Hall, Charlotte Louise;
(2020)
Identification and characterisation of novel genes and disease mechanisms in Arrhythmogenic Cardiomyopathy.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Arrhythmogenic Cardiomyopathy (ACM) is a rare cardiac condition associated with arrhythmias and sudden death. ACM encompasses a number of inherited cardiac conditions with a wide phenotypic spectrum, including arrhythmogenic right ventricular cardiomyopathy (ARVC). Currently, over 40% of patients have no mutations in known ACM genes suggesting that other, yet unidentified, genes may be implicated in the pathogenesis of the disorder. This study investigated by whole exome sequencing (WES) a cohort of 120 ACM patients who were gene negative for major genes associated with cardiomyopathy and arrhythmia syndromes. It aimed to identify rare genetic variants in known and new genes and determine their contribution to phenotypic heterogeneity and patterns of disease expression in ACM. Gene burden test analysis of WES data identified filamin C (FLNC) as a major causal gene in this ACM cohort. Extensive co-segregation studies were performed in pedigrees with FLNC variants. Clinical evaluation of affected individuals revealed unique clinical features in filamin C variant carriers which are not included in the current clinical diagnostic criteria for ARVC. Immunohistochemistry work investigated the location of key proteins in cardiac tissue of patients with FLNC variants revealing differences to protein distribution patterns associated with typical ARVC. RNA sequencing of fixed cardiac specimens with FLNC variants detected disruption of two unique signalling pathways, the focal adhesion and ILK pathway. This work has shown that filamin C is a novel causative gene for an arrhythmogenic disease entity which differs from the typical ARVC phenotype. This is supported by clinical evidence as well as data obtained by immunohistochemistry and signalling pathway analysis of the transcriptome in FLNC variant carriers. Further work is required to confirm these findings and fully elucidate the mechanisms by which mutations in filamin C underlie ACM.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Identification and characterisation of novel genes and disease mechanisms in Arrhythmogenic Cardiomyopathy |
| Event: | UCL (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: | Arrhythmogenic cardiomyopathy, ARVC, Filamin C, Integrin linked kinase pathway, Focal adhesion pathway |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices 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 > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10090945 |
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