Pagni, Susanna;
(2025)
Beyond coding sequences: investigating non-coding regulation in SCN1A and other epilepsy-associated genes.
Doctoral thesis (Ph.D), UCL (University College London).
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Thesis_SP_final.pdf - Accepted Version Access restricted to UCL open access staff until 1 February 2026. Download (5MB) |
Abstract
Pathogenic variants in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene are responsible for multiple epilepsy syndromes, including Dravet syndrome (DS), febrile seizures (FS), and genetic epilepsy with FS plus (GEFS+). A notable feature of SCN1A-related epilepsies is phenotypic heterogeneity, the causes of which remain unclear. Genetic variation in non-coding regulatory regions of SCN1A or in regulatory elements modulating other epilepsy-associated genes could be one potential causal factor. Nevertheless, a comprehensive understanding of the regulatory landscape of epilepsy-related genes is currently lacking. By integrating data from multiple genome-wide data repositories and applying bioinformatics techniques, this thesis aims to define the genomic boundaries of promoter regions, upstream open reading frames (uORFs) and enhancer regions that modulate the expression of SCN1A. By automating the workflow for gene promoter analysis, it determines the promoters and uORFs of other epilepsy-associated genes. This thesis investigates the role of regulatory variation in the phenotypic variability of 486 individuals with SCN1A-related epilepsies and as causative mutations in 996 individuals with currently unexplained epilepsy. Findings suggest that the pathogenicity of some known SCN1A disease-causing variants may be linked to their effect on uORF functionality rather than protein structure alterations. The analysis of common SCN1A enhancer variation suggests an element of genomic resilience in SCN1A-related DS, which seeks to compensate for the negative consequences of the pathogenic SCN1A coding variant. The systematic investigation of epilepsy-associated gene promoter regions reveals five rare promoter variants that could potentially explain the phenotypic presentation of affected individuals. The insights gained from this research underscore the importance of including regulatory regions in genetic studies, highlighting how understanding these regions can advance epilepsy research and lead to the development of personalised treatment strategies. Furthermore, this study establishes a framework for exploring gene regulation, which could be applied to other research areas and complex diseases.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Beyond coding sequences: investigating non-coding regulation in SCN1A and other epilepsy-associated genes |
| Language: | English |
| Additional information: | Copyright © The Author 2025. 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 Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10204099 |
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