Comparability of 22 qDS-Schizophrenia to Other Forms of Schizophrenia

22q11.2 deletion syndrome (22qDS) is a genetic syndrome associated with a chromosome 22q11.2 deletion and variable phenotypic expression that commonly includes schizophrenia. Approximately 1% of patients with schizophrenia have 22qDS. The schizophrenia in 22qDS appears broadly similar to that found in the general population with respect to core signs and symptoms, treatment response, neurocognitive profile, and MRI brain anomalies. However, individuals with a 22qDS form of schizophrenia typically have distinguishable physical features, have a lower IQ, and may differ in auxiliary clinical features. IQ, length of 22q11.2 deletions, and COMT functional allele do not appear to be major risk factors for schizophrenia in 22qDS. Ascertainment biases and small sample sizes are limitations of most studies. Larger studies over the lifespan and continuing education about this underrecognized condition are needed. 22qDSschizophrenia is an important genetic subtype and a valuable model of neurodevelopmental mechanisms involved in the pathogenesis of schizophrenia. Introduction Of schizophrenia’s many genetic forms, some of which are inherited and many of which are new mutations, only one is recurrent, clinically recognizable, and has confirmatory genetic testing available: 22q11.2 deletion syndrome (22qDS) and its associated 22q11.2 deletion [1•]. This review provides an overview of the evidence for 22qDS as the first identifiable genetic subtype of schizophrenia, the available information about 22qDS-schizophrenia, and some of the implications of this underrecognized condition for clinical practice and research. Common Features and Prevalence of 22qDS 22qDS has a highly variable clinical presentation with several dozen commonly associated features, including congenital and later-onset manifestations, such as psychiatric disorders [2••]. Classically associated features include mild facial dysmorphic features, learning difficulties, hypernasal speech, and congenital anomalies such as congenital heart defects and velopharyngeal insufficiency and/or submucous cleft palate [3]. Overt cleft palate is rare in 22qDS [2••]. Before the associated chromosomal deletion was identified, the variability of Corresponding author: Anne S. Bassett, MD, FRCPC, Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, Ontario M6J 1H4, Canada. anne.bassett@utoronto.ca. Disclosures This research was supported by grants from the Canadian Institutes of Health Research, W. Garfield Weston Foundation, the National Alliance for Research on Schizophrenia and Depression, and Canada Research Chair in Schizophrenia Genetics to Dr. Bassett. No further potential conflicts of interest relevant to this article were reported. Curr Psychiatry Rep. Author manuscript; available in PMC 2011 July 04. Published in final edited form as: Curr Psychiatry Rep. 2008 April ; 10(2): 148–157. C IH R A uhor M anscript C IH R A uhor M anscript C IH R A uhor M anscript features had led to multiple names being used to describe the syndrome (eg, DiGeorge, velocardiofacial, conotruncal anomaly face syndromes). The hemizygous 22q11.2 deletions (ie, on one chromosome 22) associated with 22qDS are too small to be seen using standard karyotyping methods. The molecular cytogenetic method, fluorescence in situ hybridization (FISH), which detects the commonly associated 22q11.2 deletions, became available to clinical laboratories in the mid-1990s. Some variability exists in the length and genomic extent of the 22q11.2 deletions, which are most commonly 3 million bases (Mb) long, but most are clinically detectable using FISH and a standard probe (eg, TUPLE1) from the typically deleted region [4]. The deletion is most commonly a spontaneous (de novo) mutation that occurs during gametogenesis (egg or sperm formation). However, in 5% to 10% of newly diagnosed cases of 22qDS, the mutation has been inherited from a parent with the syndrome who may have only mild manifestations. The true prevalence of 22qDS in the general population is unknown and is likely to vary according to the population’s demographic characteristics. Men and women are equally likely to be affected. Ethnic differences in prevalence may exist, but no studies have formally examined this issue. The best available estimates, based largely on infants with congenital anomalies leading to genetic testing, place the prevalence of 22qDS at about 1 in 4000 [5]. Evidence for the Association of 22q11.2 Deletions and Schizophrenia A meaningful association between 22qDS and schizophrenia would be suggested if 1) patients with schizophrenia have elevated rates of 22q11.2 deletions and 2) an elevated rate of schizophrenia exists in individuals with 22q11.2 deletions [6]. Several studies have now contributed data to these issues, although rates observed vary considerably. How common is 22qDS in schizophrenia? Overall, studies investigating the prevalence of 22qDS and/or 22q11.2 deletions in