Journal of the American Academy of Child & Adolescent Psychiatry
Volume 49, Issue 8 , Pages 794-809 , August 2010

Autism Spectrum Disorders and Epigenetics

  • Daria Grafodatskaya, Ph.D.

      Affiliations

    • Hospital for Sick Children, Toronto, Ontario, Canada
    • ,
  • Brian Chung, M.B.B.S.

      Affiliations

    • Hospital for Sick Children, Toronto, Ontario, Canada
    • ,
  • Peter Szatmari, M.D.

      Affiliations

    • McMaster University, Hamilton, Ontario, Canada
    • ,
  • Rosanna Weksberg, M.D., Ph.D.

      Affiliations

    • Hospital for Sick Children, Toronto, Ontario, Canada
    • Corresponding Author InformationCorrespondence to Dr. Rosanna Weksberg, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8

,Accepted 10 May 2010.

References 

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR. Fourth Edition. Washington, DC: American Psychiatric Publishing; 2000;
  2. Fombonne E. Epidemiology of autistic disorder and other pervasive developmental disorders. J Clin Psychiatry. 2005;66(Suppl 10):3–8
  3. Courchesne E, Pierce K. Why the frontal cortex in autism might be talking only to itself: local over-connectivity but long-distance disconnection. Curr Opin Neurobiol. 2005;15:225–230
  4. Courchesne E, Redcay E, Kennedy DP. The autistic brain: birth through adulthood. Curr Opin Neurol. 2004;17:489–496
  5. Pardo CA, Eberhart CG. The neurobiology of autism. Brain Pathol. 2007;17:434–447
  6. Newschaffer CJ, Croen LA, Daniels J, et al. The epidemiology of autism spectrum disorders. Annu Rev Public Health. 2007;28:235–258
  7. Abrahams BS, Geschwind DH. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet. 2008;9:341–355
  8. Bill BR, Geschwind DH. Genetic advances in autism: heterogeneity and convergence on shared pathways. Curr Opin Genet Dev. 2009;19:271–278
  9. Bird A. Perceptions of epigenetics. Nature. 2007;447:396–39824
  10. Miranda TB, Jones PA. DNA methylation: the nuts and bolts of repression. J Cell Physiol. 2007;213:384–390
  11. Suzuki MM, Bird A. DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet. 2008;9:465–476
  12. Kim JK, Samaranayake M, Pradhan S. Epigenetic mechanisms in mammals. Cell Mol Life Sci. 2009;66:596–612
  13. Horsthemke B, Buiting K. Genomic imprinting and imprinting defects in humans. Adv Genet. 2008;61:225–246
  14. Iacobuzio-Donahue CA. Epigenetic Changes in Cancer. Annu Rev Pathol. 2009;4:229–249
  15. Temple IK. Imprinting in human disease with special reference to transient neonatal diabetes and Beckwith-Wiedemann syndrome. Endocr Dev. 2007;12:113–123
  16. Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics. 2004;113:e472–e486
  17. Moss J, Howlin P. Autism spectrum disorders in genetic syndromes: implications for diagnosis, intervention and understanding the wider autism spectrum disorder population. J Intellect Disabil Res. 2009;53:852–873
  18. Schaefer GB, Mendelsohn NJ. Genetics evaluation for the etiologic diagnosis of autism spectrum disorders. Genet Med. 2008;10:4–12
  19. Lord C, Risi S, Lambrecht L, et al. The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord. 2000;30:205–223
  20. Abdul-Rahman OA, Hudgins L. The diagnostic utility of a genetics evaluation in children with pervasive developmental disorders. Genet Med. 2006;8:50–54
  21. Mount RH, Charman T, Hastings RP, Reilly S, Cass H. Features of autism in Rett syndrome and severe mental retardation. J Autism Dev Disord. 2003;33:435–442
  22. Beyer KS, Blasi F, Bacchelli E, Klauck SM, Maestrini E, Poustka A. Mutation analysis of the coding sequence of the MECP2 gene in infantile autism. Hum Genet. 2002;111:305–309
  23. Carney RM, Wolpert CM, Ravan SA, et al. Identification of MeCP2 mutations in a series of females with autistic disorder. Pediatr Neurol. 2003;28:205–211
  24. Coutinho AM, Oliveira G, Katz C, et al. MECP2 coding sequence and 3'UTR variation in 172 unrelated autistic patients. Am J Med Genet B Neuropsychiatr Genet. 2007;144B:475–483
