Triplet Repeat Expansion-associated Inherited Corneal Disease: from Genetic Mechanism to Clinical Consequences

Fuchs endothelial corneal dystrophy (FECD) is a common, late-onset cause of visual impairment and the leading indication for corneal transplantation in the United Kingdom. in up to 80% of patients, is associated with a trinucleotide repeat expansion (termed CTG18.1) within an intronic region of the transcription factor encoding gene TCF4. The relative contributions of genetic variants influence to disease onset and progression remain incompletely defined. This Thesis integrates molecular, genetic, and multimodal clinical data to characterise the determinants of FECD risk, severity, and early phenotypic expression. Using the largest genotyped multicentre FECD cohort to date, the CTG18.1 expansion was confirmed as the predominant genetic risk factor across European and South Asian populations. The well-established female preponderance observed in FECD is primarily driven by the expansion negative group. Repeat length and zygosity were modifiers of age at corneal transplantation and disease penetrance. To gain insight into somatic mosaicism at this locus, an ultra-deep, locus-specific sequencing strategy combined with a custom bioinformatic pipeline was used to profile CTG18.1 somatic instability. Expanded alleles exhibited marked, repeat-length–dependent mosaicism, with increasing structural complexity in individuals carrying longer inherited alleles. These findings position FECD within the broader class of trinucleotide repeat disorders and provide a foundation for identifying genetic modifiers of somatic expansion. Moreover, a genome-wide polygenic risk score was developed and validated, demonstrating independent predictive value for keratoplasty risk and time to surgery. Beyond genetic, detailed corneal imaging of genetically characterised participants mapped structural and neuro-morphological alterations across the disease continuum, revealing subclinical phenotypes that bridge genetic predisposition and clinical onset. Collectively, this Thesis establish a composite genetic model in which both the high impact repeat expansion and common variant burden jointly modulate clinical trajectory of FECD. The joint genetic and imaging findings thus providing a framework to support precision risk stratification, early detection, and future pre-symptomatic therapeutic trials.