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Project

In search of genetic modifiers for aortopathy in Loeys-Dietz families with a SMAD3 mutation.

Loeys-Dietz syndrome (LDS) is a genetic disorder presenting with thoracic aortic aneurysm (TAA), causing abnormal widening of the aorta, which leads to aortic rupture or dissection, a life-threatening complication that occurs unexpectedly. LDS is caused by genetic defects in six different genes of the TGF? pathway (TGFBR1/2, SMAD2/3, TGFB2/3), which is vital in the proper development of the body's connective tissue. Despite the progress in unravelling its genetic basis, there is a lack of understanding of the wide range of severity of cardiovascular involvement. In my project, I will focus on patients within families, carrying pathogenic SMAD3 variants, which show either no or early onset aortic aneurysmal disease. I hypothesize that genetic modifiers of the primary SMAD3 mutation are the main contributors to the striking aortopathy variability in LDS-SMAD3 families. In this project, an innovative strategy will be used to identify genetic modifiers. I will perform genome-wide single nucleotide polymorphism-based linkage analysis on two large SMAD3 families and whole genome sequencing on selected individuals, combined with SMAD3 iPSC-VSMC (induced pluripotent stem cell-derived vascular smooth muscle cells) model creation and characterization and subsequent CRISPR/Cas9-based validation of the identified modifier(s). The predicted outcomes will advance the LDS and TAA knowledge, contributing to the discovery and development of novel therapeutic targets and personalized medicine.
Date:1 Nov 2019 →  31 Oct 2020
Keywords:LOEYS-DIETZ SYNDROME, THORACIC AORTIC ANEURYSM
Disciplines:Vascular diseases, Molecular diagnostics, Medical genomics, Genetics