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BackgroundAs availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including as secondary findings.MethodsWe analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering.ResultsFor 36/65 gene-disease pairs, loss-of-function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using CardiacG2P as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches.ConclusionsAccess to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is pre-requisite for scalable genomic testing.

Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing. We estimated penetrance through large-scale analyses of patients referred for diagnostic sequencing for hypertrophic cardiomyopathy (HCM; 10,400 cases, 1,340 variants) and dilated cardiomyopathy (DCM; 2,564 cases, 665 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank and gnomAD). We generated updated prevalence estimates for HCM (1:543) and DCM (1:220).In aggregate, the penetrance by late adulthood of rare, pathogenic variants (23% for HCM, 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) was substantial for dominant CM. Penetrance was significantly higher for variant subgroups annotated as loss of function or ultra-rare, and for males compared to females for variants in HCM-associated genes.We estimated variant-specific penetrance for 316 recurrent variants most likely to be identified as SFs (51% HCM and 17% DCM cases). 49 variants were observed at least ten times (14% of cases) in HCM-associated genes. Median penetrance was 14.6% (±14.4% SD). We explore estimates of penetrance by age, sex, and ancestry, and simulate the impact of including future cohorts.This dataset is the first to report penetrance of individual variants at scale and will inform the management of individuals undergoing genetic screening for SFs. While most variants had low penetrance and the costs and harms of screening are unclear, some carriers of highly penetrant variants may benefit from SFs.Graphical AbstractA flowchart of the estimated penetrance for dominant cardiomyopathy by late adulthood for a variant of interest. The estimates of penetrance in this study are for carriers identified from unselected populations (e.g., consumer-initiated elective genomic testing or as secondary (2°) findings in clinical settings). If the variant is ultra-rare (i.e., identified once or less in population datasets), only estimates by variant subgroup in aggregate are available. If the variant is identified multiple times in both case and population datasets, variant-specific penetrance estimates may be available. If the variant is curated as a variant of uncertain significance (VUS), the penetrance estimate is low. If the variant is a likely pathogenic predicted loss of function (pLoF) variant and is identifiable multiple times in cases and population cohorts, penetrance estimates vary by gene (Figure 2). High aggregate penetrance represents an estimate of >25%; moderate aggregate penetrance represents 10%-25%, and low penetrance represents

BackgroundHypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes but there is no systematic framework for classifying morphology or assessing associated risks. Here we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression.MethodsWe enrolled 436 HCM patients (median age 60 years; 28.8% women) with clinical, genetic and imaging data. An independent cohort of 60 HCM patients from Singapore (median age 59 years; 11% women) and a reference population from UK Biobank (n = 16,691, mean age 55 years; 52.5% women) were also recruited. We used machine learning to analyse the three-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree.ResultsCarriers of pathogenic or likely pathogenic variants for HCM (P/LP) variants had lower left ventricular mass, but greater basal septal hypertrophy, with reduced lifespan (mean follow-up 9.9 years) compared to genotype negative individuals (hazard ratio: 2.66; 95% confidence interval [CI]: 1.42-4.96;P< 0.002). Four main phenotypic branches were identified using unsupervised learning of three-dimensional shape: 1) non-sarcomeric hypertrophy with co-existing hypertension; 2) diffuse and basal asymmetric hypertrophy associated with outflow tract obstruction; 3) isolated basal hypertrophy; 4) milder non-obstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for P/LP variants: 2.18 [95% CI: 1.93-2.28,P= 0.0001]). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalisable to an independent cohort (trustworthinessM1: 0.86-0.88).ConclusionsWe report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.

Acute myocarditis is an inflammatory condition that may herald the onset of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis. This was a population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterized cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality. Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared with

Background: Myocarditis may predispose to dilated cardiomyopathy (DCM) and sudden cardiac death (SCD). Familial data indicate a potential genetic susceptibility shared with arrhythmogenic cardiomyopathy (ACM). We present the first large-scale genotype-phenotype study of adults with acute myocarditis. Methods: A cohort comprising 336 consecutive patients with acute myocarditis was enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterised cardiomyopathy-associated genes. The burden of rare protein altering variants (PAV) in ACM genes, DCM genes, and TTN specifically, were compared with local healthy controls sequenced on the same platform (n=1053). Case ascertainment was assessed against national hospital admission data. Results: We identified rare protein-altering variants in 23% of cases compared to 16% in controls (Δ+6.8%; p=0.021), with rare truncating variants (tv) in 6% of cases compared to Conclusion: We identified enrichment of cardiomyopathy gene variants in acute myocarditis patients, dominated by DSP-tv in those with normal LVEF and TTN-tv in those with reduced LVEF. Incorporation of genetic testing may be beneficial to identify such high-risk individuals and guide family screening in acute myocarditis patients.

Background: Acute myocarditis is a complex inflammatory disease increasingly associated with dilated cardiomyopathy (DCM) and arrhythmogenic ventricular cardiomyopathy (ACM), but its underlying genetic basis is unknown. We sought to determine if there is a genetic overlap between myocarditis and inherited forms of cardiomyopathy. Methods: Population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA-sequencing for well-characterised cardiomyopathy-associated genes with comparison to healthy controls (n=1053). Case ascertainment was assessed against national admission data. Findings: Variants of known or likely pathogenicity were identified in 6% of cases compared to