Psychiatric Disorders and Behavioral Problems in Children with Velocardiofacial Syndrome: Usefulness as Phenotypic Indicators of Schizophrenia Risk Carl Feinstein, Stephan Eliez, Christine Blasey, and Allan L. Reiss Background: Velocardiofacial syndrome (VCFS), a ge- netic deletion condition with numerous cognitive sequelae, is associated with a high rate of psychiatric disorders in childhood. More recently, VCFS has been identified as a high-risk factor for developing adult onset schizophrenia. However, it has never been demonstrated that the child- hood psychiatric disorders found in children with VCFS differ from those found in children with a similar degree of cognitive impairment. Identification of a specific behav- ioral (psychiatric) phenotype in childhood VCFS offers the potential for elucidating the symptomatic precursors of adult onset schizophrenia. Methods: Twenty-eight children with VCFS and 29 age- and cognitively matched control subjects received a stan- dardized assesment of childhood psychiatric disorders and behaviors measured by the Child Behavior Checklist (CBCL). Findings from the two groups were compared. Results: The rates and types of psychiatric disorder and behavior problems in VCFS and cognitively matched control subjects were very high, but showed no significant differences. Conclusions: Psychopathology in children with VCFS may not differ from that found in cognitively matched control subjects. Another explanation is that subtle phe- notypic differences in behavior found in VCFS can not be observed using standard symptom inventories. The high rate of psychopathology in children with VCFS is not a useful phenotypic indicator of high risk for adult onset schizophrenia. Biol Psychiatry 2002;51:312–318 © 2002 Society of Biological Psychiatry Key Words: Velocardiofacial syndrome, psychiatric dis- orders, behavior problems, schizophrenia, neurodevelop- mental disorders, behavioral phenotype Introduction V elocardiofacial syndrome (VCFS) is one of the most common of the genetically based developmental disorders and is manifested by a complex of several medical abnormalities, a reduction in intelligence, learning disabilities, and psychiatric disorder (Bassett and Chow 1999; Cohen et al 1999; Feinstein and Eliez 2000; Moss et al 1999; Murphy et al 1999; Ryan et al 1997; Shaikh et al 2000; Swillen et al 1999). It is estimated to occur in at least 1 per 2000 to 4500 live births (Tezenas Du Montcel et al 1996). In most affected individuals, a de novo 3 Mb deletion at chromosome 22q11.2 is responsible for the syndrome (Carlson et al 1997; Driscoll et al 1993; Lindsay et al 1995; Scambler et al 1992; Shaikh et al 2000). Recently, investigators utilizing both psychiatric assess- ments of subjects known to have VCFS and genetic testing of patients with schizophrenia have demonstrated a strong association between VCFS and schizophrenia in adult- hood. Shprintzen and coworkers (Shprintzen et al 1992) reported that 20 –30% of his cohort of VCFS patients 16 years or older developed schizophrenia or schizoaffective disorder. Murphy and coworkers found 30% of 50 adult patients with VCFS to be psychotic (24% schizophrenia, 2% schizoaffective, 2% psychosis not otherwise specified, and 2% rapid-cycling bipolar disorder) (Murphy et al 1999). In 1995, Karayiorgou and colleagues identified by genetic testing two patients with VCFS in a random sample of 100 schizophrenic patients (Karayiorgou et al 1995). Gothelf et al (1997) identified three individuals with VCFS by genetic testing of 20 hospitalized schizo- phrenic patients who had medical anomalies suggestive of VCFS. Bassett and coworkers applied a screening proce- dure based on five types of medical or developmental anomalies characteristic of VCFS to identify VCFS in a schizophrenic sample. Ten of 15 schizophrenic patients who had at least two of these were found to have VCFS by genetic testing (Bassett and Chow 1999; Bassett et al 1998). These patients had intelligence quotients (IQs) ranging from borderline to mild mental retardation. In From the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California. Address reprint requests to Stephen Eliez, M.D., Ph.D., Professor of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Department of Psychiatry and Behavioral Sciences, 401 Quarry Road, Stanford, CA 94305-5719. Received March 2, 2001; revised June 18, 2001; accepted June 22, 2001. © 2002 Society of Biological Psychiatry 0006-3223/02/$22.00 PII S0006-3223(01)01231-8