UNIQUE, center for autism spectrum disorders with a rare genetic origin

Research has demonstrated that 64-91% of the variability in ASD can be
explained by genetic influences, as shown in twin studies (Tick, Bolton, Happe,
Rutter, & Rijsdijk, 2016). Yet, the genetic background of ASD remains complex
and hard to grasp.
The diversity of clinical phenotypes in ASD is in part caused by the underlying
genetic heterogeneity of ASD. Genes that share the same genetic pathway might
also share correlated phenotypes. Yet, duplications or deletions of the same
genes could lead to contrasting molecular, cellular and clinical phenotypes.
This illustrates how ASD might result from various types of neuropathology.

We know from previous studies that, on the one hand, ASD can be caused by a
single rare variant with a large effect (rare deleterious variants), and on the
other hand, the interaction of various genes involved, each with a small
additive effect (common variants), can also lead to an ASD phenotype
(Woodbury-Smith & Scherer, 2018).
Pathogenic single gene variants and de novo copy number variations are present
in 10 to 20% of the patients with an autism spectrum disorder (Abrahams &
Geschwind, 2008). These pathogenic variants are the types of disorders UNIEK
wants to study.

We aim to study the association between (clusters of) genes or genetic pathways
and phenotype in a population of people with a rare genetic variant and a
(suspected) ASD. We will do this by 1) describing the individual participant,
2) comparing participants with the same genetic variant (if available) and
lastly 3) by comparing clusters of genes/genetic pathways.
We want to gain more insight into the underlying pathophysiology of ASD by
biologically and behaviourally phenotyping children, adolescents and adults
known to have a rare genetic variant and a (suspected) ASD. We hope to achieve
this specifically for the unique participants in our study, but also for autism
spectrum disorders in general.

Our secondary objective is to create a national biobank and database to benefit
future ASD research.

The design used for this study is a multidisciplinary, exploratory,
longitudinal, observational study. We aim to collect data in the following
domains: genetics, physical health, mental health, cognitive functioning, brain
functioning, quality of life and demographic data.

The visit consists of the following components for the participant:
- 3D photograph of the face (15 minutes)
- Computer games (measuring cortical activity and eye movements) (45 minutes)
- Blood collection (1 x 28 ml) (10 minutes)
- Eye reflex meassurements (20 minutes)
- (Tasks and games with researcher, only if this information is missing (time
depends on the tests to be taken))

Only minimally invasive methods (peripheral blood) will be used to collect
blood. Side effects of blood collection are usually fairly minor.
There are no known risks or side effects for conducting neuropsychological
tasks ((computer) games and tasks) and completing questionnaires. The
neuropsychological tasks are adjusted to the cognitive level of the
participant. Eye tracking, fNIRS and 3dMD are particularly child-friendly to
use and there are no known medical risks associated with these measurements.

The burden is minimal because most research data will already be available and
can be requested.

This study focuses on people with a rare genetic variant and a (suspected) ASD.
Studying their developmental characteristics is crucial in finding the effect
of the genetic variants on ASD phenotypes. Diagnostic tests that are best
suited for investigating these characteristics are mostly taken when the
patients are young and benefit their care. Because of this, and because of the
rareness of the variants of interest, no other study groups can be used
instead.