Journal of the American Academy of Child & Adolescent Psychiatry
Volume 49, Issue 8 , Pages 736-751 , August 2010

Progress in Cytogenetics: Implications for Child Psychopathology

  • Ellen J. Hoffman, M.D.
  • ,
  • Matthew W. State, M.D., Ph.D.

      Affiliations

    • Corresponding Author InformationCorrespondence to Matthew W. State, M.D., Ph.D., Child Study Center, 230 South Frontage Road, P.O. Box 207900, New Haven, CT 06520-7900

,Accepted 29 March 2010.

References 

  1. McClellan JM, Susser E, King MC. Schizophrenia: a common disease caused by multiple rare alleles. Br J Psychiatry. 2007;190:194–199
  2. El-Fishawy P, State MW. The genetics of autism: key issues, recent findings and clinical implications. Psychiatr Clin North Am. 2010;33:83–105
  3. Constantino JN. The Social Responsiveness Scale. Los Angeles: Western Psychological Services; 2002;
  4. Virkud YV, Todd RD, Abbacchi AM, Zhang Y, Constantino JN. Familial aggregation of quantitative autistic traits in multiplex versus simplex autism. Am J Med Genet B Neuropsychiatr Genet. 2009;150B:328–334
  5. Constantino JN, Lajonchere C, Lutz M, et al. Autistic social impairment in the siblings of children with pervasive developmental disorders. Am J Psychiatry. 2006;163:294–296
  6. Cadenhead KS, Swerdlow NR, Shafer KM, Diaz M, Braff DL. Modulation of the startle response and startle laterality in relatives of schizophrenic patients and in subjects with schizotypal personality disorder: evidence of inhibitory deficits. Am J Psychiatry. 2000;157:1660–1668
  7. Calkins ME, Curtis CE, Iacono WG, Grove WM. Antisaccade performance is impaired in medically and psychiatrically healthy biological relatives of schizophrenia patients. Schizophr Res. 2004;71:167–178
  8. Sitskoorn MM, Aleman A, Ebisch SJ, Appels MC, Kahn RS. Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis. Schizophr Res. 2004;71:285–295
  9. Feygin DL, Swain JE, Leckman JF. The normalcy of neurosis: evolutionary origins of obsessive-compulsive disorder and related behaviors. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:854–864
  10. Happe F, Vital P. What aspects of autism predispose to talent?. Phil Trans R Soc Lond B Biol Sci. 2009;364:1369–1375
  11. Keller MC, Miller G. Resolving the paradox of common, harmful, heritable mental disorders: which evolutionary genetic models work best?. Behav Brain Sci. 2006;29:385–404discussion 405-452
  12. O'Roak BJ, State MW. Autism genetics: strategies, challenges, and opportunities. Autism Res. 2008;1:4–17
  13. Buxbaum JD. Multiple rare variants in the etiology of autism spectrum disorders. Dialogues Clin Neurosci. 2009;11:35–43
  14. Fernandez T, State MW. Assessing risk: gene discovery. In:  Martin A,  Volkmar F editor. Lewis’s Child and Adolescent Psychiatry: A Comprehensive Textbook. 4th ed.. Philadelphia: Lippincott Williams & Wilkins; 2007;p. 189–199
  15. Abrahams BS, Geschwind DH. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet. 2008;9:341–355
  16. Frazer KA, Murray SS, Schork NJ, Topol EJ. Human genetic variation and its contribution to complex traits. Nat Rev Genet. 2009;10:241–251
  17. Hardy J, Singleton A. Genomewide association studies and human disease. N Engl J Med. 2009;360:1759–1768
  18. Altshuler D, Daly MJ, Lander ES. Genetic mapping in human disease. Science. 2008;322:881–888
  19. Stefansson H, Rujescu D, Cichon S, et al. Large recurrent microdeletions associated with schizophrenia. Nature. 2008;455:232–236
  20. Bucan M, Abrahams BS, Wang K, et al. Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genet. 2009;5:e1000536
  21. Christian SL, Brune CW, Sudi J, et al. Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder. Biol Psychiatry. 2008;63:1111–1117
  22. Glessner JT, Wang K, Cai G, et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature. 2009;459:569–573
  23. Kirov G, Grozeva D, Norton N, et al. Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Hum Mol Genet. 2009;18:1497–1503
  24. Kumar RA, KaraMohamed S, Sudi J, et al. Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet. 2008;17:628–638
  25. Marshall CR, Noor A, Vincent JB, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008;82:477–488
  26. McCarthy SE, Makarov V, Kirov G, et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet. 2009;41:1223–1227
  27. Sebat J, Lakshmi B, Malhotra D, et al. Strong association of de novo copy number mutations with autism. Science. 2007;316:445–449
  28. Walsh T, McClellan JM, McCarthy SE, et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science. 2008;320:539–543
  29. 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
  30. Ji W, Foo JN, O'Roak BJ, et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet. 2008;40:592–599
  31. Romeo S, Yin W, Kozlitina J, et al. Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. J Clin Invest. 2009;119:70–79
