Contribution to elucidating the genetic aetiology of thoracic aortic aneurysms

Datum: 22 maart 2019

Locatie: UAntwerp - Campus Drie Eiken - Building Q - Promotiezaal - Universiteitsplein 1 - 2610 WILRIJK (route: UAntwerpen, Campus Drie Eiken)

Tijdstip: 16 uur

Promovendus: Elisabeth Gillis

Promotor: Prof B. Loeys, Prof L. Van Laer & Prof A. Verstraeten

Korte beschrijving: PhD defence Elisabeth Gillis - Faculty of Medicine and Health Sciences

Abstract (Presentation in Dutch)

The aorta is the largest artery in the human body. It starts from the heart and supplies the rest of the body with oxygen-carrying blood. The aorta can abnormally enlarge in diameter, this is called an aortic aneurysm. The aneurysm can then lead to dissection or rupture which is often deadly, accounting for 1-2% of all deaths in Western Europe. There are two kinds of aortic aneurysms depending on the position: thoracic aortic aneurysms (TAA) at the level of the chest cavity and abdominal aortic aneuryms in the abdomen. In this thesis, we focused on TAA, because it has a strong genetic component. About 20% of patients have a positive family history. The goal of this thesis was to contribute to the elucidation of the genetic aetiology of TAA, because many patients remain genetically undiagnosed. A genetic diagnosis is beneficial for the patient's treatment, follow-up and counselling. To better understand the genetic cause and underlying mechanism, researchers have focused on syndromic TAA, such as Marfan syndrome (MFS), Loeys-Dietz syndrome and Shprintzen-Goldberg syndrome. MFS is caused by mutations in the FBN1 gene.

Although this gene was already discovered in 1991, Chapter 1 tells the scientific story of a family with MFS and a mutation in FBN1 only diagnosed during this thesis. Even though the affected members showed clear symptoms of MFS, they did not have a molecular genetic confirmation for 10 years. By using a myriad of techniques, such as whole exome sequencing and cDNA sequencing, we were able to finally identify the causal intronic FBN1 mutation. The contribution of the TGF-β pathway to the pathomechanism of MFS was discovered in 2003. Since then, numerous TGF-β genes, such as TGFBR1/2, TGFB2, etc. have been linked to TAA-related syndromes. An extra gene was added to this list during this thesis; Chapter 2 describes the discovery of TGFB3 as an additional TAA gene. The fourth chapter describes the finding and preliminary functional experiments of a possible new TAA gene, KLF15. This gene encodes a transcription factor which might affect the TGF-β pathway as well. Chapter 3 focusses on bicuspid aortic valve (BAV) associated TAA. Between the heart and the aorta, the aortic valve prevents blood owing back into the heart. Normally the aortic valve has three leaflets, but the aortic valve of 1-2% of the general population only contains two aortic valve leaflets. This condition is often accompanied by an increased risk for the development of TAA. Unfortunately, it has been very difficult to pinpoint causal genes for isolated BAV. Because TAA and BAV most possibly share a genetic cause, we focused on BAV/TAV patients to unravel more genetic determinants. A targeted gene panel helped to identify the SMAD6 gene as a new causal gene for BAV/TAA.

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