  25. Shibayama A, Cook EH, Feng J, et al. MECP2 structural and 3'-UTR variants in schizophrenia, autism and other psychiatric diseases: a possible association with autism. Am J Med Genet B Neuropsychiatr Genet. Jul 1 2004;128B(1):50–53
  26. Lam CW, Yeung WL, Ko CH, et al. Spectrum of mutations in the MECP2 gene in patients with infantile autism and Rett syndrome. J Med Genet. 2000;37:E41
  27. Crawford DC, Acuna JM, Sherman SL. FMR1 and the fragile X syndrome: human genome epidemiology review. Genet Med. 2001;3:359–371
  28. Harris SW, Hessl D, Goodlin-Jones B, et al. Autism profiles of males with fragile X syndrome. Am J Ment Retard. 2008;113:427–438
  29. Descheemaeker MJ, Govers V, Vermeulen P, Fryns JP. Pervasive developmental disorders in Prader-Willi syndrome: the Leuven experience in 59 subjects and controls. Am J Med Genet A. 2006;140:1136–1142
  30. Veltman MW, Thompson RJ, Roberts SE, Thomas NS, Whittington J, Bolton PF. Prader-Willi syndrome—a study comparing deletion and uniparental disomy cases with reference to autism spectrum disorders. Eur Child Adolesc Psychiatry. 2004;13:42–50
  31. Hogart A, Wu D, Lasalle JM, Schanen NC. The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13. Neurobiol Dis. 2010;38:181–191
  32. Kent L, Bowdin S, Kirby GA, Cooper WN, Maher ER. Beckwith Weidemann syndrome: a behavioral phenotype-genotype study. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:1295–1297
  33. Hartshorne TS, Grialou TL, Parker KR. Autistic-like behavior in CHARGE syndrome. Am J Med Genet A. 2005;133A:257–261
  34. Johansson M, Rastam M, Billstedt E, et al. Autism spectrum disorders and underlying brain pathology in CHARGE association. Dev Med Child Neurol. 2006;48:40–50
  35. Smith IM, Nichols SL, Issekutz K, Blake K. Behavioral profiles and symptoms of autism in CHARGE syndrome: preliminary Canadian epidemiological data. Am J Med Genet A. 2005;133A:248–256
  36. Skuse DH, James RS, Bishop DV, et al. Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function. Nature. 1997;387:705–708
  37. Matijevic T, Knezevic J, Slavica M, Pavelic J. Rett syndrome: from the gene to the disease. Eur Neurol. 2009;61:3–10
  38. Nan X, Ng HH, Johnson CA, et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 1998;393:386–389
  39. Jones PL, Veenstra GJ, Wade PA, et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet. 1998;19:187–191
  40. Chahrour M, Jung SY, Shaw C, et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science. 2008;320:1224–1229
  41. Hite KC, Adams VH, Hansen JC. Recent advances in MeCP2 structure and function. Biochem Cell Biol. 2009;87:219–227
  42. Yasui DH, Peddada S, Bieda MC, et al. Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes. Proc Natl Acad Sci U S A. 2007;104:19416–19421
  43. Young JI, Hong EP, Castle JC, et al. Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. Proc Natl Acad Sci U S A. 2005;102:17551–17558
  44. Shahbazian MD, Antalffy B, Armstrong DL, Zoghbi HY. Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. Hum Mol Genet. 2002;11:115–124
  45. Smrt RD, Eaves-Egenes J, Barkho BZ, et al. Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons. Neurobiol Dis. 2007;27:77–89
  46. Chen WG, Chang Q, Lin Y, et al. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science. 2003;302:885–889
  47. Nagarajan RP, Hogart AR, Gwye Y, Martin MR, LaSalle JM. Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics. 2006;1:e1–e11
  48. Renieri A, Mari F, Mencarelli MA, et al. Diagnostic criteria for the Zappella variant of Rett syndrome (the preserved speech variant). Brain Dev. 2009;31:208–216
  49. Loat CS, Curran S, Lewis CM, et al. Methyl-CpG-binding protein 2 polymorphisms and vulnerability to autism. Genes Brain Behav. 2008;7:754–760
  50. Allan AM, Liang X, Luo Y, et al. The loss of methyl-CpG binding protein 1 leads to autism-like behavioral deficits. Hum Mol Genet. 2008;17:2047–2057
  51. Cukier HN, Rabionet R, Konidari I, et al. Novel variants identified in methyl-CpG-binding domain genes in autistic individuals. [published online ahead of print] Neurogenetics. November 18, 2009;
