Schizophrenia Research 52 (2001) 167±170

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Screening for 22q11 deletions in a schizophrenia population

T. Arinami a,*, T. Ohtsuki a, K. Takase a, H. Shimizu b, T. Yoshikawa c, H. Horigome d,
J. Nakayama a,d, M. Toru e
a
Department of Medical Genetics, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
b
Hokushin General Hospital, Nakano 383-8505, Japan
c
Laboratory for Molecular Psychiatry, RIEKN Brain Science Institute, Wako 351-0198, Japan
d
Department of Pediatrics, Institute of Clinical Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
e
Department of Neuropsychiatry, Tokyo Medical and Dental University School of Medicine, Tokyo 113-8510, Japan
Received 21 October 2000; accepted 4 December 2000

Abstract
Since the recognition that adults with velocardiofacial syndrome (VCFS), which is associated with hemizygous interstitial
deletions of chromosome 22q11, frequently show psychotic symptoms, deletion of the 22q11.2 region has been proposed as a
common genetic abnormality associated with schizophrenia. In studies of schizophrenia patients, such deletions have been
detected in more than 1% of schizophrenics, indicating the likely presence of this deletion in a signi®cant number of patients. In
this study, we screened for 22q11.2 deletions by genotyping microsatellite markers in 300 schizophrenics and 300 normal
controls. The 22q11.2 deletion was con®rmed by ¯uorescent in situ hybridization (FISH). One patient with schizophrenia was
found to have a 22q11.2 deletion. The patient was mildly retarded but did not have craniofacial, palatal, or cardiac malforma-
tions characteristic of VCFS. Our results indicate that 22q11.2 deletion does not contribute substantially to the development of
schizophrenia in general. However, our ®ndings establish the existence of physically near-normal individuals with 22q11.2
deletion among learning disabled or mildly retarded persons with schizophrenia. q 2001 Elsevier Science B.V. All rights
reserved.
Keywords: Schizophrenia; Chromosome 22q11; Velocardiofacial syndrome; FISH; Microsatellite

1. Introduction (Carlson et al., 1997a,b). There was no correlation

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
* Corresponding author. Tel.: 181-298-53-3352; fax: 181-298-
53-3333.
E-mail address: tarinami@md.tsukuba.ac.jp (T. Arinami).
0920-9964/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved.
PII: S 0920-996 4(00)00192-4
between the presence or size of the deletion and
phenotype including psychiatric disorders (Carlson
et al., 1997a,b). The estimated prevalence of the dele-
tion 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 empha-
sizes the more severe congenital physical anomalies
and may hinder identi®cation of adults with 22q11
deletion syndromes. Emphasis on the physical anoma-
lies could also prevent diagnosticians from noting
168 T. Arinami et al. / Schizophrenia Research 52 (2001) 167±170
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 ®rst 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 identi®ed more than 10
adults with schizophrenia and 22q11 deletions by
recruiting patients with both a major psychiatric disor-
der 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 varia-
tions 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 schizophre-
nia. 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 ¯uorescence in situ hybridization
(FISH).
2. Methods
2.1. Subjects
Schizophrenic subjects were 300 unrelated Japa-
nese 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 unre-
lated Japanese persons (164 men and 136 women,
aged 29±75 years (mean 47.8 years)). They were
anonymous healthy volunteers and had not been eval-
uated by psychiatrists. Patients and controls resided in
the same area of Japan. After written informed
consent was obtained from all subjects, samples of
venous blood were collected. The study was approved
by the ethics committee of the University of Tsukuba.
2.2. Genotyping and FISH
Genotyping of markers D22S941, D22S944,
D22S264, and D22S311 was carried out according
to the method of Morrow et al. (1995). The
Val158Met polymorphism of the catechol-O-methyl
transferase (COMT) gene in the 22q11 deletion
region, which has been reported to be associated
with schizophrenia (de Chaldee et al., 1999; Kunugi
et al., 1997; Ohmori et al., 1998), was genotyped
according to the method of Lachman et al. (1996).
Cytogenetic and FISH analyses were carried out on
phetohemagglutinin-stimulated peripheral T cells
using the TUBLE1 gene probe.
2.3. Statistical procedure
Deviation of genotype frequencies from Hardy±
Weinberg equilibrium and differences in allele
frequencies between patients and controls were tested
for signi®cance at the 5% con®dence level with Arle-
quin ver 2 (http://anthropologie.unige.ch/arlequin).
3. Results
Genotype distributions of the markers did not
 T. Arinami et al. / Schizophrenia Research 52 (2001) 167±170 169

Table 1
Heterozygosity frequency of polymorphisms in controls and schizophrenics

Polymorphic markers

D22S941 D22S944 COMT D22S264 D22S311

Observed heterozygosity (Expected heterozygosity)

Control 0.72 (0.72) 0.72 (0.74) 0.43 (0.45) 0.82 (0.78) 0.69 (0.76)
Schizophrenia 0.70 (0.68) 0.72 (0.73) 0.42 (0.46) 0.74 (0.78) 0.72 (0.75)
p 0.63 0.67 0.84 0.04 0.18

deviate signi®cantly 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 signi®cant differences between the patient and
control groups were observed. One patient possessed
only one allele for each of these polymorphic markers.
FISH analysis with the TUBLE1 probe indicated that
this patient with only one allele for each of the poly-
morphic markers had a deletion at 22q11.2. The
karyotype of this patient was 46, XX (by G-banding).
This patient was 28 years old at the time of examina-
tion. At age 15, she developed auditory hallucinations
consisting of argumentative and commentary voices,
somatic passivity experiences, thought broadcasting
delusions, delusional perceptions, and delusions of
persecution, which increased gradually. Other clinical
features included depressed mood, social withdrawal,
grossly disorganized and unpredictable agitation,
angry outbursts, and emotional lability. She was
hospitalized at the age of 18 years for 2 months and
at the age of 25 years for 1 month. She was treated
pharmacologically with bromperidol and experienced
partial improvement of her hallucinations and delu-
sions. She remained unmarried, had no steady
boyfriend, lived with her mother, and worked in a
semisheltered workplace. She graduated from high
school but with low achievement. Her IQ, which
was measured during her ®rst hospitalization, was
61. She had no cardiac, palatal, or minor dysmorphic
craniofacial anomalies. Slender tapered ®ngers were
the only physical features characteristic of VCFS that
were present.
4. 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 identi®ed one patient
with a 22q11.2 deletion among 300 randomly selected
schizophrenics, which leads to an estimated incidence
of schizophrenics with 22q11.2 deletions of 1 in
30,000, assuming that schizophrenia affects 1% of
the population. This estimation coincides with that
from VCFS patient populations (du Montcel et al.,
1996). Because the frequency of 22q11.2 deletions
observed in this study was lower than that observed

Table 2
Genotype distributions and allele frequencies of the Val158Met polymorphism of the COMT gene

Population n Genotype Allele

Val/Val Val/Met Met/Met Val Met

Controls 300 144 (0.48) 128 (0.43) 28 (0.09) 416 (0.69) 184 (0.31)
Schizophrenics 300 143 (0.48) 125 (0.42) 32 (0.11) 411 (0.68) 189 (0.32)
170 T. Arinami et al. / Schizophrenia Research 52 (2001) 167±170
in previous studies (1.5±2%), the present study does
not provide data to support a higher incidence of
22q11.2 deletions than that now estimated (1/4500)
nor a higher proportion of individuals with 22q11.2
deletions who develop schizophrenic symptoms than
that now estimated (more than 10%).
Deletions of 22q11.2 are thought to increase the
susceptibility for schizophrenia ten-fold, possibly
through neurodevelopmental pathogenesis and/or
accompanying cognitive dysfunction. Although the
patient with the deletion identi®ed in this study had
few physical features of VCFS, she was mildly
retarded, and learning disabilities and mild retardation
are the most common feature (99%) of VCFS (Gold-
berg et al., 1993). To date, all cases of schizophrenia
with 22q11.2 deletions have been described as
syndromic. Our results con®rm that isolated schizo-
phrenia is not likely due to 22q11.2 deletions.
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 scienti®c research grants
from the Ministry of Education, Science and Culture
of Japan.
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