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  • Print publication year: 2004
  • Online publication date: August 2010

7 - Velo-cardio-facial syndrome (deletion 22q11.2): a homogeneous neurodevelopmental model for schizophrenia


There is now a very impressive body of data supporting the neurodevelopmental hypothesis of schizophrenia. This chapter summarizes the available clinical, neuroimaging, and genetic information regarding velo-cardio-facial syndrome (VCFS), so that it may be available for clinical research in schizophrenia. Developmental delays in the preschool period may result in identification of VCFS at that time, but some children with VCFS and adults whose condition was unrecognized in childhood are never identified, because of low clinical index of suspicion. Studies of the relationship between VCFS and schizophrenia have recently stimulated interest in further molecular genetic analysis of 22q11.2 site, utilizing both family- and population-based schizophrenia samples. A review of most of the available neuroimaging studies of children with VCFS suggests that there is an early alteration of parietal lobe and cerebellum, and that the decrease of temporal lobe gray matter and hippocampus can be observed only in adults.

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Asarnow, R. F., Nuechterlein, K. H., Asamen, al. (2002a). Neurocognitive functioning and schizophrenia spectrum disorders can be independent expressions of familial liability for schizophrenia in community control children: the UCLA family study. Schizophr Res 54: 111–120
Asarnow, R. F., Nuechterlein, K. H., Subotnik, K. al. (2002b). Neurocognitive impairments in nonpsychotic parents of children with schizophrenia and attention-deficit/hyperactivity disorder: the University of California, Los Angeles Family Study. Arch Gen Psychiatry 59: 1053–1060
Bassett, A. S., Chow, E. W. (1999). 22q11 deletion syndrome: a genetic subtype of schizophrenia. Biol Psychiatry 46: 882–891
Bassett, A. S., Hodgkinson, K., Chow, E. al. (1998). 22q11 deletion syndrome in adults with schizophrenia. Am J Med Genet 81: 328–337
Bilder, R., Volavka, J., Czobor, al. (2002). Neurocognitive correlates of the COMT Val(158)Met polymorphism in chronic schizophrenia. Biol Psychiatry 52: 701–707
Bingham, P. M., Lynch, D., McDonald-McGinn, D., Zackai, E. (1998). Polymicrogyria in chromosome 22 delection syndrome. Neurology 51: 1500–1502
Bird, L. M. (2001). Cortical dysgenesis and 22q11 deletion. Clin Dysmorphol 10: 77
Cannon, M., Caspi, A., Moffitt, T. al. (2002). Evidence for early-childhood, pan-developmental impairment specific to schizophreniform disorder: results from a longitudinal birth cohort. Arch Gen Psychiatry 59: 449–456
Carlson, C., Papolos, D., Pandita, R. al. (1997a). Molecular analysis of velo-cardio-facial syndrome patients with psychiatric disorders. Am J Hum Genet 60: 851–859
Carlson, C., Sirotkin, H., Pandita, al. (1997b). Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients. Am J Hum Genet 61: 620–629
Chakravarti, A. (2002). A compelling genetic hypothesis for a complex disease, PRODHH2/DGCR6 variation leads to schizophrenia susceptibility. Proc Natl Acad Sci USA 99: 4755–4756
Chow, E., Zipursky, R. B., Mikulis, al. (1999). MRI findings in adults with 22q11 deletion syndrome (22qDS) and schizophrenia. Schizophr Res 36: 89
Chow, E. W., Zipursky, R. B., Mikulis, D. J., Bassett, A. S. (2002). Structural brain abnormalities in patients with schizophrenia and 22q11 deletion syndrome. Biol Psychiatry 51: 208–215
