Sergouniotis, P.I.; (2012) Genetic and phenotypic heterogeneity in autosomal recessive retinal disease. Doctoral thesis , UCL (University College London).

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Abstract

Molecular genetics has transformed our understanding of disease and is gradually changing the way medicine is practiced. Genetic mapping provides a powerful approach to discover genes and biological processes underlying human disorders. Recent advances in DNA microarray and sequencing technology have significantly increased the power of genetic mapping studies and have ushered in a new era for biomedicine. In this thesis, linkage analysis (including homozygosity mapping), exome sequencing and candidate gene sequencing have been utilised to genetically dissect autosomal recessive retinal disease. Subsequently, clinical findings from patients found to be similar in terms of molecular pathology have been pooled. DNA and basic phenotypic data from over 500 unrelated individuals were available for the project. Disease-causing variants in three genes that have not been previously associated with human recessive disorders are reported: (a) biallelic mutations in TRPM1 abrogate ON bipolar cell function and cause complete congenital stationary night blindness; (b) biallelic mutations in KCNJ13, a gene encoding an inwardly rectifying potassium channel subunit cause Leber congenital amaurosis; (c) biallelic mutations in PLA2G5, a gene encoding group V phospholipase A2, cause benign fleck retina. The consequences of mutations in these and other disease-related genes (RDH5, GRM6, KCNV2, OAT and SAG) on retinal structure (spectral domain optical coherence tomography, fundus autofluorescence imaging) and visual function (electrophysiology, perimetry testing) have been studied; features that may have mechanistic relevance have been identified. Additionally, DNA sequence variation of a highly polymorphic gene (C2ORF71), recently associated with photoreceptor degeneration, has been studied and quantified in patient and control samples. Basic bioinformatics tools to analyse genomic data have been developed (bash, perl, python and R programming languages). Overall, results presented in this thesis contribute to an understanding of Mendelian retinal disease that is not only observational but also mechanistic.

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