  52. Maddalena A, Richards CS, McGinniss MJ, et al. Technical standards and guidelines for fragile X: the first of a series of disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics (Quality Assurance Subcommittee of the Laboratory Practice Committee). Genet Med. 2001;3:200–205
  53. Pfeiffer BE, Huber KM. The state of synapses in fragile X syndrome. Neuroscientist. 2009;15:549–567
  54. Tan H, Li H, Jin P. RNA-mediated pathogenesis in fragile X-associated disorders. Neurosci Lett. 2009;466:103–108
  55. Hagerman RJ. Physical and behavioral phenotype. In:  Hagerman RJ editors. Fragile X Syndrome: Diagnosis, Treatment, and Research. Baltimore: John Hopkins University Press; 1996;p. 3–88
  56. de Vries BB, Wiegers AM, Smits AP, et al. Mental status of females with an FMR1 gene full mutation. Am J Hum Genet. 1996;58:1025–1032
  57. Tabolacci E, Moscato U, Zalfa F, Bagni C, Chiurazzi P, Neri G. Epigenetic analysis reveals a euchromatic configuration in the FMR1 unmethylated full mutations. Eur J Hum Genet. 2008;16:1487–1498
  58. Clifford S, Dissanayake C, Bui QM, Huggins R, Taylor AK, Loesch DZ. Autism spectrum phenotype in males and females with fragile X full mutation and premutation. J Autism Dev Disord. 2007;37:738–747
  59. Bailey DB, Hatton DD, Skinner M, Mesibov G. Autistic behavior, FMR1 protein, and developmental trajectories in young males with fragile X syndrome. J Autism Dev Disord. 2001;31:165–174
  60. Hagerman RJ, Jackson AW, Levitas A, Rimland B, Braden M. An analysis of autism in fifty males with the fragile X syndrome. Am J Med Genet. 1986;23:359–374
  61. Kau AS, Tierney E, Bukelis I, et al. Social behavior profile in young males with fragile X syndrome: characteristics and specificity. Am J Med Genet A. 2004;126A:9–17
  62. Loesch DZ, Bui QM, Dissanayake C, et al. Molecular and cognitive predictors of the continuum of autistic behaviours in fragile X. Neurosci Biobehav Rev. 2007;31:315–326
  63. Matson JL, Shoemaker M. Intellectual disability and its relationship to autism spectrum disorders. Res Dev Disabil. 2009;30:1107–1114
  64. Vig S, Jedrysek E. Autistic features in young children with significant cognitive impairment: autism or mental retardation?. J Autism Dev Disord. 1999;29:235–248
  65. Tycko B, Morison IM. Physiological functions of imprinted genes. J Cell Physiol. 2002;192:245–258
  66. Edwards CA, Ferguson-Smith AC. Mechanisms regulating imprinted genes in clusters. Curr Opin Cell Biol. 2007;19:281–289
  67. Swales AK, Spears N. Genomic imprinting and reproduction. Reproduction. 2005;130:389–399
  68. Butler MG. Prader-Willi syndrome: current understanding of cause and diagnosis. Am J Med Genet. 1990;35:319–332
  69. Jiang Y, Lev-Lehman E, Bressler J, Tsai TF, Beaudet AL. Genetics of Angelman syndrome. Am J Hum Genet. 1999;65:1–6
  70. Horsthemke B, Wagstaff J. Mechanisms of imprinting of the Prader-Willi/Angelman region. Am J Med Genet A. 2008;146A:2041–2052
  71. Nicholls RD, Knepper JL. Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes. Annu Rev Genomics Hum Genet. 2001;2:153–175
  72. Horsthemke B, Buiting K. Imprinting defects on human chromosome 15. Cytogenet Genome Res. 2006;113:292–299
  73. Sahoo T, del Gaudio D, German JR, et al. Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nat Genet. 2008;40:719–721
  74. Dimitropoulos A, Schultz RT. Autistic-like symptomatology in Prader-Willi syndrome: a review of recent findings. Curr Psychiatry Rep. 2007;9:159–164
  75. Milner KM, Craig EE, Thompson RJ, et al. Prader-Willi syndrome: intellectual abilities and behavioural features by genetic subtype. J Child Psychol Psychiatry. 2005;46:1089–1096
  76. Veltman MW, Craig EE, Bolton PF. Autism spectrum disorders in Prader-Willi and Angelman syndromes: a systematic review. Psychiatr Genet. 2005;15:243–254
  77. Veltman MW, Thompson RJ, Craig EE, et al. A paternally inherited duplication in the Prader-Willi/Angelman syndrome critical region: a case and family study. J Autism Dev Disord. 2005;35:117–127
  78. Bonati MT, Russo S, Finelli P, et al. Evaluation of autism traits in Angelman syndrome: a resource to unfold autism genes. Neurogenetics. 2007;8:169–178
