Discovering the causes of mutation-negative hypertrophic cardiomyopathy
Lead Research Organisation:
University College London
Department Name: Institute of Cardiovascular Science
Abstract
Hypertrophic cardiomyopathy (HCM) is an inherited disease defined by an abnormally thick heart muscle. It is a relatively common genetic condition, present in 1/500 individuals in the population. It is an important cause of sudden cardiac death at all ages due to an increased susceptibility to abnormal and dangerously unstable heart rhythms. It is also a relevant cause of heart failure, because of impaired pumping or delayed relaxation of the heart muscle. The link between the DNA genetic changes ("variants" or "mutations") that cause the disease (the so called "genotype") and the observed changes in the heart (the "phenotype") have been poorly understood despite many years of research; for example, some individuals with the condition may remain symptom-free for most of their lives whereas others develop progressive heart failure or die suddenly in a young age. Translation of the recent advances in genetics into direct clinical benefit for patients and families requires better understanding of these genotype-phenotype relationships. In the majority of cases, when known, genetic abnormalities reside in genes that code for proteins that play a major role in the way heart muscle cells are built and/or that are a part of the little motors (the "sarcomeres") that continuously allow the heart muscle cells to contract and relax. However, an improved diagnostic yield of genetic testing is needed, as up to half of the patients with HCM do not have an identified genetic cause, leading to uncertainty in diagnosis and sub-optimal care and surveillance for the individual and family.
With this project, I want to tackle these important knowledge gaps by finding out the causes of so-called "mutation-negative" or "genotype-negative" HCM.
Because we follow a very large cohort of patients with hypertrophic cardiomyopathy as part of our clinical activity and have collected thousands of blood samples, we have an unique opportunity to do this project. I propose to use 3 main streams of research.
1) Current genetic testing only focuses on the "coding" region of the DNA, i.e. the regions that are directly translated into amino acids, which are the constituent blocks of proteins. The "non-coding" region, where regulatory regions of genetic expression reside - like switches which augment or diminish the amount of proteins produced -has been much less explored. I expect to find causal variants in the non-coding region of the DNA.
2) Furthermore, when looking into a genetic cause, the focus has been on "rare" or "novel" variants (currently defined as present in less than 1 in 10000 individuals in the population), which are know to have stronger biological effects. However, more common DNA changes, when acting together, can also cause harm, as it is known from other conditions. I expect to find an effect of common variants in HCM.
3) Thirdly, I also want to discover new causal genes by looking into the whole of the DNA, including coding and non-coding regions, and not only to a pre-defined set of already candidate or known genes.
4) Finally, using advanced and new techniques of magnetic resonance imaging I will study in detail the changes in the heart of mutation-negative patients compared to mutation-positives, and will relate these findings to symptoms and prognosis.
With this project, I want to tackle these important knowledge gaps by finding out the causes of so-called "mutation-negative" or "genotype-negative" HCM.
Because we follow a very large cohort of patients with hypertrophic cardiomyopathy as part of our clinical activity and have collected thousands of blood samples, we have an unique opportunity to do this project. I propose to use 3 main streams of research.
1) Current genetic testing only focuses on the "coding" region of the DNA, i.e. the regions that are directly translated into amino acids, which are the constituent blocks of proteins. The "non-coding" region, where regulatory regions of genetic expression reside - like switches which augment or diminish the amount of proteins produced -has been much less explored. I expect to find causal variants in the non-coding region of the DNA.
2) Furthermore, when looking into a genetic cause, the focus has been on "rare" or "novel" variants (currently defined as present in less than 1 in 10000 individuals in the population), which are know to have stronger biological effects. However, more common DNA changes, when acting together, can also cause harm, as it is known from other conditions. I expect to find an effect of common variants in HCM.
3) Thirdly, I also want to discover new causal genes by looking into the whole of the DNA, including coding and non-coding regions, and not only to a pre-defined set of already candidate or known genes.
4) Finally, using advanced and new techniques of magnetic resonance imaging I will study in detail the changes in the heart of mutation-negative patients compared to mutation-positives, and will relate these findings to symptoms and prognosis.
Technical Summary
Hypertrophic cardiomyopathy (HCM) is defined as left ventricular hypertrophy in the absence of abnormal loading conditions. It is the commonest genetic heart disease and a major cause of sudden cardiac death and heart failure. It is usually inherited as an autosomal dominant genetic trait. Yet, the yield of genetic testing is less than 60%, even in the ~50% of patients with a family history of the disease. A genetic cause is thus unknown in a large proportion of patients. Furthermore, even when the causal genotype is known, phenotype associations and predictions are still poorly defined and currently have limited clinical actionability. These gaps in knowledge expose individuals and families to uncertainty about diagnosis and their future health. It also means that the pathophysiology of the disease is unresolved and opportunities for disease-modifying therapeutic discovery are limited. New and integrated approaches are needed to diminish these evidence gaps. One major aim of this project is to explore the importance of previously understudied rare non-coding (NC) sequence variation, in a very large cohort of ~2000 HCM patients. My preliminary quantitative analysis of NC variants in HCM suggests a significantly increased burden of deep intronic variation in sarcomere genes, which might contribute to the disease phenotype. Secondly, I will seek to discover novel causal genes, using whole-exome and whole-genome sequencing approaches in ~2000 patients previously tested for mutations in established HCM genes. Thirdly, through a Genome Wide Association Study (GWAS) approach in the same cohort, I will test the hypothesis of a polygenic cause for mutation-negative HCM. Finally, I will use novel advanced cardiac imaging linked to outcomes to explore new HCM genotype-phenotype classifications.
