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Neurodevelopmental and neuropsychiatric disorders in individuals with rare pathogenic genetic variants analysis in clinical and population-based cohorts

Ali, Nabila 2023. Neurodevelopmental and neuropsychiatric disorders in individuals with rare pathogenic genetic variants analysis in clinical and population-based cohorts. PhD Thesis, Cardiff University.
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Rare genetic variants – namely copy number variations (CNVs) and single gene variants (SGVs) - have been associated with an increased risk of neurodevelopmental and neuropsychiatric disorders (NDDs and NDPs). Specifically, 54 CNVs have been strongly associated with these disorders and are collectively called NDD-CNVs. While case-control studies have offered valuable insights into the role of these rare variants in NDDs and NPDs, population-based studies can provide more accurate estimates of their prevalence in the general population and a better understanding of their impact on the risk of NDDs and NPDs. Moreover, the majority of research on the genetic susceptibility to NDDs and NPDs has been conducted on individuals of European ancestry leaving significant knowledge gaps regarding the generalizability of these findings to other ancestry groups. However, there are now large-scale population-based studies, such as Born in Bradford (BiB) and Genes and Health (G&H), that specifically focus on individuals of South Asian (SA) ancestry. These studies offer unique and novel opportunities to explore the burden of NDD-CNVs in one of the UK's largest ethnic minority groups. This thesis showcases the findings of three projects that investigated the impact of rare variants on neurodevelopmental NDDs and NPDs in clinical and population-based cohorts. The first project examined the variation in autism trait prevalence and profile scores across 30 different rare variant genotypes and evaluated the extent to which autism traits in individuals with these variants differ from those with idiopathic autism (autism with no known genetic cause). The findings showed considerable variations in autism prevalence with stronger evidence of convergence rather than divergence across rare variant genotypes. Comparisons with young people with idiopathic autism indicated some differences in domain scores in those with SGVs but no differences with those with NDDCNVs. The second project explored the prevalence and impact of NDD-CNVs on neurodevelopmental and cognitive outcomes in the BiB multi-ethnic birth cohort. The prevalence of NDD-CNVs in children was 1.99%, which was higher in children of European than SA ancestry. Children with NDD-CNVs had greater difficulty achieving their academic potential and were more likely to be affected by neurodevelopmental traits including autism. The third project estimated the prevalence of NDD-CNVs and the association with NDDs and NPDs among adults of SA ancestry in the G&H cohort. 1.28% of the cohort had at least 1 of 54 NDD-CNVs. The prevalence of NPDs was comparable between those with and without NDD-CNVs. However, specific NDD-CNVs showed a higher risk of NPDs. For instance, 1q21 deletion and duplication were associated with SCZ, while 15q11.2 deletion was linked with depression. Overall, this thesis provides important insights into the association between rare variants and NDDs/NPDs that can inform further research and provide a basis for better support and care.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 19 December 2023
Last Modified: 19 Dec 2023 16:52

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