James Simon Ware

BACKGROUND: Evidence of the diverse genetic architecture of dilated cardiomyopathy (DCM) continues to emerge and requires reassessment of the clinical relevance of implicated disease genes. Building on the 2019-2020 Clinical Genome Resource evaluation, the DCM gene curation expert panel reconvened in 2024-2025 to conduct a reassessment of genes in DCM. METHODS: The Clinical Genome Resource semiquantitative clinical validity classification framework was applied with specifications to DCM to classify genes into categories on the basis of strength of published evidence for a DCM phenotype. Previously curated genes were reassessed, and newly reported gene–disease–mode of inheritance (MOI) relationships, termed “curations,” were evaluated. RESULTS: Sixty-eight genes were evaluated, inclusive of 72 unique gene-disease-MOI relationships across 51 previously evaluated and 17 newly assessed genes. Thirty-five curations were classified as high evidence (16 Definitive, 10 Strong, 9 Moderate), increasing by 16 from the prior assessment. Nine newly assessed genes were classified as high evidence: BAG5 , FLII , LMOD2 , MYLK3 , MYZAP , NRAP , PPA2 , PPP1R13L , and RPL3L . Twelve genes (11 newly appraised) were rated as high evidence with an autosomal recessive (AR) MOI. Five reevaluated genes from 2019-2020 had clinically significant changes in classification. Except for JPH2 , for which curation was modified to separate autosomal dominant and AR MOI curations, clinically significant changes involved upgrades from low- to high-evidence categories ( PLEKHM2 , PRDM16 , TBX20 , TNNI3K ), demonstrating the robustness of the Clinical Genome Resource gene curation process over time. An additional 29 gene-disease-MOI curations were classified as Limited, including 6 newly evaluated genes and 1 new MOI for a previously evaluated gene, MYBPC3 -AR; 4 were classified as No Known Disease Relationship, and remained Disputed. Four previously evaluated genes were curated for both AD and AR MOIs: JPH2 (AD-Strong, AR-Limited), LDB3 (AD-Limited, AR-Strong), MYBPC3 (AD-Limited, AR-Limited), and TNNI3 (AD- and AR- Strong). CONCLUSIONS: With substantial new evidence, the genetic architecture of DCM has rapidly expanded. This updated assessment of genes reported in DCM yielded 35 high-evidence curations, an increase from 19 only 5 years ago. The results of this evidence-based evaluation process inform clinical interpretation of genetic information in the care of DCM patients and families.

BACKGROUND: Conflicting evidence exists about whether sarcomeric hypertrophic cardiomyopathy (HCM) caused by genes encoding thin filament proteins ( TNNT2, TNNI3, ACTC, TPM1 , TNNC1 ; thin filament HCM) has a distinct clinical presentation and natural history from disease caused by the more commonly involved thick filament genes ( MYH7 , MYBPC3 , MYL2 , MYL3 ; thick filament HCM). METHODS: Retrospective analysis of the Sarcomeric Human Cardiomyopathy Registry. RESULTS: Four hundred eighty-eight patients with thin filament HCM were compared with 3494 patients with thick filament HCM. After controlling for age at diagnosis, sex, and proband status, thin filament HCM was associated with a higher risk of composite ventricular arrhythmias (hazard ratio, 1.48 [95% CI, 1.09–2.01]), cardiac arrest (hazard ratio, 2.02 [95% CI, 1.33–3.06]), and heart transplant or left ventricular assist device implantation (hazard ratio, 2.18 [95% CI, 1.3–3.65]). Younger age at diagnosis was associated with an increased risk for the ventricular arrhythmia composite outcome in thin and thick filament HCM (hazard ratio, 0.93 [95% CI, 0.91–0.94]; hazard ratio, 0.93 [95% CI, 0.93–0.94]; age reported as 5-year increment). Within specific thin filament genes, an increased risk of arrhythmic events or heart transplant/left ventricular assist device implantation was evident for variants in TNNT2 amino acids 92 to 94 (odds ratio versus other TNNT2 variants; odds ratio, 3.02 [95% CI, 1.17–7.49]) and TNNI3 amino acids 191 to 210 (odds ratio versus other TNNI3 variants; odds ratio, 3.5 [95% CI, 1.58–8.02]). CONCLUSIONS: Thin filament HCM seems to carry a higher risk for ventricular arrhythmias and advanced heart failure compared with thick filament HCM. Integrating gene-level and intragene-level information may improve risk stratification in patients with HCM.

