Circulation: Genomic and Precision Medicine最新文献

{"title":"Detecting and Mitigating Bias for Inclusive and Trustworthy Clinical Research: A Scientific Statement From the American Heart Association.","authors":"Judy Zhong, Salah Al-Zaiti, Derrick A Bennett, Synho Do, Mario F L Gaudino, Judy W Gichoya, Salma M A Musaad, Sanjiv M Narayan, Tolulope Sajobi, Yu Shen, Antonis A Armoundas","doi":"10.1161/HCG.0000000000000101","DOIUrl":"https://doi.org/10.1161/HCG.0000000000000101","url":null,"abstract":"<p><p>Bias in clinical research affects not only the internal validity of studies but also the equitable distribution of health benefits derived from studies. Among the most impactful forms are selection bias, attrition bias, and algorithmic bias, each of which is capable of distorting participant representation, treatment effect estimates, and model performance across important subgroups. This scientific statement provides a reference for cardiovascular researchers and clinicians, integrating detection, correction, and prevention strategies to address these biases. Selection bias may be mitigated through approaches such as inverse probability weighting and adjustment for sociodemographic imbalances; attrition bias can be addressed using intention-to-treat analyses and multiple imputation for missing data that are missing at random; algorithmic bias requires fairness-aware modeling, diverse training data sets, and explainable artificial intelligence techniques. These 3 forms of bias are not exhaustive, but their careful management is essential to achieving scientific rigor, fairness, and real-world applicability, and requires multidisciplinary collaboration to embed equity and validity throughout the research lifecycle.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e000101"},"PeriodicalIF":5.5,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Truncating Variant c.1222DupC in <i>RBM20</i> Causes Cardiomyopathy Consistent With Haploinsufficiency.","authors":"Priyanka Pant, Yong Huang, Zakiya Ghouse, Fang Bai, Elena Kemmling, Laura Konrad, Ahmed Alameldeen, Rebecca Kistler, Timon Seeger, Michael Gotthardt, Victoria N Parikh, Maarten M G van den Hoogenhof","doi":"10.1161/CIRCGEN.125.005471","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005471","url":null,"abstract":"<p><strong>Background: </strong>RBM20 (RNA binding motif protein 20) is a cardiac splicing factor responsible for the splicing of several cardiac genes such as titin (<i>TTN</i>), triadin (<i>TRDN</i>), ryanodine receptor 2 (<i>RYR2</i>), PDZ and LIM domain protein 1 (<i>PDLIM1</i>), and calcium/calmodulin-dependent protein kinase II (<i>CAMK2D</i>). Pathogenic variants in <i>RBM20</i> are a major cause of familial dilated cardiomyopathy, and lead to missplicing of RBM20 target genes.</p><p><strong>Methods: </strong>We identified a patient with a novel <i>RBM20</i> variant, and expressed the human and mouse-equivalent variant in neonatal rat cardiomyocytes and HEK293 cells. We performed splicing assays, and assessed protein expression and stability. Furthermore, we generated heterozygous <i>RBM20</i>-c.1222DupC human induced pluripotent stem cells, differentiated these into human induced pluripotent stem cell-derived cardiomyocytes, and evaluated splicing changes and calcium handling.</p><p><strong>Results: </strong>We describe a novel heterozygous truncating variant, <i>RBM20</i>-c.1222DupC, identified in a patient with mitral valve prolapse and late-onset familial dilated cardiomyopathy. The variant introduces a premature termination codon and generates a truncated protein of ≈55 kDa in vitro. Splicing assays demonstrated complete loss of activity and no dominant-negative effect on wild-type RBM20. The truncated protein localized to both the cytoplasm and nucleus, partially colocalizing with wild-type RBM20, despite lacking the RS and RRM domains. Western blot analysis of endogenous RBM20 in human induced pluripotent stem cell-derived cardiomyocytes carrying the variant revealed a strong reduction in RBM20 protein levels. Reverse transcriptase-polymerase chain reaction revealed splicing defects in canonical RBM20 targets, and RNA sequencing identified widespread splicing abnormalities, including in established RBM20 targets (<i>TTN</i>, <i>RYR2</i>, <i>CAMK2D</i>, and <i>CACNA1G</i>). Finally, we observed increased calcium transients.</p><p><strong>Conclusions: </strong>Together, these findings establish <i>RBM20</i> c.1222DupC as a truncating variant that causes dilated cardiomyopathy likely through haploinsufficiency.