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Parental Origin of the Deletion 22q11.2 and Brain Development in Velocardiofacial Syndrome
A Preliminary Study
Stephan Eliez, MD;
Stylianos E. Antonarakis, MD;
Michael A. Morris, PhD;
Sophie P. Dahoun, MD;
Allan L. Reiss, MD
Arch Gen Psychiatry. 2001;58:64-68.
ABSTRACT
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Background As children with velocardiofacial syndrome (VCFS) develop, they are
at increased risk for psychopathology; one third will eventually develop schizophrenia.
Because VCFS and the concomitant symptomatology result from a known genetic
origin, the biological and behavioral characteristics of the syndrome provide
an optimal framework for conceptualizing the associations among genes, brain
development, and behavior. The purpose of this study was to investigate the
effect of the parental origin of the 22q11.2 microdeletion on the brain development
of children and adolescents with VCFS.
Methods Eighteen persons with VCFS and 18 normal control subjects were matched
individually for age and sex. Results of DNA polymorphism analyses determined
the parental origin of the deletion. Nine persons with VCFS had a deletion
on the maternally derived chromosome 22; 9 persons, on the paternally derived
chromosome 22. High-resolution magnetic resonance imaging scans were analyzed
to provide quantitative measures of gray and white matter brain tissue.
Results Total brain volume was approximately 11% smaller in the VCFS group than
in controls. Comparisons between VCFS subgroups (maternal vs paternal microdeletion
22q11.2) indicated a significant 9% volumetric difference in total volume
of cerebral gray matter (volume was greater in patients with paternal microdeletion)
but not cerebral white matter. Significant age-related changes in gray matter
were detected for subjects whose 22q11.2 deletion was on the maternal chromosome.
Conclusions Children and adolescents with VCFS experience major alterations in brain
volumes. Significant reduction in gray matter development is attributable
to presence of 22q11.2 microdeletion on the maternal chromosome.
INTRODUCTION
VELOCARDIOFACIAL syndrome (VCFS) is a common genetic condition associated
with physical features, including heart malformations, palatal abnormalities,
and characteristic facial dysmorphism.1 The
high frequency of VCFS (1 in 2000-4000 live births)2
ranks this condition as one of the most common genetic causes of learning
disabilities and mild mental retardation. In most diagnosed cases, the syndrome
is due to a 3 megabase (Mb) de novo deletion on chromosome 22q11.2,3 and can occur on either parental chromosome. At least
30 genes are encoded in the common deleted segment.4
Among these, a few are expressed in brain tissue, and some are likely to be
essential for normal brain development.5, 6, 7
A relation between VCFS and schizophrenia has been suggested through
numerous clinical research studies. After Shprintzen et al8
published the first definition of VCFS, evidence from clinical studies demonstrated
an increased prevalence of psychiatric disorders in the population with VCFS.9, 10, 11 The early investigations
of VCFS and risk for psychopathology noted an elevated incidence of schizophrenia
and schizoaffective disorders among adults with this genetic condition.9 A subsequent investigation12
in children and young adults with VCFS proposed an etiologic link with bipolar
rather than schizophrenic disorders; 64% of subjects met the DSM-III-R13 criteria for bipolar disorders,
whereas only 6% had a diagnosis of schizoaffective disorder. More recent publications
have pointed again toward a predisposition for schizophrenia.14, 15, 16
At least 4 studies have demonstrated an overrepresentation of the 22q11.2
deletion in samples of persons with a diagnosis of schizophrenia; 2% to 6%
of persons with schizophrenia in these samples had the 22q11.2 deletion.17, 18, 19, 20 Of
46 patients with childhood-onset schizophrenia, Nicolson and Rapoport19 found that 6.4% had the 22q11.2 deletion.21 Publications that address the VCFS-schizophrenia
association generally concur that 25% to 30% of children with VCFS will eventually
develop schizophrenia or psychosis,16 making
VCFS the highest known risk factor identified to date for development of this
psychiatric disorder, and supporting the notion of VCFS as a potential genetic-developmental
model for schizophrenia.
Despite evidence of abnormal brain development in VCFS,22, 23
only one quantitative brain imaging study has been reported to date.24 That study demonstrated volumetric reductions of
total brain volume, left parietal lobe, and right cerebellum adjusted for
total brain volume in 15 subjects with VCFS compared with 15 normal control
subjects. Observation of tissue composition in this sample revealed a significant
overall decrease of total gray and white matter tissue in subjects with VCFS.
A qualitative investigation of brain morphology also described alterations
among 11 subjects with 22q11.2 deletion and schizophrenia,25
suggesting increased frequency of midline anomalies such as cavum vergae and
brain atrophy.
