Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia

Key Points

  • Children with 22q11.2 deletion syndrome (22q11.2DS) show substantial impairments in several areas of attention. Spatial aspects of attention are likely to contribute to numerical impairments, and executive attention or cognitive control impairments may have a role in later psychosis.

  • Most but not all children with 22q11.2DS develop borderline to low average intellectual functioning abilities, with strengths tending to be in verbal domains and weaknesses in non-verbal domains.

  • Neural abnormalities seem to occur more in the midline of the brain and in subcortical as well as cortical regions.

  • Up to one-third of all individuals carrying the 22q11.2 deletion develop schizophrenia or schizoaffective disorder as defined strictly in the Diagnostic and Statistical Manual of Mental Disorders, although the risk factors that are predictive of the development of psychosis remain unclear and continue to be the focus of active investigation. 22q11.2 deletions account for up to 1–2% of schizophrenia cases and represent the only confirmed recurrent structural mutation responsible for introducing sporadic cases of schizophrenia to the population.

  • Work on genetically engineered animal models of 22q11.2DS has uncovered behavioural and cognitive alterations, as well as a number of affected neural processes (such as compromised dendritogenesis, synaptogenesis, neurogenesis and long-range connectivity) and molecular pathways (including abnormal brain microRNA biogenesis, palmitoylation of proteins and dopaminergic activity) that all have important roles in the observed cognitive and behavioural dysfunction.

  • Human genetic and animal model studies suggest that the combined effect of the imbalance of several genes in the 22q11.2 deletion determines the overall phenotype.

Abstract

Recent studies are beginning to paint a clear and consistent picture of the impairments in psychological and cognitive competencies that are associated with microdeletions in chromosome 22q11.2. These studies have highlighted a strong link between this genetic lesion and schizophrenia. Parallel studies in humans and animal models are starting to uncover the complex genetic and neural substrates altered by the microdeletion. In addition to offering a deeper understanding of the effects of this genetic lesion, these findings may guide analysis of other copy-number variants associated with cognitive dysfunction and psychiatric disorders.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Altered connectivity in children with 22q11.2 deletion syndrome.
Figure 2: Mouse models of the 22q11.2 microdeletion.
Figure 3: Changes in behaviour and brain connectivity exhibited by mouse models of the 22q11.2 microdeletion.
Figure 4: A framework for the pathogenesis and pathophysiology of 22q11.2 deletion syndrome.

Similar content being viewed by others

References

  1. Shprintzen, R. J. et al. A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo-cardio-facial syndrome. Cleft Palate J. 15, 56–62 (1978).

    CAS  PubMed  Google Scholar 

  2. DiGeorge, A. A new concept of the cellular basis of immunity. Disabil. Rehabil. 67, 907–908 (1965).

    Google Scholar 

  3. Robin, N. H. & Shprintzen, R. J. Defining the clinical spectrum of deletion. 22q11.2. J. Pediatr. 147, 90–96 (2005).

    Article  PubMed  Google Scholar 

  4. Kobrynski, L. J. & Sullivan, K. E. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet 370, 1443–1452 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Botto, L. D. et al. A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 112, 101–107 (2003).

    Article  PubMed  Google Scholar 

  6. Urban, A. E. et al. High-resolution mapping of DNA copy alterations in human chromosome 22 using high-density tiling oligonucleotide arrays. Proc. Natl Acad. Sci. USA 103, 4534–4539 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Edelmann, L., Pandita, R. K. & Morrow, B. E. Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio-facial syndrome. Am. J. Hum. Genet. 64, 1076–1086 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shaikh, T. H. et al. Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum. Mol. Genet. 9, 489–501 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Maynard, T. M. et al. A comprehensive analysis of 22q11 gene expression in the developing and adult brain. Proc. Natl Acad. Sci. USA 24, 14433–14438 (2003).

    Article  CAS  Google Scholar 

  10. Ryan, A. K. et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J. Med. Genet. 34, 798–804 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Carlson, C. et al. Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients. Am. J. Hum. Genet. 61, 620–629 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sullivan, K. E. The clinical, immunological, and molecular spectrum of chromosome 22q11.2 deletion syndrome and DiGeorge syndrome. Curr. Opin. Allergy Clin. Immunol. 4, 505–512 (2004).

    Article  PubMed  Google Scholar 

  13. Cook, E. H. Jr & Scherer, S. W. Copy-number variations associated with neuropsychiatric conditions. Nature 455, 919–923 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. De Smedt, B. et al. Mathematical disabilities in children with velo-cardio-facial syndrome. Neuropsychologia 45, 885–895 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Campbell, L. & Swillen, A. in Velo-Cardio-Facial Syndrome: A Model for Understanding Microdeletion Disorders (eds Murphy, K. C. & Scambler, P. J.) 147–164 (Cambridge Univ. Press, 2005).

    Book  Google Scholar 

  16. Wang, P. P. et al. Research on behavioral phenotypes: velocardiofacial syndrome (deletion 22q11.2). Dev. Med. Child Neurol. 42, 422–427 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Moss, E. M. et al. Psychoeducational profile of the 22q11.2 microdeletion: a complex pattern. J. Pediatrics 134, 193–198 (1999).