  79. Trillingsgaard A. Autism in Angelman syndrome: an exploration of comorbidity. JR OS Autism. 2004;8:163–174
  80. Peters SU, Beaudet AL, Madduri N, Bacino CA. Autism in Angelman syndrome: implications for autism research. Clin Genet. 2004;66:530–536
  81. Steffenburg S, Gillberg CL, Steffenburg U, Kyllerman M. Autism in Angelman syndrome: a population-based study. Pediatr Neurol. 1996;14:131–136
  82. Kramer JM, van Bokhoven H. Genetic and epigenetic defects in mental retardation. Int J Biochem Cell Biol. 2009;41:96–107
  83. Williams CA, Dagli A, Battaglia A. Genetic disorders associated with macrocephaly. Am J Med Genet A. 2008;146A:2023–2037
  84. Butler MG, Dasouki MJ, Zhou XP, et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet. 2005;42:318–321
  85. Herman GE, Butter E, Enrile B, Pastore M, Prior TW, Sommer A. Increasing knowledge of PTEN germline mutations: Two additional patients with autism and macrocephaly. Am J Med Genet A. 2007;143:589–593
  86. Smith AC, Choufani S, Ferreira JC, Weksberg R. Growth regulation, imprinted genes, and chromosome 11p15.5. Pediatr Res. 2007;61:43R–47R
  87. Morrow JD, Whitman BY, Accardo PJ. Autistic disorder in Sotos syndrome: a case report. Eur J Pediatr. 1990;149:567–569
  88. Mouridsen SE, Hansen MB. Neuropsychiatric aspects of Sotos syndrome (A review and two case illustrations). Eur Child Adolesc Psychiatry. 2002;11:43–48
  89. Zapella M. Autistic features in children affected by cerebral gigantism. Brain Dysfunction. 1990;3:241–244
  90. Rayasam GV, Wendling O, Angrand PO, et al. NSD1 is essential for early post-implantation development and has a catalytically active SET domain. EMBO J. 2003;22:3153–3163
  91. Buxbaum JD, Cai G, Nygren G, et al. Mutation analysis of the NSD1 gene in patients with autism spectrum disorders and macrocephaly. BMC Med Genet. 2007;8:68
  92. Davies W, Isles A, Smith R, et al. Xlr3b is a new imprinted candidate for X-linked parent-of-origin effects on cognitive function in mice. Nat Genet. 2005;37:625–629
  93. Creswell C, Skuse DH. Autism in association with Turner syndrome: genetic implications for male vulnerability to pervasive developmental disorders. Neurocase. 1999;5:511–518
  94. Schanen NC. Epigenetics of autism spectrum disorders. Hum Mol Genet. 2006;15(Spec No 2):R138–R150
  95. Bolton PF, Roobol M, Allsopp L, Pickles A. Association between idiopathic infantile macrocephaly and autism spectrum disorders. Lancet. 2001;358:726–727
  96. Bolton PF, Veltman MW, Weisblatt E, et al. Chromosome 15q11 to 15q13 abnormalities and other medical conditions in individuals with autism spectrum disorders. Psychiatr Genet. 2004;14:131–137
  97. Thomas NS, Browne CE, Oley C, Healey S, Crolla JA. Investigation of a cryptic interstitial duplication involving the Prader-Willi/Angelman syndrome critical region. Hum Genet. 1999;105:384–387
  98. Browne CE, Dennis NR, Maher E, et al. Inherited interstitial duplications of proximal 15q: genotype-phenotype correlations. Am J Hum Genet. 1997;61:1342–1352
  99. Mao R, Jalal SM, Snow K, Michels VV, Szabo SM, Babovic-Vuksanovic D. Characteristics of two cases with dup(15)(q11.2-q12): one of maternal and one of paternal origin. Genet Med. 2000;2:131–135
  100. Mohandas TK, Park JP, Spellman RA, et al. Paternally derived de novo interstitial duplication of proximal 15q in a patient with developmental delay. Am J Med Genet. 1999;82:294–300
  101. Roberts SE, Dennis NR, Browne CE, et al. Characterisation of interstitial duplications and triplications of chromosome 15q11-q13. Hum Genet. 2002;110:227–234
  102. Depienne C, Moreno-De-Luca D, Heron D, et al. Screening for genomic rearrangements and methylation abnormalities of the 15q11-q13 region in autism spectrum disorders. Biol Psychiatry. 2009;66:349–359
  103. Ciechanover A, Schwartz AL. The ubiquitin-mediated proteolytic pathway: mechanisms of recognition of the proteolytic substrate and involvement in the degradation of native cellular proteins. FASEB J. 1994;8:182–191
  104. Nishimura Y, Martin CL, Vazquez-Lopez A, et al. Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. Hum Mol Genet. 2007;16:1682–1698
  105. Baron CA, Tepper CG, Liu SY, et al. Genomic and functional profiling of duplicated chromosome 15 cell lines reveal regulatory alterations in UBE3A-associated ubiquitin-proteasome pathway processes. Hum Mol Genet. 2006;15:853–869
  106. Hogart A, Leung KN, Wang NJ, et al. Chromosome 15q11 to 15q13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number. J Med Genet. 2009;46:86–93
  107. Samaco RC, Hogart A, LaSalle JM. Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum Mol Genet. 2005;14:483–492
  108. Hogart A, Nagarajan RP, Patzel KA, Yasui DH, Lasalle JM. 15q11 to 15q13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. Hum Mol Genet. 2007;16:691–703
  109. Buxbaum JD, Silverman JM, Smith CJ, et al. Association between a GABRB3 polymorphism and autism. Mol Psychiatry. 2002;7:311–316
  110. Cook EH, Courchesne RY, Cox NJ, et al. Linkage-disequilibrium mapping of autistic disorder, with 15q11 to 15q13 markers. Am J Hum Genet. 1998;62:1077–1083
  111. Martin ER, Menold MM, Wolpert CM, et al. Analysis of linkage disequilibrium in gamma-aminobutyric acid receptor subunit genes in autistic disorder. Am J Med Genet. 2000;96:43–48
  112. McCauley JL, Olson LM, Delahanty R, et al. A linkage disequilibrium map of the 1-Mb 15q12 GABA(A) receptor subunit cluster and association to autism. Am J Med Genet B Neuropsychiatr Genet. 2004;131B:51–59
  113. Nurmi EL, Amin T, Olson LM, et al. Dense linkage disequilibrium mapping in the 15q11-q13 maternal expression domain yields evidence for association in autism. Mol Psychiatry. 2003;8:570;624-634
  114. Shao Y, Cuccaro ML, Hauser ER, et al. Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotypic subtypes. Am J Hum Genet. 2003;72:539–548
  115. Weiss LA, Shen Y, Korn JM, et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med. 2008;358:667–675
  116. Ulrey CL, Liu L, Andrews LG, Tollefsbol TO. The impact of metabolism on DNA methylation. Hum Mol Genet. 2005;14(Spec No 1):R139–R147
  117. Pasca SP, Dronca E, Kaucsar T, et al. One carbon metabolism disturbances and the C667T MTHFR gene polymorphism in children with autism spectrum disorders. [published online ahead of print] J Cell Mol Med. August 9, 2008;
  118. Boris M, Goldblatt A, James J. Association of MTHFR gene variants with autism. J G J Am Phys Surgeons. 2004;9:106–108
  119. Adams M, Lucock M, Stuart J, Fardell S, Baker K, Ng X. Preliminary evidence for involvement of the folate gene polymorphism 19bp deletion-DHFR in occurrence of autism. Neurosci Lett. 2007;422:24–29
  120. Goin-Kochel RP, Porter AE, Peters SU, Shinawi M, Sahoo T, Beaudet AL. The MTHFR 677C→T polymorphism and behaviors in children with autism: exploratory genotype-phenotype correlations. Autism Res. 2009;2:98–108
  121. Mohammad NS, Jain JM, Chintakindi KP, Singh RP, Naik U, Akella RR. Aberrations in folate metabolic pathway and altered susceptibility to autism. Psychiatr Genet. 2009;19:171–176
  122. James SJ, Melnyk S, Jernigan S, et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:947–956
  123. Ebbing M, Bonaa KH, Nygard O, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA. 2009;302:2119–2126
  124. Lucock M, Yates Z. Folic acid fortification: a double-edged sword. Curr Opin Clin Nutr Metab Care. 2009;12:555–564
  125. Lamb JA, Barnby G, Bonora E, et al. Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects. J Med Genet. 2005;42:132–137
  126. Bonora E, Bacchelli E, Levy ER, et al. Mutation screening and imprinting analysis of four candidate genes for autism in the 7q32 region. Mol Psychiatry. 2002;7:289–301
  127. Hamilton SP, Woo JM, Carlson EJ, Ghanem N, Ekker M, Rubenstein JL. Analysis of four DLX homeobox genes in autistic probands. BMC Genet. 2005;6:52
  128. Nakashima N, Yamagata T, Mori M, Kuwajima M, Suwa K, Momoi MY. Expression analysis and mutation detection of DLX5 and DLX6 in autism. Brain Dev. 2010;32:98–104
