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Hypertrophic cardiomyopathy (HCM) is a genetic myocardial disease. In 20% to 30% of patients, a disease-causing variant can be identified and may also be present in relatives. Individuals carrying a pathogenic variant (G+) without left ventricular hypertrophy (LVH) are classified as genotype-positive/phenotype-negative (G+/P-). Their risk of developing LVH or HCM-related events remains uncertain. The aim of the article is to describe the clinical course of G+/P- individuals during long-term follow-up. G+/P- individuals were recruited from relatives of HCM patients at a tertiary center. All underwent clinical assessment, electrocardiography (ECG), and transthoracic echocardiography (TTE). Phenotype-negative status was defined as maximal left ventricular wall thickness (MLVWT) <13 mm. HCM was diagnosed when MLVWT ≥13 mm was observed without hypertension or other hemodynamic causes. Genetic testing used targeted Sanger sequencing, with variants classified per ACMG/AMP criteria. Thirty-four individuals were classified as G+/P-; the mean age was 31.7 ± 14.8 years, and 27% were men. Variants occurred in MYBPC3 (76%) and MYH7 (24%). Most were asymptomatic (85%), and 71% had a normal ECG. Mean follow-up was 6.6 ± 3.7 years, with complete ECG and TTE data in 88%. MLVWT increased from 9.6 ± 1.6 mm to 10.7 ± 3.3 mm (p = 0.01), while other echocardiographic parameters and ECG findings remained stable. Nine individuals (26%) developed LVH after a mean of 5.1 ± 4.1 years. One patient developed nonsustained ventricular tachycardia and received a primary prevention implantable cardioverter-defibrillator. In conclusion, G+/P- individuals were young and largely asymptomatic, yet 26% progressed to HCM. These results support regular TTE and ECG surveillance to enable early identification of disease progression and guide risk stratification. Show less

Hypertrophic cardiomyopathy (HCM), the most common inherited cardiomyopathy, is characterized by phenotypic and genetic heterogeneity. The present study describes the genotype data of a Swedish cohort of patients with HCM, the largest genetics study on Swedish HCM patients to date. The primary aims of this study were to unravel the main genetic findings and explore genotype-phenotype associations in this HCM cohort. Longitudinal data on 225 unrelated HCM index patients from the Southeast health care region in Sweden from 2010 until 2021 were assessed retrospectively. Patients were 46 ± 15.5 years-old, 67.6% males. In the cohort, 172/225 (76.4%) had genetic testing, of whom, 65/172 (38%) were considered genotype positive (G +) for a pathogenic/ likely pathogenic variant, mainly in the two most common sarcomeric genes: MYBPC3 (57%) and MYH7 (34%). In 43% (74/172) of patients, no reportable variants were detected, classified as genotype negative (G-). In the remaining 33 patients (19%), variants of uncertain significance (VUS) were identified; this group was not included in the comparative analyses. Genotype positive patients (G +) were characterized by younger age (p = 0.010), higher prevalence of family history of HCM (p < 0.001), greater maximum left ventricle wall thickness (p = 0.03) and an increased incidence of sudden cardiac death (SCD) (p = 0.045). At first clinical screening, HCM was diagnosed in 28/65(43%) in the G + families and in 2/74 (2.7%) G-families (p < 0.001). Genotype-positive HCM patients differ with respect to age at presentation, family history of the disease, morphology, incidence of SCD and presence of HCM in their family members at first clinical assessment from genotype-negative patients. Genotype negative status in this HCM cohort, though, did not confer immunity from adverse complications. Show less

Bi-allelic pathogenic variants in A two-month-old infant died from sudden-onset acute heart failure. We performed a full forensic autopsy with detailed histological examination and conducted trio-based whole-exome sequencing (WES) on the proband and parents to identify the genetic etiology. Postmortem examination revealed severe HCM, an atrial septal defect (ASD), and extensive myocardial necrosis and fibrosis. WES identified compound heterozygous pathogenic variants in This "molecular autopsy" established a definitive cause for the infant's death, linking a novel variant to a severe pathological phenotype. Crucially, the diagnosis guided the clinical management of the asymptomatic carrier parents, prompting long-term cardiac surveillance and enabling preimplantation genetic testing (PGT) for future family planning. This case demonstrates how integrating molecular diagnostics with forensic pathology facilitates a systems medicine approach, transforming a fatal index case into actionable preventive care for the entire family. Show less

