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.