Cardiovascular Genetics and Genomics

Lead Research Organisation: MRC London Institute of Medical Sciences

Abstract

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.

Technical Summary

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

Publications

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Ingles J (2019) Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes. in Circulation. Genomic and precision medicine

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Lahrouchi N (2017) Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome. in Journal of the American College of Cardiology

 
Guideline Title Pending publication
Description AlleleFreqApp cited in international guidelines
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact Web tool (and underlying method) recommended for clinical genome interpretation. Widely adopted by healthcare laboratories internationally
URL http://cardiodb.org/allelefrequencyapp/
 
Guideline Title ACGS Best Practice Guidelines for Variant Classification 2017
Description Citation in ACGS Best Practice document
Geographic Reach National 
Policy Influence Type Citation in clinical guidelines
Impact Improved genome interpretation
URL http://www.acgs.uk.com/media/1059605/uk_practice_guidelines_for_variant_classification_2017_24_05_17...
 
Guideline Title Adaptation and Validation of the ACMG/AMP variant classification framework for specific genes and disorders: Recommendations of ClinGen's Inherited Cardiomyopathy Expert Panel for MYH7-associated cardiomyopathies
Description Citation in ClinGen recommendations for MYH7
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact Genome interpretation
 
Description Citation in PHGF document
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Genome interpretation
URL http://www.phgfoundation.org/documents/Variant%20classification%20and%20identification%20June%202017...
 
Description ClinGen
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact Participation in the ClinGen (Clinical Genome Resource) Cardiovascular Disease Working group. Defining standardised workflows and preparing guidelines for the interpretation of genetic variation wrt inherited cardiovascular diseases
URL https://www.clinicalgenome.org/working-groups/clinical-domain/sub-groups/cardiovascular/
 
Description Genomics in Mainstream Medicine Committee
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact Membership of JGenomics in Mainstream Medicine Working Group established by the Joint Committee for Genomics in Medicine (JCGM) of the Royal College of Physicians, the Royal College of Pathologists and British Society for Genetic Medicine in 2013. Design of materials and strategy for provision of an genome-literate healthcare workforce
URL http://www.phgfoundation.org/project/mainstream_medicine/
 
Description BHF Clinical Research Training Fellowship
Amount £138,286 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2017 
End 10/2020
 
Description BHF Project Grant
Amount £97,140 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2018 
End 01/2020
 
Description BHF Special Project Grant
Amount £2,000,000 (GBP)
Funding ID SP/17/11/32885 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2018 
End 04/2021
 
Description ITMAT Push for Impact Award
Amount £142,384 (GBP)
Organisation Imperial College Healthcare NHS Trust 
Sector Hospitals
Country United Kingdom
Start 10/2017 
End 10/2019
 
Description Imperial BRC
Amount £294,804 (GBP)
Organisation Imperial College Healthcare NHS Trust 
Sector Hospitals
Country United Kingdom
Start 10/2017 
End 10/2020
 
Description Rosetrees / Stoneygate Imperial College Research Fellowship
Amount £250,000 (GBP)
Organisation Rosetrees Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2018 
End 10/2022
 
Title CardioClassifier 
Description Genome interpretation platform for inherited cardiovascular conditions 
Type Of Material Data analysis technique 
Year Produced 2017 
Provided To Others? Yes  
Impact Tool widely used throughout NHS & internationally 
URL http://cardioclassifier.org
 
Title variantFx 
Description Aggregated data from cardiovascular disease genes 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? No  
Impact Will be available this year. 
URL http://variantfx.org
 
Description Broad Center for Mendelian Genomics 
Organisation Broad Institute
Country United States 
Sector Charity/Non Profit 
PI Contribution Recruitment, data analysis
Collaborator Contribution Sequencing, data analysis
Impact Diagnosis of rare disease patients
Start Year 2016
 
Description Mendelian Hypertension (Nottingham) 
Organisation University of Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Whole exome sequencing and analysis of cohort with Gordon's syndrome
Collaborator Contribution Sample collection and phenotyping of cohort
Impact No publication yet
Start Year 2015
 
Title Methods, systems and apparatus for identifying pathogenic gene variants 
Description Methods, systems and apparatus for identifying pathogenic gene variants for clinical genome interpretation 
IP Reference WO2018042185 
Protection Patent application published
Year Protection Granted
Licensed No
Impact Underpins software tool that is freely available (and widely adopted) by NHS. Commercial license available.
 
Title ARRY-371797 
Description Drug for LMNA-related DCM. Entering phase III clinical trial. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2017
Development Status Under active development/distribution
Clinical Trial? Yes
Impact pending 
URL https://clinicaltrials.gov/show/NCT03439514
 
Title ACGV 
Description A database of cardiac genetic variation, and interpretive portal 
Type Of Technology Webtool/Application 
Year Produced 2016 
Impact Highly accessed resource Adopted into workflow for variant interpretation internationally 
URL http://cardiodb.org/ACGV
 
Title AlleleFrequencyApp 
Description App for clinical genome interpretation: assesses genetic architecture of a condition to determine appropriate allele frequency threshold to apply to filter variants as potentially disease-causing 
Type Of Technology Webtool/Application 
Year Produced 2016 
Open Source License? Yes  
Impact Cited in guidelines & widely used in diagnostic laboratories internationally 
URL http://cardiodb.org/allelefrequencyapp/
 
Title CardioClassifier 
Description A tool for the interpretation of variation in genes associated with Inherited Cardiac Conditions 
Type Of Technology Webtool/Application 
Year Produced 2017 
Impact Only just launched, so limited impact assessment. Already received enquiries from diagnostic laboratories and ClinGen interested in using the resource 
URL http://www.cardioclassifier.org