Hypertrophic cardiomyopathy (HCM) is marked by asymmetric cardiac wall thickening, hypercontractility, diastolic dysfunction, and fibrosis. Pathogenic sarcomere gene variants cause HCM, but comparable abnormalities occur in patients with unexplained disease, albeit with fewer adverse events. To investigate stage- and genotype-specific disease mechanisms, we performed single-nucleus RNA sequencing of cardiac tissues from 47 patients with HCM, spanning obstructive HCM with preserved systolic function and end-stage HCM, and compared them with nonfailing donor and dilated cardiomyopathy hearts. We identified transcriptional programs associated with cardiomyocyte hypertrophy, fibrosis, and vascular remodeling. Pathogenic variant–positive early-stage HCM samples showed reduced cardiomyocyte abundance and expansion of a proarrhythmogenic cardiomyocyte state. We identified proline-rich 16 ( PRR16 ) as a cardiomyocyte growth–associated gene in HCM and validated its increased expression by RNA in situ hybridization and in a human induced pluripotent stem cell–derived cardiomyocyte HCM model. In HCM samples, fibroblast compositional shifts were associated with profibrotic activation and adverse extracellular matrix remodeling, accompanied by reduced collagen IV ( COL4A1/COL4A2 ) expression and ultrastructural basement membrane abnormalities. HCM samples also exhibited extensive vascular alterations, including shifts in endothelial cell subpopulations, reduced pericyte abundance suggestive of microvascular dysfunction, and increased lymphangiogenic vascular endothelial growth factor C signaling. Unsupervised and supervised machine learning approaches distinguished HCM from dilated cardiomyopathy and accurately predicted genotype status in early-stage HCM from cell type–resolved transcriptional profiles, revealing widespread genotype-driven remodeling. Together, our findings uncover multicellular, genotype-associated remodeling programs in HCM, providing insight into mechanisms underlying arrhythmia, fibrosis, microvascular dysfunction, and heart failure progression.

Background and Aims: Dilated cardiomyopathy (DCM) is a genetically heterogeneous cause of heart failure and sudden cardiac death. Many patients remain without a molecular diagnosis. MAP3K7 encodes TAK1, a serine/threonine kinase important for cardiac homeostasis . MAP3K7 variants are an established cause of syndromic disease, including cardiospondylocarpofacial syndrome (CSCF), in which DCM has been occasionally reported. Here, we demonstrate that MAP3K7 variants can cause apparently isolated DCM, expanding the phenotypic spectrum of MAP3K7 -related disorders. Methods: We integrated four lines of genetic evidence: de novo variation, common variant association, familial segregation, and rare variant enrichment, alongside functional characterisation. Results: In 117 paediatric cardiomyopathy trios from the 100,000 Genomes Project, two probands harboured rare de novo MAP3K7 missense variants, significantly more than expected (Bonferroni-adjusted p=0.036). Independent GWAS implicated MAP3K7 as a susceptibility locus for adult DCM. Across global DCM cohorts, we identified families harbouring rare MAP3K7 variants, including one with segregation in nine affected relatives (p.(Tyr125Cys), estimated LOD = 2.7). Rare damaging non-truncating variants were enriched in DCM versus INTERVAL (OR 22, P=0.007) and gnomAD controls (OR 14, P=6.2×10⁻⁴), while truncating variants were associated with DCM in Genomics England and increased left ventricular volumes in UK Biobank. DCM-associated variants reduced TAK1 kinase activity, supporting a loss-of-function mechanism consistent with CSCF-associated alleles. Conclusion: Multiple independent lines of evidence establish an association between MAP3K7 loss of function variants and DCM. Several affected individuals lacked overt syndromic features, demonstrating that MAP3K7 -related disease may present as apparently isolated DCM across the lifespan and supporting inclusion of MAP3K7 in DCM diagnostic pipelines. GRAPHICAL Key Question: Do MAP3K7 variants cause isolated dilated cardiomyopathy?: MAP3K7 variants are known to cause rare syndromic disease, including cardiospondylocarpofacial syndrome (CSCF). Some patients with CSCF develop dilated cardiomyopathy (DCM), however we do not know whether MAP3K7 variants cause primary or isolated DCM without overt syndromic disease. Key Finding: We present multiple orthogonal data sources supporting an association between MAP3K7 loss-of-function variants and DCM. The collective evidence for this gene-disease association encompasses paediatric trio de novo discovery, GWAS, familial segregation, rare variant case-control analysis and variant categorisation in vitro . Strong segregation evidence was obtained for p.(Tyr125Cys), with nine clinically affected genotype-positive individuals in one pedigree (estimated LOD score 2.7). Further, p.(Cys266del) was observed in three affected individuals in one family and a de novo paediatric case. Take-Home Message: Loss-of-function variants in MAP3K7 are associated with DCM and several affected individuals lack overt syndromic features. MAP3K7 -related disease may present as apparently isolated DCM across the lifespan. These findings support the incorporation of MAP3K7 testing into DCM diagnostic pipelines.