  129. Richler E, Reichert JG, Buxbaum JD, McInnes LA. Autism and ultraconserved non-coding sequence on chromosome 7q. Psychiatr Genet. 2006;16:19–23
  130. Kotzot D, Utermann G. Uniparental disomy (UPD) other than 15: phenotypes and bibliography updated. Am J Med Genet A. 2005;136:287–305
  131. Engel E, DeLozier-Blanchet CD. Uniparental disomy, isodisomy, and imprinting: probable effects in man and strategies for their detection. Am J Med Genet. 1991;40:432–439
  132. Wassink TH, Losh M, Frantz RS, et al. A case of autism and uniparental disomy of chromosome 1. Hum Genet. 2005;117:200–206
  133. Bonora E, Beyer KS, Lamb JA, et al. Analysis of reelin as a candidate gene for autism. Mol Psychiatry. 2003;8:885–892
  134. Li H, Li Y, Shao J, et al. The association analysis of RELN and GRM8 genes with autistic spectrum disorder in Chinese Han population. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:194–200
  135. Serajee FJ, Zhong H, Mahbubul Huq AH. Association of Reelin gene polymorphisms with autism. Genomics. 2006;87:75–83
  136. Skaar DA, Shao Y, Haines JL, et al. Analysis of the RELN gene as a genetic risk factor for autism. Mol Psychiatry. 2005;10:563–571
  137. Tissir F, Goffinet AM. Reelin and brain development. Nat Rev Neurosci. 2003;4:496–505
  138. Fatemi SH, Snow AV, Stary JM, et al. Reelin signaling is impaired in autism. Biol Psychiatry. 2005;57:777–787
  139. Abdolmaleky HM, Cheng KH, Russo A, et al. Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report. Am J Med Genet B Neuropsychiatr Genet. 2005;134B:60–66
  140. Persico AM, D'Agruma L, Maiorano N, et al. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol Psychiatry. 2001;6:150–159
  141. Zhang H, Liu X, Zhang C, et al. Reelin gene alleles and susceptibility to autism spectrum disorders. Mol Psychiatry. 2002;7:1012–1017
  142. Persico AM, Levitt P, Pimenta AF. Polymorphic GGC repeat differentially regulates human reelin gene expression levels. J Neural Transm. 2006;113:1373–1382
  143. Tom N, Assinder SJ. Oxytocin in health and disease. Int J Biochem Cell Biol. 2010;42:202–205
  144. Jacob S, Brune CW, Carter CS, Leventhal BL, Lord C, Cook EH. Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism. Neurosci Lett. 2007;417:6–9
  145. Lerer E, Levi S, Salomon S, Darvasi A, Yirmiya N, Ebstein RP. Association between the oxytocin receptor (OXTR) gene and autism: relationship to Vineland Adaptive Behavior Scales and cognition. Mol Psychiatry. 2008;13:980–988
  146. Liu X, Kawamura Y, Shimada T, et al. Association of the oxytocin receptor (OXTR) gene polymorphisms with autism spectrum disorder (ASD) in the Japanese population. J Hum Genet. 2010;55:137–141
  147. Wu S, Jia M, Ruan Y, et al. Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population. Biol Psychiatry. 2005;58:74–77
  148. Gregory SG, Connelly JJ, Towers AJ, et al. Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med. 2009;7:62
  149. Cheng L, Ge Q, Xiao P, et al. Association study between BDNF gene polymorphisms and autism by three-dimensional gel-based microarray. Int J Mol Sci. 2009;10:2487–2500
  150. Djalali S, Holtje M, Grosse G, et al. Effects of brain-derived neurotrophic factor (BDNF) on glial cells and serotonergic neurones during development. J Neurochem. 2005;92:616–627
  151. Martinowich K, Hattori D, Wu H, et al. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science. 2003;302:890–893
  152. Nishimura K, Nakamura K, Anitha A, et al. Genetic analyses of the brain-derived neurotrophic factor (BDNF) gene in autism. Biochem Biophys Res Commun. 2007;356:200–206
  153. Rumajogee P, Madeira A, Verge D, Hamon M, Miquel MC. Up-regulation of the neuronal serotoninergic phenotype in vitro: BDNF and cAMP share Trk B-dependent mechanisms. J Neurochem. 2002;83:1525–1528
  154. Chugani DC. Serotonin in autism and pediatric epilepsies. Ment Retard Dev Disabil Res Rev. 2004;10:112–116
  155. Kim SJ, Cox N, Courchesne R, et al. Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder. Mol Psychiatry. 2002;7:278–288
  156. Sutcliffe JS, Delahanty RJ, Prasad HC, et al. Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. Am J Hum Genet. 2005;77:265–279
  157. Wassink TH, Hazlett HC, Epping EA, et al. Cerebral cortical gray matter overgrowth and functional variation of the serotonin transporter gene in autism. Arch Gen Psychiatry. 2007;64:709–717
  158. Ornoy A. Valproic acid in pregnancy: how much are we endangering the embryo and fetus?. Reprod Toxicol. 2009;28:1–10
  159. Rosenberg G. The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees?. Cell Mol Life Sci. 2007;64:2090–2103
  160. Moore SJ, Turnpenny P, Quinn A, et al. A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet. 2000;37:489–497
  161. Rasalam AD, Hailey H, Williams JH, et al. Characteristics of fetal anticonvulsant syndrome associated autistic disorder. Dev Med Child Neurol. 2005;47:551–555
  162. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem. 2001;276:36734–36741
  163. Yildirim E, Zhang Z, Uz T, Chen CQ, Manev R, Manev H. Valproate administration to mice increases histone acetylation and 5-lipoxygenase content in the hippocampus. Neurosci Lett. 2003;345:141–143
  164. Sharma RP, Rosen C, Kartan S, et al. Valproic acid and chromatin remodeling in schizophrenia and bipolar disorder: preliminary results from a clinical population. Schizophr Res. 2006;88:227–231
  165. Milutinovic S, D'Alessio AC, Detich N, Szyf M. Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes. Carcinogenesis. 2007;28:560–571
  166. Kolozsi E, Mackenzie RN, Roullet FI, Decatanzaro D, Foster JA. Prenatal exposure to valproic acid leads to reduced expression of synaptic adhesion molecule neuroligin 3 in mice. Neuroscience. 2009;163:1201–1210
  167. Rivera RM, Stein P, Weaver JR, Mager J, Schultz RM, Bartolomei MS. Manipulations of mouse embryos prior to implantation result in aberrant expression of imprinted genes on day 9.5 of development. Hum Mol Genet. 2008;17:1–14
  168. Fernandez-Gonzalez R, Moreira P, Bilbao A, et al. Long-term effect of in vitro culture of mouse embryos with serum on mRNA expression of imprinting genes, development, and behavior. Proc Natl Acad Sci U S A. 2004;101:5880–5885
  169. Sato A, Otsu E, Negishi H, Utsunomiya T, Arima T. Aberrant DNA methylation of imprinted loci in superovulated oocytes. Hum Reprod. 2007;22:26–35
  170. DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet. 2003;72:156–160
  171. Doornbos ME, Maas SM, McDonnell J, Vermeiden JP, Hennekam RC. Infertility, assisted reproduction technologies and imprinting disturbances: a Dutch study. Hum Reprod. 2007;22:2476–2480
  172. Halliday J, Oke K, Breheny S, Algar E, D JA. Beckwith-Wiedemann syndrome and IVF: a case-control study. Am J Hum Genet. 2004;75:526–528
  173. Maher ER, Brueton LA, Bowdin SC, et al. Beckwith-Wiedemann syndrome and assisted reproduction technology (ART). J Med Genet. 2003;40:62–64
  174. Orstavik KH, Eiklid K, van der Hagen CB, et al. Another case of imprinting defect in a girl with Angelman syndrome who was conceived by intracytoplasmic semen injection. Am J Hum Genet. 2003;72:218–219
  175. Hvidtjorn D, Schieve L, Schendel D, Jacobsson B, Svaerke C, Thorsen P. Cerebral palsy, autism spectrum disorders, and developmental delay in children born after assisted conception: a systematic review and meta-analysis. Arch Pediatr Adolesc Med. 2009;163:72–83
  176. Klemetti R, Sevon T, Gissler M, Hemminki E. Health of children born as a result of in vitro fertilization. Pediatrics. 2006;118:1819–1827
  177. Knoester M, Helmerhorst FM, van der Westerlaken LA, Walther FJ, Veen S. Matched follow-up study of 5 8-year-old ICSI singletons: child behaviour, parenting stress and child (health-related) quality of life. Hum Reprod. 2007;22:3098–3107
  178. Maimburg RD, Vaeth M. Do children born after assisted conception have less risk of developing infantile autism?. Hum Reprod. 2007;22:1841–1843
  179. Tsankova N, Renthal W, Kumar A, Nestler EJ. Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci. 2007;8:355–367
  180. Szyf M. Epigenetics, DNA methylation, and chromatin modifying drugs. Annu Rev Pharmacol Toxicol. 2009;49:243–263