  32. McCarroll SA, Hadnott TN, Perry GH, et al. Common deletion polymorphisms in the human genome. Nat Genet. 2006;38:86–92
  33. Lubs HA. A marker X chromosome. Am J Hum Genet. 1969;21:231–244
  34. Sherman SL, Jacobs PA, Morton NE, et al. Further segregation analysis of the fragile X syndrome with special reference to transmitting males. Hum Genet. 1985;69:289–299
  35. Fu YH, Kuhl DP, Pizzuti A, et al. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell. 1991;67:1047–1058
  36. Cornish K, Turk J, Hagerman R. The fragile X continuum: new advances and perspectives. J Intellect Disabil Res. 2008;52(Pt 6):469–482
  37. Bassell GJ, Warren ST. Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron. 2008;60:201–214
  38. Waung MW, Huber KM. Protein translation in synaptic plasticity: mGluR-LTD, fragile X. Curr Opin Neurobiol. 2009;19:319–326
  39. McBride SM, Choi CH, Wang Y, et al. Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroom body defects in a Drosophila model of fragile X syndrome. Neuron. 2005;45:753–764
  40. Tucker B, Richards RI, Lardelli M. Contribution of mGluR and Fmr1 functional pathways to neurite morphogenesis, craniofacial development and fragile X syndrome. Hum Mol Genet. 2006;15:3446–3458
  41. Yan QJ, Rammal M, Tranfaglia M, Bauchwitz RP. Suppression of two major fragile X syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology. 2005;49:1053–1066
  42. Hagerman RJ, Berry-Kravis E, Kaufmann WE, et al. Advances in the treatment of fragile X syndrome. Pediatrics. 2009;123:378–390
  43. Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics. 2004;113:e472–e486
  44. Venkitaramani DV, Lombroso PJ. Molecular basis of genetic neuropsychiatric disorders. Child Adolesc Psychiatr Clin North Am. 2007;16:541–556
  45. Veenstra-VanderWeele J, Cook EH. Molecular genetics of autism spectrum disorder. Mol Psychiatry. 2004;9:819–832
  46. Green T, Gothelf D, Glaser B, et al. Psychiatric disorders and intellectual functioning throughout development in velocardiofacial (22q11.2 deletion) syndrome. J Am Acad Child Adolesc Psychiatry. 2009;48:1060–1068
  47. Thomas NS, Sharp AJ, Browne CE, Skuse D, Hardie C, Dennis NR. Xp deletions associated with autism in three females. Hum Genet. 1999;104:43–48
  48. Jamain S, Quach H, Betancur C, et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet. 2003;34:27–29
  49. Laumonnier F, Bonnet-Brilhault F, Gomot M, et al. 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. 2004;74:552–557
  50. Blasi F, Bacchelli E, Pesaresi G, Carone S, Bailey AJ, Maestrini E. Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:220–221
  51. Gauthier J, Bonnel A, St-Onge J, et al. NLGN3/NLGN4 gene mutations are not responsible for autism in the Quebec population. Am J Med Genet B Neuropsychiatr Genet. 2005;132B:74–75
  52. Vincent JB, Kolozsvari D, Roberts WS, Bolton PF, Gurling HM, Scherer SW. Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands. Am J Med Genet B Neuropsychiatr Genet. 2004;129B:82–84
  53. Yan J, Oliveira G, Coutinho A, et al. Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients. Mol Psychiatry. 2005;10:329–332
  54. Tabuchi K, Blundell J, Etherton MR, et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science. 2007;318:71–76
  55. Chadman KK, Gong S, Scattoni ML, et al. Minimal aberrant behavioral phenotypes of neuroligin-3 R451C knockin mice. Autism Res. 2008;1:147–158
  56. Durand CM, Betancur C, Boeckers TM, et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet. 2007;39:25–27
  57. Moessner R, Marshall CR, Sutcliffe JS, et al. Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet. 2007;81:1289–1297
  58. Feng J, Schroer R, Yan J, et al. High frequency of neurexin 1beta signal peptide structural variants in patients with autism. Neurosci Lett. 2006;409:10–13
  59. Szatmari P, Paterson AD, Zwaigenbaum L, et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet. 2007;39:319–328
  60. Sudhof TC. Neuroligins and neurexins link synaptic function to cognitive disease. Nature. 2008;455:903–911
  61. Fernandez T, Morgan T, Davis N, et al. Disruption of contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome. Am J Hum Genet. 2004;74:1286–1293
  62. Fernandez TV, Garcia-Gonzalez IJ, Mason CE, et al. Molecular characterization of a patient with 3p deletion syndrome and a review of the literature. Am J Med Genet A. 2008;146A:2746–2752
  63. Roohi J, Montagna C, Tegay DH, et al. Disruption of contactin 4 in three subjects with autism spectrum disorder. J Med Genet. 2009;46:176–182
  64. Alarcon M, Abrahams BS, Stone JL, et al. Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet. 2008;82:150–159
  65. Arking DE, Cutler DJ, Brune CW, et al. A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am J Hum Genet. 2008;82:160–164
