Background: Pathogenic and likely pathogenic variants associated with arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy (HCM) are recommended to be reported as secondary findings in genome sequencing studies. This provides opportunities for early diagnosis, but also fuels uncertainty in variant carriers (G+), since disease penetrance is incomplete. We assessed the prevalence and disease expression of G+ in the general population. Methods: We identified pathogenic and likely pathogenic variants associated with ARVC, DCM and/or HCM in 200 643 UK Biobank individuals, who underwent whole exome sequencing. We calculated the prevalence of G+ and analyzed the frequency of cardiomyopathy/heart failure diagnosis. In undiagnosed individuals, we analyzed early signs of disease expression using available electrocardiography and cardiac magnetic resonance imaging data. Results: We found a prevalence of 1:578, 1:251, and 1:149 for pathogenic and likely pathogenic variants associated with ARVC, DCM and HCM respectively. Compared with controls, cardiovascular mortality was higher in DCM G+ (odds ratio 1.67 [95% CI 1.04; 2.59], P =0.030), but similar in ARVC and HCM G+ ( P ≥0.100). Cardiomyopathy or heart failure diagnosis were more frequent in DCM G+ (odds ratio 3.66 [95% CI 2.24; 5.81], P =4.9×10 ⁻⁷ ) and HCM G+ (odds ratio 3.03 [95% CI 1.98; 4.56], P =5.8×10 ⁻⁷ ), but comparable in ARVC G+ ( P =0.172). In contrast, ARVC G+ had more ventricular arrhythmias ( P =3.3×10 ⁻⁴ ). In undiagnosed individuals, left ventricular ejection fraction was reduced in DCM G+ ( P =0.009). Conclusions: In the general population, pathogenic and likely pathogenic variants associated with ARVC, DCM, or HCM are not uncommon. Although G+ have increased mortality and morbidity, disease penetrance in these carriers from the general population remains low (1.2–3.1%). Follow-up decisions in case of incidental findings should not be based solely on a variant, but on multiple factors, including family history and disease expression.

Dysfunction of either the right or left ventricle can lead to heart failure (HF) and subsequent morbidity and mortality. We performed a genome-wide association study (GWAS) of 16 cardiac magnetic resonance (CMR) imaging measurements of biventricular function and structure. Cis- Mendelian randomization (MR) was used to identify plasma proteins associating with CMR traits as well as with any of the following cardiac outcomes: HF, non-ischemic cardiomyopathy, dilated cardiomyopathy (DCM), atrial fibrillation, or coronary heart disease. In total, 33 plasma proteins were prioritized, including repurposing candidates for DCM and/or HF: IL18R (providing indirect evidence for IL18), I17RA, GPC5, LAMC2, PA2GA, CD33, and SLAF7. In addition, 13 of the 25 druggable proteins (52%; 95% confidence interval, 0.31 to 0.72) could be mapped to compounds with known oncological indications or side effects. These findings provide leads to facilitate drug development for cardiac disease and suggest that cardiotoxicities of several cancer treatments might represent mechanism-based adverse effects.

B-lineage acute lymphocytic leukemia (B-ALL) is characterized by different genetic aberrations at a chromosomal and gene level which are very crucial for diagnosis, prognosis and risk assessment of the disease. However, there is still controversial arguments in regard to disease outcomes in specific genetic abnormalities, e.g., 9p-deletion. Moreover, in absence of cytogenetic abnormalities it is difficult to predict B-ALL progression. Here, we use the advantage of Next-generation sequencing (NGS) technology to study the mutation landscape of 12 patients with B-ALL using Comprehensive Cancer Panel (CCP) which covers the most common mutated cancer genes. Our results describe new mutations in CSF3R gene including S661N, S557G, and Q170X which might be associated with disease progression.

