Genetic modifiers associated with the variability of the aortic phenotype in patients with inheritable connective tissue disorders(ICTDs)
Date
2022-05-27
Type:
Thesis
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110 p.
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Acceso abierto
Authors
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Publisher
Universidad del Desarrollo. Facultad de Medicina
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Abstract
Inheritable Connective Tissue Disorders (ICTDs) are rare genetic diseases that involve variants in genes that encode for proteins of the extracellular matrix (ECM). ICTDs affect patients from birth and their symptoms are present in the cardiovascular system, musculoskeletal system, the skin, the eye and the respiratory system. This family of diseases includes Marfan Syndrome (MFS), Loeys-Dietz Syndrome types I, II, III and IV (LDS), Ehlers- Danlos Syndrome type IV (vEDS), among others, and are caused by
variants in genes that code for different effectors or regulators of the Transforming Growth Factor beta (TGFβ) signaling pathway, including genes that encode for ECM components that play active roles in the signaling activity of this pathway. The cardinal feature of these diseases is the enlargement and rupture of big vessels and, most prominently, the
aorta. Aneurysm and dissection of the aorta is the main cause of mortality in these patients but the clinical course of MFS and other ICTDs differs considerably in terms of age of onset and severity, even among individuals who share the same causative variant.
This led us to hypothesize the existence of genetic variants elsewhere in the genome that influence the severity of the cardiovascular phenotype in MFS.
We recruited familial and sporadic MFS patients that were subsequently classified as having severe (n=8) or mild aortic phenotype (n=14) according to the age of presentation of the first cardiovascular manifestation and/or catastrophe related to the aorta. We used Exome Sequencing (ES) to identify genetic variants that may be associated with the severity of this clinical manifestation, and we performed linkage analysis using the software VAAST. We identified 5 genes associated with severe aortic phenotype and
3 genes that could be protective of this phenotype in MFS. These genes regulate components of the ECM, TGFβ pathway and other signaling pathways that are involved in the maintenance of the ECM and/or angiogenesis. Further studies will be required to understand the functional effect of these variants and explore novel, personalized risk management strategies and, potentially, new therapies for these patients.
Description
Thesis presented to the School of Medicine Clínica Alemana-Universidad del Desarrollo in order to apply for doctoral degree (PhD) in Sciences and Innovation in Medicine
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Citation
Keywords
Inheritable connective tissue disorders, Aortic aneurysm, Genetic modifiers, Exome sequencing Identificación, 090036S