Hypertrophic cardiomyopathy (HCM) is a prevalent cardiovascular disorder affecting populations worldwide, characterized by abnormal thickening of the heart muscle.(Supporting S1) The development of HCM is influenced by multiple factors, including genetic mutations, geographical conditions, lifestyle, and environmental exposures. The availability of extensive genomic datasets in public repositories provides an opportunity to identify potential genetic contributors and functional biomarkers associated with HCM. Previous studies have highlighted the pivotal role of the MYBPC3 gene in the pathogenesis of HCM. In this study, computational analyses were performed to predict gene mutations and functional biomarkers using RNA-sequencing and whole exome sequencing datasets. A total of 12 RNA-sequencing samples, comprising four healthy controls and eight HCM cases, along with 12 exome sequencing datasets, were retrieved from the Gene Expression Omnibus (GEO) database. RNA-sequencing analysis identified the top 20 differentially expressed genes associated with HCM, including MIB2, ZBTB48, MYBPC3, PRPF40B, CD27-AS1, MYH7, WDR90, KDM8, BCAM, ZSWIM9, KANK3, CCDC85A, ZNF512B, POLR3H, NUP210, PSMG4, GPLD1, GNL1, SH2D3C, and COL4A6. Among these, MYH7 exhibited the highest expression level, showing strong similarity to MYBPC3 in its association with HCM. Whole exome sequencing analysis further identified a panel of variant genes including MYBPC3, MYH6, MYH7, TNT, Titin, Desmin, ACE1, TGF-beta, Ang-2, SGCG, SGCA, DMD, and LaminA/C, all previously implicated in HCM pathophysiology. This integrative study underscores the correlation between differential gene expression patterns and clinical variants in HCM, providing valuable insights into the molecular mechanisms underlying the disease. Show less

Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is an RNA-binding protein known to play critical roles in metabolism, cell proliferation, and tumorigenesis. Although its involvement in muscle development has been documented in several species, the function of goose IGF2BP2 remains largely unexplored. In this study, we cloned and characterized the full-length cDNA and genomic DNA sequences of goose IGF2BP2. The cDNA is 2957 bp in length and contains a 1662 bp open reading frame encoding a 553-amino acid protein with five conserved RNA-binding domains. The genomic sequence spans 12,183 bp and consists of 12 exons and 11 introns. A total of 60 genetic variants were identified, including a deletion of a G base at position 2299 (g.2299delG) that results in a frameshift mutation. Expression analysis revealed high levels of IGF2BP2 mRNA in the liver, heart, and muscle tissues of female geese across embryonic (E25d), growing (A70d), and laying (L270d) stages, consistent with a potential role in muscle development ( Show less

Left ventricular hypertrophy (LVH) refers to the pathological thickening of the myocardial wall and is strongly associated with several adverse cardiac outcomes and sudden cardiac death. While the biomechanical drivers of LVH are well established, growing evidence points to a critical role for cardiac and systemic metabolism in modulating hypertrophic remodeling and disease pathogenesis. Despite the efficiency of fatty acid oxidation (FAO), LVH hearts preferentially increase glucose uptake and catabolism to drive glycolysis and oxidative phosphorylation (OXPHOS). The development of therapies to increase and enhance LFCA FAO is underway, with promising results. However, the mechanisms of systemic metabolic states and LCFA dynamics in the context of cardiac hypertrophy remain incompletely understood. Further, it is unknown to what extent cardiac metabolism is influenced by whole-body energy balance and lipid profiles, despite the common occurrence of lipotoxicity in LVH. In this study, we measured whole-body and cellular respiration along with analysis of lipid and glycogen stores in a mouse model of LVH. We found that loss of the cardiac-specific gene, Show less