To date, investigations have failed to reveal any effect of parental
origin of the deletion on the physical phenotype or degree of cognitive impairment
in affected individuals.26 However, recent
studies reported that familial transmission of the disorder was associated
with lower cognitive performance.26, 27
This finding suggests a genetic mechanism leading to a transgenerational deterioration,
but genetic evidence for this has not been reported. On the other hand, investigators
have found that parental origin of a genetic deletion can have a significant
effect on the physical and cognitive phenotype of genetic disorders (eg, Angelman
and Prader-Willi syndrome caused by a deletion of 15q11 or uniparental disomy
of chromosome 15). This observation relates to a mechanism of gene expression
regulation referred to as imprinting. Imprinting
of a gene means that this gene is expressed in a manner that depends on the
parent of origin of the chromosome, thus resulting, eg, only in expression
of the gene located on the maternally derived chromosome.
We present the first evidence that the parental origin of the 22q11.2
deletion has a significant effect on brain development and morphology, and
we discuss the potential impact of this finding on the association between
schizophrenia and VCFS.
SUBJECTS AND METHODS
SUBJECTS
Eighteen subjects (Table 1),
11 male and 7 female, with a mean (± SD) age of 11.9 ± 3.3 years
(range, 6.3-17.9 years) and a diagnosis of a 22q11.2 de novo microdeletion
confirmed by fluorescent in situ hybridization (FISH) were included in the
study. All subjects were identified as having the typical "large" 3 Mb deletion.28 Recruitment was performed through the Northern California
VCFS association and advertising on our Web site (http://www-cap.stanford.edu). After providing a complete description of the study to the persons
with VCFS and their parents, written informed consent was obtained under protocols
approved by the institutional review board of Stanford University, Stanford,
Calif. A previous report on brain development in VCFS used a subsample of
the subjects reported in this article.
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Table 1. Demographic Characteristics of Study Subjects
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Eighteen normal control subjects were matched for sex and age (each
subject was individually matched within 14 months; mean [± SD] age,
12.5 ± 3.8 years; range, 5.8-19.1 years). Controls were recruited through
advertisement in local newspapers and parent groups' newsletters or among
nonaffected siblings of children with identified genetic conditions (fragile
X and Turner syndromes). A minimum IQ of 85 (1 SD below the population mean)
and absence of previous neurologic or psychiatric disorder were used as an
inclusion criteria for controls.
GENETIC ANALYSIS
The deletions were verified and their extent was determined by means
of 2-color FISH, with cosmid probes DO832 (catechol-O-methyl transferase gene [COMT])
and N48C12 (D22S264) as described.17
The probes are specific for the proximal and distal deletion regions, respectively.29 Parental origins of the deletions were established
using DNA polymorphism analysis with standard techniques.17
Subjects and their parents underwent genotyping for D22S941,
D22S944, and D22S264, 3 polymorphic dinucleotide
repeat markers located within the commonly deleted region. Nine subjects (3
female and 6 male) had deletions of maternal origin; 9 (4 female and 5 male),
paternal origin.
MAGNETIC RESONANCE IMAGING PROTOCOL, IMAGE PROCESSING, AND MEASUREMENT
Magnetic resonance images of each subject's brain were acquired using
a 1.5-T scanner (GE-Signa; General Electric, Milwaukee, Wis). Coronal images
were acquired using a 3D-volumetric radio frequency spoiled gradient echo
(SPGR) pulse sequence with the following scan parameters: repetition time,
35 milliseconds; echo time, 6 milliseconds; flip angle, 45°; number of
excitation, 1; matrix size, 256 x 192 pixels; field of view, 24 cm2; slice thickness, 1.5 mm; 124 slices. The SPGR image data were imported
into a publicly available program (BrainImage; A.L.R., Stanford [available
at:
http://www-cap.stanford.edu/research/neuroimaging/imageanalysis/brainimage.html]) for semiautomated image-processing analysis and quantification. In
summary, the image-processing steps are (1) correction of voxel intensity
nonuniformity (secondary to inhomogeneity of the radio-frequency field); (2)
removal of nonbrain tissues such as scalp, skull, and vasculature; (3) segmentation
of the brain into constituent gray and white tissue types using a constrained
fuzzy algorithm based on voxel intensity and tissue boundaries; and (4) measurements
of gray and white total brain tissue volumes (total brain tissue equals gray
plus white tissue). These procedures have been described and validated elsewhere.30
STATISTICAL ANALYSIS
Distributions were checked for normality and homogeneity of variances.
Analyses of total brain tissue, total gray matter, and total white matter
were performed using 1-way analyses of variance (ANOVAs), with diagnosis (VCFS
vs controls) as a between-subject factor. Post hoc analyses using the Scheffé
test were performed to compare further between VCFS subgroups of different
parental origin (paternal vs maternal 22q11.2 microdeletion) and controls.