  66. Bakkaloglu B, O'Roak BJ, Louvi A, et al. Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am J Hum Genet. 2008;82:165–173
  67. Strauss KA, Puffenberger EG, Huentelman MJ, et al. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med. 2006;354:1370–1377
  68. Vernes SC, Newbury DF, Abrahams BS, et al. A functional genetic link between distinct developmental language disorders. N Engl J Med. 2008;359:2337–2345
  69. Boyle ME, Berglund EO, Murai KK, Weber L, Peles E, Ranscht B. Contactin orchestrates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve. Neuron. 2001;30:385–397
  70. Abelson JF, Kwan KY, O'Roak BJ, et al. Sequence variants in SLITRK1 are associated with Tourette’s syndrome. Science. 2005;310:317–320
  71. Stillman AA, Krsnik Z, Sun J, et al. Developmentally regulated and evolutionarily conserved expression of SLITRK1 in brain circuits implicated in Tourette syndrome. J Comp Neurol. 2009;513:21–37
  72. Zuchner S, Cuccaro ML, Tran-Viet KN, et al. SLITRK1 mutations in trichotillomania. Mol Psychiatry. 2006;11:887–889
  73. O'Roak BJ, Morgan TM, Fishman DO, et al. Additional support for the association of SLITRK1 var321 and Tourette syndrome. Mol Psychiatry. 2010;[published on-line ahead of print Mar 30;]
  74. Miranda DM, Wigg K, Kabia EM, Feng Y, Sandor P, Barr CL. Association of SLITRK1 to Gilles de la Tourette Syndrome. Am J Med Genet B Neuropsychiatr Genet. 2009;150B:483–486
  75. Scharf JM, Moorjani P, Fagerness J, et al. Lack of association between SLITRK1var321 and Tourette syndrome in a large family-based sample. Neurology. 2008;70(Pt 2):1495–1496
  76. Millar JK, Wilson-Annan JC, Anderson S, et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet. 2000;9:1415–1423
  77. Blackwood DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ. Schizophrenia and affective disorders—cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet. 2001;69:428–433
  78. Camargo LM, Wang Q, Brandon NJ. What can we learn from the disrupted in schizophrenia 1 interactome: lessons for target identification and disease biology?. Novartis Found Symp. 2008;289:208–216discussion 216-221, 238-240
  79. Sebat J, Lakshmi B, Troge J, et al. Large-scale copy number polymorphism in the human genome. Science. 2004;305:525–528
  80. Iafrate AJ, Feuk L, Rivera MN, et al. Detection of large-scale variation in the human genome. Nat Genet. 2004;36:949–951
  81. Yu CE, Dawson G, Munson J, et al. Presence of large deletions in kindreds with autism. Am J Hum Genet. 2002;71:100–115
  82. Elia J, Gai X, Xie HM, et al. Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Mol Psychiatry. 2010;[published on-line ahead of print Jun 23, 2009;]
  83. Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K. A comprehensive review of genetic association studies. Genet Med. 2002;4:45–61
  84. Volkmar F, Cook E, Pomeroy J, Realmuto G, Tanguay P. Summary of the practice parameters for the assessment and treatment of children, adolescents, and adults with autism and other pervasive developmental disorders (American Academy of Child and Adolescent Psychiatry). J Am Acad Child Adolesc Psychiatry. 1999;38:1611–1616
  85. Filipek PA, Accardo PJ, Ashwal S, et al. Practice parameter: screening and diagnosis of autism: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society. Neurology. 2000;55:468–479
  86. Johnson CP, Myers SM. Identification and evaluation of children with autism spectrum disorders. Pediatrics. 2007;120:1183–1215
  87. Schaefer GB, Lutz RE. Diagnostic yield in the clinical genetic evaluation of autism spectrum disorders. Genet Med. 2006;8:549–556
  88. Lintas C, Persico AM. Autistic phenotypes and genetic testing: state-of-the-art for the clinical geneticist. J Med Genet. 2009;46:1–8
  89. Potocki L, Bi W, Treadwell-Deering D, et al. Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am J Hum Genet. 2007;80:633–649
  90. Korbel JO, Urban AE, Affourtit JP, et al. Paired-end mapping reveals extensive structural variation in the human genome. Science. 2007;318:420–426

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

 This article can be used to obtain continuing medical education (CME) category 1 credit at jaacap.org.

 This article was reviewed under and accepted by Associate Editor James J. Hudziak, M.D.

 This work was funded in part by the Yale Clinical and Translational Science Award UL1 RR024139 (to Dr. Hoffman), and T32MH18268 (to Dr. Hoffman).

 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.

 Disclosure: Drs. Hoffman and State report no biomedical financial interests or potential conflicts of interest.

PII: S0890-8567(10)00316-3

doi: 10.1016/j.jaac.2010.03.016

Journal of the American Academy of Child & Adolescent Psychiatry
Volume 49, Issue 8 , Pages 736-751 , August 2010