Jurkute, Neringa; (2023) Elucidation of the missing heritability in mitochondrial eye disorders - clinical, molecular and functional investigations. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Mitochondrial diseases are a clinically and genetically heterogeneous group of disorders that can affect any part of the human body. The phenotypic spectrum can range from isolated ocular disease to a severe early-onset multisystemic disorder. Since 1988, numerous disease causing genes have been identified and this continues to expand rapidly. There is a compelling need to improve molecular diagnosis in inherited eye diseases as current genetic testing strategies within the UK fail to identify the molecular cause of disease in a significant proportion of patients. The lack of a confirmed molecular diagnosis limits access to effective clinical care, family testing, genetic counselling, and importantly, access to potential treatment or the possibility of taking part in experimental treatment trials. It is likely that variants outside of the coding regions or undetected structural variants of known genes, and variants outside of these genes may be involved in the pathogenesis of the mitochondrial eye diseases. The aim of this project was to tackle the issue of missing heritability in inherited mitochondrial eye diseases, and in such advancing diagnostics and understanding the potential disease mechanisms. In order to identify the underlying genetic defect in the group of patients with a suspected inherited optic neuropathy/mitochondrial eye disease, analysis of Whole Genome Sequencing (GS) data collected as part of the National Institute for Health Research BioResource rare-disease project (NIHR-RD) and UK Genomics England 100,000 Genomes Project (UK’s 100KGP) was performed. Unbiased interrogation of genomic variants by applying analysis pipelines developed in-house allowed the entire human genome to be interrogated and enabled the identification of variant/s missed by current genetic testing strategies. Functional investigation of selected/novel variants/genotypes demonstrated a pathogenic effect that could lead to vision loss.

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