Boleti, Olga Dimitra;
(2025)
Deep phenotyping of paediatric Rasopathy-associated hypertrophic
cardiomyopathy… Natural history and
outcomes.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Background: Hypertrophic cardiomyopathy (HCM) associated with Rasopathy syndromes is the second most common cause of HCM in childhood and represents a unique clinical entity characterized by early-onset disease, variable phenotypic expression, and increased risk of morbidity and mortality in childhood. Objectives: To characterize the phenotypic spectrum, natural history, electrocardiographic (ECG) and imaging features, and risk predictors for major adverse cardiovascular events (MACE) and sudden cardiac death (SCD) in a large, multicentre cohort of children with RAS-HCM (RAS-HCM). Methods: This retrospective cohort study included data from paediatric patients with genetically or clinically confirmed Rasopathy syndromes and HCM (RAS-HCM), recruited across multiple international centres. Longitudinal data on clinical course, cardiac imaging, ECG and ambulatory monitoring were analysed. Results: RAS-HCM presents with a heterogeneous phenotype, with marked differences in severity and outcomes based on specific syndromes and genotypes. Key findings included a more severe cardiac phenotype in patients with a RAF1 and RIT1 gene variant, and in the whole cohort the finding of progressive left atrial dilation, diastolic dysfunction, and the emergence of complex atrial arrhythmias in early adulthood. Functional status (NYHA/Ross class > I), presence of NSVT, unexplained syncope, and elevated LVOT gradient were independently associated with adverse outcomes. The risk model currently used to predict sudden cardiac death (SCD) in children with non-syndromic HCM, HCM Risk-Kids, underperformed in risk stratification for this population. Conclusions: RAS-HCM is a distinct clinical entity requiring tailored approaches to diagnosis, monitoring, and risk stratification. Early identification of high-risk patients is essential. Multimodal longitudinal assessment should be considered to guide therapy and surveillance
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Deep phenotyping of paediatric Rasopathy-associated hypertrophic cardiomyopathy… Natural history and outcomes |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2025. 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. |
| Keywords: | RAS/MAPK, Noonan, Hypertrophic cardiomyopathy |
| 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 Population Health Sciences > Institute of Cardiovascular Science |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10219327 |
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