Schizophrenia and 22q11.2 Deletion Syndrome

Frederick Sundram, Royal College of Surgeons in Ireland, Dublin, Ireland
Kieran C Murphy, Royal College of Surgeons in Ireland, Dublin, Ireland

Published online: January 2011

DOI: 10.1002/9780470015902.a0005229.pub2

22q11.2 deletion syndrome (22q11.2DS), also known as velocardiofacial syndrome, is the most frequent known interstitial deletion found in humans. It is associated with high rates of psychiatric disorder and, in particular, schizophrenia (approximately 30%) and schizophrenia-spectrum disorders. The 22q11.2 region is rich in genes coding for brain development, and consequently, deletion of 22q11.2 provides a useful neurodevelopmental model for understanding the evolution of psychotic disorders in both 22q11.2DS and the nondeleted general population. 22q11.2DS is also associated with significant structural and functional neuroanatomical abnormalities, which underlie the high rates of psychosis seen in affected individuals. Further research is currently underway to determine the cognitive, genetic and neuroanatomical correlates of psychosis seen in the disorder.

Key Concepts:

  • 22q11.2DS provides for a genetic and neurodevelopmental model for understanding psychotic disorder seen not only with the syndrome but can also be extrapolated to the general nondeleted population.
  • Although 22q11.2DS is associated with marked phenotypic variability, psychiatric disorder and, in particular, schizophrenia-spectrum disorders occur in approximately 30% of deleted individuals.
  • Schizophrenia-spectrum disorders arise as prodromal or subthreshold psychotic symptoms during childhood and adolescence followed by subsequent expression during adulthood where it is largely indistinguishable from the psychosis seen in the nondeleted population.
  • Apart from being the monozygotic co-twin of a proband with psychosis or being the offspring of parents with schizophrenia, 22q11.2 deletion is the highest known risk factor for the development of schizophrenia.

Keywords: VCFS; velocardiofacial syndrome; schizophrenia; chromosome 22q11; psychosis; 22q11DS

Figure 1. Chromosome 22q11 microdeletion identified by fluorescence in situ hybridisation (FISH).
Figure 2. Characteristic facial dysmorphism in 22q11.2 deletion syndrome.
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 References
    van Amelsvoort T, Daly E, Robertson D et al. (2001) Structural brain abnormalities associated with deletion at chromosome 22q11: quantitative neuroimaging study of adults with velo-cardio-facial syndrome. British Journal of Psychiatry 178: 412–419.
    van Amelsvoort T, Henry J, Morris R et al. (2004a) Cognitive deficits associated with schizophrenia in velo-cardio-facial syndrome. Schizophrenia Research 70(2–3): 223–232.
    van Amelsvoort T, Daly E, Henry J et al. (2004b) Brain anatomy in adults with velocardiofacial syndrome with and without schizophrenia: preliminary results of a structural magnetic resonance imaging study. Archives of General Psychiatry 61(11): 1085–1096.
    Antshel KM, Fremont W and Kates WR (2008) The neurocognitive phenotype in velo-cardio-facial syndrome: a developmental perspective. Developmental Disabilities Research Reviews 14(1): 43–51.
    Arinami T (2006) Analyses of the associations between the genes of 22q11 deletion syndrome and schizophrenia. Journal of Human Genetics 51(12): 1037–1045.
    Badner JA and Gershon ES (2002) Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Molecular Psychiatry 7(4): 405–411.
    Baker KD and Skuse DH (2005) Adolescents and young adults with 22q11 deletion syndrome: psychopathology in an at-risk group. British Journal of Psychiatry 186: 115–120.
    Barnea-Goraly N, Menon V, Krasnow B et al. (2003) Investigation of white matter structure in velocardiofacial syndrome: a diffusion tensor imaging study. American Journal of Psychiatry 160(10): 1863–1869.
    Basser PJ, Mattiello J and LeBihan D (1994) Estimation of the effective self-diffusion tensor from the NMR spin echo. Journal of Magnetic Resonance. Series B 103(3): 247–254.
    Bassett AS, Chow EW, AbdelMalik P et al. (2003) The schizophrenia phenotype in 22q11 deletion syndrome. American Journal of Psychiatry 160(9): 1580–1586.
    Bassett AS, Caluseriu O, Weksberg R, Young DA and Chow EW (2007) Catechol-O-methyl transferase and expression of schizophrenia in 73 adults with 22q11 deletion syndrome. Biological Psychiatry 61(10): 1135–1140.
    Botto LD, May K, Fernhoff PM et al. (2003) A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 112(1 part 1): 101–107.
    Carlson C, Sirotkin H, Pandita R et al. (1997) Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients. American Journal of Human Genetics 61(3): 620–629.
    Chow EW, Watson M, Young DA and Bassett AS (2006) Neurocognitive profile in 22q11 deletion syndrome and schizophrenia. Schizophrenia Research 87(1–3): 270–278.
    Debbane M, Glaser B, David MK, Feinstein C and Eliez S (2006) Psychotic symptoms in children and adolescents with 22q11.2 deletion syndrome: neuropsychological and behavioral implications. Schizophrenia Research 84(2–3): 187–193.
    Feinstein C, Eliez S, Blasey C and Reiss AL (2002) Psychiatric disorders and behavioral problems in children with velocardiofacial syndrome: usefulness as phenotypic indicators of schizophrenia risk. Biological Psychiatry 51(4): 312–318.
    Fine SE, Weissman A, Gerdes M et al. (2005) Autism spectrum disorders and symptoms in children with molecularly confirmed 22q11.2 deletion syndrome. Journal of Autism and Developmental Disorders 35(4): 461–470.
    Funke BH, Lencz T, Finn CT et al. (2007) Analysis of TBX1 variation in patients with psychotic and affective disorders. Molecular Medicine 13(7–8): 407–414.
    Gothelf D, Eliez S, Thompson T et al. (2005) COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nature Neuroscience 8(11): 1500–1502.
    Gothelf D, Feinstein C, Thompson T et al. (2007a) Risk factors for the emergence of psychotic disorders in adolescents with 22q11.2 deletion syndrome. American Journal of Psychiatry 164(4): 663–669.
    Gothelf D, Penniman L, Gu E, Eliez S and Reiss AL (2007b) Developmental trajectories of brain structure in adolescents with 22q11.2 deletion syndrome: a longitudinal study. Schizophrenia Research 96(1–3): 72–81.
    Green T, Gothelf D, Glaser B et al. (2009) Psychiatric disorders and intellectual functioning throughout development in velocardiofacial (22q11.2 deletion) syndrome. Journal of the American Academy of Child and Adolescent Psychiatry 48(11): 1060–1068.
    Henry JC, van Amelsvoort T, Morris RG et al. (2002) An investigation of the neuropsychological profile in adults with velo-cardio-facial syndrome (VCFS). Neuropsychologia 40(5): 471–478.
    Horowitz A, Shifman S, Rivlin N, Pisante A and Darvasi A (2005) A survey of the 22q11 microdeletion in a large cohort of schizophrenia patients. Schizophrenia Research 73(2-3): 263–267.
    Ikeda M, Williams N, Williams HJ et al. (2010) Failure to confirm association between PIK4CA and psychosis in 22q11.2 deletion syndrome. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 153B(4): 980–982.
    Jungerius BJ, Hoogendoorn ML, Bakker SC et al. (2008) An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia. Molecular Psychiatry 13(11): 1060–1068.
    Karayiorgou M, Morris MA, Morrow B et al. (1995) Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proceedings of the National Academy of Sciences of the USA 92(17): 7612–7616.
    Karayiorgou M, Simon TJ and Gogos JA (2010) 22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia. Nature Reviews. Neuroscience 11(6): 402–416.
    Kates WR, Burnette CP, Jabs EW et al. (2001) Regional cortical white matter reductions in velocardiofacial syndrome: a volumetric MRI analysis. Biological Psychiatry 49(8): 677–684.
    Kobrynski LJ and Sullivan KE (2007) Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet 370(9596): 1443–1452.
    Lewis CM, Levinson DF, Wise LH et al. (2003) Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: schizophrenia. American Journal of Human Genetics 73(1): 34–48.
    Merscher S, Funke B, Epstein JA et al. (2001) TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell 104(4): 619–629.
    Murphy KC, Jones LA and Owen MJ (1999) High rates of schizophrenia in adults with velo-cardio-facial syndrome. Archives of General Psychiatry 56(10): 940–945.
    Niklasson L, Rasmussen P, Oskarsdottir S and Gillberg C (2001) Neuropsychiatric disorders in the 22q11 deletion syndrome. Genetics in Medicine 3(1): 79–84.
    Oskarsdottir S, Vujic M and Fasth A (2004) Incidence and prevalence of the 22q11 deletion syndrome: a population-based study in Western Sweden. Archives of Disease in Childhood 89(2): 148–151.
    Pulver AE, Nestadt G, Goldberg R et al. (1994) Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. Journal of Nervous and Mental Disease 182(8): 476–478.
    Purcell SM, Wray NR, Stone JL et al. (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460(7256): 748–752.
    Raux G, Bumsel E, Hecketsweiler B et al. (2007) Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome. Human Molecular Genetics 16(1): 83–91.
    Robin NH and Shprintzen RJ (2005) Defining the clinical spectrum of deletion 22q11.2. Journal of Pediatrics 147(1): 90–96.
    Schaer M, Debbane M, Bach Cuadra M et al. (2009) Deviant trajectories of cortical maturation in 22q11.2 deletion syndrome (22q11DS): a cross-sectional and longitudinal study. Schizophrenia Research 115(2–3): 182–190.
    Shprintzen RJ, Goldberg R, Golding-Kushner KJ and Marion RW (1992) Late-onset psychosis in the velo-cardio-facial syndrome. American Journal of Medical Genetics 42(1): 141–142.
    Shprintzen RJ, Higgins AM, Antshel K et al. (2005) Velo-cardio-facial syndrome. Current Opinion in Pediatrics 17(6): 725–730.
    Simon TJ, Ding L, Bish JP et al. (2005) Volumetric, connective, and morphologic changes in the brains of children with chromosome 22q11.2 deletion syndrome: an integrative study. NeuroImage 25(1): 169–180.
    Sundram F, Campbell LE, Azuma R et al. (2010) White matter microstructure in 22q11 deletion syndrome: a pilot diffusion tensor imaging and voxel-based morphometry study of children and adolescents. Journal of Neurodevelopmental Disorders 2(2): 77–92.
    Tan GM, Arnone D, McIntosh AM and Ebmeier KP (2009) Meta-analysis of magnetic resonance imaging studies in chromosome 22q11.2 deletion syndrome (velocardiofacial syndrome). Schizophrenia Research 115(2-3): 173–181.
    Urban AE, Korbel JO, Selzer R et al. (2006) High-resolution mapping of DNA copy alterations in human chromosome 22 using high-density tiling oligonucleotide arrays. Proceedings of the National Academy of Sciences of the USA 103(12): 4534–4539.
    Vorstman JA, Morcus ME, Duijff SN et al. (2006) The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms. Journal of the American Academy of Child and Adolescent Psychiatry 45(9): 1104–1113.
    Vorstman JA, Chow EW, Ophoff RA et al. (2009) Association of the PIK4CA schizophrenia-susceptibility gene in adults with the 22q11.2 deletion syndrome. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 150B(3): 430–433.
    Williams NM, Glaser B, Norton N et al. (2008) Strong evidence that GNB1L is associated with schizophrenia. Human Molecular Genetics 17(4): 555–566.
    Xu B, Roos JL, Levy S et al. (2008) Strong association of de novo copy number mutations with sporadic schizophrenia. Nature Genetics 40(7): 880–885.
    Yagi H, Furutani Y, Hamada H et al. (2003) Role of TBX1 in human del22q11.2 syndrome. Lancet 362(9393): 1366–1373.
 Further Reading
    Akbarian S, Bunney WE Jr, Potkin SG et al. (1993) Altered distribution of nicotamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development. Archives of General Psychiatry 50: 169–177.
    Blouin JL, Dombroski BA, Nath SK et al. (1998) Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. Nature Genetics 20: 70–73.
    Lindsay EA, Botta A, Jurecic V et al. (1999) Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature 401: 379–383.
    Murphy KC and Owen MJ (1996) Minor physical anomalies and their relationship to the aetiology of schizophrenia. British Journal of Psychiatry 168: 139–142.
    Murphy KC and Owen MJ (2001) Velocardio facial syndrome (VCFS): a model for understanding the genetics and pathogenesis of schizophrenia. British Journal of Psychiatry 179: 397–402.
    Murphy KC (2002) Schizophrenia and velocardiofacial syndrome. Lancet 359: 426–430.
    Shaw SH, Kelly M, Smith AB et al. (1998) A genome-wide search for schizophrenia susceptibility genes. American Journal of Medical Genetics 81: 364–376.
    Swillen A, Devriendt K, Legius E et al. (1997) Intelligence and psychological adjustment in velocardiofacial syndrome: a study of 37 children and adolescents with VCFS. Journal of Medical Genetics 34: 453–458.
    Weinberger DR (1995) From neuropathology to neurodevelopment. Lancet 346: 552–557.

Related Sub-Topics:

Neurobiology of Disease | Genetics of Intelligence and Cognition | Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease | Genomic Disorders
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Article Title: Schizophrenia and 22q11.2 Deletion Syndrome
 
How to Cite close
Sundram, Frederick, and Murphy, Kieran C(Jan 2011) Schizophrenia and 22q11.2 Deletion Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005229.pub2]