Planned Impact
Healthcare is moving rapidly towards a model that aspires to personalised medicine in which emergent diagnostic technologies, molecular biology, data analysis and real time monitoring are used to better target therapies and thereby improve health, social outcomes and cost efficiency. Genomics, transcriptomics, proteomics and metabolomics are a key component of personalised medicine as they provide mechanistic insights and biological markers that can be used to separate patients into specific groups that require tailored therapy at an earlier stage and more effectively than is currently possible. However, the potential of these sciences to transform human health can only be realised by integrating biological data into holistic disease models that reflect the complex clinical phenotypes seen in patients. This is particularly true for people with genetic diseases of the heart and blood vessels who characteristically have diverse and evolving phenotypes throughout their life-course. My project proposes new approaches addressed to tackle the needed integration between molecular medicine and personalized clinical stratification and aligns with the the key disease research themes underpinning the UCL Centre for Heart Muscle Disease's scientific strategy: Stratified patient cohorts, Cardiac Imaging, Non-invasive and invasive electrophysiological phenotyping, Bioinformatics and computational modelling, Functional genomics, Biomarker discovery.
This research will impact and benefit a wide range of stakeholders. At least one million people in Europe are affected with HCM. Recent European guidelines on the screening of families affected with the disease will result in identification of an even larger population of patients with asymptomatic disease that could benefit from early pharmacological intervention to prevent disease progression and reduce suffering. The rationale of this project is to increase understanding of the genetic background of the disease, which can then be translated into therapeutic interventions of direct relevance to the quality of life and longevity of patients. By applying the original methodologies described above, I expect to: 1) increase the yield of genetic testing in families where individuals currently have uncertainty about their future health; 2) understand the hitherto unknown effects of noncoding variation to the HCM phenotype 3) develop a new polygenic disease model that can be used to predict new genotype-phenotype associations in HCM. The research outcomes will not only benefit cardiologists and geneticists who manage HCM patients. Some of the findings will have a ground-breaking impact in genomic medicine as a whole. This project will have major implications for the counselling and clinical surveillance of individuals and families, because non-coding variation is completely ignored at the moment. It will contribute to personalized clinical management of these and other inherited heart disease patients. New potential therapeutic targets are likely to emerge (please see "academic beneficiaries"). These new genetic insights could be used in personalised algorithms based on clinical and genetic parameters to guide decisions on prophylactic device (implantable cardioverter defibrillator) therapy in patients.
The deliverables from this project will be used to support research grants to national and international research organisations.
The UCL Centre has established international partnerships with centres in North America, Europe, Middle and Far East. Examples include the European Reference Network (ERN) for Rare Cardiovascular Disease-Guard Heart (http://guardheart.ern-net.eu); the Hypertrophic Cardiomyopathy Outcomes Investigators (N=4000) [the Hypertrophic Cardiomyopathy EVIDENCE study: O'Mahony C et al Circulation. 2017]; paediatric HCM consortium (>1400 patients (Europe, South America, Australia). International collaboration will be one of the next steps to validate some of the findings.
This research will impact and benefit a wide range of stakeholders. At least one million people in Europe are affected with HCM. Recent European guidelines on the screening of families affected with the disease will result in identification of an even larger population of patients with asymptomatic disease that could benefit from early pharmacological intervention to prevent disease progression and reduce suffering. The rationale of this project is to increase understanding of the genetic background of the disease, which can then be translated into therapeutic interventions of direct relevance to the quality of life and longevity of patients. By applying the original methodologies described above, I expect to: 1) increase the yield of genetic testing in families where individuals currently have uncertainty about their future health; 2) understand the hitherto unknown effects of noncoding variation to the HCM phenotype 3) develop a new polygenic disease model that can be used to predict new genotype-phenotype associations in HCM. The research outcomes will not only benefit cardiologists and geneticists who manage HCM patients. Some of the findings will have a ground-breaking impact in genomic medicine as a whole. This project will have major implications for the counselling and clinical surveillance of individuals and families, because non-coding variation is completely ignored at the moment. It will contribute to personalized clinical management of these and other inherited heart disease patients. New potential therapeutic targets are likely to emerge (please see "academic beneficiaries"). These new genetic insights could be used in personalised algorithms based on clinical and genetic parameters to guide decisions on prophylactic device (implantable cardioverter defibrillator) therapy in patients.
