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The Genetics of Primary Immunodeficiency in Children

Maimaris, Jesmeen S; (2021) The Genetics of Primary Immunodeficiency in Children. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Studies of children with recurrent infection demonstrate that primary immunodeficiency (PID) has a significant genetic component. In PID, over 300 genes of high penetrance inherited mostly in autosomal recessive manner have already been identified. However, many children, including those with early onset immunodeficiency have not received a genetic diagnosis, despite use of targeted sequencing methods. I performed bioinformatic analysis in whole genome sequencing data in patients with immunodeficiency. These analyses were initially in a small cohort of affected children at Great Ormond Street in whom a genetic diagnosis was not known. I devised and utilised bioinformatic programs to identify novel genetic variants in this cohort. I evaluated the performance of whole genome sequence analyses with targeted gene panel analyses, which is the most utilised method of genetic diagnosis. To expand my analysis, I looked at a larger cohort of young people and adults with immunodeficiency as part of the large national collaborative project NIHR Bioresource Rare Diseases BRIDGE-PID project. I quantified the burden of rare coding variation in a case cohort compared to controls and used rare variant association analysis to identify potential novel candidate genes in primary immunodeficiency. The final chapter focuses on 2 novel genetic variants found in the cohort and our initial functional testing to verify genetic diagnosis. The work presented in this thesis demonstrates novel genetic causes of immunodeficiency and their functional implications. The results of my work have improved understanding of the genetic architecture of primary immunodeficiencies and has clinical utility in the diagnosis and subsequent treatment of immunodeficiency.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The Genetics of Primary Immunodeficiency in Children
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/10130699
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