Hypertrophic cardiomyopathy (HCM) is a genetic heart disease characterized by left ventricular hypertrophy (LVH =15 mm) in the absence of other causes. It affects 1 in 500 individuals, with an autosomal dominant inheritance pattern involving MYH7 and MYBPC3, the most commonly affected genes. Diagnosis relies on echocardiography, with cardiac magnetic resonance providing additional insights, including late gadolinium enhancement, aneurysms, and microvascular dysfunction linked to adverse outcomes. Risk stratification for sudden cardiac death includes the HCM Risk-SCD (adults) and HCM Risk-Kids (pediatrics) models, guiding implantable cardioverter defibrillator therapy. Management depends on phenotype: 1. Obstructive HCM: First-line therapy includes beta-blockers or non-dihydropyridine calcium channel blockers. Myosin inhibitors offer new options for symptom control. In refractory cases, surgical myectomy or alcohol septal ablation is recommended. 2. Non-Obstructive HCM: Treatment focuses on diastolic dysfunction and arrhythmia management, with emerging pharmacologic options under investigation. 3. Atrial fibrillation: Common in HCM, requiring anticoagulation, rate control, or ablation. Advances in genetic testing, imaging, and targeted therapies have significantly reduced HCM-related mortality to 0.5% per year, transforming it into a manageable condition. Future research will enhance precision medicine, surgical expertise, and equitable access to care. Show less

Pediatric primary cardiomyopathies (PCMs) are rare diseases with complex causes and nonspecific treatment. The influence of electrolytes and amino acids (AAs) on cardiomyopathies has not been extensively studied. This study aimed to explore clinical characteristics and the usage of electrolytes and AAs in children with PCMs. Children diagnosed with PCMs who had genetic test reports were included. Relevant information was collected and processed, and clinical characteristics and mutated genes were clarified. Gene databases were searched to explore related electrolytes and AAs in the treatment of PCMs. The effect of calcium was explored in children with DCM. Paired samples T tests and nonparametric Wilcoxon signed-rank tests were performed for comparison between before and after using calcium. In this study, 27 children with gene test results were enrolled to perform gene-related analysis. The median age was 2.5 years old. Mutated genes were collected, including pathogenic, likely pathogenic, uncertain significance, and other mutations. The most frequently mutated genes related to dilated cardiomyopathy (DCM) were For children with DCM, calcium supplements may be beneficial. AAs, including serine, cysteine, and arginine, could be used for supplementary treatment in children with DCM and HCM. Show less

Genetic testing is valuable to confirm molecular diagnosis in nearly 60% of cases suspected of hypertrophic cardiomyopathy (HCM). However, the interpretation of variants, especially those of uncertain significance (VUSs), remains challenging for laboratories and clinicians. In April 2024, the ClinGen Cardiomyopathy Variant Curation Expert Panel (VCEP) adapted the ACMG/AMP criteria for eight of the sarcomeric genes ( Here, two groups of curators reinterpreted variants with the most recent data using the Cardiomyopathy VCEP specifications until a consensus was reached. To streamline the process, we created a semiautomated decision support tool based on these gene-specific rules. The application of the Cardiomyopathy VCEP specifications resulted in the reclassification of 17.4% ( Using gene-specific ACMG/AMP criteria reduces the rate of VUS, increasing diagnostic yield, and informing clinical management in the context of HCM. Nonetheless, ongoing efforts to generate evidence and promote standardization remain essential to improve variant interpretation. Show less

ObjectiveTo analyze the clinical characteristics, etiological composition, genetic variations, and survival outcomes of children with hypertrophic cardiomyopathy.Materials and methodsThis retrospective study included 41 pediatric patients diagnosed with hypertrophic cardiomyopathy at The First Affiliated Hospital of Guangxi Medical University from 2013 to 2024. Clinical data were reviewed, including symptoms, echocardiography, electrocardiography, genetic testing, and follow-up outcomes. Comparisons were made between patients with primary and secondary hypertrophic cardiomyopathy.ResultsAmong the 41 patients, 27 were men and 14 were women, with a median age at onset of 4 years and 3 months. Genetic testing was performed in 24 cases, identifying 13 cases of primary hypertrophic cardiomyopathy and 11 cases of secondary hypertrophic cardiomyopathy, most commonly associated with Noonan syndrome. The most frequent symptoms were fatigue (28.95%) and dyspnea (23.68%). Common pathogenic genes in primary hypertrophic cardiomyopathy included Show less

Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disorder characterized by left ventricular hypertrophy and an elevated risk of sudden cardiac death. Cardiac myosin binding protein C (MYBPC3) is the most frequently mutated gene leading to HCM. In this study, peripheral blood mononuclear cells isolated from an HCM patient harboring a heterozygous MYBPC3 missense mutation (c.3072C > A; p.S1024R) were reprogrammed via Sendai virus vectors to generate a patient-specific induced pluripotent stem cell (iPSC) line. The iPSC line exhibits normal morphology and karyotype, alongside definitive hallmarks of pluripotency, including trilineage differentiation potential. Show less

MYBPC3 (Myosin-binding site protein C3) alterations are associated with hypertrophic cardiomyopathy (HCM). However, the neuroimaging features of these patients are not well-described in the literature. We present a unique case of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)-like neuroimaging features in a middle-aged female, who harbors a heterozygous likely pathogenic splice site variant [c.26-2 A > G] in MYBPC3 [NM₀₀₀₂₅₆.3]. The patient had negative genetic and electron microscopy test results for CADASIL. Our observations suggest that CADASIL-like cerebral vasculopathy may occur in MYBPC3-related disorders, thus highlighting the need for further characterization of neuroimaging features of patients with MYBPC3-related disorders. Show less

Heart failure (HF) is a serious cardiovascular condition resulting from abnormalities in multiple biological processes, affecting over 64 million people worldwide. We sought to expand our understanding of the genetic basis of HF and more specific NICM subtype in the East Asian populations and evaluate the biological pathways underlying subclinical left ventricular dysfunction. We conducted a meta-analysis of genome-wide association studies (GWAS) for all-cause HF in the East Asian populations (N cases ~ 13,385) and a more precise definition of nonischemic cardiomyopathy (NICM) subtype in multi-ancestry populations (N cases~3,603). We identified a low-frequency East-Asian enriched coding variant near MYBPC3 and a NICM specific locus. Follow up analyses demonstrated male-specific HF association at the MYBPC3 locus, and highlighted SVIL as a candidate causal gene for NICM. Moreover, we demonstrated that SVIL deficiency aggravated cardiomyocyte hypertrophy, apoptosis and impaired cell viability in phenylephrine (PE)-treated H9C2 cells. In addition, the gene expression level of B-type natriuretic peptide (BNP) which was deemed as a hallmark for HF was further elevated by SVIL silencing in PE-stimulated H9C2 cells. RNA-sequencing analysis of H9C2 cells revealed that the function of SVIL might be mediated through pathways relevant to regulation and differentiation of heart muscle. These results enhance our understanding of the genetic architecture of HF in the East Asian populations, and provide important insight into the biological pathways underlying NICM and sex-specific relevance of the MYBPC3 locus that warrants further replication in another datasets. Show less

Hypertrophic cardiomyopathy (HCM) represents the most prevalent form of hereditary cardiomyopathy, and mutation in the cardiac myosin-binding protein C (MYBPC3) gene have been identified as a major contributor to the pathogenesis of HCM. While the desmoplakin (DSP) gene is primarily associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM), its role in HCM has been less frequently documented. This case report describes a Chinese patient with obstructive HCM harboring rare variants in both the MYBPC3 and DSP genes. These findings provide valuable insights for future investigations into the genetic underpinnings and disease associations. Show less

Cardiomyopathies (DCM, HCM, and ACM) and primary arrhythmogenic disorders (BrS, LQTS, and CPVT) represent the most common causes of sudden cardiac death (SCD) in young individuals. Systematic genome-wide single-nucleotide polymorphism (SNP) analyses and genome-wide association studies (GWASs) have enabled the identification of numerous genetic variants associated with cardiovascular diseases. Body: Genetic testing for cardiomyopathies and inherited channelopathies primarily involves panel testing of genes with definitive and strong evidence of disease association; genes supported by moderate evidence may also be considered. Cardiomyocytes express a variety of proteins implicated in the pathogenesis of genetic cardiomyopathies, including sarcomeric, cytoskeletal, desmosomal, and nuclear envelope proteins. Inherited cardiac channelopathies result from mutations in genes encoding cellular components that influence calcium ion availability or affect membrane ion channels, including sodium, potassium, and calcium channels. Common variants associated with SCD are found in genes encoding cardiac ion channels (e.g., This review demonstrates that specific genetic variants are significantly associated with an increased risk of SCD. The evidence underscores the importance of genetic screening and early intervention in individuals with a family history of SCD or other risk factors for inherited cardiac disorders predisposing to SCD. Future research should focus on gene-specific management strategies for familial cardiomyopathies and inherited channelopathies, with the goal of improving targeted genetic therapies and reducing the burden of sudden cardiac death. Show less

