| Summary: | 22q11.2 Deletion Syndrome (22q11.2DS) is a genetic disorder that results from a hemizygous deletion at chromosome 22q11.2, occurring at an incidence of 1 in 4000 live births. It is associated with a wide range of clinical features, such as congenital heart disorders and abnormal facial features. 22q11.2DS patients also have an increased risk of neuropsychiatric disorders, with deletions at 22q11.2 being the highest known risk factor for schizophrenia. However, the mechanisms underlying 22q11.2DS symptomatic variability are still unclear. This thesis addresses this issue by investigating genetic, epigenetic and transcriptomic changes related to 22q11.2DS. Firstly, by using a polygenic risk score profiling approach it shows that the increased risk of schizophrenia in 22q11.2DS patients is partly due to an increased burden of common genetic variants associated with this neuropsychiatric disorder. This thesis also presents evidence that DNA methylation, an epigenetic mark, is altered in 22q11.2DS patients compared to a control population that do not carry a deletion at 22q11.2. Microarray-based whole epigenome analysis showed that these patients have an altered DNA methylation profile that affects genes and biological pathway relevant to schizophrenia. Finally, the CRISPR/Cas9 genome editing technology has been employed in human embryonic stem cells to delete one of the genes spanned by the 22q11.2 deletion. This gene, DGCR8, is a major component of the microRNA biogenesis pathway that is involved in the regulation of gene expression. The knock-out cell lines generated in this study were differentiated into neural progenitor cells to investigate transcriptome changes due the deletion of this gene during neurodevelopment. In conclusion, this thesis shows that the increased risk for schizophrenia in 22q11.2DS patients depends in parts on common genetic variants located outside of the deletion. Moreover, different mechanisms involved in genetic regulation (DNA methylation, microRNAs) can possibly modulate the schizophrenia phenotype by affecting relevant genes and pathways.
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