    Article  CAS  Google Scholar 

  18. Gerdes, M. et al. Cognitive and behavior profile of preschool children with chromosome 22q11.2 deletion. Am. J. Med. Genet. 85, 127–133 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Scherer, N. J., D'Antonio, L. L. & Kalbfleisch, J. H. Early speech and language development in children with velocardiofacial syndrome. Am. J. Med. Genet. 88, 714–723 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Solot, C. B. et al. Communication disorders in the 22Q11.2 microdeletion syndrome. J. Commun. Disord. 33, 187–203 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Solot, C. B. et al. Communication issues in 22q11.2 deletion syndrome: children at risk. Genet. Med. 3, 67–71 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Swillen, A. et al. Neuropsychological, learning and psychosocial profile of primary school aged children with the velo-cardio-facial syndrome (22q11 deletion): evidence for a nonverbal learning disability? Child Neuropsychol. 5, 230–241 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Woodin, M. et al. Neuropsychological profile of children and adolescents with the 22q11.2 microdeletion. Genet. Med. 3, 34–39 (2001). An early comprehensive review of the neuropsychological profile of school-aged children with 22q11.2DS.

    Article  CAS  PubMed  Google Scholar 

  24. Bearden, C. E. et al. The neurocognitive phenotype of the 22q11.2 deletion syndrome: selective deficit in visual-spatial memory. J. Clin. Exper. Neuropsychol. 23, 447–464 (2001).

    Article  CAS  Google Scholar 

  25. Lajiness-O'Neill, R. R. et al. Memory and learning in children with 22q11.2 deletion syndrome: evidence for ventral and dorsal stream disruption? Neuropsychol. Dev. Cogn. C Child Neuropsychol. 11, 55–71 (2005).

    Google Scholar 

  26. Sobin, C. et al. Neuropsychological characteristics of children with the 22q11 deletion syndrome: a descriptive analysis. Neuropsychol. Dev. Cogn. C Child Neuropsychol. 11, 39–53 (2005).

    Google Scholar 

  27. Sobin, C. et al. Networks of attention in children with the 22q11 deletion syndrome. Dev. Neuropsychol. 26, 611–626 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Simon, T. J. et al. Overlapping numerical cognition impairments in children with chromosome 22q11.2 deletion or Turner syndromes. Neuropsychologia 46, 82–94 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Cavanagh, P. in Cognitive Neuroscience of Attention (ed. Posner, M. I.) 13–28 (Guilford Press, New York, 2004).

    Google Scholar 

  30. Fan, J., McCandliss, B. D., Sommer, T., Raz, A. & Posner, M. I. Testing the efficiency and independence of attentional networks. J. Cogn. Neurosci. 14, 340–347 (2002).

    Article  PubMed  Google Scholar 

  31. Posner, M. I. & Petersen, S. E. The attention system of human brain. Ann. Rev. Neurosci. 13, 25–42 (1990).

    Article  CAS  PubMed  Google Scholar 

  32. Simon, T. J. et al. Volumetric, connective, and morphologic changes in the brains of children with chromosome 22q11.2 deletion syndrome: an integrative study. Neuroimage 25, 169–180 (2005).

    Article  PubMed  Google Scholar 

  33. Simon, T. J. et al. A multiple levels analysis of cognitive dysfunction and psychopathology associated with chromosome 22q11.2 deletion syndrome in children. Dev. Psychopathol. 17, 753–784 (2005). An integrative review of evidence from cognitive experimental studies, standardized measures, neuroimaging and genetics concerning children with 22q11.2DS.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Bish, J. P. et al. Domain specific attentional impairments in children with chromosome 22q11.2 deletion syndrome. Brain Cogn. 64, 265–273 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Corbetta, M. & Shulman, G. L. Control of goal-directed and stimulus-driven attention in the brain. Nature Rev. Neurosci. 3, 201–215 (2002).

    Article  CAS  Google Scholar 

  36. Simon, T. J. et al. Atypical cortical connectivity and visuospatial cognitive impairments are related in children with chromosome 22q11.2 deletion syndrome. Behav. Brain Funct. 4, 25 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Piazza, M., Giacomini, E., Le Bihan, D. & Dehaene, S. Single-trial classification of parallel pre-attentive and serial attentive processes using functional magnetic resonance imaging. Proc. Biol. Sci. 270, 1237–1245 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Sathian, K. et al. Neural evidence linking visual object enumeration and attention. J. Cogn. Neurosci. 11, 36–51 (1999).

    Article  CAS  PubMed  Google Scholar 

  39. Simon, T. J. & Vaishnavi, S. Subitizing and counting depend on different attentional mechanisms: evidence from visual enumeration in afterimages. Percept. Psychophys. 58, 915–926 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Debbané, M., Glaser, B., Gex-Fabry, M. & Eliez, S. Temporal perception in velo-cardio-facial syndrome. Neuropsychologia 43, 1754–1762 (2005).

    Article  PubMed  Google Scholar 

  41. Ansari, D., Lyons, I. M., van Eimeren, L. & Xu, F. Linking visual attention and number processing in the brain: the role of the temporo-parietal junction in small and large symbolic and nonsymbolic number comparison. J. Cogn. Neurosci. 19, 1845–1853 (2007).

    Article  PubMed  Google Scholar 

  42. Molko, N. et al. Functional and structural alterations of the intraparietal sulcus in a developmental dyscalculia of genetic origin. Neuron 40, 847–858 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Shuman, M. & Kanwisher, N. Numerical magnitude in the human parietal lobe; tests of representational generality and domain specificity. Neuron 44, 557–569 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Zorzi, M., Priftis, K., Meneghello, F., Marenzi, R. & Umiltà, C. The spatial representation of numerical and non-numerical sequences: evidence from neglect. Neuropsychologia 44, 1061–1067 (2006).

    Article  PubMed  Google Scholar 

  45. Bish, J. P. et al. Maladaptive conflict monitoring as evidence for executive dysfunction in children with chromosome 22q11.2 deletion syndrome. Dev. Sci. 8, 36–43 (2005).

    Article  PubMed  Google Scholar 

  46. Gratton, G., Coles, M. G. & Donchin, E. Optimizing the use of information: strategic control of activation of responses. J. Exp. Psychol. 121, 480–506 (1992).

