CANDY MULTIPLEX STUDY

Neurodevelopmental disorders (NDDs) are frequent and significantly impact
peoples* lives. According to the DSM-5, NDDs include Autism Spectrum Disorder
(ASD), Attention Deficit Hyperactivity Disorder (ADHD), Intellectual Disability
(ID), specific learning disorders, language disorders and motor disorders.
ADHD, ID and epilepsy co-occur more often within an individual with ASD than in
the general population. Further, NDDs are highly heritable and cluster in
partly the same families. Most studies investigate families with a single
affected member but few studies have investigated the other family members who
are likely to be affected by NDDs or epilepsy. The relationship between
genotype and phenotype is only partially understood, especially in families in
which several individuals are affected by heterogeneous forms of NDDs.
In the current study, we will investigate the shared and distinct genetic and
biologic mechanisms involved in those NDDs by recruiting so-called multiplex
(MPX) families in which there are at least two patients, one proband with ASD,
and at least one other first-degree or second-degree relative with epilepsy,
ASD, ID or ADHD.

1) Assess the whole genome sequence (WGS) and clinical profile of the MPX
families to identify how rare and common genetic variants interact to produce
shared versus distinct NDDs and clinical features in individuals, or different
combinations of NDDs and/or epilepsy in an individual.

Nota Bene: We will not perform whole genome sequencing analysis in participants
younger than 16 years, but only assess variation in "common genes".

2) Identify the molecular pathways that are involved in the clinical phenotype
and cut across NDD in relationship with the genetics variants by combining
different technique used to identify (i) mutated genes; (ii) common genetic
variants; (iii) the genetic background; and (iv) the clinical profile of the
individual.

The CANDY multiplex study is an observational multi-centre study conducted at
five sites: Robert-Debré Hospital (Paris), King*s College London (London),
Radboudumc (Nijmegen), Ghent University and Karolinska Institutet (Stockholm).
The study will be conducted over 36 months (time between the first and last
visit).

We will collect biosamples by means of venapuncture in all participants for
genetic studies and immune profiling, and collect data by questionnaires and
interviews. In addition to adults and adolescents, children of 3 years and
older will be included in this study, as we are also investigating the
development of and emergence of NDDs over a wide age range. A study of very
young and young children through to adults is vital to understanding how the
clinical and genetic/ biomarker profile of NDDs changes at different time
points. As this is an explorative study, the hypotheses that are generated as a
result of these experiments will stimulate and inform future NDD research.
Overall, this work will lead to new insights into the common and distinct
genetic and biologic mechanisms that underpin ASD, ADHD, ID and epilepsy. This
will lead to better counseling of families with NDDs and development of
targeted treatments.