The deliverables from this project will be used to support research grants to national and international research organisations.
The UCL Centre has established international partnerships with centres in North America, Europe, Middle and Far East. Examples include the European Reference Network (ERN) for Rare Cardiovascular Disease-Guard Heart (http://guardheart.ern-net.eu); the Hypertrophic Cardiomyopathy Outcomes Investigators (N=4000) [the Hypertrophic Cardiomyopathy EVIDENCE study: O'Mahony C et al Circulation. 2017]; paediatric HCM consortium (>1400 patients (Europe, South America, Australia). International collaboration will be one of the next steps to validate some of the findings.
Publications
Khanji MY
(2020)
Cardiovascular magnetic resonance imaging volume criteria for arrhythmogenic right ventricular cardiomyopathy: need for update?
in European heart journal
Lamounier Junior A
(2022)
Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant.
in Revista espanola de cardiologia (English ed.)
Lopes LR
(2021)
Iterative Reanalysis of Hypertrophic Cardiomyopathy Exome Data Reveals Causative Pathogenic Mitochondrial DNA Variants.
in Circulation. Genomic and precision medicine
Lopes LR
(2021)
Prevalence of Hypertrophic Cardiomyopathy in the UK Biobank Population.
in JAMA cardiology
Lopes LR
(2020)
The challenge of assessing variant pathogenicity in candidate Z-disc genes: The example of TCAP in hypertrophic cardiomyopathy.
in Revista portuguesa de cardiologia
Lopes LR
(2020)
Cryptic Splice-Altering Variants in MYBPC3 Are a Prevalent Cause of Hypertrophic Cardiomyopathy.
in Circulation. Genomic and precision medicine
Lopes LR
(2021)
Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.
in European heart journal
Lopes LR
(2019)
Prevalence of TTR variants detected by whole-exome sequencing in hypertrophic cardiomyopathy.
in Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis
Lopes LR
(2022)
Association between common cardiovascular risk factors and clinical phenotype in patients with hypertrophic cardiomyopathy from the European Society of Cardiology (ESC) EurObservational Research Programme (EORP) Cardiomyopathy/Myocarditis registry.
in European heart journal. Quality of care & clinical outcomes
Lopez-Sainz A
(2020)
Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis.
in Journal of the American College of Cardiology
Lorenzini M
(2020)
Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers.
in Journal of the American College of Cardiology
Maltês S
(2020)
New perspectives in the pharmacological treatment of hypertrophic cardiomyopathy.
in Revista portuguesa de cardiologia
Marques N
(2020)
Specific Therapy for Transthyretin Cardiac Amyloidosis: A Systematic Literature Review and Evidence-Based Recommendations.
in Journal of the American Heart Association
McNamara J
(2023)
Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle
in Nature Cardiovascular Research
Ochoa JP
(2020)
Deletions of specific exons of FHOD3 detected by next-generation sequencing are associated with hypertrophic cardiomyopathy.
in Clinical genetics
Protonotarios A
(2022)
Importance of genotype for risk stratification in arrhythmogenic right ventricular cardiomyopathy using the 2019 ARVC risk calculator.
in European heart journal
Protonotarios A
(2021)
The Novel Desmin Variant p.Leu115Ile Is Associated With a Unique Form of Biventricular Arrhythmogenic Cardiomyopathy.
in The Canadian journal of cardiology
Rees M
(2023)
Structure determination and analysis of titin A-band fibronectin type III domains provides insights for disease-linked variants and protein oligomerisation.
in Journal of structural biology
Rodrigues T
(2021)
Prognostic relevance of exercise testing in hypertrophic cardiomyopathy. A systematic review.
in International journal of cardiology
Salazar-Mendiguchía J
(2020)
The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals.
in European journal of medical genetics
Savvatis K
(2022)
Cardiac Outcomes in Adults With Mitochondrial Diseases
in Journal of the American College of Cardiology
Description | : Investigating the causes of mutation-negative hypertrophic cardiomyopathy: Role of cryptic RNA missplicing in myosin binding protein C (MYBPC3) |
Amount | £22,111,137 (GBP) |
Funding ID | PG/20/10170 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2021 |
End | 12/2024 |
Description | Deep structural phenotype of hypertrophic cardiomyopathy: from mutation to hypertrophy |
Amount | £209,391 (GBP) |
Funding ID | FS/CTRF/21/24269 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 02/2022 |
Description | Investigating the causes of mutation-negative hypertrophic cardiomyopathy: Role of cryptic RNA missplicing in myosin binding protein C (MYBPC3) |
Organisation | University of Lisbon |
Department | Institute for Molecular Medicine |
Country | Portugal |
Sector | Academic/University |
PI Contribution | Selection of candidate splicing MYBPC3 variants and family studies |
Collaborator Contribution | Generation of hIPSC-CM models |
Impact | Successful BHF project application |
Start Year | 2020 |