James S. Ware

This paper shows that loss-of-function variants in MAP3K7 cause dilated cardiomyopathy (DCM), both as part of syndromic disease and as apparently isolated DCM.

The paper maps and redesigns the MYBPC3 promoter to enhance expression and treat haploinsufficient hypertrophic cardiomyopathy.

The paper reclassifies genetic variants in HCM patients using a large registry, finding 10% of variants were reclassified, with most VUS unlikely to be causal.

This study identifies SVIL haploinsufficiency as a cause of hypertrophic cardiomyopathy by impairing mechanotransduction and cellular energetics, with potential therapeutic implications for mitochondrial-targeted treatments.

The paper integrates genomic and structural data to identify variant intolerance regions in cardiac sarcomere genes and links them to disease mechanisms in hypertrophic cardiomyopathy.

This study identifies 42 genetic loci associated with cardiac structure and contractility using a spatially-resolved genome-wide association study in 47,549 UK Biobank participants.

This study shows that loss of CnAβ1 enhances brown adipocyte differentiation and metabolic activity through FoxO1 activation, leading to improved insulin sensitivity and reduced body weight on a high-fat diet.

The paper evaluates the clinical validity of heterozygous ALPK3 loss-of-function variants as a cause of hypertrophic cardiomyopathy, finding strong gene-disease association with reduced penetrance.

The paper returns actionable genetic results to 4,198 Scottish volunteers from the Viking Genes cohort, identifying 108 actionable genotypes in 23 genes and notifying 64 participants.

This study evaluates polygenic scores for hypertrophic cardiomyopathy (HCM) in the general population and clinical settings, showing increased risk with higher scores and potential for clinical application.

LAVASET improves feature importance estimation in correlated datasets by incorporating correlation factors, achieving non-inferior prediction accuracy compared to Random Forests.

The paper reports a rare splice-site variant in TNNT2 found in Oceanian ancestry individuals, highlighting the need for diverse genomic datasets to avoid misclassification of variants.

The paper identifies 88 novel rare disease-gene associations using a burden analysis framework on whole genome sequencing data from the 100,000 Genomes Project, with potential clinical impact for undiagnosed cases.

This paper standardizes terminology for describing disease-gene relationships to improve variant classification and genetic test interpretation.

The paper structures evidence on inheritance, allelic requirement, and variant classes for inherited cardiac conditions to improve variant filtering in genomic testing.

This paper estimates the penetrance of rare variants in cardiomyopathy genes using cross-sectional data from genetic testing, finding substantial penetrance for dominant cardiomyopathies and variant-specific differences.

This paper introduces Paralogue Annotation, a method using homologous protein variants to predict disease-causing missense variants with high precision.

The paper describes the formation of the Gene Curation Coalition to standardize gene-disease validity terminology and create a unified database for curated gene-disease assertions.

This paper introduces HMC, a high-resolution genetic constraint score for missense variants, improving variant prioritization and gene discovery for developmental disorders.

This study examines the clinical impact of rare variants in HCM-associated genes in the UK Biobank, finding that pathogenic variants are linked to increased cardiovascular risk and subclinical phenotypes, while non-pathogenic variants show minimal effect.

The paper identifies a frameshift variant in MYH7 associated with HCM in an Egyptian cohort, revealing a new pathogenic mechanism involving distal PTC escape from NMD.

The paper curates and classifies genetic evidence for dilated cardiomyopathy (DCM), identifying 19 genes with strong or moderate evidence and highlighting gaps in understanding.

The paper uses STRUM to predict subdomain stability in MYBPC3 variants, showing that variants causing misfolding are associated with higher adverse event rates in HCM patients.

This study identifies genetic overlaps and distinct variant classes in LVNC compared to DCM and HCM, revealing both shared and unique genetic mechanisms.

The paper describes the EHVol study, a genomic database of 391 Egyptian healthy volunteers to improve representation in global genomic databases and aid in variant interpretation for North African populations.

This paper introduces CardioBoost, a disease-specific variant classifier for inherited cardiac conditions, showing improved accuracy in predicting pathogenicity compared to genome-wide tools.

The paper introduces UTRannotator, a tool to annotate 5'UTR variants that create or disrupt uORFs, annotating 30.8% of ClinVar 5UTR pathogenic variants.

The paper identifies genetic associations with myocardial trabecular complexity using UK Biobank data and shows a causal link to ventricular function and electrical activity.

The paper evaluates potential drug targets using loss-of-function genetic variants from gnomAD, highlighting the importance of deep curation and targeted recall studies for drug discovery.

From 125,748 exomes and 15,708 genomes, 443,769 high-confidence predicted loss-of-function variants yield LOEUF, a continuous gene intolerance score tracking mouse lethality, cell essentiality, and disease associations.