Facial dysmorphologies associated with CNV expression in psychiatric illness

There is a strong genetic component in the development of psychiatric
disorders, but mechanisms of inheritance turn out to be complex. Highly
penetrant genetic variations are rare, but recent findings suggest a higher
prevalence of pathogenic variants in phenotypically-defined high risk subgroups
of patients with psychiatric illness. Pathogenic Copy Number Variants (CNVs)
were recently demonstrated to be present in nearly a quarter of patients with
syndromic forms of psychiatric disorder (Bouwkamp et al., American Journal of
Psychiatry 2017), most prominently involving facial dysmorphology and
intellectual disability. Moreover, rare exonic variation has been shown to
contribute importantly to psychiatric disease pathogenesis (Genovese et al.,
Nature Neuroscience 2016; Lek et al. Nature 2016). However, literature on
pathogenic CNVs and other rare coding variants in patients with psychiatric
illness remains limited, in particular regarding the criteria for
implementation of clinical genetic testing. Therefore, the current study will
investigate the relationship between psychiatric diagnosis, intellectual
disability, dysmorphic facial features and pathogenic genomic variation.

Primary objective: To evaluate whether intellectual disability and facial
dysmorphology are associated with an increased clinical diagnostic yield of
genetic testing among patients with a psychiatric illness.

Secondary objective: To investigate the multi-dimensional relationship between
pathogenic genomic variation, intellectual function, facial dysmorphology and
psychiatric diagnoses.

This study will be a naturalistic, multicentre investigation. Clinicians of the
participating mental health care centres (Erasmus MC, Antes and *s Heeren Loo)
will be informed of the study background and objectives, along with the
inclusion and exclusion criteria for enrollment. Additionally, a healthy
demographically-matched control group of adults from the general population
will be included. Subjects expressing interest to participate in the study will
be provided verbal and written information about the study by a member of the
research team. After obtaining written informed consent, the study procedure
will be performed either at the local clinic at which they were recruited, at
the outpatient clinic of the Erasmus MC, or at their home, with the choice of
location made by each subject. Blood samples will be drawn for genetic testing
and cell banking for future scientific use. Facial morphology will be
photographed using the 3dMD Face System and evaluated by a team of experienced
clinical geneticists. If a standardized psychiatric diagnosis has not been
documented in the medical record, the Diagnostic Interview for Genetic Studies
(DIGS) will be performed. If not recently measured clinically (within the prior
5 years), IQ will be assessed by means of the Wechsler Adult Intelligence Scale
(WAIS). The maximum estimated time required for the research visit is 3 hours,
for which participants will have the option to divide the visit into two visits
of 90 minutes each. Parents of the probands, if available, will be asked to
cooperate as additional control subjects by providing a blood sample for
genetic testing in order to determine whether pathogenic variants identified in
the proband are inherited or de novo. Enrollment and examination of all
subjects in this study will be conducted over a period of approximately three
years.

The risks of participation are minimal. Adverse events may include minor
bruising or local tenderness at the site of venous blood sampling. No side
effects of neuropsychological testing or imaging are known. A recent similar
study by this research group suggested there may be potential benefits to the
subject. A genetic diagnosis may improve standard-of-care treatment and
treatment of medical comorbidity. Subjects and their families often reported a
feeling of empowerment after receiving an etiological genetic explanation of
the disorder (Bouwkamp et al, 2017) and genetic counselling and testing for
relatives becomes an option. It is important to include patients with
intellectual disability in order to study its influence on the rate of copy
number variations.