Cardiomyopathy (CM) is a heterogeneous group of diseases characterized by structural and functional changes in the heart, with the exact cause often remaining unknown. CM can arise from both inherited and acquired metabolic disturbances. Alterations in energy production and substrate utilization impair the heart's contractile function and limit its ability to respond to stress. Given the complexity and dynamic nature of CM, as well as the multiple etiologies involved, we reviewed metabolomic studies employing high-throughput platforms to understand how metabolic pathways shift across CM subtypes and how these perturbations may inform clinical translation. Several recurring disruptions emerge across CM with alterations in amino acid metabolism (valine, leucine, methionine, tryptophan, tyrosine); mitochondrial redox imbalance (NAD/NADH shifts, niacinamide, acylcarnitines); and oxidative stress as central hallmarks. Each subtype, however, displays a different emphasis. For instance, hypertrophic CM is characterized by nucleotide remodeling, particularly in cases involving Show less

Hypertrophic cardiomyopathies (HCMs) are among the most common genetic disorders; however, they might be underdiagnosed. Sequencing core sarcomere gene panels remain the main diagnostic tool. We present the results of HCM genetic testing performed at Lithuania's tertiary care center. All patients with diagnosed or clinically suspected HCM underwent next-generation panel sequencing. Of 204 patients, 34 (16.7%) received a genetic diagnosis. The most commonly affected genes were Show less

Regulation of myosin motor extension and conformation is central to cardiac muscle contraction-relaxation, with myosin playing a critical role in mechanosensing during the cardiac cycle. Direct assessment of in vivo dynamic interplay between myosin head position, cross-bridge cycling, sarcomere shortening (filament sliding), muscle stress-strain rates and pressure-volume (PV) relationships is key to understanding both normal cardiac function and ventricle pathological states. This work aims to demonstrate that in vivo temporal regulation of myosin head transfer to actin filaments in systole and diastole has important points of difference from current models based on in vitro and ex vivo muscle studies, particularly in settings of diastolic dysfunction. The first study investigated myosin activation-deactivation in a mouse model of diet-induced obesity (high-fat high-sugar diet) with moderate contraction-relaxation impairment. In a second study myosin regulation was investigated in a novel hypertrophic cardiomyopathy mouse model due to a truncation mutation in the sarcomeric gene encoding cardiac myosin binging protein-C, Mybpc3 (Exon 33 deletion). We demonstrate with in vivo small-angle X-ray scattering (SAXS) simultaneous with PV loop analysis in the beating heart that dynamic regulation of myosin is often non-uniform across the left ventricle from the epicardium to subendocardium, with large differences in myosin head behaviour in both systole and diastole, at least in rodents. Our findings underscore that myosin activation-deactivation is intricately tuned to the mechanical demands of the heart and the work of each myocardial layer. Regional myosin filament dysregulation underpins muscle relaxation impairment, offering new insights into potential therapeutic targets. KEY POINTS: This small-angle X-ray scattering (SAXS) study demonstrates that in vivo myosin activation-deactivation and myosin interfilament spacing vary across myocardial layers and are influenced by diet, exercise and pathological conditions in vivo in the murine heart. During the isovolumetric contraction phase, myosin heads exhibit strong cross-bridge binding in response to mechanical load, which increases in the ejection phase, highlighting the critical role of mechanosensing in early force development. In the absence of myosin binding protein-C within the thick filament complex this strong cross-bridge formation is not sustained during ejection. Impaired myosin cross-bridge detachment likely contributes to sustained cross-bridge activation in the isovolumetric relaxation phase and prolongation of relaxation in hypertrophic cardiomyopathy. This study highlights how disturbed myosin mechanosensing evoked by metabolic stress and genetic mutations can impair myosin motor function and correlates with global cardiac dysfunction. Show less

