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Genotype-Phenotype Correlations in Fuchs Corneal Endothelial Dystrophy

Muthusamy, Kirithika; (2022) Genotype-Phenotype Correlations in Fuchs Corneal Endothelial Dystrophy. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Fuchs endothelial corneal dystrophy (FECD) is the most common form of corneal dystrophy and the leading indication of corneal transplant surgery worldwide. Over the past decade, greater insight into the genetic changes causative of FECD has provided clinicians with an opportunity to improve our understanding of this dystrophy and to explore new potential therapeutic avenues. In this thesis, I investigate the genotype-phenotype correlations identified in a cohort of 342 FECD patients recruited from Moorfields Eye Hospital. By first studying the CTG trinucleotide repeat expansion within the TCF4 gene (termed CTG18.1), the causal variant in the majority of FECD patients, I have shown the existence of significant demographic differences between FECD patients who carry this mutation (ExpPos) and those who do not (ExpNeg). I have also demonstrated a significant correlation between repeat expansion size and disease severity in ExpPos subjects, as longer repeat length was associated with younger age at transplantation. I then carried out phenotype analysis on ExpNeg patients who were identified to harbour other FECDassociated variants via whole exome sequencing. The findings within this subgroup support the classification of corneal decompensation secondary to mutations in the COL8A2 gene as a clinical entity distinct from FECD, in view of significant differences in both disease onset and severity. Investigation of the FECD cohort further highlighted the rare concurrent presentation of keratoconus in this population. Although we found no definitive genetic link between the two diseases, this study highlights the clinical challenges that arise in the diagnosis and management of patients presenting with the dual pathology. Finally, to translate the advances made in the field of molecular genetics into improved treatment options for FECD patients, I discuss the design of a Phase 1 clinical trial to evaluate the therapeutic potential and safety of an antisense oligonucleotide therapy targeting ExpPos FECD.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Genotype-Phenotype Correlations in Fuchs Corneal Endothelial Dystrophy
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2022. 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 > 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 > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10157798
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