Research Ilse Luyckx

Abstract

Bicuspid aortic valve (BAV) is the most common congenital heart defect affecting 1-2% of the general population. BAV patients develop valvular dysfunction and/or vascular complications like thoracic aortic aneurysm (TAA, 20-30%), with the latter being a prominent cause of morbidity and mortality in the Western population. Historically, TAA formation in a BAV patient was thought to be the consequence of aberrant blood flow, as a result of the valve defect, causing stress on the vascular wall leading to wall weakness. However, our current belief states that both blood flow disturbances as well as genetic factors contribute to the development of BAV and TAA. Over the past decades, extensive gene discovery efforts have identified about 30 BAV/TAA-associated genes, explaining less than 6% of the BAV-related aortopathy patients. Their identification, and functional characterisation, have been key steps in acquiring our current molecular knowledge on this disease. Though, the still incomplete pathogenic picture hampers the identification of individuals at-risk for TAA, and the discovery of novel therapeutic targets to prevent and/or stop TAA formation. Our research group identified the SMAD6 gene as a novel cause for BAV/TAA disease, which accounts for 4.8% of the 6% genetically solved BAV-related aortopathy patients. More recently, I developed a Smad6 knockout mouse model mimicking human BAV-related aortopathy. In this project, I aim to improve significantly our knowledge by the identification of early cell-specific disease genes for BAV-related aortopathy using transcriptome-wide spatial profiling of a representative Smad6 mutant mouse model. The project's anticipated outcomes will advance our current understanding on the molecular basis of the most important known genetic factor implicated in human BAV-related aortopathy.

Researcher(s)

• Promoter: Luyckx Ilse

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Bicuspid aortic valve (BAV) is the most common congenital heart defect affecting 1-2% of the general population. Many BAV patients develop valvular dysfunction and/or vascular complications like thoracic aortic aneurysm (TAA, 20-30%), with the latter being a prominent cause of morbidity and mortality in the Western population. Over the past decades, extensive gene discovery efforts have identified about 30 disease-associated genes, explaining less than 6% of the BAV/TAA patients. Their identification, and functional characterisation, have been key in acquiring our current molecular knowledge on this disease. Though, the incomplete genetic picture hampers the identification of individuals at-risk for TAA, and the discovery of novel therapeutic targets to prevent and/or stop TAA formation. During my PhD, we identified the largest causative gene for BAV/TAA disease i.e. SMAD6. However, genetic counselling of SMAD6-mutation positive BAV/TAA patients remains challenging due to the unpredictable reduced penetrance. Another intriguing observation is that patients within a family carrying an identical SMAD6 mutation develop uniquely BAV/TAA disease or a craniofacial anomaly, never both. In this project, I aim to further unravel the (epi)genetic landscape of BAV/TAA disease in SMAD6-mutation positive patients beyond the classical Mendelian inheritance pattern in order to improve (BAV/)TAA management. More specifically, I will test three potential genetic mechanisms to identify second hits in SMAD6-mutation positive BAV/TAA patients explaining the unpredictable reduced penetrance: (1) i.e. computational methods to predict pathogenic bi-allelic variant combinations in unrelated patients; (2) i.e. a genome-wide DNA methylation BeadChip to identify disease penetrant-related DNA methylation patterns in DNA derived from whole-blood samples; (3) i.e. delineation of a disease risk haplotype in SMAD6-mutation positive trios using long-read sequencing. The project's anticipated outcomes will advance counselling of BAV/TAA patients, and will add valuable information to our understanding on the molecular basis of other SMAD6-related phenotypes.

Researcher(s)

