Genetics and psychopathology in the 22q11.2 deletion syndrome: A follow up study

Schizophrenia and autism are debilitating psychiatric disorders for which a
curative treatment is not yet available. The most important reason for the lack
of an effective treatment is the currently limited insight in the biological
mechanisms that lead to these diseases. One approach to further our
understanding of the (abnormal) biological processes is the identification of
genes associated with the disease. A gene encodes a protein, which in turn
fulfills a specific biological role. Thus, uncovering an association between a
gene and a disease opens ways to new research into the biological functions of
the implicated protein. This way the (abnormal) biological processes involved
in the disease can be clarified, a first, highly important step towards the
development of better treatments for these diseases.

However, despite the available evidence pointing towards an important role of
genetics in both autism and schizophrenia, the identification of the actual
culprit genes has thus far been very challenging. This may be because (amongst
others): 1) in most patients multiple genes with each a modest effect may be
involved, 2) in a supgroup of patients extremely rare genetic variants with a
large effect may be the cause of the disease, and 3) both autism and
schizophrenia are heterogenic diseases; i.e. several different biological
pathways may lead to the same clinical phenotype in different patients. The
motivation for the the current study can be formulated in the context of these
difficulties.


In adults with 22q11.2DS, the prevalence of schizophrenia is strongly elevated
in comparison to the general population (respectively 20-30% versus 1% in the
general population), also the incidence of autism spectrum disorder in children
with 22q11.2DS is 21, 2. Vice versa, the prevalence of 22q11.2 deletions in
schizophrenia patients is approximately 30 to 50%.

There are two main reasons why longitudinal studies of the psychiatric symptoms
in individuals with 22q11.2DS are of particular value:
a. The 22q11.2DS population can be viewed as one of the strongest high risk
groups for psychosis.
b. All 22q11.2DS individuals share a chromosomal deletion which involves the
same genomic region.
c. In contrast to the high biological heterogeneity of these
diseases in the general population, one can assume that in different patients
with schizophrenia and 22q11DS, one and the same biological mechanism is
involved.

Thus, the 22q11.2 region is one of several genomic regions associated with
schizophrenia. Therefore it can be assumed that one or more genes within this
region contribute to psychosis in this population which significantly reduces
the number of potential candidate genes to 30 - 50. By comparison: a study of
the genetic variants involved in schizophrenia in the general population needs
to take intoe account ~25,000 potential risk genes.

During the planned follow-up measurements, (T1 and T2), we anticipate that
approximately 20% of the cohort will develop schizophrenia. The partition of
the sample into *cases* and *controls* with respect to this diagnosis is the
basis of all studies proposed in this research project.

Aim 1: The identification of early clinical predictors for schizophrenia.

Aim 2: The identification of susceptibility genetic variants for schizophrenia
and autism

Aim 3: The identification of structural and functional brain abnormalities that
can be correlated to a) schizophrenia development, b) autism and language
abnormalities, and c) genetic variation within the 22q11.2 region.

At least four hundred individuals with a confirmed 22q11.2 deletion will be
measured multiple times (T0, T1, T2 or Tx) with an interval 3 to 4 years, of
which at least two hundred and fifty participants will be aged 25 years or
older at time of the last assessment.
The measurements will consist of the following examinations:

- psychiatric assessment
- neuropsychological evaluation including cognitive testing and language testing
- assessment of the concentration of proline in the blood
- genotyping for specific DNA polymorphisms as well as genome wide RNA
expression profiling
- neuroimaging studies, including functional and structural studies of the
brain using MRI techniques.

- DNA study in the biological parents (n=400) in order to examine parent of
origin of the chromosome 22 which harbors the deletion in the patient affects
the psychiatric phenotype in the patient.

Except for the limited risk associated with a blood draw, there are no risks
associated with the studies in this protocol. Blood withdrawal for research
purposes (DNA and RNA extraction and proline measurement) does however, in
principle not cause an extra invasive procedure for the study's participants.
The study will take advantage of blood withdrawals that take place as part of
normal clinical practice for individuals with 22q11.2DS.

For all youngster with 22q11.2DS, including those who choose not to participate
in the study, a psychiatric and neuropsychologic evaluation is part of standard
clinical care. Extra burden associated with the participation in the study thus
mainly pertains to the (optional) additional language study the neuro imaging
(MRI) study. The MRI study is free of any risk and lasts 90 minutes per
measurement, including preparation and explanation time. Also, the amount of
blood withdrawn in participants is slightly higher than in those who do not
participate. In addition, participants will be asked to fasten overnight
(starting at 10 pm) before the morning of the blood withdrawal.

One blood draw in the biological parents of the participants will be performed,
exclusively for the purpose of the scientific study.

It is noteworthy that participants and parents are free to elect which
components of the study they wish, or do not wish to participate in.