Fel d1, the major cat allergen responsible for over 90% of human IgE-mediated allergies, has an incompletely defined physiological role. To explore its function and assess the feasibility of producing hypoallergenic cats, we knocked out the CH2 domain of Fel d1 using CRISPR/Cas9 in feline skin cells. An optimized sgRNA introduced a frameshift mutation, with knockout efficiency validated by sequencing, qRT-PCR, and Western blot. Transcriptomic alterations were profiled by RNA-seq, and functional consequences were investigated via GO, KEGG, and GSEA analyses. Key findings were confirmed by qPCR, and phenotypes were assessed using CCK-8, EdU, and flow cytometry. The approach successfully generated a three-base insertion, resulting in near-complete loss of CH2 mRNA and Fel d1 protein. RNA-seq identified 3,469 differentially expressed genes (DEGs), with significant enrichment in pathways for hypertrophic cardiomyopathy (HCM) and rheumatoid arthritis (RA). Key genes in these pathways (e.g., Show less

Sudden cardiac death (SCD) is a known risk of hypertrophic cardiomyopathy (HCM), especially in asymptomatic and younger (<35 years old) populations. There are several mutations that cause HCM, most notably within the MYBPC3 and MYH7 genes. ALPK3 (alpha protein kinase 3) has been identified as a gene of interest in HCM, specifically associated with late-onset adult HCM or pediatric cases which typically present with musculoskeletal and facial deformities. In this report, we present a case of SCD due to HCM in a young, reportedly asymptomatic patient without dysmorphia that had a specific mutation of the ALPK3 gene and a striking gross pathological appearance previously undiscussed in literature. Show less

Sudden cardiac arrest (SCA) is a leading cause of mortality in young individuals, often linked to structural heart disease or primary electrical disorders. However, in some cases, the etiology remains unidentified despite extensive diagnostic efforts. This case report describes a 23-year-old male with a family history of hypertrophic cardiomyopathy (HCM) who experienced a sudden cardiac arrest without prior symptoms and had negative genetic testing. The patient, previously healthy, suffered a cardiac arrest while traveling to college. Advanced cardiopulmonary resuscitation (CPR) and multiple defibrillator shocks were necessary to achieve return of spontaneous circulation (ROSC). Transthoracic echocardiography performed immediately post-ROSC showed global hypokinesia with reduced ejection fraction (35%). Coronary angiography at 24 hours post-ROSC was normal. Transient ST-segment elevations resolved within hours and were attributed to post-resuscitation myocardial stunning, with no evidence of ischemia or myocarditis on cardiac magnetic resonance imaging (MRI), which revealed mild interventricular septal hypertrophy without left ventricular outflow tract obstruction. Genetic testing, including a targeted cardiomyopathy panel and whole exome sequencing, did not identify any pathogenic variants, including in MYH7 or MYBPC3. The patient was treated with amiodarone and received an implantable cardioverter-defibrillator (ICD) for secondary prevention. He recovered fully, with no neurologic deficits. This case underscores the challenges of diagnosing and managing SCA in young adults, emphasizing the critical role of genetic and structural assessments. Early intervention, multidisciplinary care, and comprehensive follow-up are essential to reduce recurrence and improve patient outcomes. Show less

This study examines pediatric cardiomyopathies by analyzing genetic and clinical data from 55 patients (2021-2024) at Beijing Anzhen Hospital. Four subtypes were studied: dilated (DCM, 24), hypertrophic (HCM, 22), arrhythmogenic right ventricular (ARVC, 7), and restrictive (RCM, 2). Clinical data, imaging, labs, and family histories were collected, with whole-exome sequencing (WES) identifying disease-causing variants classified via ACMG guidelines. Statistical analysis revealed a median age of 11 years, a proportion of 58% male participants, and ethnic diversity (21 northern Han, 29 southern Han, 5 minorities). In the cohort, 13 cases had an LVEF below 35%. Pathogenic/likely pathogenic (P/LP) variants were found in 21.8% of the patients, and variants of uncertain significance (VUS) were present in 38.2%, with Show less