samples of patients with schizophrenia and related psychotic disorders suggest that 22qDS is likely to be found in about 1 of 100 patients with schizophrenia (Table 1). Our group found that 2 (1.1%) of 178 patients with schizophrenia screened at a community clinic had 22qDS (Bassett and Chow, unpublished data). The observed prevalence is influenced by the characteristics of the sample population studied and the clinical and molecular methods used to detect the syndrome and/or deletion (Table 1). Samples with many individuals who have high intellectual levels, are physically healthy, are older, and/or have relatives with schizophrenia tend to have a lower prior probability of containing individuals with 22qDS. This is because although only a minority have mental retardation, most individuals with 22qDS have learning difficulties, have multiple physical health problems (eg, recurrent seizures), may be prone to premature death, and carry a de novo 22q11.2 deletion [2••]. One half would be expected to be women. Thus, many studies of schizophrenia would have inclusion and exclusion criteria and sampling strategies that would bias against ascertainment of individuals with 22qDS. However, high rates of 22qDS result from screening for patients with physical features of the syndrome and/or borderline to mild mental retardation [3] or childhood-onset schizophrenia (Table 1). Bassett and Chow Page 2 Curr Psychiatry Rep. Author manuscript; available in PMC 2011 July 04. C IH R A uhor M anscript C IH R A uhor M anscript C IH R A uhor M anscript Risk for developing schizophrenia in 22qDS The most prevalent psychiatric disorder in adults with 22qDS is schizophrenia [2••,7,8]. The only study using a sample that did not include psychiatric ascertainment, which was systematically collected from a congenital cardiac clinic, reported 22.6% (95% CI, 7.0% to 38%) of adults with 22qDS had schizophrenia or schizoaffective disorder [2••]. Other studies using mixed-ascertainment strategies that included psychiatric sources reported slightly higher rates of 27% (13/48) [7] and 31% (4/13) [8]. Other psychotic disorders are also found, but sample sizes are still small (Table 2). In contrast, rates of bipolar disorder appear to be similar to those in the general population [7]. One case of bipolar disorder was found in the 105 adults with 22qDS we assessed through our center; rates of anxiety, depressive, and attention-deficit disorders are higher than population expectations (Bassett and Chow, unpublished data). These studies indicate the relative risk for schizophrenia in a patient with 22qDS is about 20 to 25 times the lifetime general population risk of 1% [6,9]. Therefore, 22qDS represents the highest known genetic risk group for schizophrenia development aside from two very rare groups of individuals: children of two parents with schizophrenia or monozygotic co-twins of affected individuals [6,9]. Comparability of 22qDS-Schizophrenia to Other Forms of Schizophrenia Table 2 summarizes clinical features from studies involving nonoverlapping samples of four or more patients with 22qDS and schizophrenia. Results for a total of 82 individuals with 22qDS-schizophrenia reported to date indicate a range of clinical findings likely relating to inherent variability of expression and the small sample sizes obtained from diverse ascertainment sources. Clinical signs and symptoms of schizophrenia Several (but not all) reports [7,10] have indicated that with respect to schizophrenia’s major clinical features, 22qDS-schizophrenia is largely indistinguishable from other forms of schizophrenia [11]. Ascertainment may play a role in differences observed. For example, median age at onset varies from 12 years for a sample restricted to childhood-onset schizophrenia [10] to 26 years when case identification involved parents who had transmitted the deletion to affected children [7]. The latter ascertainment strategy may also explain a finding of less severe negative symptoms [7] that was not found in a larger sample with no transmitting parents [12]. However, there may be some differences in auxiliary clinical features (eg, lower rates of comorbid substance use disorders) [12,13]. Also, some evidence indicates that patients with 22qDS-schizophrenia may have neurobehavioral characteristics other than schizophrenia’s core symptoms [14]. These include greater severity of excitement and impulsivity [12] that may be associated with the short-lived temper or emotional outbursts commonly observed in patients with 22qDS-schizophrenia [11,14]. These features are not those of manic episodes, in which there are more prolonged mood changes. Consistent with this, a study of 86 children with 22qDS found no evidence of elevated rates of manic symptoms [15]. Bassett and Chow Page 3 Curr Psychiatry Rep. Author manuscript; available in PMC 2011 July 04. C IH R A uhor M anscript C IH R A uhor M anscript C IH R A uhor M anscript Management issues Bassett et al. [2••] have proposed general clinical