Macken, William Logan; (2023) The application of genomic medicine to primary mitochondrial diseases. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Primary Mitochondrial Diseases (PMDs) are genetic disorders due to mutations in nuclear or mitochondrial DNA which lead to defective mitochondrial physiology. Genomic medicine is an emerging discipline that leverages the growing availability of genomic data to improve diagnostics and deliver personalised care. A genomic medicine approach could improve diagnostic rates and patient management for PMDs. Aims: 1) To review the state of the art in genomic technology in the context of PMDs; 2) To develop a clinically focused approach for whole genome sequencing (WGS) analysis to maximise diagnoses in the National Health Service (NHS); 3) To explore the role of RNA sequencing in an NHS setting as an adjunct to WGS; 4) To consider the ethical implications of PMD diagnoses arising from WGS. Methods: I conducted a literature review and curated a cohort of complex patients who had undergone WGS with semiautomated high throughput analysis. Next, I undertook a clinically focused reanalysis of WGS data and supplemented this with RNA sequencing on a group of undiagnosed patients. Finally, through case examples, I studied the complex ethical implications of PMD diagnoses using WGS data. Results: PMD phenotypes and biochemical features are poorly predictive of a diagnosis as they overlap heavily with phenocopies. A specialist multidisciplinary approach to WGS interpretation is associated with improved diagnostic rates. RNA sequencing should be considered in fibroblast and muscle RNA as an adjunct to WGS, especially as a source of functional data for splicing variants. PMD diagnostics are rife with unanticipated ethical complexities for patients and unaffected family members. Conclusions: Genomic medicine holds great promise for suspected PMDs, especially if applied by clinical specialists in a patient-centred manner. Such an approach can ensure high diagnostic rates, continued innovations in the diagnostic process, and a sensitive patient-specific approach to genomic counselling.

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