Screening for 22q11 deletions in a schizophrenia population
Introduction
Interstitial deletions of chromosome 22q11 are associated with several genetic syndromes and anomalies including velocardiofacial syndrome (VCFS), DiGeorge syndrome (DGS), and conotruncal anomaly face syndrome. More than 80% of VCFS patients had 22q11 deletions, and more than 90% of the deletions encompassed similar 3-Mb regions (Carlson et al., 1997a, Carlson et al., 1997b). There was no correlation between the presence or size of the deletion and phenotype including psychiatric disorders (Carlson et al., 1997a, Carlson et al., 1997b). The estimated prevalence of the deletion is 1 in 4500 in the general population (du Montcel et al., 1996), with sporadic occurrence representing the majority of cases. The term ‘22q11 deletion syndrome’ has been proposed as a replacement for the collective acronym ‘CATCH 22’, which emphasizes the more severe congenital physical anomalies and may hinder identification of adults with 22q11 deletion syndromes. Emphasis on the physical anomalies could also prevent diagnosticians from noting important cognitive and behavioral components of the phenotype that may emerge over time (Bassett et al., 1998, Thomas and Graham, 1997).
Because serious psychiatric illnesses have been reported in a subset of adult patients with VCFS, such illnesses may be associated causally with 22q11 deletion. The first study examining a possible association between psychiatric illness and VCFS showed that more than 10% of adults with VCFS developed some psychiatric disorders with chronic schizophrenia being most prevalent (Shprintzen et al., 1992). Recent studies identified more than 10 adults with schizophrenia and 22q11 deletions by recruiting patients with both a major psychiatric disorder and physical features associated with VCFS (Bassett et al., 1998, Chow et al., 1997, Karayiorgou et al., 1995, Sugama et al., 1999, Usiskin et al., 1999). Individuals with 22q11.2 deletions exhibit great variations in their phenotypic features, and the occurrence of major features varies with different ascertainment strategies (Bassett et al., 1998).
Schizophrenia, affecting approximately 1% of the world's population, is likely a heterogeneous illness of variable etiology and expression. Karayiorgou et al. (1995) reported that 2 of 100 randomly selected patients with schizophrenia were found to have a 22q11 deletion and, on retrospective assessment, facial features of VCFS. They later reported that 3 of 207 schizophrenics had 22q11.2 deletions (Karayiorgou et al., 1997), and Chow et al. (1997) reported that 2 of 100 randomly selected Chinese schizophrenics had 22q11.2 deletions. Therefore, 22q11.2 deletion syndrome may be the most common microdeletion syndrome associated with schizophrenia (Bassett, 1992, Bassett et al., 1998). However, if these reported frequencies (about 2%) of 22q11.2 deletions in schizophrenics are accurate, the prevalence of schizophrenics with 22q11.2 deletions would be approximately 1 in 5000, suggesting that the majority of VCFS patients develop schizophrenia. Another possibility is that the prevalence of 22q11.2 deletions is much higher than the reported 1 in 4500, with the majority being undetected. In this study, we screened 22q11.2 deletions in 300 unrelated Japanese patients with schizophrenia and 300 control subjects using microsatellite markers and chromosome fluorescence in situ hybridization (FISH).
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Subjects
Schizophrenic subjects were 300 unrelated Japanese patients (167 men and 133 women, aged 19–78 years (mean 44.3 years); age at disease onset 12–39 years (mean 22.6 years)) who met the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) (1987) diagnostic criteria for schizophrenia. Patients were receiving treatment at one of eight hospitals within 200 km of Tokyo. Control subjects were 300 unrelated Japanese persons (164 men and 136 women, aged
Results
Genotype distributions of the markers did not deviate significantly from expected values based on Hardy–Weinberg equilibrium. Table 1 shows the frequencies of heterozygotes for the microsatellite markers and the Val158Met polymorphism of the COMT gene in patients with schizophrenia and in controls.
Table 2 shows the genotype and allele distributions of the Val158Met polymorphism of the COMT gene. No significant differences between the patient and control groups were observed. One patient
Discussion
The incidence of 22q11.2 deletion is estimated at 1 in 4500 in the general population, and more than 10% of persons with such a deletion reportedly manifest symptoms of schizophrenia (Shprintzen et al., 1992). Therefore, only 1 in 45,000 persons in the general population is expected to have both schizophrenia and VCFS. In this study, we identified one patient with a 22q11.2 deletion among 300 randomly selected schizophrenics, which leads to an estimated incidence of schizophrenics with 22q11.2
Acknowledgements
This study was supported by a Research Grant for Nervous and Mental Disorders and a Koseikagaku Research Grant for Brain Science from the Ministry of Health and Welfare and scientific research grants from the Ministry of Education, Science and Culture of Japan.
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