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Fuchs’ endothelial corneal dystrophy (FECD) is a bilateral, often hereditary degenerative corneal disease, in which the disrupted endothelial cell function causes corneal swelling and reduced vision. An early clinical sign of FECD is corneal guttata, an irregularity of the endothelial layer. Ocular surgery, not least cataract surgery, can lead to endothelial damage and progression of FECD. In Sweden and most Western countries, FECD is the most common indication for corneal transplantation. It has been considered a genetically heterogeneous disease but is increasingly associated with a (CTG)n repeat expansion in transcription factor 4 gene (TCF4). 

In this thesis, the association between (CTG)n repeat expansion in TCF4 and FECD was investigated, and it was hypothesised that the repeat length correlates with disease severity. The results show that FECD in Northern Sweden is associated with (CTG)n expansion in the TCF4 gene to a large extent. More precisely, expansion with more than 50 repeats in TCF4 was present in nearly 90% of the 85 tested FECD cases compared to only 3.9% in controls, which is the highest published prevalence to date. The disease's severity was associated with the repeat length in the TCF4 gene with an adjusted odds ratio (OR) of 2.13 (95% CI, 1.34-3.39) per repeat length unit. 

Further, we studied the impact of corneal guttata on cataract surgery outcome, using the data from nationwide eye registries. We show that patients with corneal guttata/FECD benefit from cataract surgery with improved visual acuity and self-assessed visual function, but that they have a greater risk of corneal transplantation and worse results of the cataract surgery than patients without FECD. The risk of corneal transplantation after cataract surgery in patients with corneal guttata was 68 times higher than in patients without corneal guttata. The risk was highest the first year after cataract surgery and decreased after that. Complicated cataract surgery with a dense lens and posterior capsule rupture, both individually and together, increased the risk of corneal transplantation, independent of corneal guttata. 

In conclusion, most patients with FECD and concomitant symptomatic cataract benefit from cataract surgery. It is not surprising that the risk of corneal transplantation after cataract surgery is increased in patients with FECD, as FECD is an indication for corneal transplantation. Still, the vast majority of FECD patients do not undergo a corneal transplant after cataract surgery. With the results of this thesis as a basis, we recommend, to start with cataract surgery before planning for corneal transplantation in most cases of FECD. Additionally, the surgery should be performed before the lens becomes hazardly dense and with caution to minimise the risk of posterior capsule rupture.

Inherited eye disorders (IED) are groups of genetically and clinically heterogenous conditions affecting different tissues in the eye. IED are most often progressive with reduced vision or legal blindness as outcome. This thesis is focused on investigating the underlying mechanisms in Fuchs’ endothelial corneal dystrophy (FECD) and two retinal dystrophies, Stargardt disease (STGD1) and autosomal recessive Retinitis pigmentosa (arRP, RP25).

In FECD, we studied the association between FECD and the (CTG)n repeat expansion at the CTG18.1 locus in the TCF4 gene, in patients from northern Sweden. By using STR-PCR and TP-PCR, we found that 90% of FECD patients carry an expanded CTG18.1 allele, establishing the highest prevalence among FECD patients world-wide. With droplet digital PCR, we showed that transcripts spanning over the CTG18.1 have lower fractions in human corneal endothelium (CE) compared to skin, brain, muscle, and white blood cells. With Illumina Methylation arrays (850K), we detected a decreased global methylation in the CE at advanced age, that could possibly contribute to the late onset of FECD. We also found distinct differences in methylation between FECD patients and controls, that led us to two coagulation factors, found to be over-expressed in the CE from FECD patients.

For the two retinal dystrophies, STGD1 and RP25, we investigated the functional effect of four genetic variants residing adjacent to or in splice consensus sequence of the ABCA4 gene (STDG1) and the EYS gene (RP25). With an in vitro mini-gene splicing assay we showed that all four genetic variants caused exon skipping in Retinal Pigment Epithelial cell line (ARPE-19) and Human Embryonic kidney cell line (HEK293T). Our results functionally proved these variants to be pathogenic and causative of STGD1 and RP25.

In RP25, we also investigated the prevalence of pathogenic EYS variants in a cohort of patients from northern Sweden. DNA from 81 patients with a clinical diagnosis of RP were interrogated with a "cascade-targeted mutation analysis" approach, where NGS, MLPA and Sanger sequencing was used to find common EYS variants in this acknowledged genetically homogenous population. EYS mutations were present in at least 16% of all arRP patients and the most recurrent mutation in the study was an 8-bp deletion, previously found in the Finnish population.

In conclusion, this thesis provides knowledge on disease causative mechanisms in IED and contributes with valuable information for future genetic counselling and genetic testing for affected families.