Exploring bleeding risk and platelet function combined with multiple omics techniques in 22q11.2 deletion syndrome

22q11.2 Deletion syndrome (22q11.2DS) is caused by recurrent hemizygous
microdeletions on chromosome 22q11.2, encompassing up to 90 genes. This
syndrome is characterized by a multi-organ disorder with a variable phenotype,
intellectual disability, cognitive deterioration, schizophrenia, early-onset
Parkinson*s disease, recurrent epistaxis, and macrothrombocytopenia; ~30% of
the adults with 22q11.2DS have thrombocytopenia (<150,000 platelets per mL).
Importantly, platelets have a critical role in haemostasis. Also, they show
similarities to neurons concerning several morphologic and biochemical
characteristics, are easier to investigate, and may therefore serve as a window
to the brain.
Only a limited number of studies has investigated bleeding risk and platelet
function in 22q11.2DS, and those who did only included children. Some of these
studies indicated impaired platelet function and increased bleeding risk, and
one reported a negative correlation between platelet count and age, which may
suggest that platelet-associated problems increase with increasing age.
The combination of bleeding risk score and platelet function analysis with
platelet transcriptomics and metabolomics may: 1) provide insight into bleeding
risk, which is of direct relevance for patient care, and 2) provide insight in
mechanisms underlying neurodevelopmental and neuropsychiatric disorders, like
schizophrenia, that are frequently seen in 22q11.2DS.

- To assess platelet (dys)function in adults with 22q11.2DS and its association
with bleeding history.
- To identify alterations in metabolic pathways in 22q11.2DS that may be of
relevance to mechanisms underlying neurodevelopmental and neuropsychiatric
disorders like schizophrenia.

The proposed project is a case-control study. We estimate that 12 months are
needed for patient inclusion and 8 months for data analysis. We will include 40
adults with 22q11.2DS and 20 healthy controls.
22q11.2DS patients will be included via the outpatient clinic for adults with
22q11.2DS at MUMC+, which takes place once every 2 months and is visited by 3-4
patients a day. In addition to this, 22q11.2DS patients will be recruited via
22q11 patient advocacy organizations or will be contacted by the research team
if they have given permission to be contacted for research purposes previously.
Blood drawl at the 22q11 outpatient clinic at MUMC+ is part of routine care for
patients with 22q11.2DS; for those visiting this clinic, 6 extra tubes of blood
will be collected in addition to the regular blood drawl. For healthy controls,
and those patients with 22q11.2DS participating in the study who do not visit
the 22q11 outpatient clinic, 7 blood samples will be taken at Maastricht
University or a place familiar to the adult with 22q11.2DS.
Healthy control subjects will be recruited via posters at several outpatient
clinics such as the ear-nose- throat, ophthalmology and anesthesia outpatient
clinics. Healthy subjects will also be recruited through advertising posters at
Maastricht University and patient*s family members or supervisors who accompany
the 22q11.2DS patient to the outpatient clinic will be informed about the
studying can contact the research team to participate.

All participants will complete a validated questionnaire; ISTH-BAT.
Administration time of the ISTH-BAT questionnaire is approximately 30 minutes.
In addition, seven tubes of 4-9 mL of blood will be drawn (totally 43 mL of
whole blood). This will be done during 1 site visit. Blood drawl may cause
local bruising, which usually recovers within a few days. However, for
22q11.2DS adults who visit the outpatient clinic for 22q11.2DS, we will combine
the blood drawl with their regular blood drawl for diagnostic purposes. In
accordance with treatment guidelines, adults with 22q11.2DS, undergo a
venipuncture at least once a year to check various somatic parameters.
Participation in this study therefore hardly enhances the burden for adults
with 22q11.2DS. For those who are not capable of providing answers on the
ISTH-BAT questionnaire due to cognitive impairments, we will ask the substitute
decision or caregiver to (help) complete the questionnaire. For healthy
volunteers and adults with 22q11.2DS who do not visit the outpatient clinic,
the whole study (including informed consent procedure, questionnaire, and blood
drawl) will take 1 hour in total.

Group relatedness
The study is group related; it is only possible to extent the knowledge of
platelet (dys)function, and the relationship of the metabolome with the
presence of schizophrenia, using this group of persons. Given that ~40% of the
individuals with 22q11.2DS has an intellectual disability, and only 1:3000
people has a 22q11.2DS in the general population, we would not be able to
include enough subjects if we would exclude those mentally incompetent.
Therefore, inclusion of mentally incompetent subjects is necessary.