Hersheson, Joshua;
(2024)
Exploring next generation sequencing in the diagnosis of inherited ataxia and other neurological diseases.
Doctoral thesis (Ph.D), UCL (University College London).
Preview |
Text
Joshua Hersheson_PhD_thesis_final.pdf - Accepted Version Download (4MB) | Preview |
Abstract
Neurodegenerative diseases are a complex and heterogeneous group of disorders characterised by progressive loss of cells from the central nervous system which can result in a broad range of clinical phenotypes including cognitive impairment, motor dysfunction, epilepsy and visual loss. Next generation sequencing technologies have greatly facilitated the search for novel genes underlying neurodegenerative disorders. In this thesis, I present the results of my efforts to understand and clarify the genetic bases for a range of neurological disorders with a focus on cerebellar ataxia. I have used a range of techniques including whole exome sequencing, together with traditional genetic approaches to investigate several families with hitherto genetically undiagnosed neurological syndromes. The first project I present is the identification of a novel gene (TUBB4A) underlying a form of dominantly inherited dystonia (DYT4). With the understanding I gained in the application of exome sequencing and mapping strategies, I go on to present my findings of a further novel gene underlying a recessive cerebellar ataxia (CAPN1). I describe the identification of the genetic cause in several families with recessive ataxia and explore functional studies to confirm the pathogenicity of novel mutations in a rare form of neuronal ceroid lipofuscinosis (CLN10). I present a study in which I developed a next-generation sequencing panel for large scale sequencing of a cohort of autosomal dominant ataxia patients. Finally, I present data on the identification of PNPLA6 mutations as the genetic cause of a rare form of spastic ataxia associated with hypogonadrotropic hypogonadism – Oliver McFarlane syndrome.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Exploring next generation sequencing in the diagnosis of inherited ataxia and other neurological diseases |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL 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: | https://discovery.ucl.ac.uk/id/eprint/10196118 |
Archive Staff Only
 |
View Item |
