Cardiovascular Genomics and Precision Medicine
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
People |
ORCID iD |
James Simon Ware (Principal Investigator) |
Publications

Horvat C
(2019)
A gene-centric strategy for identifying disease-causing rare variants in dilated cardiomyopathy.
in Genetics in medicine : official journal of the American College of Medical Genetics

Kelly MA
(2018)
Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel.
in Genetics in medicine : official journal of the American College of Medical Genetics

Miller DC
(2017)
Ajmaline blocks I and I without eliciting differences between Brugada syndrome patient and control human pluripotent stem cell-derived cardiac clusters.
in Stem cell research

Adler A
(2020)
An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome.
in Circulation

Thomson K
(2018)
Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield
in Genetics in Medicine

Lek M
(2016)
Analysis of protein-coding genetic variation in 60,706 humans.
in Nature

Fumagalli C
(2020)
Association of Obesity With Adverse Long-term Outcomes in Hypertrophic Cardiomyopathy.
in JAMA cardiology


Whiffin N
(2018)
CardioClassifier: disease- and gene-specific computational decision support for clinical genome interpretation.
in Genetics in medicine : official journal of the American College of Medical Genetics

Furqan A
(2017)
Care in Specialized Centers and Data Sharing Increase Agreement in Hypertrophic Cardiomyopathy Genetic Test Interpretation.
in Circulation. Cardiovascular genetics


Zhang X
(2017)
ClinVar data parsing.
in Wellcome open research

Oates EC
(2018)
Congenital Titinopathy: Comprehensive characterization and pathogenic insights.
in Annals of neurology

Homsy J
(2015)
De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.
in Science (New York, N.Y.)

Walsh R
(2017)
Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes.
in European heart journal

Finocchiaro G
(2020)
Diagnostic yield of hypertrophic cardiomyopathy in first-degree relatives of decedents with idiopathic left ventricular hypertrophy.
in Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology

Domínguez F
(2018)
Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations.
in Journal of the American College of Cardiology

Domínguez F
(2018)
Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations.
in Journal of the American College of Cardiology


Ingles J
(2019)
Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes
in Circulation: Genomic and Precision Medicine

Rhodes CJ
(2019)
Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.
in The Lancet. Respiratory medicine

Ware JS
(2018)
Genetic Etiology for Alcohol-Induced Cardiac Toxicity.
in Journal of the American College of Cardiology

Garcia-Pavia P
(2019)
Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.
in Circulation

Wright CF
(2019)
Genomic variant sharing: a position statement.
in Wellcome open research
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/ |
Description | Cardiomyopathy UK Clinical Advisory Group |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
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 | Membership of a guideline committee - JCMG "consent and confidentiality in clinical genetic practice" |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
Description | NIH-NHGRI and Wellcome Trust Strategy Meeting - Grand Challenges in Genomics |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Gave evidence to a government review |
Guideline Title | 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy |
Description | Three papers cited in international guidelines for arrhythmogenic cardiomyopathies |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Citation in clinical guidelines |
Description | BHF Centre of Research Excellence sub-project |
Amount | £128,060 (GBP) |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2020 |
End | 01/2022 |
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 Programme Grant |
Amount | £1,011,285 (GBP) |
Funding ID | RG/19/6/34387 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 02/2020 |
End | 02/2025 |
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 | Designing, developing and delivering integrated foundations for genomic medicine |
Amount | £5,363,815 (GBP) |
Funding ID | 200990/A/16/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2019 |
End | 04/2022 |
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 |
Description | The Heart Hive |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | The Heart Hive is a web portal for closer engagement with potential research participants. We ran a crowdfunding campaign to fund this portal & community We received matched funding from the major UK patient association in our area |
Year(s) Of Engagement Activity | 2019,2020 |
URL | http://thehearthive.org |