    Article  CAS  Google Scholar 

  47. Takarae, Y., Schmidt, L., Tassone, F. & Simon, T. J. Catechol-O-methyltransferase polymorphism modulates cognitive control in children with chromosome 22q11.2 deletion syndrome. Cogn. Affect. Behav. Neurosci. 9, 83–90 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Sobin, C., Kiley-Brabeck, K. & Karayiorgou, M. Lower prepulse inhibition in children with the 22q11 deletion syndrome. Am. J. Psychiatry 162, 1090–1099 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Baker, K. et al. COMT Val108/158Met modifies mismatch negativity and cognitive function in 22q11 deletion syndrome. Biol. Psychiatry 58, 23–31 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Cheour, M. et al. The first neurophysiological evidence for cognitive brain dysfunctions in children with CATCH. Neuroreport 8, 1785–1787 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Kates, W. et al. The neural correlates of non-spatial working memory in velocardiofacial syndrome (22q11.2 deletion syndrome). Neuropsychologia 45, 2863–2873 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  52. van Amelsvoort, T. et al. Cognitive deficits associated with schizophrenia in velo-cardio-facial syndrome. Schizophr. Res. 70, 223–232 (2004).

    Article  PubMed  Google Scholar 

  53. Karayiorgou, M. et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc. Natl Acad. Sci. USA 92, 7612–7616 (1995). A seminal paper that provided the first evidence to support the importance of CNVs in schizophrenia vulnerability.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Xu, B. et al. Strong association of de novo copy number mutations with sporadic schizophrenia. Nature Genet. 40, 880–885 (2008). A systematic study that confirms the extensive contribution of de novo CNVs, such as the 22q11.2 microdeletions, in schizophrenia vulnerability.

    Article  CAS  PubMed  Google Scholar 

  55. Arnold, P. D. et al. Velo-cardio-facial syndrome: implications of microdeletion 22q11 for schizophrenia and mood disorders. Am. J. Med. Genet. 105, 354–362 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Feinstein, C. et al. Psychiatric disorders and behavioral problems in children with velocardiofacial syndrome: usefulness as phenotypic indicators of schizophrenia risk. Biol. Psychiatry 51, 312–318 (2002).

    Article  PubMed  Google Scholar 

  57. Antshel, K. M. et al. ADHD, major depressive disorder, and simple phobias are prevalent psychiatric conditions in youth with velocardiofacial syndrome. J. Am. Acad. Child Adolesc. Psychiatry 45, 596–603 (2006).

    Article  PubMed  Google Scholar 

  58. Antshel, K. M. et al. Autistic spectrum disorders in velo-cardiofacial syndrome (22q11.2 deletion). J. Autism Dev. Disord. 37, 1776–1786 (2007).

    Article  PubMed  Google Scholar 

  59. Vorstman, J. A. et al. The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms. J. Am. Acad. Child Adolesc. Psychiatry 45, 1104–1113 (2006).

    Article  PubMed  Google Scholar 

  60. Flint, J. & Yule W. Behavioural Phenotypes, Child and Adolescent Psychiatry 3rd edn (eds Rutter, M., Taylor, E. & Hersov, L.) 666–687 (Blackwell Scientific, Oxford, 1994).

    Google Scholar 

  61. Flint, J. Behavioral phenotypes: conceptual and methodological issues. Am. J. Med. Genet. 81, 235–240 (1998).

    Article  CAS  PubMed  Google Scholar 

  62. Ogilvie, C. M., Moore, J., Daker, M., Palferman, S. & Docherty, Z. Chromosome 22q11 deletions are not found in autistic patients identified using strict diagnostic criteria. IMGSAC. International Molecular Genetics Study of Autism Consortium. Am. J. Med. Genet. 96, 15–17 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Elia, J. et al. Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Mol. Psychiatry 23 Jun 2009 (doi: 10.1038/mp.2009.57).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Glessner, J. T. et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459, 569–573 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Eliez, S. Autism in children with 22Q11.2 deletion syndrome. J. Am. Acad. Child Adolesc. Psychiatry 46, 433–434 (2007).

    Article  PubMed  Google Scholar 

  66. Pulver, A. E. et al. Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. J. Nerv. Ment. Dis. 182, 476–478 (1994).

    Article  CAS  PubMed  Google Scholar 

  67. Murphy, K. C., Jones, L. A. & Owen, M. J. High rates of schizophrenia in adults with velocardio-facial syndrome. Arch. Gen. Psychiatry 56, 940–945 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Gothelf, D. et al. Risk factors for the emergence of psychotic disorders in adolescents with 22q11.2 deletion syndrome. Am. J. Psychiatry 164, 663–669 (2007).

    Article  PubMed  Google Scholar 

  69. Green, T. et al. Psychiatric disorders and intellectual functioning throughout development in velocardiofacial (22q11.2 deletion) syndrome. J. Am. Acad. Child Adolesc. Psychiatry 48, 1060–1068 (2009).

    Article  PubMed  Google Scholar 

  70. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th edn (American Psychiatric Publishing, Washington, DC, 1994).

  71. International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237–241 (2008). A comprehensive large-scale study that confirmed the role of 22q11.2 microdeletions in schizophrenia and identified additional candidate pathogenic CNVs.

  72. Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Bassett, A. S. et al. The schizophrenia phenotype in 22q11 deletion syndrome. Am. J. Psychiatry 160, 1580–1586 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Bassett, A. S. et al. 22q11 deletion syndrome in adults with schizophrenia. Am. J. Med. Genet. 81, 328–337 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Johnson, M. H., Halit, H., Grice, S. J. & Karmiloff-Smith, A. Neuroimaging of typical and atypical development: a perspective from multiple levels of analysis. Dev. Psychopathol. 14, 521–536 (2002). An important review of special interpretive assumptions as they relate to neuroimaging studies of typically and, more importantly, atypically developing children.

