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Brittle cornea syndrome (BCS) is an autosomal recessive, multisystemic connective tissue disorder characterised by extreme corneal thinning and fragility. Mutations in transcription factors ZNF469 and PRDM5 cause BCS types 1 and 2, respectively. Both genes are believed to regulate the transcription of extracellular matrix (ECM) components, particularly fibrillar collagens, and are suggested to act on a common pathway. Molecular diagnosis is available for affected patients, and those at risk of being heterozygous carriers. Chapter 3 presents the identification of mutations in ZNF469 in 14 families with BCS, and evidence for the downregulation of ECM-associated transcripts in skin fibroblasts from patients with ZNF469-associated disease by Q-PCR.Chapters 4 and 5 focus on PRDM5-associated disease. Chapter 4 highlights previously undescribed and potentially phenotype-related aspects of PRDM5- associated BCS. In chapter 4, a potential role for PRDM5 in development of Bruch’s membrane is suggested, by the observation of significantly reduced expression of major components of Bruch’s membrane, including collagens types I, III, and IV in patients with PRDM5-associated disease using immunohistochemistry. A first description of PRDM5 expression in the human eye is also presented in chapter 4. In chapter 5, a potential role for PRDM5 in retinal vasculogenesis is suggested. PRDM5-related disease also offers an in vivo opportunity to observe a subset of epigenetic regulatory mechanisms in an inherited eye disease, providing mechanistic insights, presented in chapter 5. Examination of PRDM5 interaction partners by pull-down and mass spectrometry reveals the diminished interaction of a PRDM5 construct carrying a BCS-associated mutation with repressive complexes, and, through studies on fibroblasts and retinal tissue from patients, we suggest a role for dysregulation of the repressive histone mark H3K9 di- methylation in vivo. These findings suggest a role for a molecular network surrounding dysregulated H3K9 di-methylation in PRDM5-associated disease. Finally, chapter 6 expands the study of a rare disease into more common diseases investigating the role of genetic variations in ZNF469 and PRDM5 in keratoconus, an ocular disorder resulting in progressive corneal thinning. I identified enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients, highlighting ZNF469 as the most significant genetic factor responsible for keratoconus identified to date. In conclusion, this study of a rare disease, BCS, has provided translational research insights (chapter 3), functional insights (chapter 4) mechanistic insights (chapter 5) and has expanded into other, less rare, diseases (chapter 6).