Background22q11.2 Deletion Syndrome (22q11DS) is a genetic disorder characterized by the deletion of adjacent genes at a location specified as q11.2 of chromosome 22, resulting in an array of... Show moreBackground22q11.2 Deletion Syndrome (22q11DS) is a genetic disorder characterized by the deletion of adjacent genes at a location specified as q11.2 of chromosome 22, resulting in an array of clinical phenotypes including autistic spectrum disorder, schizophrenia, congenital heart defects, and immune deficiency. Many characteristics of the disorder are known, such as the phenotypic variability of the disease and the biological processes associated with it; however, the exact and systemic molecular mechanisms between the deleted area and its resulting clinical phenotypic expression, for example that of neuropsychiatric diseases, are not yet fully understood.ResultsUsing previously published transcriptomics data (GEO:GSE59216), we constructed two datasets: one set compares 22q11DS patients experiencing neuropsychiatric diseases versus healthy controls, and the other set 22q11DS patients without neuropsychiatric diseases versus healthy controls. We modified and applied the pathway interaction method, originally proposed by Kelder et al. (2011), on a network created using the WikiPathways pathway repository and the STRING protein-protein interaction database. We identified genes and biological processes that were exclusively associated with the development of neuropsychiatric diseases among the 22q11DS patients. Compared with the 22q11DS patients without neuropsychiatric diseases, patients experiencing neuropsychiatric diseases showed significant overrepresentation of regulated genes involving the natural killer cell function and the PI3K/Akt signalling pathway, with affected genes being closely associated with downregulation of CRK like proto-oncogene adaptor protein. Both the pathway interaction and the pathway overrepresentation analysis observed the disruption of the same biological processes, even though the exact lists of genes collected by the two methods were different.ConclusionsUsing the pathway interaction method, we were able to detect a molecular network that could possibly explain the development of neuropsychiatric diseases among the 22q11DS patients. This way, our method was able to complement the pathway overrepresentation analysis, by filling the knowledge gaps on how the affected pathways are linked to the original deletion on chromosome 22. We expect our pathway interaction method could be used for problems with similar contexts, where complex genetic mechanisms need to be identified to explain the resulting phenotypic plasticity. Show less
The studies described in this thesis aim to provide a better understanding of the mechanisms that result in vulnerability to autism and ADHD symptomatology in individuals with the 22q11 deletion... Show moreThe studies described in this thesis aim to provide a better understanding of the mechanisms that result in vulnerability to autism and ADHD symptomatology in individuals with the 22q11 deletion syndrome (22q11DS). The objective of the current thesis was to investigate the association between neurocognitive functioning and severity of autism and ADHD symptomatology in individuals with 22q11DS. For this purpose intellectual functioning, executive functioning and social cognition were assessed in a sample of children and adolescents (aged 9-18.5 years) with 22q11DS. Our findings show that children and adolescents with 22q11DS present with severe impairments on various domains of neurocognitive functioning. Some of these impairments are associated with the variable expression of social behavioral problems within the syndrome, underlining the importance of monitoring the cognitive development within this population. This knowledge can be used as a starting point for the development and adjustment of preventive interventions and for treatments of children and adolescents with 22q11DS who are at risk of these developmental problems. For clinical practice and future research it is important to be aware of the role of both genetic factors and neurocognitive functioning in the presence and severity of behavioral problems in syndromes like 22q11DS. Show less
