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Next‐generation sequencing in the diagnosis of Dementia and Huntington’s disease Phenocopy Syndromes

Koriath, Carolin Anna Maria; (2020) Next‐generation sequencing in the diagnosis of Dementia and Huntington’s disease Phenocopy Syndromes. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Dementia is a major cause of disability worldwide, especially in the elderly. While Mendelian causes of dementia only account for a small proportion of cases, their role in elucidating the pathophysiology has been paramount. Genetically defined cohorts also offer opportunities for trials of disease‐modifying treatments, even before the onset of symptoms. Previously, only a small number of genes could be selected for genetic testing because of cost‐restrictions, but the advent of next‐generation sequencing has enabled its more widespread use. This thesis explored the use of next‐generation sequencing in patients living with dementia and HD phenocopy (HDPC) syndromes, who include patients with mixed presentations of dementia and motor symptoms. Using a validated 17 gene Dementia Gene panel supplemented by C9orf72 expansion testing and Apolipoprotein (ApoE) genotyping in over 3000 patients and controls, I determined the success rate of genetic panel testing in dementia; I developed an algorithm for the selection of patients for genetic testing based on the clinical presentation and common predictors of genetic causes of dementia. A detailed analysis of the ApoE data in the frontotemporal dementia cohort revealed strong effects of ApoE4 on age at onset in the subset with proven or suspected tau neuropathology, as well as opposite effects of amyloid‐beta pathology. In order to improve the definition and diagnostic rate of HDPC syndromes, patients who were referred for HD testing from two clinics were compared based on their clinical presentation; patients could not be distinguished based on clinical presentation alone, even if analysed as patterns. Given the low success rate of dementia gene panel testing in the HDPC cohort, 50 patients were selected for whole‐genome sequencing based on their HD‐likeness and their likelihood of harbouring a Mendelian variant. The results revealed a number of variants of interest but require replication.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Next‐generation sequencing in the diagnosis of Dementia and Huntington’s disease Phenocopy Syndromes
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/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.
Keywords: next-generation sequencing, dementia, Huntington's disease phenocopy syndromes
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 Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10111466
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