Mukherjee, R; (2016) Dominantly inherited retinal degeneration – exploring the spectrum of human retinal dysfunction and the underlying molecular pathology. Doctoral thesis , UCL (University College London).

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Abstract

The prevalence of retinal dystrophies among people with European ancestry is 1 in 3500-4000. Large majority of these conditions are caused by mutations in single genes inherited in autosomal recessive, autosomal dominant, X-linked recessive or mitochondrial fashion. Identification of the genotype and elucidation of the phenotype of these disorders help in improving the understanding of the pathophysiology and eventually devising novel management strategies. This thesis concentrated on autosomal dominant retinal dystrophies caused by mono-allelic mutations. The overall prevalence of the different genotypes causing autosomal dominant retinitis pigmentosa in the British population was explored. The consequence on the retinal structure (fundus examination, spectral domain optical coherence tomography, fundus autofluorescence imaging) and visual function (visual acuity, perimetry, electrophysiology) of the patients with novel mutations in the RHO, PRPF31, PRPH2, NR2E3 and IMPDH1 genes were considered. The genotypes and the phenotypes of retinitis pigmentosa due to RP1 mutations were explored which provided insight into the understanding of the natural history of the disorder. Intrafamilial variability and reduced penetrance are phenomena observed in families with inherited retinal disorders. In families with PRPF8 mutations, these observations were identified and studied. All dominant alleles appear first in families as a de novo mutation. Families with de novo mutations within the dominant GUCY2D and semi-dominant CHM genes were examined which enhanced current knowledge on the counselling of patients with these conditions. In addition, families with mono-allelic mutations in the RPE65 gene were analysed and unique phenotypes determined. Overall, results presented in this thesis contribute to an understanding of Mendelian dominant retinal disease that enhances our knowledge of the variability and natural history of the phenotypes.

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