Steel, Dora Batia Dyne;
(2023)
Whole-genome sequencing in early-onset movement disorders: diagnosis, discovery, and deepening understanding of rare conditions.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Early-onset movement disorders include dystonia, chorea, myoclonus, parkinsonism, tremor, spasticity, ataxia or a combination of these. While some occur due to identifiable pre- or perinatal insults, many are suspected to be due to genetic faults. Diagnosing these remains challenging, partly because many genes responsible for early-onset movement disorders have yet to be identified, and partly because the phenotypic spectrum of ultra-rare genetic disorders is often incompletely described, complicating the interpretation of results. In this thesis I describe using whole-genome sequencing (WGS) to investigate 166 families with suspected genetic movement disorders. Utilizing a combination of detailed clinical phenotyping and either very broad gene panels or panel-free/gene-agnostic analysis, I aimed to identify variants in genes previously known to have an associated disease phenotype, or for which the phenotype was inadequately reported. Where a likely new disease-gene relationship was identified, I investigated further by laboratory experimentation including studies of splicing, gene expression and protein localisation and by case-finding in collaboration with other research groups. My analysis resulted in findings suspected to be relevant in 45.8% (76/166) of participants, including a probable or definite diagnosis in 31.3% (55/166). I identified three genes not previously reported in disease: VPS16, VPS41 and DRD1. I also contributed to the index case series of three more previously undescribed genetic conditions. Many participants had presentations which expanded the known phenotypic spectrum of their disorder, including those with variants in SLC30A9, RHOBTB2 and JPH3. Overall, I identified one participant with an identifiable previously undescribed genetic disorder for every 19 analyses conducted. This high rate of significant findings confirms the value of WGS in populations with rare childhood movement disorders as a tool for both diagnosis and gene discovery. I discuss the challenges and opportunities of the use of WGS in this field.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Whole-genome sequencing in early-onset movement disorders: diagnosis, discovery, and deepening understanding of rare conditions |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. 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 > 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 Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10167621 |
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