Background Genomic testing will occasionally identify a highly actionable genetic variant or other finding that is not related to the reason for testing. Such incidental findings may be relevant to the patient undergoing testing or to their family members. Methods This guidance on managing incidental findings was developed by the British Society for Genetic Medicine to support clinicians requesting genomic tests and clinical scientists working in genomic laboratories within the National Health Service. Results Clinicians should include the possibility of incidental findings with a patient/parent(s) in discussions around genomic testing. Decisions regarding the reporting of a genetic variant unrelated to the referral reason will depend on clinical actionability, penetrance and the variant classification. Pathogenic variants may be reported if there is evidence of high penetrance and available treatment or surveillance that is likely to improve clinical outcome. Testing using large next generation sequencing gene panels and genome-wide array analysis increases the likelihood of revealing heterozygous carrier status for autosomal recessive disorders unrelated to the reason for testing. Reporting incidental heterozygous carrier status for autosomal recessive conditions is not recommended. Conclusion This guidance provides a framework for the reporting of incidental findings with case examples and a cancer susceptibility gene list. Decision-making in accordance with guidelines will achieve greater consistency than case by case decisions. This guidance may be of use to healthcare professionals in other publicly funded healthcare systems with evolving genomic testing services.

Right ventricular (RV) trabeculation may reflect adaptation to loading conditions and imprinting of early developmental processes, yet its genetic determinants and clinical relevance in adults remain poorly understood. In contrast to the left ventricle, the RV has distinct developmental origins, geometry and loading conditions, suggesting chamber-specific mechanisms of trabecular remodelling. Using deep learning-based image segmentation and fractal dimension analysis, we quantified RV trabecular complexity in diastole and systole in 48,118 UK Biobank participants with genetic data. RV trabecular morphology was associated with systolic function, as well as cardiometabolic and respiratory conditions. Genetic analyses across the allele frequency spectrum identified 52 common loci and 45 genes with a burden of protein-altering variants, implicating sarcomeric function, cytoskeletal organisation, and early cardiac patterning. Although many loci showed shared effects across both ventricles, we also identified RV-specific genetic associations linked to congenital heart disease and respiratory phenotypes. Notably, associations at CFTR suggest a connection between airway-associated mucus regulation and RV remodelling, whereas MYH6 implicates sarcomeric and developmental mechanisms in adult RV patterning. Together, these findings establish RV trabeculation as a trait that captures both shared and chamber-specific mechanisms relevant to cardiovascular health and disease.

