Evans, CJ; (2017) Molecular genetics and genotype-phenotype correlation of inherited corneal dystrophies. Doctoral thesis , UCL (University College London).

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Abstract

Corneal dystrophies are a group of inherited, primarily monogenic, disorders that compromise the transparency of the cornea and cause visual impairment. A large cohort, consisting of 191 corneal dystrophy probands, was recruited to the study with the aim of investigating the genetic basis of phenotypically heterogeneous corneal dystrophy diagnoses. Following genetic investigation, genotype data was combined with clinical data to investigate genotype-phenotype correlations. The most common cause of corneal dystrophy in this cohort was heterozygous dominant mutations in TGFBI, which were identified in 70 probands with epithelial-stromal dystrophies. The majority of TGFBI mutations displayed genotype-phenotype correlation, however a p.(Gly623Asp) mutation was unexpectedly associated with a broad phenotypic spectrum of disease, including epithelial basement membrane dystrophy (EBMD). There was evidence for additional locus heterogeneity for EBMD; two families were identified in which TGFBI coding mutations were excluded, however no compelling candidate gene(s) were identified following whole exome sequence (WES) analysis. Novel and previously reported mutations in CHST6, UBIAD1 and TACTSD2 were identified for other anterior corneal dystrophies; recessive macular corneal dystrophy, dominant Schnyder corneal dystrophy and recessive gelatinous drop-like dystrophy, respectively. Dominant mutations in ZEB1 were identified in 8 patients with an endothelial dystrophy, posterior polymorphous corneal dystrophy (PPCD3), with novel heterozygous deletions encompassing the ZEB1 gene confirming haploinsufficiency as the mechanism of pathogenicity. Investigation of dominant endothelial dystrophy families using whole genome sequencing (WGS), including PPCD1 and congenital hereditary endothelial dystrophy (CHED1), revealed that mutations in the promoter of OVOL2 are a novel cause of disease and therefore that PPCD1 and CHED1 are allelic disorders. OVOL2 is a transcription factor, which is a direct repressor of ZEB1. OVOL2 was not expressed in normal corneal endothelial cells, therefore it was hypothesised that aberrant expression of OVOL2 in corneal endothelial cells causes transcriptional repression of ZEB1 expression. A novel locus causing dominant PPCD (PPCD4) was identified in a large family from the Czech Republic and linkage analysis and WGS revealed a non-coding mutation in a novel gene as likely to be causative in this family. Interestingly, a proportion of patients clinically diagnosed with a corneal dystrophy were found, on further genetic and clinical investigation, to have an inherited syndrome which was responsible for the presence of corneal opacities, the most common of which was Meretoja syndrome. In some cases, a phenocopy of disease was responsible, including paraproteinemic keratopathy. Genetic screening can therefore significantly improve clinical care for patients and their families. In summary, this study provides insight into the genetic causes of corneal dystrophies including the identification of novel corneal dystrophy genes and mechanisms of disease, which is a pre-requisite for the development of targeted genetic therapies. Furthermore, it provides further understanding of genotype-phenotype correlation for specific corneal dystrophy genes and mutations that can result in improved diagnostic and prognostic accuracy for patients.

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