Background: Drug development and disease prevention of heart failure (HF) and atrial fibrillation (AF) are impeded by a lack of robust early-stage surrogates. We determined to what extent cardiac magnetic resonance (CMR) measurements act as surrogates for the development of HF or AF. Methods: Genetic data were sourced on the association with 21 atrial and ventricular CMR measurements. Mendelian randomization was used to determine CMR associations with AF, HF, non-ischaemic cardiomyopathy (NICM), and dilated cardiomyopathy (DCM), noting that the definition of NICM includes DCM as a subset. Additionally, for the CMR surrogates of AF and HF, we explored their association with non-cardiac traits potentially influenced by cardiac disease liability. Results: In total we find that 7 CMR measures (biventricular ejection fraction (EF) and end-systolic volume (ESV), as well as LV systolic volume (SV), end-diastolic volume (EDV), and mass to volume ratio (MVR)) associate with the development of HF, 5 with the development of NICM (biventricular EDV and ESV, LV-EF), 7 with DCM (biventricular EF, ESV, EDV, and LV end-diastolic mass (EDM), and 3 associate with AF (LV-ESV, RV-EF, RV-ESV). Higher EF of both ventricles associate with lower risk of HF and DCM, with biventricular ESV associating with all four cardiac outcomes. Higher values of biventricular EDV associate with lower risk of HF, and DCM. Exploring the associations of these CMR cardiac disease surrogates with non-cardiac traits confirms a strong link with diastolic blood pressure, as well as more specific associations with lung function (LV-ESV), HbA1c (LV-EDM), and type 2 diabetes (LV-SV). Conclusions: The current paper identifies key CMR measurements that may act as surrogate endpoints for the development of HF (including NICM and DCM) or AF.

Background: Pathogenic and likely pathogenic variants associated with arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are recommended to be reported as secondary findings in genome sequencing studies. This provides opportunities for early diagnosis, but also fuels uncertainty in variant carriers (G+), since disease penetrance is incomplete. We assessed the prevalence and disease expression of G+ in the general population. Methods: We identified pathogenic and likely pathogenic variants associated with ARVC, DCM and/or HCM in 200,643 UK Biobank individuals, who underwent whole exome sequencing. We calculated the prevalence of G+ and analysed the frequency of cardiomyopathy/heart failure diagnosis. In undiagnosed individuals, we analysed early signs of disease expression using available electrocardiography and cardiac magnetic resonance imaging data. Results: We found a prevalence of 1:578, 1:251 and 1:149 for pathogenic and likely pathogenic variants associated with ARVC, DCM and HCM respectively. Compared to controls, cardiovascular mortality was higher in DCM G+ (OR 1.67 [95% CI 1.04;2.59], p=0.030), but similar in ARVC and HCM G+ (p≥0.100). Cardiomyopathy or heart failure diagnosis were more frequent in DCM G+ (OR 3.66 [95% CI 2.24;5.81], p=4.9×10 ⁻⁷ ) and HCM G+ (OR 3.03 [95% CI 1.98;4.56], p=5.8×10 ⁻⁷ ), but comparable in ARVC G+ (p=0.172). In contrast, ARVC G+ had more ventricular arrhythmias (p=3.3×10 ⁻⁴ ). In undiagnosed individuals, left ventricular ejection fraction was reduced in DCM G+ (p=0.009). Conclusions: In the general population, pathogenic and likely pathogenic variants associated with ARVC, DCM or HCM are not uncommon. Although G+ have increased mortality and morbidity, disease penetrance in these carriers from the general population remains low (1.2-3.1%). Follow-up decisions in case of incidental findings should not be based solely on a variant, but on multiple factors, including family history and disease expression.

Motivation: Loss-of-Function (LoF) variants in human genes are important due to their impact on clinical phenotypes and frequent occurrence in the genomes of healthy individuals. Current approaches predict high-confidence LoF variants without identifying the specific genes or the number of copies they affect. Moreover, there is a lack of methods for detecting knockout genes caused by compound heterozygous (CH) LoF variants. Results: We have developed the Loss-of-Function ToolKit (LoFTK), which allows efficient and automated prediction of LoF variants from both genotyped and sequenced genomes. LoFTK enables the identification of genes that are inactive in one or two copies and provides summary statistics for downstream analyses. LoFTK can identify CH LoF variants, which result in LoF genes with two copies lost. Using data from parents and offspring we show that 96% of CH LoF genes predicted by LoFTK in the offspring have the respective alleles donated by each parent. Availability and implementation: LoFTK is an open source software and is freely available to non-commercial users at https://github.com/CirculatoryHealth/LoFTK Contact: j.vansetten@umcutrecht.nl Supplementary information: Supplementary data are available at Bioinformatics online.