    Article  PubMed  Google Scholar 

  76. Campbell, L. E. et al. Brain and behaviour in children with 22q11.2 deletion syndrome: a volumetric and voxel-based morphometry MRI study. Brain 129, 1218–1228 (2006).

    Article  PubMed  Google Scholar 

  77. Eliez, S. et al. Children and adolescents with velocardiofacial syndrome: a volumetric study. Am. J. Psychiatry 3, 409–415 (2000).

    Article  Google Scholar 

  78. Kates, W. R. et al. Regional cortical white matter reductions in velocardiofacial syndrome: a volumetric MRI analysis. Biol. Psychiatry 49, 677–684 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Kates, W. R. et al. Frontal and caudate alterations in velocardiofacial syndrome (deletion at chromosome 22q11.2). J. Child Neurol. 5, 337–342 (2004).

    Article  Google Scholar 

  80. Simon, T. J. et al. Visuospatial and numerical cognitive deficits in children with chromosome 22q11.2 deletion syndrome. Cortex 2, 145–155 (2005).

    Article  Google Scholar 

  81. Tan, G. et al. Meta-analysis of magnetic resonance imaging studies in chromosome 22q11.2 deletion syndrome (velocardiofacial syndrome). Schizophr. Res. 115, 173–181 (2009). An extensive review of structural neuroimaging findings in 22q11.2DS.

    Article  PubMed  Google Scholar 

  82. Bearden, C. et al. Mapping cortical thickness in children with 22q11.2 deletions. Cereb. Cortex 8, 1889–1898 (2006).

    Google Scholar 

  83. Bearden, C. E. et al. Alterations in midline cortical thickness and gyrification patterns mapped in children with 22q11.2 deletions. Cereb. Cortex 19, 115–126 (2009).

    Article  PubMed  Google Scholar 

  84. Schaer, M. et al. Abnormal patterns of cortical gyrification in velo-cardio-facial syndrome (deletion 22q11.2): an MRI study. Psychiatry Res. 146, 1–11 (2006).

    Article  PubMed  Google Scholar 

  85. Schaer, M. et al. Congenital heart disease affects local gyrification in 22q11.2 deletion syndrome. Dev. Med. Child Neurol. 51, 746–753 (2009).

    Article  PubMed  Google Scholar 

  86. Van Essen, D. C. et al. Symmetry of cortical folding abnormalities in Williams syndrome revealed by surface-based analyses. J. Neurosci. 26, 5470–5483 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Barnea-Goraly, N. et al. Investigation of white matter structure in velocardiofacial syndrome: a diffusion tensor imaging study. Am. J. Psychiatry 160, 1863–1869 (2003).

    Article  PubMed  Google Scholar 

  88. Machado, A. M. et al. Corpus callosum morphology and ventricular size in chromosome 22q11.2 deletion syndrome. Brain Res. 1131, 197–210 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Barnea-Goraly, N. et al. Arithmetic ability and parietal alterations: a diffusion tensor imaging study in velocardiofacial syndrome. Brain Res. Cogn. Brain Res. 25, 735–740 (2005).

    Article  PubMed  Google Scholar 

  90. Eliez, S. et al. Functional brain imaging study of mathematical reasoning abilities in velocardiofacial syndrome (del22q11.2). Genet. Med. 3, 49–55 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Gothelf, D. et al. Abnormal cortical activation during response inhibition in 22q11.2 deletion syndrome. Hum. Brain Mapp. 28, 533–542 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  92. van Amelsvoort, T. et al. Brain anatomy in adults with velocardiofacial syndrome with and without schizophrenia: preliminary results of a structural magnetic resonance imaging study. Arch. Gen. Psychiatry 61, 1085–1096 (2004).

    Article  PubMed  Google Scholar 

  93. Chow, E. W. et al. Structural brain abnormalities in patients with schizophrenia and 22q11 deletion syndrome. Biol. Psychiatry 51, 208–215 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Chow, E. W., Watson, M., Young, D. A. & Bassett, A. S. Neurocognitive profile in 22q11 deletion syndrome and schizophrenia. Schizophr. Res. 87, 270–278 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Gothelf, D. et al. COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nature Neurosci. 8, 1500–1502 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Raux, G. et al. Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome. Hum. Mol. Genet. 16, 83–91 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Vorstman, J. A. et al. Proline affects brain function in 22q11DS children with the low activity COMT158 allele. Neuropsychopharmacology 34, 739–746 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Taddei, I. et al. Genetic factors are major determinants of phenotypic variability in a mouse model of the DiGeorge/del22q11 syndromes. Proc. Natl Acad. Sci. USA 98, 11428–11431 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Karayiorgou, M. & Gogos, J. A. The molecular genetics of the 22q11-associated schizophrenia. Brain Res. Mol. Brain Res. 132, 95–104 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Arinami, T. Analyses of the associations between the genes of 22q11 deletion syndrome and schizophrenia. J. Hum. Genet. 51, 1037–1045 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. Mukai, J. et al. Evidence that the gene encoding ZDHHC8 contributes to the risk of schizophrenia. Nature Genet. 36, 725–731 (2004).

    Article  CAS  PubMed  Google Scholar 

  102. Liu, H. et al. Genetic variation in the 22q11 locus and susceptibility to schizophrenia. Proc. Natl Acad. Sci. USA 26, 16859–16864 (2002).

    Article  CAS  Google Scholar 

  103. Liu, H. et al. Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc. Natl Acad. Sci. USA 99, 3717–3722 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Karayiorgou, M. et al. Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder. Proc. Natl Acad. Sci. USA 94, 4572–4575 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Karayiorgou, M. et al. Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder. Biol. Psychiatry 45, 1178–1189 (1999).

    Article  CAS  PubMed  Google Scholar 

  106. Pooley, E. C., Fineberg, N. & Harrison, P. J. The met158 allele of catechol-O-methyltransferase (COMT) is associated with obsessive-compulsive disorder in men: case–control study and meta-analysis. Mol. Psychiatry 12, 556–561 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. Williams, N. M. et al. Strong evidence that GNB1L is associated with schizophrenia. Hum. Mol. Genet. 17, 555–566 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Goldstein, D. B. Common genetic variation and human traits. N. Engl. J. Med. 360, 1696–1698 (2009).

    Article  CAS  PubMed  Google Scholar 

  109. Arguello, P. A. & Gogos, J. A. Modeling madness in mice: one piece at a time. Neuron 52, 179–196 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Wise, S. P. Forward frontal fields: phylogeny and fundamental function. Trends Neurosci. 31, 599–608 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Meyer-Lindenberg, A. S. et al. Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia. Arch. Gen. Psychiatry 62, 379–386 (2005).

    Article  PubMed  Google Scholar 

  112. Lawrie, S. M. et al. Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biol. Psychiatry 51, 1008–1011 (2002).

    Article  PubMed  Google Scholar 

  113. Ford, J. M., Mathalon, D. H., Whitfield, S., Faustman, W. O. & Roth, W. T. Reduced communication between frontal and temporal lobes during talking in schizophrenia. Biol. Psychiatry 51, 485–492 (2002).

    PubMed  Google Scholar 

  114. Stark, K. L. et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nature Genet. 40, 751–760 (2008). This paper provided compelling evidence that the 22q11.2 microdeletion results in abnormal processing of brain miRNAs, which results in altered neuronal connectivity, behaviour and cognition in mice, including deficits in WM.

    Article  CAS  PubMed  Google Scholar 

  115. Ambros, V. The functions of animal microRNAs. Nature 431, 350–355 (2004).

    Article  CAS  PubMed  Google Scholar 

  116. Tomari, Y. & Zamore, P. D. MicroRNA biogenesis: drosha can't cut it without a partner. Curr. Biol. 15, R61–R64 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Hornstein, E. & Shomron, N. Canalization of development by microRNAs. Nature Genet. 38, S20–S24 (2006).

    Article  CAS  Google Scholar 

  118. Mukai, J. et al. Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion. Nature Neurosci. 11, 1302–1310 (2008). This paper provided evidence that the 22q11.2 microdeletion results in impaired development of dendrites, dendritic spines and excitatory synapses, in part due to abnormal palmitoylation of neuronal proteins.

    Article  CAS  PubMed  Google Scholar 

  119. Yuste, R. & Tank, D. W. Dendritic integration in mammalian neurons, a century after Cajal. Neuron 16, 701–716 (1996).

    Article  CAS  PubMed  Google Scholar 

  120. Mainen, Z. F. & Sejnowski, T. J. Influence of dendritic structure on firing pattern in model neocortical neurons. Nature 382, 363–366 (1996).

    Article  CAS  PubMed  Google Scholar 

  121. Meechan, D. W., Tucker, E. S., Maynard, T. M. & LaMantia, A. S. Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome. Proc. Natl Acad. Sci. USA 106, 16434–16445 (2009). This paper provided evidence that diminished dosage of 22q11.2 genes subtly compromises neurogenesis and subsequent neuronal differentiation in the cerebral cortex.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Kosik, K. S. The neuronal microRNA system. Nature Rev. Neurosci. 7, 911–920 (2006).

    Article  CAS  Google Scholar 

  123. Fiore, R. et al. Mef2-mediated transcription of the miR379–410 cluster regulates activity-dependent dendritogenesis by fine-tuning Pumilio2 protein levels. EMBO J. 28, 697–710 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Schratt, G. M. et al. A brain-specific microRNA regulates dendritic spine development. Nature 439, 283–289 (2006); erratum in 441, 902 (2006).

    Article  CAS  PubMed  Google Scholar 

  125. Fukata, M., Fukata, Y., Adesnik, H., Nicoll, R. A. & Bredt, D. S. Identification of PSD-95 palmitoylating enzymes. Neuron 44, 987–996 (2004).

    Article  CAS  PubMed  Google Scholar 

  126. Mitchell, D. A., Vasudevan, A., Linder, M. E. & Deschenes, R. J. Protein palmitoylation by a family of DHHC protein S-acyltransferases. J. Lipid Res. 47, 1118–1127 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Ohno, Y., Kihara, A., Sano, T. & Igarashi, Y. Intracellular localization and tissue-specific distribution of human and yeast DHHC cysteine-rich domain-containing proteins. Biochim. Biophys. Acta 1761, 474–483 (2006).

    Article  CAS  PubMed  Google Scholar 

  128. Maynard, T. M. et al. Mitochondrial localization and function of a subset of 22q11 deletion syndrome candidate genes. Mol. Cell. Neurosci. 39, 439–451 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. El-Husseini, A. E. D. & Bredt, D. S. Protein palmitoylation: a regulator of neuronal development and function. Nature Rev. Neurosci. 3, 791–802 (2002).

