The role of DNA Methylation, Chromatin Remodelling and Histone Modification in Syndromic and Non-Syndromic Congenital Heart Disease.

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Congenital Heart Disease (CHD) is a change to the structure of the heart at birth. As the commonest birth defect, over 4,500 babies per year in the UK are born with CHD. CHD can cause a significant effect on a child, often needing specialist treatments or surgery, and can be associated with a shortened life-span. We know that CHD is more common if someone else in the family is also affected, but the exact genetic causes of this common condition are still not well understood. Genes are instructions to the body on how to grow and develop. They are made up of DNA in our body's cells. DNA inside cells is packaged using proteins called histones: these can be tagged by chemical groups (such as "methylation"), that can change how a gene is turned "on" and "off" in each cell of the body. There is some evidence to suggest that so-called "epigenetic" changes, such as histone methylation, can cause a proportion of CHD cases. To investigate this hypothesis, we have gained access to very detailed genetic testing data (Whole Genome Sequencing data) from nearly 600 families with CHD recruited to the 100,000 Genomes Project. Also, in a previous study, we identified a number of families where more than one individual had CHD. We plan to conduct further, more detailed genetic testing in these families, to understand better the cause of CHD. Once we have identified new causes of CHD, we will use cell models of disease to confirm our findings. The second part of the project will involve investigation of a specific protein, called KMT2D, which is also involved in histone methylation. We showed that this protein is associated with a new syndrome that has CHD as an important feature. We now want to investigate how a genetic change or "mutation" in this protein causes such severe disease, and how this links to CHD. We will do this by using new "gene-editing" tools in stem cells, which we will use to make a model of patient nerve cells. We will then investigate specific characteristics of these cell models, and how the mutations affect them. This will allow us to understand better how KMT2D works and to link this to CHD.The PI is an experienced Clinical Geneticist with a particular interest in CHD and a PhD in detailed genetic data analysis in relation to CHD. The candidate therefore has the experience and skills needed for the proposed project. The PI will join an experienced research group, led by the CO-I, with a proven track record of success in this field. They work with state-of-the-art technology, such as new gene-editing tools and novel cellular models, to investigate the genetic basis of human disease. The candidate and research group have strong support from the University and Hospital Trust. They have worked together on projects since 2013 and can bring complementary skills and experience to this project to tackle an important question for both the clinical and research partners. Finding new genetic causes of CHD and understanding the link between CHD and "histone methylation" will increase scientific understanding of the detailed processes involved in forming a fetal heart, and the ways in which this may be affected in disease. This will help in deciding upon medical or surgical managements for CHD, since we suspect that patients with different genetic causes of CHD may respond differently to medicines or surgery. Because the specific group of proteins we are studying are important drug targets, our scientific studies may be of key importance to discovering new drugs. This project is ideally placed in Leeds, where a new Children's Hospital is to be built over the next 5 years, to create a hub for state-of-the-art patient care, research, training and innovation.