Background: Rare heterozygous loss-of-function (LoF) variants in SVIL , encoding the Z-disk and costameric protein supervillin, have recently been identified as a cause of hypertrophic cardiomyopathy (HCM). Although supervillin is implicated in actin-dependent mechanotransduction, the mechanisms linking SVIL deficiency to cardiomyopathy remain poorly understood. Homozygous LoF cause a novel skeletal Myofibrillar Myopathy-10 (MFM-10) while heterozygous LoF cause HCM without skeletal myopathy. In this study we use a human model system to disentangle the LoF pathomechanism of the scaffolding protein supervillin in cardiomyocytes and its clinical implications. Methods: Using CRISPR/Cas-9 we engineered a representative pathogenic LoF variant Q255X into an isogenic induced pluripotent stem cell (iPSC) line creating the heterozygous SVIL ^Q255X/+ and homozygous SVIL ^Q255X/Q255X cell lines. These lines were differentiated into iPSC-derived cardiomyocytes (iPSC-CMs) and cellular phenotypes were assessed using bulk RNA-sequencing, LC-MS proteomics, electrophysiological and calcium handling analyses, contractility measurements, sarcomere organization analysis, Seahorse metabolic flux assay, and pharmacological intervention with mavacamten. Results: The Q255X variant resulted in SVIL haploinsufficiency at both RNA and protein levels with no evidence of a truncated protein. Compared with isogenic controls, SVIL ^Q255X/+ iPSC-CMs demonstrated action potential shortening, calcium transient elongation, sarcomeric disorganization and hypertrophy, and impaired mitochondrial respiration. Multi-omic analyses of SVIL ^Q255X/+ iPSC-CMs showed a profile of cellular stress and inflammation, hypertrophic and pro-fibrotic signalling, and a pseudohypoxic state driven by decreased respiration and a HIF-induced glycolytic shift. These abnormalities were not present in SVIL ^Q255X/Q255X cardiomyocytes, consistent with a relatively limited cardiac phenotype reported in homozygous variant carriers. Mavacamten improved sarcomeric disorganization and hypertrophy in SVIL ^Q255X/+ cells but did not rescue energetic compromise. Conclusions: Pathogenic heterozygous SVIL LoF produces a distinct cellular phenotype characterized by impaired mechanotransduction, mitochondrial dysfunction, and maladaptive metabolic remodelling that promotes hypertrophic and pro-fibrotic signalling. These findings define a mechanistic basis for SVIL -associated cardiomyopathy and identify metabolic dysfunction as a potential therapeutic target beyond sarcomere-directed therapy. Clinical Perspective: What Is New?: SVIL haploinsufficiency causes HCM through a mechanism distinct from canonical sarcomeric disease, characterized by impaired mechanotransduction, mitochondrial dysfunction, and pseudohypoxia-driven metabolic remodeling. Heterozygous SVIL loss of function produces a substantially more severe cardiomyocyte phenotype than homozygous loss of function, providing a mechanistic explanation for the predominance of cardiac disease in heterozygous variant carriers. Mavacamten improves sarcomeric organization but does not restore impaired mitochondrial respiration, demonstrating that energetic dysfunction persists despite sarcomere-directed therapy. What Are the Clinical Implications?: Our findings give functional evidence to support SVIL as a clinically relevant HCM disease gene and its inclusion in clinical genetic testing panels. These findings establish SVIL -associated cardiomyopathy as a mechanistically distinct form of HCM and offer insight into the pathomechanism of Z-disk and costameric HCM The persistence of mitochondrial dysfunction despite myosin inhibition suggests that drugs targeting mitochondrial bioenergetics may be a therapeutic strategy in patients with SVIL -associated cardiomyopathy.

Atrial fibrillation (AF), the most common sustained arrhythmia, has a complex genetic basis; however, the molecular mechanisms linking rare and common variants remain poorly understood. Polygenic risk score (PRS) analysis in the UK Biobank and All of Us cohorts reveals that carriers of protein-altering LMNA variants (PAVs) have a significantly higher risk of incident AF than predicted by PRS alone, supporting an additive effect of common polymorphisms and LMNA variants. Induced pluripotent stem cell derived atrial cardiomyocytes (iPSC-aCMs) from individuals carrying the pathogenic missense variant p.S143P in LMNA exhibit widespread disruption of chromatin architecture and perturbation of atrial gene regulatory networks, particularly at loci harboring AF-associated variants and transcription factors essential for atrial rhythm control and contractility. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based epigenetic editing validates the function of several AF-associated regulatory elements and their downstream targets. Notably, reduced accessibility at an intronic SCN10A enhancer harboring the AF-associated SNP rs6801957 is associated with reduced sodium current in p.S143P iPSC-aCMs. These findings are reproduced in iPSC-aCMs derived from an additional individual carrying a distinct pathogenic LMNA variant, supporting a broader mechanism in which rare LMNA variants and common polymorphisms converge on shared regulatory networks to influence AF susceptibility and highlighting the value of integrating both in arrhythmia risk assessment.