Chelban, Viorica; (2020) Approaches to discovery of disease-genes and biomarkers in rare neurological disorders: from discovery to translation into therapeutic research advances and improved clinical care. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

These are exciting times for studying the molecular basis of diseases. However, despite performing ever-increasing numbers of genome sequencing, the diagnostic rate in clinical practice is currently estimated at around 25%, an important improvement, but ultimately unsatisfactory. As a neurologist, I set out to answer the question: How can we help the remaining 75% of unsolved cases, after extensive investigations for known causes have failed to find the definite diagnosis. Two strategies were prioritised: the first looking for new disease- causing genes; the second to establish new approaches for investigating known disease-genes. The unifying theme of this thesis is that the research starts from a patient-centred perspective. I show how studying the patient’s phenotype provides insights into the underlying genetics causing disease, yielding a powerful combination of clinical research with genome-wide discovery. This simple, yet powerful tool for disease-gene discovery can advance our understanding of the gene and the protein function that they encode, providing an efficient model for studying genes and their functions, alongside the potential for new therapeutic approaches. The combination of basic research in the field of high-throughput genome analysis, functional work, biomarkers and in-depth clinical validation in a series of extensively investigated but undiagnosed patients, is a model for disease-causing gene discovery and the translation of results into improved diagnosis, treatment and drug trials in rare neurological conditions. Using these strategies, I discovered three new disease-causing genes, two of which have since been independently validated and catalogued as new diseases by the Online Mendelian Inheritance in Man (OMIM). The first is PDXK-related Neuropathy, 3 hereditary motor and sensory, type VI C, with optic atrophy (OMIM: 618511). The second is NKX6-2-related Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy (OMIM: 617560). Remarkably, in the PDXK-related neuropathy, by defining the disease-mechanism, I was able to identify the effective therapy that led to patients who had been wheelchair-bound for several years being able to walk independently again, treatment that proved life changing for the patients involved and others now being treated around the world. The third example of a disease-causing gene, described here, is NAA60-related primary familial brain calcifications. The phenotype of patients and associated functional work has led me to define the role of this previously functionally uncharacterised gene. Secondly, I show that a large proportion of recent rare disease genes’ discoveries are associated with mutations in previously known genes rather than new disease genes. Here, using the example of a group of neurodegenerative disorders called hereditary spastic paraplegias (HSPs), I show a wider perspective of how a genetic variant in a known gene that is responsible for a new disease or phenotype may be identified. Finally, I take the experience accumulated working with genetic conditions into studying molecular pathways and biomarkers in multiple system atrophy, a rare sporadic neurodegenerative condition that currently can have a definite diagnosis only at post-mortem. I show that a combination of genomics, clinical, imaging and fluid biomarkers can help improve diagnosis and quantify progression, helping to facilitate the first disease-modifying clinical trials in MSA. In conclusion, in this thesis I show new insights for disease-gene discovery that enable the identification of disease-mechanisms, reflect specific facets of neuropathology and address knowledge gaps of major importance for translational research into rare neurological diseases.

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