• Promoter: Luyckx Ilse

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Bicuspid aortic valve (BAV) is the most common congenital heart defect, affecting 1-2% of the general population. This aortic valve defect, which has a male predominance (3:1), is characterized by two semilunar leaflets instead of the normal three. BAV usually remains unnoticed, until patients develop clinical complications such as valvular dysfunction and/or thoracic aortic aneurysm (TAA, 20-30%). TAA is a pathological widening of the aorta in the thorax caused by vascular wall weakness, entailing a high risk for acute dissection and/or rupture (mortality rates ≥70%). Over the past decades, extensive gene discovery efforts have identified about 30 BAV/TAA-associated genes, explaining less than 6% of the BAV-related aortopathy patients. Their identification, and functional characterisation, have been key steps in acquiring our current molecular knowledge on this disease. Though, the still incomplete pathogenic picture hampers the identification of individuals at-risk for TAA, and the discovery of novel therapeutic targets to prevent and/or stop TAA formation. Our research group identified the SMAD6 gene as a novel cause for BAV/TAA disease, which accounts for 4.8% of the 6% genetically solved BAV-related aortopathy patients. More recently, I developed a Smad6 knockout mouse model mimicking human BAV-related aortopathy. In this project, I aim to identify disease-associated genes by using the transcriptomic profiling of Smad6-deficient mice with a highly penetrant outflow tract phenotype in order to prioritize, and strengthen the genetic link of novel and candidate genes with BAV-related aortopathy in humans. The project's anticipated outcomes will advance our current understanding on the molecular basis of the most important known genetic factor implicated in human BAV-related aortopathy.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Luyckx Ilse

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Thoracic aortic aneurysm (TAA) is an abnormal widening of the thoracic aorta caused by blood vessel wall weakness. TAAs entail a high risk for aortic rupture or dissection, commonly leading to sudden death. This dramatic event may leave family members of the deceased terrified and oblivious. To date, genetic defects in >30 genes have been linked with TAA, providing a molecular cause for about 30% of patients. Their identification and functional characterization have been key in acquiring our current pathomechanistic aortopathy knowledge. Yet, the genetic and mechanistic picture for TAA is far from complete, hampering identification of predictive markers for aneurysm formation and development of therapies capable of stopping or reversing aneurysm formation. In search for novel TAA genes, we most recently identified recessive truncating mutations in IPO8 as a novel cause of syndromic TAA. This project builds on this exciting finding. More specifically, we aim to significantly improve our current TAA pathomechanistic insight and future TAA patient management by (1) aortic phenotyping and functional characterization of an Ipo8 null mouse line, (2) validation of the mouse findings in the human context using patient- and control-derived iPSC-VSMCs, and (3) identifying putative drug compounds for IPO8-related aortopathy using a cell-based matrix metalloproteinase inhibition assay.

Researcher(s)

• Promoter: Verstraeten Aline
• Co-promoter: Luyckx Ilse

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Bicuspid aortic valve (BAV) is the most common congenital heart malformation affecting 1-2% of the population. This aortic valve defect is characterized by two leaflets instead of the normal three. While most BAV patients remain asymptomatic, approximately 35% of patients develop cardiovascular complications including dangerous thoracic aortic aneurysms (TAAs) and lethal dissections. To date, BAV/TAA remains a serious health problem due to the high heritability of BAV and no curative pharmacological therapies for (BAV-related) TAA are currently available. In 2017, we demonstrated a significant enrichment of deleterious SMAD6 variants in BAV/TAA patients compared to the general population. SMAD6 is highly expressed in the cardiovascular system, particularly in endothelial cells. It encode an inhibitory SMAD protein which negatively regulates BMP and TGF-β signaling. Both pathways have been previously and independently described to associate with defects of the aortic valve and thoracic aortic wall including aneurysms. Furthermore, endothelial cell dysfunction is gaining momentum as potential disease contributor, or even disease driver in both valve and aortic aneurysmal disease. Our knowledge on genetic SMAD6 data will serve as the perfect starting point to significantly expand our understanding on the mechanistic insights on BAV/TAA disease. Hence, this projects aims to relate SMAD6 deficiency to abnormalities of the aortic valve and wall by interrogating distinctive cellular and molecular processes in embryonic endothelial cells isolated from a Madh6 mouse model. The anticipated results will aid to elucidate the pathogenesis as well as initiate the identification of novel therapeutic targets for (BAV-related) TAA.

Researcher(s)

• Promoter: Luyckx Ilse

Research team(s)

Project type(s)

• Research Project

Abstract

Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation with a population prevalence of 1 to 2%. Ten to twenty percent of the BAV patients develop thoracic aortic aneurysms (TAA). Untreated TAA will lead to life-threatening aortic dissections and ruptures. Therefore, it is important to identify TAA in BAV patients, to monitor continuously the progression of TAA and to treat TAA. The general aim of this project is to unravel the underlying genetic basis of BAV/TAA, to characterise the identified genes and to gain insights into the pathogenic mechanisms.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Van Laer Lut
• Fellow: Luyckx Ilse

Research team(s)

Project type(s)

• Research Project