 This article is discussed in an editorial by Drs. James J. Hudziak and Stephen V. Faraone on page 729.

 Funding for this work was provided by the Canadian Institute of Heath Research.

 This is one of several articles published in the August and September issues of the Journal of the American Academy of Child and Adolescent Psychiatry that explores the intersection of genetics and mental health disorders in children and adolescents. The editors invite the reader to investigate the additional articles on this burgeoning area of developmental psychopathology.

 The authors thank Cheryl Cytrynbaum, Cheryl Shuman, Sanaa Choufani, and Darci Butcher for their helpful suggestions regarding the manuscript, and Khadine Wiltshire and Deborah Taylor for their technical help. Ms. Cytrynbaum, Ms. Shuman, Ms. Wiltshire, Ms. Taylor, and Drs. Choufani and Butcher are with the Hospital for Sick Children.

 Disclosure: Dr. Grafodatskaya is funded by a post-doctoral fellowship from the Autism Research Training Program. Drs. Chung, Weksberg, and Szatmari report no biomedical interests or potential conflicts of interest.

PII: S0890-8567(10)00391-6

doi: 10.1016/j.jaac.2010.05.005

Journal of the American Academy of Child & Adolescent Psychiatry
Volume 49, Issue 8 , Pages 794-809 , August 2010

Article Tools

* Image Usage & Resolution