Phenotypic and genetic characterisation of an extended pustular psoriasis dataset

Student thesis: Doctoral ThesisDoctor of Philosophy


Autoinflammatory diseases are a group of conditions (often monogenic) that are characterised by episodes of inflammation driven by the innate immune system. One example is pustular psoriasis, a rare and severe disorder that manifests with the eruption of sterile pustules on erythematous skin. The condition has been classified into three subtypes, (generalised pustular psoriasis, acrodermatitis continua of Hallopeau and palmoplantar pustulosis), which can be distinguished based on the localisation and extent of skin lesions, and on the presence or absence of general symptoms. 
Previous genetic studies have identified variants in IL36RN, AP1S3 and CARD14 in a proportion of affected individuals. Such patients, however, account for fewer than 30% of disease cases. Moreover, the growing use of IL36RN sequencing as a diagnostic tool has raised issues relating to the interpretation of discovered missense variants. 
In this context, the aim of the project was to improve our understanding of pustular psoriasis genetics and phenotypic variability. 
In the first stage of the study, the analysis of an extended patient cohort (n=863) revealed clinical, demographic and genetic factors that differentiated palmoplantar pustulosis from the other forms of the disease. A significant (P = 0.003), dose-dependent association between IL36RN status and age of onset was also observed. 
In the second part of the research, a set of in-vitro assays were designed to measure the impact of IL36RN missense changes on protein function. Comparison with predictions generated by online tools demonstrated the classification errors which can arise when in-silico methods alone are utilised to assess missense changes. 
Finally, the study sought to identify new genetic determinants for pustular psoriasis, by the means of whole-exome sequencing. Two candidate genes were uncovered and followed-up in a larger dataset. This highlighted the genetic heterogeneity of the condition as well as the importance of analysing representative control populations. 
Taken together, these findings have improved our understanding of known pustular psoriasis genes and paved the way for the identification of novel genetic determinants for the disease.
Date of Award1 Jul 2019
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorFrancesca Capon (Supervisor) & Jonathan Barker (Supervisor)

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