    Article  CAS  Google Scholar 

  130. Kang, R. et al. Neural palmitoyl-proteomics reveals dynamic synaptic palmitoylation. Nature 456, 904–909 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Hsu, R. et al. Nogo receptor 1 (RTN4R) as a candidate gene for schizophrenia: analysis using human and mouse genetic approaches. PLoS ONE 2, e1234 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Tsang, C. W. et al. Superfluous role of mammalian septins 3 and 5 in neuronal development and synaptic transmission. Mol. Cell. Biol. 28, 7012–7029 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Su, Q., Mochida, S., Tian, J. H., Mehta, R. & Shen, Z. H. SNAP-29: a general SNARE protein that inhibits SNARE disassembly and is implicated in synaptic transmission. Proc. Natl Acad. Sci. USA 98, 14038–14043 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Park, T. J. & Curran, T. Crk and Crk-like play essential overlapping roles downstream of disabled-1 in the Reelin pathway. J. Neurosci. 28, 13551–13562 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Sprecher, E. et al. A mutation in SNAP29, coding for a SNARE protein involved in intracellular trafficking, causes a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma. Am. J. Hum. Genet. 77, 242–251 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Jurata, L. W. et al. Altered expression of hippocampal dentate granule neuron genes in a mouse model of human 22q11 deletion syndrome. Schizophr. Res. 88, 251–259 (2006).

    Article  PubMed  Google Scholar 

  137. Yavich, L., Forsberg, M. M., Karayiorgou, M., Gogos, J. A. & Männistö, P. T. Site-specific role of catechol-O-methyltransferase in dopamine overflow within prefrontal cortex and dorsal striatum. J. Neurosci. 27, 10196–10209 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Huotari, M. et al. Brain catecholamine metabolism in catechol-O-methyltransferase (COMT)-deficient mice. Eur. J. Neurosci. 15, 246–256 (2002).

    Article  PubMed  Google Scholar 

  139. Huotari, M., García-Horsman, J. A., Karayiorgou, M., Gogos, J. A. & Männistö, P. T. D-Amphetamine responses in catechol-O-methyltransferase (COMT) disrupted mice. Psychopharmacology (Berlin) 172, 1–10 (2004).

    Article  CAS  Google Scholar 

  140. Hayward, D. C. et al. The sluggish-A gene of Drosophila melanogaster is expressed in the nervous system and encodes proline oxidase, a mitochondrial enzyme involved in glutamate biosynthesis. Proc. Natl Acad. Sci. USA 90, 2979–2983 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Goodman, B. K., Rutberg, J., Lin, W. W., Pulver, A. E. & Thomas, G. H. Hyperprolinaemia in patients with deletion (22)(q11.2) syndrome. J. Inherit. Metab. Dis. 23, 847–848 (2000).

    Article  CAS  PubMed  Google Scholar 

  142. Jacquet, H. et al. The severe form of type I hyperprolinaemia results from homozygous inactivation of the PRODH gene. J. Med. Genet. 40, e7 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Jacquet, H. et al. PRODH mutations and hyperprolinemia in a subset of schizophrenic patients. Hum. Mol. Genet. 11, 2243–2249 (2002).

    Article  CAS  PubMed  Google Scholar 

  144. Jacquet, H. et al. Hyperprolinemia is a risk factor for schizoaffective disorder. Mol. Psychiatry 10, 479–485 (2005).

    Article  CAS  PubMed  Google Scholar 

  145. Gogos, J. A. et al. The gene encoding proline dehydrogenase modulates sensorimotor gating in mice. Nature Genet. 21, 434–439 (1999).

    Article  CAS  PubMed  Google Scholar 

  146. Paterlini, M. et al. Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. Nature Neurosci. 8, 1586–1594 (2005). This paper and reference 96 provided the first demonstration of an epistatic interaction between two candidate schizophrenia risk genes in the 22q11.2 locus and showed the power of iterative human genetic and animal model studies for dissecting the genetic and neural substrates of the 22q11.2DS.

    Article  CAS  PubMed  Google Scholar 

  147. Arguello, P. A. & Gogos, J. A. Cognition in mouse models of schizophrenia susceptibility genes. Schizophr. Bull. 36, 289–300 (2010).

    Article  PubMed  Google Scholar 

  148. Paylor, R. et al. Mice deleted for the DiGeorge/velocardiofacial syndrome region show abnormal sensorimotor gating and learning and memory impairments. Hum. Mol. Genet. 10, 2645–2650 (2001).

    Article  CAS  PubMed  Google Scholar 

  149. Kimber, W. L. et al. Deletion of 150 kb in the minimal DiGeorge/velocardiofacial syndrome critical region in mouse. Hum. Mol. Genet. 8, 2229–2237 (1999).

    Article  CAS  PubMed  Google Scholar 

  150. Gogos, J. A. et al. Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc. Natl Acad. Sci. USA 95, 9991–9996 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Papaleo, F. et al. Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice. J. Neurosci. 28, 8709–8723 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Babovic, D. et al. Phenotypic characterization of cognition and social behavior in mice with heterozygous versus homozygous deletion of catechol-O-methyltransferase. Neuroscience 155, 1021–1029 (2008).

    Article  CAS  PubMed  Google Scholar 

  153. Long, J. M. et al. Behavior of mice with mutations in the conserved region deleted in velocardiofacial/DiGeorge syndrome. Neurogenetics 7, 247–257 (2006).

    Article  PubMed  Google Scholar 

  154. Paylor, R. et al. Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome. Proc. Natl Acad. Sci. USA 103, 7729–7734 (2006). This paper described the first traditional deletion-mapping approach to dissect genotype–phenotype relationships in the 22q11.2 locus.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Nitta, T. et al. Size-selective loosening of the blood–brain barrier in claudin-5-deficient mice. J. Cell Biol. 161, 653–660 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Steriade, M., Gloor, P., Llinas, R. R., Lopes de Silva, F. H. & Mesulam, M. M. Report of IFCN Committee on Basic Mechanisms. Basic mechanisms of cerebral rhythmic activities. Electroencephalogr. Clin. Neurophysiol. 76, 481–508 (1990).

