Discovering the causes of mutation-negative hypertrophic cardiomyopathy

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.

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.

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.