Elizabeth Ormondroyd

Background and Aims: Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods: An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results: A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions: Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

Large national genomic programmes have been created in many countries, including France, England and Germany, to advance the realisation of the potential genomic medicine holds to significantly contribute to society by improving health, and driving science, innovation and the economy. To reach this ambition, these programmes collect, manage and analyse big genomic datasets. While there is much talk about the promises, and hence the importance of genomics, there is little in-depth analysis of the actual contribution or value—here understood as benefits—of genomics for society at large. To explore the issue of the value of large-scale genomic programmes for society, UK-FR-D+ GENE held an international workshop focusing on a variety of levels—societal, economic, clinical, scientific, and population-wide level—at which such benefits might be observed. First, the broader societal implications of large genome programmes and their impact for public trust were discussed. Second, the meaning of fair and just allocation of public resources, based on considerations of the economic costs and benefits of genomic innovations, was examined. Third, the benefits of these innovations for stakeholders (clinicians, patients, and families) at the clinical level were investigated. Fourth, the scope and limitations of genomics at the scientific level were discussed. Finally, the potential of genomics to improve health at the population level was explored. Providing an insight into the benefits of large genomic programmes on various levels, the workshop concluded by defining several criteria that should be considered to ensure benefits for society when implementing large genomic programmes.

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Here, we report results from a large genome-wide association study and multitrait analysis including 5,900 HCM cases, 68,359 controls and 36,083 UK Biobank participants with cardiac magnetic resonance imaging. We identified 70 loci (50 novel) associated with HCM and 62 loci (20 novel) associated with relevant left ventricular traits. Among the prioritized genes in the HCM loci, we identify a novel HCM disease gene, SVIL , which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants confer a roughly tenfold increased risk of HCM. Mendelian randomization analyses support a causal role of increased left ventricular contractility in both obstructive and nonobstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, these findings increase our understanding of the genetic basis of HCM, with potential implications for disease management.

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality, with pathogenic variants found in about a third of cases. Large-scale genome-wide association studies (GWAS) demonstrate that common genetic variation contributes to HCM risk. Here we derive polygenic scores (PGS) from HCM GWAS and genetically correlated traits and test their performance in the UK Biobank, 100,000 Genomes Project, and clinical cohorts. We show that higher PGS significantly increases the risk of HCM in the general population, particularly among pathogenic variant carriers, where HCM penetrance differs 10-fold between those in the highest and lowest PGS quintiles. Among relatives of HCM probands, PGS stratifies risks of developing HCM and adverse outcomes. Finally, among HCM cases, PGS strongly predicts the risk of adverse outcomes and death. These findings support the broad utility of PGS across clinical settings, enabling tailored screening and surveillance and stratification of risk of adverse outcomes.

The ALPK3 gene encodes alpha-protein kinase 3, a cardiac pseudo-kinase of unknown function. Heterozygous truncating variants ( ALPK3tv) can cause dominant adult-onset Hypertrophic Cardiomyopathy (HCM). Here we confirm an excess of ALPK3tv in sarcomere-gene negative HCM patients. Moreover, we generated a novel knock-in mouse model carrying an ALPK3tv (K201X). Homozygous animals displayed hypertrophy and systolic dysfunction. Heterozygous animals demonstrated no obvious baseline; however, they had an aggravated hypertrophic response upon chronic adrenergic challenge. Isolated cardiomyocytes from heterozygous and homozygous mice showed reduced basal sarcomere length with prolonged relaxation, whilst calcium transients showed increased diastolic calcium levels and prolonged re-uptake. We also observed reduced fractional shortening. Protein kinase A-mediated phosphorylation, including that of cardiac troponin I, was significantly decreased. In agreement with the cellular HCM phenotype, reduced ratios of myosin heads in the super-relaxed state were measured. Contractile and calcium handling defects were partly corrected by treatment with mavacamten, a novel myosin inhibitor. For the first time with a non-sarcomere HCM variant, we have demonstrated hallmark changes in cardiac contractility and calcium handling, some resembling sarcomere-positive HCM, while others are distinct and DCM-like. Mavacamten is able to partially rescue the cellular phenotype, hence could be beneficial to HCM patients with ALPK3tv .

Cardiomyopathies are a group of inherited heart muscle disorders. Expressivity is variable and while sometimes mild, complications can result in sudden cardiac death (SCD) at any age, heart failure and stroke. In around a third of patients a monogenic cause is identifiable, and development of genetic therapies that aim to correct the underlying genetic defect is underway. Here we describe results of a survey designed to understand preliminary views of the patient community about genetic therapies in the context of disease burden. The internet survey was publicized with a bespoke information video via patient support groups in the UK and USA; 634 people responded of whom 96% had a personal and/or family history of cardiomyopathy. Findings show that concern about cardiomyopathy-related issues with a future dimension, such as disease progression, is significantly greater than concern about current issues. A total of 93.6% thought that genetic therapies should be developed for cardiomyopathy. A majority would consider participation in a genetic therapy trial in six scenarios varying by age and clinical situation significantly more in the scenario of an adult with symptomatic disease and evident progression than an asymptomatic adult with SCD risk, or a child. In all scenarios, a majority said that the chance genetic therapy would stop or slow progression, and risk of serious adverse and unintended effects, were important considerations. Qualitative analysis of free-text responses found that concern was often informed by family experience. Patient consideration of genetic therapy is likely to require individualized assessment of the benefits and risks.

Direct‐to‐consumer genetic tests (DTC‐GT) offer a variety of genetic health risk information. Understanding evidence of impacts is required for effective policy to protect consumers and healthcare services. We undertook a systematic review according to PRISMA guidelines, searching five literature databases for articles assessing analytic or clinical validity, or reporting consumer or healthcare professional experience with health risk information derived from DTC‐GT, published between November 2014 and July 2020. We performed a thematic synthesis to identify descriptive and analytical themes. Forty‐three papers met inclusion criteria. Many consumers submit raw DTC‐GT data for third‐party interpretation (TPI). DTC‐GT sometimes report ‘false positive’ or incorrectly interpreted rare variants, or that such information can result from TPI. Consumers have high expectations of DTC‐GT and TPI, and are broadly satisfied, although many do not act on results. A minority of consumers experience adverse psychological impacts. Healthcare consultations can be complex, and professionals have reservations about the validity and utility of DTC‐GT‐derived information. The contrast between consumer and health professional perceptions can result in mutual dissatisfaction with consultations. Health risk information from DTC‐GT and TPI is broadly valued by consumers but presents complex challenges for healthcare services and some consumers.