Lynch, David S;
(2017)
The genetics of inherited disorders of white matter and related neurodegenerative diseases.
Doctoral thesis (Ph.D), UCL (University College London).
Abstract
In this thesis, I use a range of techniques to explore the genetics of syndromes that primarily affect the white matter of the central nervous system. Broadly, these include the genetic leukodystrophies and leukoencephalopathies, and hereditary spastic paraplegia (HSP). In recent years, the wider availability and reduced costs of next generation sequencing have altered our approach to genetic diagnosis, and these changes are reflected in the chapters of my thesis, which begins with traditional Sanger sequencing and ends with the use of whole genome sequencing. The first results chapter describes the use of a custom-designed targeted panel to characterise the clinical and mutational spectrum of HSP in Greece for the first time. In the next chapter, I describe the collection of a cohort of adult onset leukodystrophy cases, and the screening of the CSF1R gene by Sanger sequencing. I describe the clinical, radiological and pathological findings of the CSF1R positive cases. Next, I describe how I used focused exome sequencing to determine that mutations in the AARS2 gene cause an autosomal recessive leukoencephalopathy that mimics mutations in CSF1R. I then discuss the collection of a larger, expanded cohort of undiagnosed leukoencephalopathy cases, which is characterized using focused and whole exome sequencing. The final chapter of results refers to studies performed in single families, including the use of whole genome sequencing to identify GLS mutations as a novel cause of spastic ataxia and the identification of FDX1L mutations as the cause of a complex phenotype of optic atrophy, myopathy and axonal neuropathy. I place these results in context, and discuss the relevance of genetic diagnosis in neurology. Finally I discuss how the work described in this thesis is relevant for patients, and how advances in genetic technology must be matched by advances in clinical phenotyping.
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