Clinical and Molecular Analysis of Inherited Corneal and Anterior Segment Ocular Disease

Abstract

An astounding recent increase in the knowledge of the genetic basis for disease is aided by newer techniques and technologies with which to characterise DNA and genes, in particular the Human Genome project. Combined with robust bioinformatic resources, the availability of this vast amount of genomic information in the public domain has facilitated worldwide investigation into genetic disease. Within the field of ophthalmology, sophisticated examination and imaging devices have also enabled in-depth clinical characterisation of disease entities allowing distinction of subtle differences between similar phenotypes, frequently rendering the existing classification and nomenclature systems inadequate. The challenge to the Ophthalmologist is how to make this vast amount of information relevant to clinical practice, to be used in the clinical setting to facilitate management and treatment, and to ultimately reduce visual impairment. This MD thesis will cover the basic principles of ocular embryology, and anatomy of the cornea and anterior segment. The importance of comprehensive clinical disease characterisation, phenotyping, will be demonstrated. Tools for molecular analysis including Polymerase chain reaction (PCR), pedigree construction, and gene identification will also be covered in the search to identify causative genes in ocular disease. This includes a candidate gene approach, and linkage analysis. The ocular disorders covered involve the structures of the anterior segment of the eye, specifically the cornea, and the angle of the eye, involved in glaucoma, and other structures in the anterior segment including the iris, and the lens. Work undertaken during my fellowship at the Hospital for Sick Children involved Identification of a novel genotype correlation in Peters anomaly lead the way to further characterisation in a larger glaucoma population, with a digenic inheritance observed. Extrapolation of this same screening method in a New Zealand population also suggests a multiallelic inheritance for glaucoma. Within the group of corneal dystrophies, much phenotypic and genotypic variation occurs. Molecular characterisation of a New Zealand cohort of families and individuals has defined the spectrum of TGFBI changes, identified novel genotype-phenotype variations in this gene, and identified individuals with similar dystrophies without TGFBI mutation. This has lead to further novel genotypephenotype discoveries such as the atypical lattice dystrophy associated with amyloidoisis, and a family with an anterior membrane/fleck dystrophy that has a likely novel genetic mechanism. The genetics involved in Posterior polymorphous dystrophy with an overlap into keratoconus are also explored in relation to the ZEB1 and VSX1 genes. This thesis provides insights over a decade into the advancing knowledge of the genetics involved in the glaucomas and inherited corneal dystrophies.