Sadan, Amanda Nicole; (2023) Exploring the genetic architecture of Fuchs Endothelial Corneal Dystrophy, a common, age-related, and visually disabling disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Fuchs endothelial corneal dystrophy (FECD) is a common, age-related, genetically heterogenous and visually disabling disease. Expansion (defined as ≥50 copies) of a triplet repeat (termed CTG18.1) in an intron of TCF4 has been significantly associated with FECD. Other rare genetic causes of FECD have been reported and further genetic heterogeneity is hypothesised. In this thesis I present the genetic characterization of 990 FECD patients recruited at Moorfields Eye Hospital (London) and General University Hospital (Prague). DNA samples were genotyped for CTG18.1 length using a short tandem repeat assay and triplet-primed-PCR. Genotyping demonstrated approximately 80% of cases had at least one expanded CTG18.1 allele. FECD cases with one or more expanded alleles were further analysed by an ultra-deep and high-throughput MiSeq-based sequencing approach to determine CTG18.1 allelic structure in the expanded state, and to identify potential sequence variants. Furthermore, data was used to estimate progenitor allele lengths and calculate somatic expansions scores for all expanded alleles. Corresponding samples were also concurrently genotyped using a kompetitive allele-specific PCR assay to consider polymorphisms within DNA repair genes, previously identified to act as trans-acting genetic modifiers of other repeat-expansion mediated diseases. Regression analysis identified a significant association between CTG18.1 expansion rates and several polymorphisms in DNA mismatch repair genes. For expansion negative individuals (<50 repeats; n=141) exome sequencing was performed. Data were interrogated for rare (minor allele frequency ≤0.01) potentially causative variants in FECD-associated genes, which led to the identification of presumed pathogenic variants in genes including COL8A2, SLC4A11 and ZEB1. However, the vast majority of this group remained genetically unsolved and hence a subsequent gene burden case-control analysis was performed and led to the identification of a number of novel and significant associations. In conclusion, this thesis provides new insights into the complex and genetically heterogenous landscape of FECD.

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