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Using next-generation sequencing to understand the aetiology of dystonia and other neurological diseases

Charlesworth, G; (2016) Using next-generation sequencing to understand the aetiology of dystonia and other neurological diseases. Doctoral thesis , UCL (University College London). Green open access

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Abstract

This thesis presents my work using both next-generation and traditional genetic techniques aimed at further clarifying the aetiology of hereditary neurological disorders, with a particular focus on dystonia. A large part of this was focused on the identification, clinical phenotyping, and genetic analysis of kindreds with neurological disease inherited in a Mendelian fashion but for which no causal mutation had yet been identified. My work led directly to the discovery of two new dystonia genes, ANO3 and HPCA, and the identification of two novel phenotypes for the known disease-associated genes, ATM and NUBPL. Mutations in a third novel gene, SLC25A46, was identified as the most likely cause of disease in a kindred with a complex neurological disorder consisting of optic atrophy, severe action myoclonus and peripheral neuropathy, but could not be confirmed due to lack of a second segregating kindred – it was published, a year and a half after we had first identified it, by another group, just as I was in the process of submitting thesis. Taken together, these results confirm that whole exome sequencing in combination with linkage analysis or homozygosity mapping represents a powerful means of dissecting out the genetic aetiology of Mendelian disease. In addition, this thesis summarises my foray in the world of association analyses, a technique which underpins the recent explosion in knowledge regarding the genetic architecture of so-called ‘complex’ disease. I use this technique to show that the association signal over MAPT in Parkinson’s disease survives when affectation status is defined neuropathologically. Finally, I present my work using traditional Sanger sequencing to better understand the prevalence of already published Mendelian disease genes for both dystonia and Parkinson’s disease.

Type: Thesis (Doctoral)
Title: Using next-generation sequencing to understand the aetiology of dystonia and other neurological diseases
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
URI: http://discovery.ucl.ac.uk/id/eprint/1503396
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