    Article  CAS  PubMed  Google Scholar 

  157. Singer, W. Neuronal synchrony: a versatile code for the definition of relations? Neuron 24, 49–65 (1999).

    Article  CAS  PubMed  Google Scholar 

  158. Jones, M. W. & Wilson, M. A. Theta rhythms coordinate hippocampal–prefrontal interactions in a spatial memory task. PLoS Biol. 3, e402 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Sigurdsson, T., Stark, K. L., Karayiorgou, M., Gogos, J. A. & Gordon, J. A. Impaired hippocampal–prefrontal synchrony in a genetic mouse model of schizophrenia. Nature 464, 763–767 (2010). Building on the findings of reference 114, this paper provides compelling evidence that impaired long-range connectivity and synchrony of neural activity is one consequence of the 22q11.2 deletion and could be a fundamental component of the pathophysiology underlying schizophrenia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Bertolino, A. et al. Prefrontal–hippocampal coupling during memory processing is modulated by COMT val158met genotype. Biol. Psychiatry 60, 1250–1258 (2006).

    Article  CAS  PubMed  Google Scholar 

  161. Esslinger, C. et al. Neural mechanisms of a genome-wide supported psychosis variant. Science 324, 605 (2009).

    Article  CAS  PubMed  Google Scholar 

  162. Bodmer, W. & Bonilla, C. Common and rare variants in multifactorial susceptibility to common diseases. Nature Genet. 40, 695–701 (2008).

    Article  CAS  PubMed  Google Scholar 

  163. Van Veen, V. & Carter, C. S. The anterior cingulated as a conflict monitor: fMRI and ERP studies. Physiol. Behav. 77, 477–482 (2002).

    Article  CAS  PubMed  Google Scholar 

  164. Devrim-Uçok, M., Keskin-Ergen, H. Y. & Uçok, A. Mismatch negativity at acute and post-acute phases of first-episode schizophrenia. Eur. Arch. Psychiatry Clin. Neurosci. 258, 179–185 (2008).

    Article  PubMed  Google Scholar 

  165. Carroll, C. A., Boggs, J., O'Donnell, B. F., Shekhar, A. & Hetrick, W. P. Temporal processing dysfunction in schizophrenia. Brain Cogn. 67, 150–161 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Elvevåg, B. & Goldberg, T. E. Cognitive impairment in schizophrenia is the core of the disorder. Crit. Rev. Neurobiol. 14, 1–21 (2000).

    Article  PubMed  Google Scholar 

  167. Debbané, M., Glaser, B., David, M. K., Feinstein, C. & Eliez, S. Psychotic symptoms in children and adolescents with 22q11.2 deletion syndrome: neuropsychological and behavioral implications. Schizophr. Res. 84, 187–193 (2006).

    Article  PubMed  Google Scholar 

  168. Sugama, S. et al. Morphometry of the head of the caudate nucleus in patients with velocardiofacial syndrome (del 22q11.2). Acta Paediatr. 89, 546–549 (2000).

    Article  CAS  PubMed  Google Scholar 

  169. Eliez, S. et al. Increased basal ganglia volumes in velo-cardio-facial syndrome (deletion 22q11.2). Biol. Psychiatry 52, 68–70 (2002).

    Article  PubMed  Google Scholar 

  170. Eliez, S. et al. A quantitative MRI study of posterior fossa development in velocardiofacial syndrome. Biol. Psychiatry 49, 540–546 (2001).

    Article  CAS  PubMed  Google Scholar 

  171. Bish, J. P. et al. Specific cerebellar reductions in children with chromosome 22q11.2 deletion syndrome. Neurosci. Lett. 399, 245–248 (2006).

    Article  CAS  PubMed  Google Scholar 

  172. Fanselow, M. S. & Poulos, A. M. The neuroscience of mammalian associative learning. Annu Rev. Psychol. 56, 207–234 (2005).

    Article  PubMed  Google Scholar 

  173. Aultman, J. M. & Moghaddam, B. Distinct contributions of glutamate and dopamine receptors to temporal aspects of rodent working memory using a clinically relevant task. Psychopharmacology (Berlin) 153, 353–364 (2001).

    Article  CAS  Google Scholar 

  174. Lee, I. & Kesner, R. P. Time-dependent relationship between the dorsal hippocampus and the prefrontal cortex in spatial memory. J. Neurosci. 23, 1517–1523 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Goldberg, M. C., Maurer, D. & Lewis, T. L. Developmental changes in attention: the effects of endogenous cueing and of distractors. Dev. Sci. 4, 209–219 (2001).

    Article  Google Scholar 

  176. Posner, M. I. et al. Effects of parietal injury on covert orienting of attention. J. Neurosci. 4, 1863–1874 (1984).

    Article  CAS  Google Scholar 

  177. Rueda, M. R. et al. Development of attentional networks in childhood. Neuropsychologia 42, 1029–1040 (2004).

    Article  PubMed  Google Scholar 

  178. Egly, R., Driver, J. & Rafal, R. D. Shifting visual attention between objects and locations: evidence from normal and parietal lesion subjects. J. Exp. Psychol. Gen. 123, 161–177 (1994).

    Article  CAS  PubMed  Google Scholar 

  179. Klein, R. M. Inhibition of return. Trends Cogn. Sci. 4, 138–147 (2000).

    Article  CAS  PubMed  Google Scholar 

  180. MacPherson, A. C., Klein, R. M. & Moore, C. Inhibition of return in children and adolescents. J. Exp. Child Psychol. 85, 337–351 (2003).

    Article  PubMed  Google Scholar 

  181. Chi, M. T. & Klahr, D. Span and rate of apprehension in children and adults. J. Exp. Child Psychol. 19, 434–439 (1975).

