Cardiovascular Genetics and Genomics

Our aims are to understand the how inherited (genetic) factors influence the heart and circulation, and to use genetic information to improve patient care.

Gene discovery in rare heart diseases – we are using state-of-the-art approaches to find genes that cause rare heart diseases that run in families, particularly severe heart muscle diseases in children. As well as providing answers for the families affected, we also hope to find new treatments for these conditions.

Gene interpretation – having found genes that are linked to a disease, we need to understand precisely what changes in those genes cause problems. We all have some genetic changes that are unique to us, and most of these do not cause any problems. We are trying to find ways of distinguishing between those genetic changes that cause disease, and those that do not.

Precision medicine – for any particular disease, there is seldom a single best treatment that works for everybody. Tailoring treatments to individual patients is a high priority, as it leads to better outcomes and saves money (that is wasted if people receive ineffective treatment). We are finding genetic markers that predict which patients with heart muscle diseases need specific therapies.

The group’s overarching research aims are to understand the impact of genetic variation on the heart and circulation, and to use genome information to improve patient care. Several research themes contribute to these aims:

Gene discovery in rare cardiovascular disease – we are using exome and genome sequencing approaches in humans to find genes that cause rare Mendelian disease, particularly severe childhood cardiomyopathies (heart muscle diseases), both to provide answers to the families affected, and also to find new therapeutic targets for the treatment of these conditions. Having identified candidate disease genes through sequencing in humans, we are using genome engineering in stem-cell derived cardiomyocytes to further characterise the role of these genes in the heart, to determine mechanisms of pathogenicity, and to identify targets for therapeutic modulation.

Variant interpretation – all of us carry rare variants that alter important genes. Distinguishing between those that cause disease and those that are innocent bystanders is a key challenge in contemporary clinical genetics. We are developing and applying new methods to address this challenge, and collaborating globally to refine our understanding of variation in genes associated with heart disease. We are aggregating large cohorts of subjects with inherited cardiac conditions (mainly cardiomyopathies) and reference samples both locally and through collaboration (e.g. the NIHR Royal Brompton Cardiovascular BRU BioBank, the Exome Aggregation Consortium, the Clinical Genome Resource, Genomics England, Oxford Molecular Genetics Laboratory, Laboratory for Molecular Medicine at Partners Healthcare, the SHaRe Cardiomyopathy Registry, the NIHR Rare Diseases Translational Research Collaboration) to develop and evaluate new computational methods.

Precision medicine – we are evaluating the use of genetics and biomarkers to stratify patients and predict their response to therapy and long-term outcomes. Ultimately, we are working to interpret genome information so that it can be used to optimise treatment choice for our patients. We are particularly focusing on genetic stratification of cohorts with hypertrophic and dilated cardiomyopathies. We integrate genetics, biomarkers, and precision phenotyping with electronic medical records and clinical outcome data to identify determinants of prognosis and treatment response.

Titin – we have a particular focus on the Titin gene, which encodes the largest human protein, a key component of muscles throughout the body. Recently identified as the most important cause of inherited dilated cardiomyopathy, we are working to understand the effects of Titin variants on the heart, their mechanisms of action, and their clinical significance. Our group focuses on computational approaches and statistical genetics in human subjects, and we integrate these data with genomic, transcriptomic, proteomic, and physiological data from model organisms and cellular models through collaboration within and without the MRC Clinical Sciences Centre.

Software – web resources, software, and other tools developed by the group are available at cardiodb.org