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Title: A molecular analysis of 22q11.2 deletion syndrome
Author: Salaka, Afnan
ISNI:       0000 0004 6349 4124
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2017
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22q11.2 Deletion Syndrome is a genetic syndrome that occurs in incidence of 1:4000 and is associated with variable phenotypic expression. It is caused by a deletion at chromosome 22q11.2. Individuals with 22q11.2DS have a greatly increased risk of developing neuropsychiatric disorders, in particular schizophrenia in adulthood, and ADHD and ASD in childhood. This thesis sought to investigate the possible molecular mechanisms that underlie the psychiatric variability in 22q11.2DS by studying a well-characterized cohort of 76 children with 22q11.2DS. Four mechanisms were investigated: (a) dosage sensitivity of genes within 22q11.2 region, (b) a disruption of the expression of genes flanking the deletion i.e. positional effect and genome-wide, (c) the presence of additional genetic risk variants within the 22q11.2 region, and (d) the presence of additional CNVs outside of the 22q11.2 deleted region. While this work revealed significant evidence for differential expression of 39 of the genes spanned by the deletion, there was no significant evidence for a positional effect at other genes on chromosome 22. The genome-wide differential gene expression analysis revealed four significantly enriched biological networks (FDR < 0.05) that are involved in: 1) translation, protein synthesis machinery, and post-translation modifications; 2) apoptosis; 3) regulation of the immune system; and 4) intramembrane organelles. The association analyses of genetic variants present on the non-deleted 22q11.2 chromosome did not identify any that were significantly associated with psychiatric phenotypes in 22q11.2DS. The genome-wide screen for additional CNVs identified a non-significant trend that large, rare CNVs were enriched in 22q11.2DS patients with psychiatric phenotypes, however there was no evidence that these additional CNVs were enriched for CNVs that had been previously implicated in developmental delay and neuropsychiatric disease. In addition, in this thesis also investigated the role of deletions at 22q11.2 in a large cohort of individuals with idiopathic Parkinson’s disease. This provided significant evidence that deletions at 22q11.2 increase the risk of Parkinson’s disease, particularly the early-onset form. Taken together,the data presented in this PhD suggested that the mechanism by which haploinsufficiency at 22q11.2 increases risk to psychiatric illness is likely to be complex. To follow up this work, future studies should utilise larger numbers of samples, use neurologically relevant tissue and apply more sophisticated approaches to screen for changes in gene expression and additional genetic variants.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH426 Genetics ; RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry