Cardiology Research Groups
Derrick Group
Research Aims & Objectives
We aim to understand the developmental origins of congenital heart defects by:
- Understanding how the heart develops normally
- Testing pathogenicity of patient genetic variants using animal models to identify the cause and improve genetic counselling
- Using animal models of patient disease to develop approaches to alleviate symptoms of the disease (long-term)
Details of research interests
Congenital heart defects (CHDs) are structural abnormalities of the heart that arise due to improper development and are the most common cause of birth-defect related deaths worldwide.
Despite advances in genome sequencing, most CHDs do not have a clear genetic cause and for others, animal studies using conditional knockouts or null mutant lines in the proposed gene – which do not reflect the patient mutation – frequently report severe cardiac defects that often do not copy the patient disease. Without accurate patient modelling, almost all patient variants remain defined as variants of unknown significance (VUS). This prevents accurate prognosis, advancement of genetic testing and discussion of risk to family members.
This crisis of variant interpretation is most acute for Bicuspid Aortic Valve (BAV), the most common CHD that is present in at least 2% of the population. Although frequently undetected at birth, BAV can lead to progressive valve dysfunction and often co-exists with life-threatening aortopathies. Numerous large genomic studies have identified VUS associated with BAV, but almost all remain unproven.
To bridge the gap between clinical genetics and developmental biology, our lab carries out in vivo functional testing of VUS associated with CHDs. Crucially, this is underpinned by our expertise and continuing advancement in the understanding of normal development of the heart. To achieve this, we use zebrafish and mouse models, as well as human tissue to ensure clinical relevance. We have expertise in CRISPR-based genetic engineering, transgenesis approaches, live imaging, immunohistochemistry, histological and anatomical techniques.
Our current focus is on testing VUS identified in cases of familial BAV (in collaboration with the BRAVE study in Leicester) and Hypoplastic Left Heart Syndrome (the most severe CHD); and developing testing pipelines for multiple VUS in the same gene to provide semi-high throughput, in vivo, functional readouts, with the goal of supporting genetic diagnoses.
Group Leader
Group Members
Collaborators
Collaborators - Oxford:
- Steve Twigg, MRC Weatherall Institute of Molecular Medicine
Collaborators - External:
- Tom Webb, Leicester University
- Radek Debiec, East Midlands Congenital Heart Centre and Leicester University
- Aidan Bolger, East Midlands Congenital Heart Centre
- Karen Liu, King’s College London
- Shaine Morris, Texas Children’s Hospital and Baylor College of Medicine
- Zeynep Coban-Akdemir, University of Texas and Baylor College of Medicine
- Abhijit Dixit, Nottingham University Hospital
Funders
- British Heart Foundation (BHF)
- Medical Research Council (MRC)
Our Place in the IDRM Community
IDRM fosters a collaborative environment for cutting edge research. The British Heart Foundation Cardiovascular Research floor holds a wealth of expertise across model organisms, techniques and developmental mechanisms that is opening new areas of research.
Public Engagement
We participate actively in outreach, engaging with patients, families and fundraisers.