Burleigh, Alice Georgia;
(2023)
Monogenic mimics of Behçet’s Disease.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Behçet’s Disease (BD) is a rare multisystemic variable vessel vasculitis with a chronic and relapsing disease course. BD is polygenic, and genome wide association studies in cohorts around the world have defined risk alleles across various loci which predispose individuals to the disease. The strongest associated genotype is HLA-B*51. Several monogenic autoinflammatory disorders and primary immunodeficiencies can present with features that may be mistaken for BD, and it is important that they are diagnosed as the treatments and prognoses can differ significantly. In this thesis, patients with clinically suspected BD were recruited from four specialist BD care centres in the UK. I designed a novel genetic workflow specifically to identify variants causing monogenic disease and perform HLA-typing from the same dataset. All participants underwent whole exome sequencing, and genetic analysis was undertaken thereafter by 1. examining germline and somatic variants in genes known to cause monogenic immunodeficiency, autoinflammation or vasculitis by virtual gene panel application; 2. scrutiny of data prioritised by human phenotype ontology using Exomiser; 3. identification of copy number variants using ExomeDepth; 4. HLA and ERAP1 genotyping using OptiType and ERAPlotype. Using this approach, I identified a series of patients with monogenic diseases mimicking BD, including some with novel variants in TNFAIP3 and ISG15. HLA-B*51 positivity was also confirmed in some cases. I characterised the novel variants through functional investigation of these patients, which led to the first case of successful targeted treatment of ISG15 deficiency with Janus kinase inhibition. In summary, I have described a novel genetic workflow for BD facilitating precise genetic diagnoses, and more accurate patient classification based on characterisation of the genetic architecture of BD. This approach can efficiently detect known and potentially novel monogenic forms of BD, whilst additionally providing HLA-typing which can be helpful for the classification of typical polygenic BD.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Monogenic mimics of Behçet’s Disease |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/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 Population Health Sciences > UCL GOS Institute of Child Health |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10171824 |
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