Cohen, E., Chow, E., Weksberg, R., Bassett, A. S. (1999). Phenotype of adults with the 22q11 deletion syndrome. Am J Med Genet 86: 359–365
Cooper, J., Bloom, F., Roth, R. (1996): The Biochemical Basis of Neuropharmacology, 7th edn. New York: Oxford University Press
Driscoll, D. A., Salvin, J., Sellinger, al. (1993). Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: implications for genetic counselling and prenatal diagnosis. J Med Genet 30: 813–817
Dunham, I., Shimizu, N., Roe, B. al. (1999). The DNA sequence of human chromosome 22. Nature 402: 489–495
Eliez, S., Schmitt, J. E., White, C. D., Reiss, A. L. (2000). Children and adolescents with velocardiofacial syndrome: a volumetric MRI study. Am J Psychiatry 157: 409–415
Eliez, S., Schmitt, J. E., White, C. D., Wellis, V. G., Reiss, A. L. (2001a). A quantitative MRI study of posterior fossa development in velocardiofacial syndrome. Biol Psychiatry 49: 540–546
Eliez, S., Blasey, C. M., Schmitt, E. al. (2001b). Velocardiofacial syndrome: are structural changes in the temporal and mesial temporal regions related to schizophrenia?Am J Psychiatry 158: 447–453
Eliez, S., Antonarakis, S. E., Morris, M. A., Dahoun, S. P., Reiss, A. L. (2001c). Parental origin of the deletion 22q11.2 and brain development in velocardiofacial syndrome: a preliminary study. Arch Gen Psychiatry 58: 64–68
Erlenmeyer-Kimling, L., Rock, D., Roberts, al. (2000). Attention, memory, and motor skills as childhood predictors of schizophrenia-related psychosis. Am J Psychiatry 157: 1416–1422
Feinstein, C., Reiss, A. L. (1996). Psychiatric disorders in mentally retarded children and adolescents. Child Adolesc Psychiatr Clin N Am 5: 827–852
Feinstein, C., Weiner, J. (1997). Developmental disorders of learning, motor skills, and communication. In Textbook of Child and Adolescent Psychiatary, ed. J. Weiner. Washington, DC: American Psychiatry Press, pp. 281–300
Feinstein, C., Eliez, S., Blasey, C., Reiss, A. L. (2002). Psychiatric disorders and behavioral problems in children with velocardiofacial syndrome: usefulness as phenotypic indicators of schizophrenia risk. Biol Psychiatry 51: 312–318
Fish, B. (1977). Neurobiologic antecedents of schizophrenia in children. Evidence for an inherited, congenital neurointegrative defect. Arch Gen Psychiatry 34: 1297–1313
Fish, B., Marcus, J., Hans, S. L., Auerbach, J. G., Perdue, S. (1992). Infants at risk for schizophrenia: sequelae of a genetic neurointegrative defect. A review and replication analysis of pandsymaturation in the Jerusalem Infant Development Study. Arch Gen Psychiatry 49: 221–235
Fokstuen, S., Arbenz, U., Artan, S., et al. (1998). 22q11.2 deletions in a series of patients with non-selective congenital heart defects: incidence, type of defects and parental origin. Clin Genet 53: 63–69
Fraser, W., Nolan, M. (1994). Psychiatric disorders in mental retardation. In Mental Health in Mental Retardation, ed. N. Bouras. Cambridge: Cambridge University Press, pp. 79–92
Fuller, R., Nopoulos, P., Arndt, al. (2002). Longitudinal assessment of premorbid cognitive functioning in patients with schizophrenia through examination of standardized scholastic test performance. Am J Psychiatry 159: 1183–1189
Funke, B., Saint-Jore, B., Puech, al. (1997). Characterization and mutation analysis of goosecoid-like (GSCL), a homeodomain-containing gene that maps to the critical region for VCFS/DGS on 22q11. Genomics 46: 364–372
Gerdes, M., Solot, C., Wang, P. al. (1999). Cognitive and behavior profile of preschool children with chromosome 22q11.2 deletion. Am J Med Genet 85: 127–133
Ghariani, S., Dahan, K., Saint-Martin, al. (2002). Polymicrogyria in chromosome 22q11 deletion syndrome. Eur J Paediatr Neurol 6: 73–77
Glaser, B., Mumme, D. L., Blasey, al. (2002). Language skills in children with velocardiofacial syndrome (deletion 22q11.2). J Pediatr 140: 753–758
Gold, S., Arndt, S., Nopoulos, P., O'Leary, D. S., Andreasen, N. C. (1999). Longitudinal study of cognitive function in first-episode and recent-onset schizophrenia. Am J Psychiatry 156: 1342–1348
Goldberg, R., Motzkin, B., Marion, R., Scambler, P. J., Shprintzen, R. J. (1993). Velo-cardio-facial syndrome: a review of 120 patients. Am J Med Genet 45: 313–319
Golding-Kushner, K. J., Weller, G., Shprintzen, R. J. (1985). Velo-cardio-facial syndrome: language and psychological profiles. J Craniofac Genet Dev Biol 5: 259–266
Gong, W., Emanuel, B. B., Collins, J. al. (1996). A transcription map of the DiGeorge and velocardiofacial syndrome minimal critical region. Hum Mol Genet 5: 789–800
Gothelf, D., Frisch, A., Munitz, al. (1997). Velocardiofacial manifestations and microdeletions in schizophrenic inpatients. Am J Med Genet 72: 455–461
Gottlieb, S., Emanuel, B. S., Driscoll, D. al. (1997). The DiGeorge syndrome minimal critical region contains a goosecoid-like (GSCL) homeobox gene that is expressed early in human development. Am J Hum Genet 60: 1194–1201
Gottlieb, S., Hanes, S. D., Golden, J. A., Oakey, R. J., Budarf, M. L. (1998). Goosecoid-like, a gene deleted in DiGeorge and velocardiofacial syndromes, recognizes DNA with a bicoid-like specificity and is expressed in the developing mouse brain. Hum Mol Genet 7: 1497–1505
Gur, R. E., Turetsky, B. I., Bilker, W. B., Gur, R. C. (1999). Reduced gray matter volume in schizophrenia. Arch Gen Psychiatry 56: 905–911
Hans, S. L., Marcus, J., Nuechterlein, K. al. (1999). Neurobehavioral deficits at adolescence in children at risk for schizophrenia: the Jersualem Infant Development Study. Arch Gen Psychiatry 56: 741–748
Jacquet, H., Raux, G., Thibaut, al. (2002). PRODH mutations and hyperprolinemia in a subset of schizophrenic patients. Hum Mol Genet 11: 2243–2249
Jerome, L. A., Papaioannou, V. E. (2001). DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat Genet 27: 286–291
Karayiorgou, M., Morris, M. A., Morrow, al. (1995). Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci USA 92: 7612–7616
Kates, W. R., Burnette, C. P., Jabs, E. al. (2001). Regional cortical white matter reductions in velocardiofacial syndrome: a volumetric MRI analysis. Biol Psychiatry 49: 677–684
Kawame, H., Kurosawa, K., Akatsuka, A., Ochiai, Y., Mizuno, K. (2000). Polymicrogyria is an uncommon manifestation in 22q11.2 deletion syndrome. Am J Med Genet 94: 77–78
Kirov, G., Murphy, K. C., Arranz, al. (1998). Low activity allele of catechol-O-methyltransferase gene associated with rapid cylcing bipolar disorder. Mol Psychiatry 3: 342–345
Kunugi, H., Vallada, H., Sham, al. (1997). Catechol-O-methyltransferase polymorphisms and schizophrenia: a transmission disequilibrium study in multiply affected families. Psychiatr Genet 7: 97–101
Lachman, H. M., Morrow, B., Shprintzen, al. (1996a). Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome. Am J Med Genet 67: 468–472
Lachman, H. M., Papolos, D. F., Saito, al. (1996b). Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6: 243–250
Lachman, H., Kelsoe, J., Moreno, L., Katz, S., Papolos, D. (1997). Lack of association of catechol-O-methyltransferase (COMT) functional polymorphism in bipolar affective disorder. Psychiatr Genet 7: 13–17
Lindsay, E. A., Greenberg, F., Shaffer, L. G., et al. (1995). Submicroscopic deletions at 22q11.2: variability of the clinical picture and delineation of a commonly deleted region. Am J Med Genet 56: 191–197
Lindsay, E. A., Harvey, E., Scambler, P., Baldini, A. (1998). ES2, a gene deleted in DiGeorge syndrome, encodes a nuclear protein and is expressed during early mouse development, where it shares an expression domain with a goosecoid-like gene. Hum Mol Genet 7: 629–635
Lindsay, E. A., Vitelli, F., Su, al. (2001). Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410: 97–101
Liu, H., Heath, S. C., Sobin, al. (2002a). Genetic variation at the 22q11 PRODH 2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc Natl Acad Sci USA 99: 3717–3722
Liu, H., Abecasis, G. R., Heath, S. al. (2002b). Genetic variation in the 22q11 locus and susceptibility to schizophrenia. Proc Natl Acad Sci USA 99: 16859–16864
Liu, H., Heath, S. C., Sobin, al. (2002c). 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
Marcus, J., Hans, S. L., Auerbach, J. G., Auerbach, A. G. (1993). Children at risk for schizophrenia: the Jerusalem Infant Development Study II. Neurobehavioral deficits at school age. Arch Gen Psychiatry 50: 797–809
McDermid, H. E., Morrow, B. E. (2002). Genomic disorders on 22q11. Am J Hum Genet 70: 1077–1088
McDonald-McGinn, D. M., Kirschner, R., Goldmuntz, al. (1999). The Philadelphia story: the 22q11.2 deletion. Report on 250 patients. Genet Couns 10: 11–24
McGlashan, T. H., Hoffman, R. E. (2000). Schizophrenia as a disorder of developmentally reduced synaptic connectivity. Arch Gen Psychiatry 57: 637–648
Merscher, S., Funke, B., Epstein, J. al. (2001). TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell 104: 619–629
Mitnick, R. J., Bello, J. A., Shprintzen, R. J. (1994). Brain anomalies in velo-cardio-facial syndrome. Am J Med Genet 54: 100–106
Mohamed, S., Paulsen, J. S., O'Leary, D., Arndt, S., Andreasen, N. (1999). Generalized cognitive deficits in schizophrenia: a study of first-episode patients. Arch Gen Psychiatry 56: 749–754
Moss, E. M., Batshaw, M. L., Solot, C. al. (1999). Psychoeducational profile of the 22q11.2 microdeletion: a complex pattern. J Pediatr 134: 193–198
Murphy, K. C., Jones, L. A., Owen, M. J. (1999). High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry 56: 940–945
Palmatier, M. A., Kang, A. M., Kidd, K. K. (1999). Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles. Biol Psychiatry 46: 557–567
Papolos, D. F., Faedda, G. L., Veit, al. (1996). Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder?Am J Psychiatry 153: 1541–1547
Papolos, D. F., Veit, S., Faedda, G. L., Saito, T., Lachman, H. M. (1998). Ultra-ultra rapid cycling bipolar disorder is associated with the low activity catecholamine-O-methyltransferase allele. Mol Psychiatry 3: 346–349
Pulver, A. E., Nestadt, G., Goldberg, al. (1994). Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. J Nerv Ment Dis 182: 476–478
Reichenberg, A., Weiser, M., Rabinowitz, al. (2002). A population-based cohort study of premorbid intellectual, language, and behavioral functioning in patients with schizophrenia, schizoaffective disorder, and nonpsychotic bipolar disorder. Am J Psychiatry 159: 2027–2035
Roberts, C., Daw, S. C., Halford, S., Scambler, P. J. (1997). Cloning and developmental expression analysis of chick Hira (Chira), a candidate gene for DiGeorge syndrome. Hum Mol Genet 6: 237–245
Ryan, A. K., Goodship, J. A., Wilson, D. al. (1997). Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet 34: 798–804
Saint-Jore, B., Puech, A., Heyer, al. (1998). Goosecoid-like (Gscl), a candidate gene for velocardiofacial syndrome, is not essential for normal mouse development. Hum Mol Genet 7: 1841–1849
Saito, T., Stopkova, P., Diaz, al. (2003). Polymorphism screening of PIK4CA: possible candidate gene for chromosome 22q11-linked psychiatric disorders. Am J Med Genet 116: 77–83
Scambler, P. J., Kelly, D., Lindsay, al. (1992). Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus. Lancet 339: 1138–1139
Scherer, N. J., D'Antonio, L. L., Kalbfleisch, J. H. (1999). Early speech and language development in children with velocardiofacial syndrome. Am J Med Genet 88: 714–723
Shaikh, T. H., Kurahashi, H., Saitta, S. al. (2000). Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum Mol Genet 9: 489–501
Shenton, M. E., Dickey, C. C., Frumin, M., McCarley, R. W. (2001). A review of MRI findings in schizophrenia. Schizophr Res 49: 1–52
Shifman, S., Bronstein, M., Sternfeld, al. (2002). A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 71: 1296–1302
Shprintzen, R. J. (1999). Historic overview of VCFS. Genet Couns 10: 1–2
Shprintzen, R. J., Goldberg, R. B., Lewin, M. al. (1978). A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo-cardio-facial syndrome. Cleft Palate J 15: 56–62
Shprintzen, R. J., Goldberg, R., Golding-Kushner, K. J., Marion, R. W. (1992). Late-onset psychosis in the velo-cardio-facial syndrome. Am J Med Genet 42: 141–142
Strous, R., Bark, N., Parsia, S., Vovlavka, J., Lachman, H. (1997). Analysis of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association with aggressive and antisocial behavior. Psychiatr Res 69: 71–77
Swillen, A., Devriendt, K., Legius, al. (1997). Intelligence and psychosocial adjustment in velocardiofacial syndrome: a study of 37 children and adolescents with VCFS. J Med Genet 34: 453–458
Swillen, A., Devriendt, K., Legius, al. (1999). The behavioural phenotype in velo-cardio-facial syndrome (VCFS): from infancy to adolescence. Genet Couns 10: 79–88
Tezenas Du Montcel, S., Mendizabai, al. (1996). Prevalence of 22q11 microdeletion [letter]. J Med Genet 33: 719
Thompson, P. M., Vidal, C., Giedd, J. al. (2001). Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci USA 98: 11650–11655
Toppelberg, C., Shapiro, T. (2000). Language disorders: a 10-year research update review. J Am Acad Child Adolesc Psychiatry 39: 143–152
Usiskin, S. I., Nicolson, R., Krasnewich, D. al. (1999). Velocardiofacial syndrome in childhood-onset schizophrenia. J Am Acad Child Adolesc Psychiatry 38: 1536–1543
Amelsvoort, T., Daly, E., Robertson, al. (2001). Structural brain abnormalities associated with deletion at chromosome 22q11: quantitative neuroimaging study of adults with velo-cardio-facial syndrome. Br J Psychiatry 178: 412–419
Vantrappen, G., Devriendt, K., Swillen, al. (1999). Presenting symptoms and clinical features in 130 patients with the velo-cardio-facial syndrome. The Leuven experience. Genet Couns 10: 3–9
Weinberger, D. R. (1987). Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44: 660–669
Weinberger, D. R., Egan, M. F., Bertolino, al. (2001). Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 50: 825–844
Weinshilboum, R. M. (1978). Human biochemical genetics of plasma dopamine-beta-hydroxylase and erythrocyte catechol-O-methyltransferase. Hum Genet Suppl 1: 101–112
Worthington, S., Turner, A., Elber, J., Andrews, P. I. (2000). 22q11 deletion and polymicrogyria: cause or coincidence?Clin Dysmorphol 9: 193–197
Yamagishi, H., Garg, V., Matsuoka, R., Thomas, T., Srivastava, D. (1999). A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects. Science 283: 1158–1161