Multiplexed assays of variant effect (MAVEs) systematically measure variant function but have been limited to cancer cell lines rather than disease-relevant cell types. We developed saturation genome editing in human iPSCs (iPSC-SGE) to introduce variant libraries into a single allele of a target gene while programming the genetic background of the second allele, enabling variant assessment across differentiated cell types and genetic contexts at scale. We edited 1,137 variants into Show less

Hypertrophic cardiomyopathy (HCM) progressing to end-stage heart failure and heart transplantation (HT) is a rare clinical scenario with an insufficiently explored genetic background. In this single-center retrospective cohort study, we aimed to characterize the genetic spectrum, variants of HCM adverse remodeling, and aspects of molecular pathogenesis of this subgroup. The study included 14 patients (9 females), among whom 10 developed a dilated/hypokinetic phenotype and 4 a restrictive phenotype. In 13 patients (93%), at least one pathogenic or likely pathogenic genetic variant was identified. Dilated remodeling/hypokinesis was associated with loss-of-function variants in Show less

Arrhythmogenic cardiomyopathy (ACM) is typically linked to variants in desmosomal genes (eg, DSG2), whereas MYBPC3 variants are associated with hypertrophic cardiomyopathy. Concurrent variants from both pathways are rare and poorly characterized. A 35-year-old man who presented with congestive heart failure fulfilled the criteria for biventricular ACM. Genetic analysis identified 3 heterozygous variants, in DSG2 (c.136C>T, p.Arg46Trp and c.806T>C, p.Ile269Thr) and MYBPC3 (c.529C>T, p.Arg177Cys; variant of uncertain significance). The patient was treated with guideline-directed therapy, remained clinically stable with reduced premature ventricular complex burden and improved biventricular function on cardiac magnetic resonance, and was listed for heart transplantation. Concurrent DSG2 and MYBPC3 variants represent an uncommon genetic profile in ACM, contributing to variable phenotype and adverse outcomes. This case highlights the value of genetic testing combined with advanced imaging in refining the characterization of inherited cardiomyopathies. Concurrent genetic variants may influence phenotype and prognosis. Comprehensive testing and longitudinal follow-up are essential for risk stratification and personalized care. Show less

This brief report details the initial findings from a Phase 1b/2 trial of TN-201, an adeno-associated virus serotype 9 (AAV9) gene therapy for MYBPC3-associated hypertrophic cardiomyopathy (HCM), a condition with significant morbidity, increased risk of mortality, and no approved therapy for the majority of patients. TN-201 was well tolerated, and changes to the management of potential immune responses resulted in a shorter period of immunosuppression. These results show consistent transduction and expression of TN-201 in cardiomyocytes, corresponding with increases in MyBP-C levels, reductions or stabilization of cardiac biomarkers, and reductions in key measures of left ventricular (LV) hypertrophy. Show less

Inherited arrhythmias and cardiomyopathies are a group of potentially lethal genetic cardiac disorders which are often passed down through generations and pose risks to several family members. While individually rare, these conditions are collectively common and pose significant challenges for clinical management given their variable severity, age of onset, and response to treatments. Earlier genetic analyses revealed crucial insights into the main genetic culprits of these disorders, such as Show less

Phenotypic heterogeneity is apparent among individuals with putative monogenic disease, such as familial hypertrophic cardiomyopathy. Genome sequencing (GS) allows interrogation of the full spectrum of inborn genetic variation in an individual and RNA profiling provides a snapshot of the cardiac-specific pathogenic effects on gene expression. Identify candidate genetic modifiers of hypertrophic cardiomyopathy phenotype. We performed GS of 48 individuals with variants in GS identified the Evaluation of the whole genome, even in the case of alleged monogenic disease, leads to important new insights. The identified variants, regions, and genes are candidates to modify disease presentation in cardiomyopathy. Show less

A woman in her 50s with known MYBPC3-associated obstructive hypertrophic cardiomyopathy was evaluated for septal reduction therapy. The electrocardiogram, echocardiogram, and cardiac magnetic resonance found several features inconsistent with the diagnosis. Targeted screening confirmed adult-onset Fabry disease. Enzyme replacement therapy was started. Show less