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Investigating the Genetic and Environmental Causes of Congenital Heart Disease

E17.5 embryonic mouse hearts imaged by High-Resolution Episcopic Microscopy (HREM). The heart on the left is normal, the heart on the right has a ventricular spetal defect induced by environmental perturbation of embryonic development (VSD, red arrow). LA, left atrium; RA, right atrium; LV, left ventricle; RV, right ventricle. Embryonic heart prepared by Dr Duncan Sparrow, HREM imaging by Dr Tim Mohun
E17.5 embryonic mouse hearts imaged by High-Resolution Episcopic Microscopy (HREM). The heart on the left is normal, the heart on the right has a ventricular spetal defect induced by environmental perturbation of embryonic development (VSD, red arrow). LA, left atrium; RA, right atrium; LV, left ventricle; RV, right ventricle.

One out of every 180 babies born in the UK, an average of 12 per day, is diagnosed with an abnormally formed heart - congenital heart disease (CHD). This is the most common type of birth defect, and it is the leading cause of infant death. CHD is more prevalent than most chronic childhood diseases such as autism, cancer or type 1 diabetes, and yet even with the application of the most modern genetic and genomic technologies, the causes of fewer than 1 in 5 cases can be explained genetically. This is partly because our understanding of how the heart forms in the embryo is incomplete, but also because non-genetic factors, such as exposure of the mother or embryo to environmental stresses during pregnancy, can also cause CHD.

I am investigating both genetic and environmental causes of CHD, using genetically-modified mouse models in a project funded by the Oxford BHF Centre of Research Excellence.

Ÿ• To discover new genes required for embryonic heart formation, I am collaborating with the Deciphering the Mechanisms of Developmental Disorders (DMDD) programme to characterise heart defects in mouse knockout lines made by the International Knockout Mouse Consortium. These new heart development genes will be candidates for causing human CHD. I will determine if deleterious variants in these new genes are present in human CHD genome/exome datasets, such as the UK10K project, the Genome England 100k genomes, the NHLBI Pediatric Cardiac Genomics Consortium and the Australian CHD project. My results will be a valuable tool for genetic counselling of families with a child born with CHD, for example by allowing determination of the chances of them having another child affected with the same type of CHD (which could be as low as 1 in 100; or as high as 1 in 2).

Ÿ• Environmental risk factors that significantly increase the incidence of CHD in humans include smoking, viral infection and fever (e.g. Rubella virus), medications taken during pregnancy (e.g. anti-epilepsy or anti-heart arrhythmia drugs), or maternal illnesses (e.g. pre-gestational diabetes). I am investigating how such environmental conditions perturb the process of heart formation in the embryo at both cellular and molecular levels. The potential benefits of my research will be to allow formulation of better advice to women planning pregnancy about what the high risk environmental factors are, and how to minimize exposure to them. Ultimately my results could be used to design and test therapies to reduce the incidence of environmentally-caused CHD, following the folic acid/neural tube defects paradigm.

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