Elsevier

The Lancet

Volume 359, Issue 9304, 2 February 2002, Pages 426-430
The Lancet

Review
Schizophrenia and velo-cardio-facial syndrome

https://doi.org/10.1016/S0140-6736(02)07604-3Get rights and content

Summary

Velo-cardio-facial syndrome (VCFS), the most frequent known interstitial deletion identified in man, is associated with chromosomal microdeletions in the q11 band of chromosome 22. The VCFS phenotype is complex, with multiple congenital abnormalities affecting several tissues and organs, many of which are derived from neural crest cells. Although phenotypic variability occurs, individuals with VCFS have high rates of psychiatric disorder, especially schizophrenia. Additionally, an increased prevalence of chromosome 22q11 deletions has been reported in populations of people with schizophrenia. Furthermore, results of molecular genetic studies suggest that a schizophrenia susceptibility locus maps to chromosome 22q. These data indicate that aside from being the child of two parents with schizophrenia or the monozygotic co-twin of an affected individual, VCFS and deletion 22q11 represents the highest known risk factor for the development of schizophrenia. Since the entire sequence of chromosome 22 has now been identified, the study of VCFS offers a timely and uniquely powerful opportunity to identify susceptibility genes for schizophrenia in the general population. Furthermore, the strength of the association between schizophrenia and VCFS has important implications for the clinical management of these disorders.

Section snippets

Do people with VCFS have increased rates of schizophrenia?

There have been few studies of psychiatric disorders in children or adults with VCFS. Moreover, many are confounded by methodological constraints, including lack of operational criteria for psychiatric diagnosis, sample heterogeneity (with children and adults included in the same sample), small sample size, and lack of control groups. Nevertheless, several common temperamental features have been described in studies of children and adolescents with VCFS, including behavioural excitation, an

Do people with schizophrenia have increased rates of VCFS?

Several studies have reported an increased prevalence of chromosome 22q11 deletions in populations of people with schizophrenia. Karayiorgou and colleagues17 reported that two of 100 randomly selected individuals with schizophrenia had a 22q11 deletion. No deletions were seen in a sample of 200 healthy controls. Also, in a study of 47 individuals with childhood-onset schizophrenia, Usiskin and colleagues18 reported that three (6%) patients had a 22q11 deletion.

A more targeted approach to

Does a susceptibility locus for schizophrenia reside on chromosome 22q11?

In view of the relatively low frequency of deletion of chromosome 22q11 compared with schizophrenia, VCFS can only account for a small proportion of risk to the development of schizophrenia in the general population. However, more common mutations or polymorphisms in genes within the VCFS region might make a more general and widespread contribution to susceptibility to schizophrenia. This hypothesis is supported by linkage studies, which provide evidence for a susceptibility locus for non-VCFS

Identification of susceptibility genes for schizophrenia

There seems to be a strong argument to support the validity of an association between schizophrenia and VCFS. If this is the case, how can such an association facilitate the identification of susceptibility genes for schizophrenia in VCFS and in the wider population?

There are at least three possible strategies that can be adopted to identify the part that deletion of individual genes might play in determining the high rates of schizophrenia in VCFS. The first approach is to attempt to correlate

Clinical implications

If we accept that the association between VCFS and schizophrenia is valid, such an observation leads to important implications for clinical practice. First, clinical geneticists will need to consider the risk of schizophrenia when patients with VCFS are referred for genetic counselling. Second, doctors will need to consider a chromosome 22q11 deletion in patients with schizophrenia who present with one or more of the following: learning disability, congenital heart disease, cleft lip or cleft

Conclusions

Individuals with VCFS have high rates of psychotic disorders, particularly schizophrenia.14, 15 Furthermore, such individuals have been identified when patients with schizophrenia have been screened for the presence of chromosome 22q11 deletions.17, 19, 20 Additionally, results of molecular genetic studies suggest that a schizophrenia susceptibility locus maps to chromosome 22q11.23, 24, 25 These data lend support to the validity of an association between schizophrenia and VCFS and suggest

Search strategy and selection criteria

Published data for this review were identified by a search of Medline. The search terms used were “schizophrenia”, “psychosis”, “22q11”, and “VCFS”. We included all important studies identified that showed on association between schizophrenia and VCFS. We excluded reports not written in English and case-reports.

References (54)

  • McGueM et al.

    A single dominant gene still cannot account for the transmission of schizophrenia

    Arch Gen Psych

    (1989)
  • McGuffinP et al.

    Molecular genetic studies of schizophrenia

    Cold Spring Harb Symp Quant Biol

    (1996)
  • KarayiorgouM et al.

    Dissecting the genetic complexity of schizophrenia

    Mol Psychiatry

    (1997)
  • PapolosDF et al.

    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

    (1996)
  • DriscollDA et al.

    Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome

    Am J Med Genet

    (1992)
  • MurphyKC et al.

    Chromosome 22q11 deletions: an under-recognised cause of idiopathic learning disability

    Br J Psychiatry

    (1998)
  • MurphyKC et al.

    Schizophrenia, CATCH 22 and FISH

    Br J Psychiatry

    (1996)
  • Golding-KushnerKJ et al.

    Velo-cardio-facial syndrome: language and psychological profiles

    J Craniofac Genet Dev Biol

    (1985)
  • SwillenA et al.

    Intelligence and psychological adjustment in velocardiofacial syndrome: a study of 37 children and adolescents with VCFS

    J Med Genet

    (1997)
  • HafnerH et al.

    Epidemiology of schizophrenia

    Can J Psychiatry

    (1997)
  • ShprintzenRJ et al.

    Late-onset psychosis in the velo-cardio-facial syndrome

    Am J Med Genet

    (1992)
  • PulverAE et al.

    Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives

    J Nerv Ment Dis

    (1994)
  • MurphyKC et al.

    High rates of schizophrenia in adults with velo-cardio-facial syndrome

    Arch Gen Psych

    (1999)
  • FraserW et al.

    Psychiatric disorders in mental retardation

  • KarayiorgouM et al.

    Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11

    PNAS USA

    (1995)
  • GothelfD et al.

    Velocardiofacial manifestations and microdeletions in schizophrenic inpatients

    Am J Med Genet

    (1997)
  • BassettAS et al.

    22q11 deletion syndrome in adults with schizophrenia

    Am J Med Genet

    (1998)
  • Cited by (256)

    • Translational medicine in psychiatry: challenges and imaging biomarkers

      2021, Principles of Translational Science in Medicine: From Bench to Bedside, Third Edition
    • Animal Models of Psychosis in Alzheimer Disease

      2020, American Journal of Geriatric Psychiatry
      Citation Excerpt :

      In bipolar disorder and schizophrenia, psychotic symptom severity has been correlated with striatal dopamine synthesis capacity.101 Catechol-O-methyltransferase is an enzyme that participates in the degradation of dopamine, and is encoded within the region of chromosome 22q11, a region implicated in DiGeorge syndrome, a disorder which confers increased risk of bipolar disorder and schizophrenia.102 The deletion of COMT in mice results in a 60% increase in the concentration of dopamine in the prefrontal cortex.103

    View all citing articles on Scopus
    View full text