Abstract

Velocardiofacial syndrome (VCFS), the most common chromosomal microdeletion syndrome in humans, is caused by a heterozygous deletion of chromosome 22q11.2. With an incidence of 1/2000-1/6000, it is associated with a vast array of abnormalities such as congenital heart disease, palatal dysfunction, immune deficiency, hypoparathyroidism and cognitive impairment. In addition to the numerous medical and developmental problems, retrospective studies in the last decade have reported a markedly high incidence (∼ 40%) of schizophrenia, bipolar disorder and depression in late adolescence and adulthood in individuals with the deletion. This risk of schizophrenia spectrum disorders in VCFS approaches that of a monozygotic twin of a patient with schizophrenia, or that of an individual with both parents with schizophrenia. These observations provide the strongest known link between psychosis and an identified genetic condition. In recent years, schizophrenia has been viewed as a neurodevelopmental disorder. This neurodevelopmental theory suggests that neurocognitive and neuroanatomical abnormalities often precede the development of overt psychosis. Genetic factors are thought to be contributory to these neurodevelopmental anomalies that are thought to ultimately culminate in schizophrenia spectrum disorders. However, gene identification has largely been unsuccessful, due to the complex nature of the inheritance of the genes and the probability that multiple genes of individual modest effect are involved. Identification of predisposing genetic markers would enable identification of a high-risk group that would enable the prospective study of the factors contributing to psychosis. The presence of a known genetic abnormality that causes neurodevelopmental deficits, confers a high-risk of psychosis and since the signs, symptoms and response to treatment of schizophrenia secondary to VCFS are thought to be no different to that in primary schizophrenic illness, it has been suggested that VCFS represents an ideal model for the study of the factors contributing to schizophrenia. This article delineates the current understanding of the psychological and psychiatric findings, brain morphometric abnormalities and genetic studies in VCFS and their relevance to schizophrenia spectrum disorders.