Regression analyses were used to test for predictive relationships between
age and gray matter volumes. A P value of .05 (2-tailed)
was considered significant. Follow-up comparison of correlation coefficients
was conducted using Fisher transformations31
with a P value of .05 (1-tailed).
RESULTS
Similar to results of a previous study from our laboratory,24 total brain tissue volume was approximately 11% smaller
(ANOVA; F1,34 = 22.0; P<.001) in the
VCFS group (1154 ± 97 cm3) relative to controls (1309 ±
102 cm3). Gray (F1,34 = 7.6; P<.01)
and white (F1,34 = 22.0; P<.001) matter
contributed to this difference.
The ANOVA comparisons (Table 2)
indicated a significant difference between the control and VCFS subgroups
when comparing total volume of cerebral gray (F2,33 = 7.8; P<.01; Figure 1)
and white (F2,33 = 12.2; P<.001) matter.
When both subgroups were compared with the controls (follow-up Scheffé
tests), the VCFS subgroup with maternal-origin deletions showed significantly
decreased volumes of gray (P<.005) and white (F2,33 = 12.2; P<.001) matter compartments.
In contrast, the subgroup with deletions of paternal origin showed only decreased
cerebral white matter relative to controls (P<.05).
Finally, the follow-up Scheffé tests comparing VCFS subgroups indicated
that children with the deletion on the maternal chromosome 22 had significantly
decreased (P<.05) gray matter volume but no significant
difference in white matter volume (P = .41).
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Table 2. Gray Matter and White Matter Volumes*
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Figure 1. Differences in total cerebrum
gray tissue volume between subjects with maternal and paternal 22q11.2 deletion
and normal control subjects.
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Regression analyses indicated that age significantly predicted gray
matter volume decrease only for subjects with maternal-origin deletions (R2 = 0.58; P = .02;
Figure 2). Using a follow-up Fisher r-to-z
transformation, the age–gray matter correlations of controls and subjects
with VCFS with the deletion on the maternal chromosome 22 were compared; this
comparison did not reach statistical significance (z
= 1.61; P = .11).
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Figure 2. Developmental paths of gray matter
volumes of subjects with maternal and paternal 22q11.2 deletion and normal
control subjects. The uppermost regression line shows gray matter volume changes
with age in normal controls; the middle line, in subjects with velocardiofacial
syndrome (VCFS) due to a paternally derived deletion; and the lowermost line,
in subjects with VCFS due to a maternally derived deletion.
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COMMENT
A previous publication24 showed that
children and adolescents with VCFS experience reduction of gray and white
matter tissue volumes. To date, no study has investigated the potential impact
of parental origin of the deletion on brain development in VCFS. Our results
indicate a significant effect of the parental origin of 22q11.2 microdeletions
on brain development in children and adolescents with VCFS (Figure 1). Subjects who inherit their unique set of 22q11.2 genes
through the paternal germ line (ie, who have a deletion on the maternal chromosome
22) have reduced volumes of gray matter compared with normal control subjects
and patients inheriting these genes only from the maternal germ line. Imprinting
and inhibition of the expression of at least 1 gene affecting neuronal proliferation
or cell death, dendritic arborization, or creation and elimination of synapses
is a possible explanation for this phenomenon. Because white matter tissue
tends to be reduced independent of parental origin of the deletion, it seems
likely that haplo-insufficiency of another distinct gene(s) also coded in
the 22q11.2 region is responsible for this effect. Clear limitations of this
preliminary study reside in the limited sample sizes and the cross-sectional
nature of data.
Previous evidence that genetic paternal imprinting affects neuronal
and brain development has been demonstrated in 2 lines of research. First,
support for paternal genetic imprinting is derived from knowledge of another
genetic disorder, Angelman syndrome. Persons with this condition, due to paternal
uniparental disomy (UPD, abnormal inheritance of both homologue chromosomes
from the same parent) for chromosome 15 or maternal deletion of 15q11.1-12,
manifest severe mental retardation, absent speech, ataxia, jerky limb movement,
and inappropriate laughter.32 Neuropathology
studies33, 34 of Angelman syndrome
show decreased dendritic arborization and reduction in number of dendritic
spines of pyramidal neurons in cortical layers 3 and 5. Second, animal models
have provided additional information regarding the involvement of imprinting
mechanisms in normal brain development. The creation of maternal and paternal
disomic chimeras in mice has been made possible recently through experimental
chromosomal rearrangement during early embryonic development.35, 36, 37
These chimeras are embryos consisting of a mixture of cells maternally disomic/normal
(ie, a mixture of maternally disomic cells and normal cells [mixed populations])
or paternally disomic/normal. Observations of cerebral and neuronal development
in these chimeric mice have suggested that, compared with normal mice and
paternal chimeras, augmented development of neurons in the neocortex and the
striatum occurs in maternal chimeras. Further, compared with normal littermates,
brains of mice with maternal disomy are enlarged, likely the result of double-expressed
gene dosage, whereas brains with paternal disomy are reduced in volume. These
findings in animal models are consistent with reduction of gray matter in
subjects with VCFS who have deletion of the maternal allele as described herein,
and suggest an essential role for maternally expressed alleles in cortical
and telencephalic development.