    Article  CAS  PubMed  Google Scholar 

  182. Trick, L. M. & Pylyshyn, Z. W. Why are small and large numbers enumerated differently? A limited-capacity preattentive stage in vision. Psychol. Rev. 101, 80–102 (1994).

    Article  CAS  PubMed  Google Scholar 

  183. Ansari, D. & Karmiloff-Smith, A. Atypical trajectories of number development: a neuroconstructivist perspective. Trends Cogn. Sci. 6, 511–516 (2002).

    Article  PubMed  Google Scholar 

  184. Dehaene, S. & Cohen, L. Towards an anatomical and functional model of number processing. Math. Cogn. 1, 83–120 (1995).

    Google Scholar 

  185. Ornitz, E. M., Guthrie, D., Kaplan, A. R., Lane, S. J. & Norman, R. J. Maturation of startle modulation. Psychophysiology 23, 624–634 (1986).

    Article  CAS  PubMed  Google Scholar 

  186. Ahmmed, A. U., Clarke, E. M. & Adams, C. Mismatch negativity and frequency representational width in children with specific language impairment. Dev. Med. Child Neurol. 50, 938–944 (2008).

    Article  PubMed  Google Scholar 

  187. Näätänen, R. Mismatch negativity (MMN): perspectives for application. Int. J. Psychophysiol. 37, 3–10 (2000).

    Article  PubMed  Google Scholar 

  188. Casey, B. J. et al. Activation of prefrontal cortex in children during a nonspatial working memory task with functional MRI. Neuroimage 2, 221–229 (1995).

    Article  CAS  PubMed  Google Scholar 

  189. Durston, S., Thomas, K. M., Worden, M. S., Yang, Y. & Casey, B. J. The effect of preceding context on inhibition: an event-related fMRI study. Neuroimage 16, 449–453 (2002).

    Article  CAS  PubMed  Google Scholar 

  190. Schulz, K. P. et al. Response inhibition in adolescents diagnosed with attention deficit hyperactivity disorder during childhood: an event-related FMRI study. Am. J. Psychiatry 161, 1650–1657 (2004).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge grant support for their work from the US National Institutes of Health (grant R01MH67068 to M.K. and J.A.G. and grant R01HD42974 to T.J.S.). J.A.G. also gratefully acknowledges support from the Simons Foundation and M.K. from the McKnight and March of Dimes Foundations. The authors wish to thank A. Arguello for help with creating figures 2,3 and 4, B. Xu for help with Supplementary information S1 (table) and Supplementary information S3 (figure) and S. Srivastava for help with box 3 and figure 1. The authors also thank A. Arguello, L. Drew, B. Xu and other members of their laboratories for comments and critical feedback.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Maria Karayiorgou.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (table)

RefSeq genes located in the most common 3-Mb 22q11.2 microdeletiona (PDF 86 kb)

Supplementary information S2 (table)

DTI results from children with 22q11.2DS (PDF 84 kb)

Supplementary information S3 (figure)

miRNA dysregulation and altered gene expression in 22q11.2 animal models. (PDF 397 kb)

Related links

Related links

DATABASES

miRBase 

mHir-185

mir-649

OMIM

22q11.2DS

FURTHER INFORMATION

Maria Karayiorgou and Joseph A. Gogos' homepage

Tony J. Simon's homepage

Schizophrenia Research Forum

Glossary

Microdeletion

A submicroscopic loss of a segment of DNA of varying size, typically several kilobases long.

Breakpoint

A specific site of chromosomal breakage associated with a chromosomal abnormality.

Full scale IQ

A standardized composite measure of global intellectual functioning generated from scores in specific domains, such as verbal, perceptual, memory and speeded functions. Typically the median age-adjusted score is 100 ± 15 points.

Attention

A cognitive process that is mainly thought to be involved in selectively processing or focusing on one aspect of the environment at the expense of others. Several types of attention are thought to exist, including focused, sustained and divided attention, each of which seems to depend on different cognitive, neural and neurotransmitter systems.

Executive function

Also referred to as 'cognitive control', this is a broad category of cognitive functions that are generally associated in typical humans with the prefrontal cortex. Executive functions are thought to modulate or control the use of other cognitive resources and include planning, problem solving, error monitoring, decision making and the use of working memory.

Prepulse inhibition

A reduction in the magnitude of the startle reflex that occurs when an organism is presented with a non-startling stimulus (a prepulse) before being presented with the startling stimulus. Deficits in prepulse inhibition have been observed in patients with schizophrenia as well as in patients with other psychiatric and neurological disorders.

Mismatch negativity

A component of the electro-encephalographic (EEG) brain response that is typically generated 150–250 ms after an unusual stimulus is detected in a sequence of similar stimuli.

Diffusion tensor imaging

An MRI imaging technique that takes advantage of the restricted diffusion of water through myelinated nerve fibres in the brain to map the anatomical connectivity among brain areas.

Genetic modifiers

Genetic variation in (cis) or outside (trans) a gene or genetic locus that alters the phenotypic expression of the gene.

Oligogenic

A phenotypic trait produced by two or more (but only a few) genes working together.

Next-generation sequencing

High-throughput parallel sequencing of several megabases of DNA.

Haploinsufficiency

The situation in which one copy of a gene is incapable of providing sufficient protein production to ensure normal function.

Endophenotype

A state-independent biomarker or cognitive marker of an illness (present whether or not the illness is active) that is heritable and present in unaffected relatives of subjects that have the illness.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Karayiorgou, M., Simon, T. & Gogos, J. 22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia. Nat Rev Neurosci 11, 402–416 (2010). https://doi.org/10.1038/nrn2841

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn2841

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing