholar
  129. Turunen JA, Rehnström K, Kilpinen H, Kuokkanen M, Kempas E, Ylisaukko-Oja T (2008) Mitochondrial aspartate/glutamate carrier SLC25A12 gene is associated with autism. Autism Res 1:189–192PubMedGoogle Scholar
  130. van Bon BW, Mefford HC, Menten B, Koolen DA, Sharp AJ, Nillesen WM, Innis JW, de Ravel TJ, de Ravel TJ, Mercer CL, Fichera M, Stewart H, Connell LE, Ounap K, Ounap K, Lachlan K, Castle B, Van der Aa N, van Ravenswaaij C, Nobrega MA, Nobrega MA, Serra-Juhé C, Simonic I, de Leeuw N, Pfundt R, Bongers EM, Baker C, Finnemore P, Huang S, Huang S, Huang S, Maloney VK, Crolla JA, van Kalmthout M, Elia M, Vandeweyer G, Vandeweyer G, Fryns JP, Janssens S, Foulds N, Reitano S, Smith K, Parkel S, Loeys B, Woods CG, Speleman F, Pereira AC, Kurg A, Willatt L, Knight SJ, Vermeesch JR, Vermeesch JR, Romano C, Barber JC, Mortier G, Pérez-Jurado LA, Kooy F, Brunner HG, Brunner HG, Eichler EE, Kleefstra T, de Vries BB (2009) Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J Med Genet 46:511–523PubMedGoogle Scholar
  131. Van der Zwaag B, Staal WG, Hochstenbach R, Poot M, Spierenburg HA, de Jonge MV, Verbeek NE, van 't Slot R, van Es MA, Staal FJ, Freitag CM, Buizer-Voskamp JE, Nelen MR, van den Berg LH, van Amstel HK, van Engeland H, Burbach JP (2010) A co-segregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorder. Am J Med Genet B Neuropsychiatr Genet 153B:960–966PubMedGoogle Scholar
  132. Verkerk AJ, Mathews CA, Joosse M, Eussen BH, Heutink P, Oostra BA (2003) Tourette Syndrome Association International Consortium for Genetics. CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder. Genomics 82:1–9PubMedGoogle Scholar
  133. Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, Salyakina D, Imielinski M, Bradfield JP, Sleiman PM, Kim CE, Hou C, Frackelton E, Chiavacci R, Takahashi N, Sakurai T, Rappaport E, Lajonchere CM, Munson J, Estes A, Korvatska O, Piven J, Sonnenblick LI, Alvarez Retuerto AI, Herman EI, Dong H, Hutman T, Sigman M, Ozonoff S, Klin A, Owley T, Sweeney JA, Brune CW, Cantor RM, Bernier R, Gilbert JR, Cuccaro ML, McMahon WM, Miller J, State MW, Wassink TH, Coon H, Levy SE, Schultz RT, Nurnberger JI, Haines JL, Sutcliffe JS, Cook EH, Minshew NJ, Buxbaum JD, Dawson G, Grant SF, Geschwind DH, Pericak-Vance MA, Schellenberg GD, Hakonarson H (2009) Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459:528–533PubMedGoogle Scholar
  134. Wang X, McCoy PA, Rodriguiz RM, Pan Y, Je HS, Roberts AC, Kim CJ, Berrios J, Colvin JS, Bousquet-Moore D, Lorenzo I, Wu G, Weinberg RJ, Ehlers MD, Philpot BD, Beaudet AL, Wetsel WC, Jiang YH (2011) Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum Mol Genet 20:3093–3108PubMedGoogle Scholar
  135. Weiss LA, Kosova G, Delahanty RJ, Jiang L, Cook EH, Ober C, Sutcliffe JS (2006) Variation in ITGB3 is associated with whole-blood serotonin level and autism susceptibility. Eur J Hum Genet 14:923–931PubMedGoogle Scholar
  136. Weiss LA, Arking DE, Gene Discovery Project of Johns Hopkins & the Autism Consortium, Daly MJ, Chakravarti A (2009) A genome-wide linkage and association scan reveals novel loci for autism. Nature 461:802–808PubMedGoogle Scholar
  137. Williams JM, Beck TF, Pearson DM, Proud MB, Cheung SW, Scott DA (2009) A 1q42deletion involving DISC1, DISC2, and TSNAX in an autism spectrum disorder. Am J Med Genet A 149A:1758–1762PubMedGoogle Scholar
  138. Wiznitzer M (2004) Autism and tuberous sclerosis. J Child Neurol 19:675–679PubMedGoogle Scholar
  139. Yu L, Goda Y (2009) Dendritic signalling and homeostatic adaptation. Curr Opin Neurobiol 19:327–335PubMedGoogle Scholar
  140. Zhang C, Milunsky JM, Newton S, Ko J, Zhao G, Maher TA, Tager-Flusberg H, Bolliger MF, Carter AS, Boucard AA, Powell CM, Südhof TC (2009) A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export. J Neurosci 29:10843–10854PubMedGoogle Scholar
  141. Zweier C, de Jong EK, Zweier M, Orrico A, Ousager LB, Collins AL, Bijlsma EK, Oortveld MA, Ekici AB, Reis A, Schenck A, Rauch A (2009) CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am J Hum Genet 85:655–666PubMedGoogle Scholar

Databases Used in this Review

  1. Autism Genetic Database (AGD), http://wren.bcf.ku.edu/
  2. UCSC Genome browser, http://genome.ucsc.edu

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Human Genetics and Cognitive Functions, Institut PasteurParisFrance
  2. 2.CNRS URA 2182 “Genes, synapses and cognition,” Institut PasteurParisFrance
  3. 3.Sorbonne Paris Cité, Human Genetics and Cognitive FunctionsUniv. Paris DiderotParisFrance

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