The number of publications reporting UPD and the effect of parental
imprinting on chromosome 22 is very limited,38
with only a single case report of paternal UPD.39
No obvious impact of UPD of chromosome 22 on clinical phenotype has been detected.
However, these reports did not investigate brain development and morphology,
and did not assess cognitive abilities using standardized tools.39, 40, 41, 42
Similarly, previous studies looking at the molecular pathophysiology or physical
phenotype of VCFS have not pointed to an imprinting effect. Although studies
have observed that familial transmission of the disorder results in more severe
intellectual disabilities than de novo cases,26, 27
investigators have not explained this finding adequately. It is possible that
this observation is a consequence of a recruitment bias of subjects with a
maternally deleted deletion, because women with VCFS seem more likely to reproduce
than men and are more likely to be identified when a parent of a child with
VCFS is affected.16, 26
The differential effect of parental origin of 22q11 deletion on gray
matter development has several implications for research on VCFS as well as
schizophrenia. First, discovery of a potentially imprinted gene contributing
to decreased gray matter in VCFS considerably narrows the number of gene candidates
whose hemizygosity is responsible for neuronal development in the 22q11.2
region. Second, smaller gray matter volume exhibited by children with maternal
origin of the deletion may place these subjects at increased risk for childhood-
or adult-onset schizophrenia. Recent publications in schizophrenia have demonstrated
the potential significance of cortical gray matter reduction and support the
hypothesis of a premorbid neurodevelopmental etiologic process. Adolescents
with childhood-onset schizophrenia experienced a 4-fold decrease of cortical
gray matter relative to their normal counterparts.43
In patients with adult-onset schizophrenia, gray matter volume reduction is
already evident at first clinical presentation of the disorder44, 45
and appears to explain at least partially the morbid44, 46, 47
and premorbid cognitive features48 associated
with this condition. If VCFS, like schizophrenia, is a developmental disorder
associated with excessive gray matter reduction, it could provide a potential
model for studying etiologic pathways leading to schizophrenia or associated
neuropsychiatric disorders. Parental origin of predisposing alleles should
be considered when constructing genetic models for schizophrenia, particularly
as pertaining to the potential influence of imprinting on the pathogenesis
of this neuropsychiatric disorder49 and on
cortical development.50
The small subsample sizes of the present study represent an important
limitation and necessitate replication with larger groups. In addition, because
of statistical power limitation, we did not investigate subregions of the
brain to further identify potential differences in neuroanatomical patterns
among VCFS subgroups and controls. Future studies will need to validate our
preliminary results using larger samples and to investigate potential differences
in brain development using longitudinal data. Identification of the parental
origin of 22q11.2 microdeletion in adult subjects with VCFS and schizophrenia
awaits future research that integrates neuroanatomy, cognition, and psychopathology.
AUTHOR INFORMATION
Accepted for publication September 25, 2000.
The research presented in this article was supported by the Swiss National
Research Fund (Dr Eliez) and grants MH01142 and HD31715 from the National
Institutes of Health, Bethesda, Md (Dr Reiss). This work also was partially
supported by grants from the MIND (Medical Investigation of Neurodevelopmental
Disorders) Institute, University of California, Davis, and the Packard Foundation,
Stanford, Calif (Dr Reiss).
We thank Eric Schmitt and Christopher White for their image acquisition
and processing work, Christine Monso-Hinard for the fluorescent in situ hybridization
and polymerase chain reaction analyses, Laura van Hertzen and Anni Schönbörner
for technical expertise, and Christine Blasey, PhD, for her statistical consultation.
From the Department of Psychiatry, Stanford University School of Medicine,
Stanford, Calif (Drs Eliez and Reiss); and Division of Medical Genetics, Geneva
University School of Medicine, Geneva, Switzerland (Drs Antonarakis, Morris,
and Dahoun).
Corresponding author and reprints: Stephan Eliez, MD, Department
of Psychiatry, Stanford University School of Medicine, 401 Quarry Rd, Stanford,
CA 94305-5719 (e-mail: eliez{at}stanford.edu).
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