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005471"},"PeriodicalIF":5.5,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated Genomic and Transcriptomic Study Reveals <i>MAPK11</i> and <i>PER1</i> as Important Obesity Susceptibility Genes in a High-Risk Hispanic/Latino Population.","authors":"Daeeun Kim, Hannah G Polikowsky, Heather M Highland, Hung-Hsin Chen, Wanying Zhu, Xinruo Zhang, Madeline G Gillman, Elizabeth G Frankel, Rashedeh Roshani, Joshua M Landman, Yujie Wang, Kristin L Young, Mohammad Yaser Anwar, Mohanraj Krishnan, Victoria L Buchanan, Sonja I Berndt, Joshua D Arias, Laura M Raffield, Absalon D Gutierrez, Faraz Bishehsari, Miryoung Lee, Joseph B McCormick, Susan P Fisher-Hoch, Jennifer E Below, Kari E North, Mariaelisa Graff","doi":"10.1161/CIRCGEN.125.005298","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005298","url":null,"abstract":"<p><strong>Background: </strong>While GWAS (genome-wide association studies) have identified over 1000 obesity-associated loci, their functional impact on gene expression remains unclear. Moreover, many studies have not fully captured the genetic architecture of obesity in high-risk populations or considered the complexity of adiposity beyond traditional measures. To address these gaps, this study explores the genetic and transcriptomic pathways of obesity using diverse obesity phenotypes in a high-risk population.</p><p><strong>Methods: </strong>We analyzed genomic and whole-blood transcriptomic data from the CCHC (Cameron County Hispanic Cohort), performing GWAS on 13 obesity-related traits. Differential expression analysis was conducted for genes near GWAS-identified single nucleotide polymorphisms (<i>P</i><5×10^-6) followed by expression quantitative trait loci mapping and GWAS-expression quantitative trait loci colocalization.</p><p><strong>Results: </strong>GWAS identified 486 trait associations, including 6 genome-wide significant (<i>P</i><5×10^-8) loci, with 3 novel signals linked to abdominal subcutaneous adipose tissue, body fat percentage, and waist circumference. Among 3024 genes near these loci, 60 showed differential expression. Further expression quantitative trait loci analysis suggested 2 single nucleotide polymorphism-gene-trait relationships: rs543314376-<i>MAPK11</i>, associated with subcutaneous adipose tissue volume in females, and rs963018484-<i>PER1</i>, linked to body mass index in females. Both genes play key roles in obesity-related pathways, including inflammation and circadian rhythm regulation.</p><p><strong>Conclusions: </strong>This integrative genomic-transcriptomic analysis uncovers 2 novel candidate genes for obesity and underscores the critical need for involving all populations and comprehensive adiposity measures in obesity research. By expanding beyond body mass index in a Hispanic/Latino population, we move closer to a deeper and more inclusive understanding of obesity's genetic architecture.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005298"},"PeriodicalIF":5.5,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13127804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnostic Yield of Exome Sequencing in Patients With Congenital Heart Disease From Southern Africa.","authors":"Timothy F Spracklen, Thomas Aldersley, John Lawrenson, Paul Human, Blanche Cupido, Fenny Shidhika, George Comitis, Barend Fourie, Andre Brooks, Lenise Swanson, Rik De Decker, Kélin Engel, Alexia Joachim, Phaphama Magadla, Hope-Kirsten Edwards, Karen Sliwa, Gasnat Shaboodien, Raj Ramesar, Bernard D Keavney, Liesl J Zühlke","doi":"10.1161/CIRCGEN.125.005463","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005463","url":null,"abstract":"<p><strong>Background: </strong>Congenital heart disease (CHD) is a leading cause of pediatric morbidity and mortality worldwide. The genetics of CHD in African populations is not well understood, although it has been shown in other settings that a genetic diagnosis can have implications for patient management and risk stratification. In this study, we aimed to identify pathogenic and likely pathogenic (P/LP) variants in a cohort of patients with CHD from Southern Africa.</p><p><strong>Methods: </strong>Exome sequencing was used to screen 356 patients with diverse cardiac phenotypes from South Africa and Namibia.</p><p><strong>Results: </strong>A P/LP variant was identified in 28 patients (7.9%). Analysis of 11 parent-child trios revealed a further LP variant in <i>MYLK</i> in 1 patient, bringing the overall yield to 8.1%. Variants of uncertain significance with high pathogenic potential were found in 30 additional patients. <i>NOTCH1</i>, <i>MYH11</i>, and <i>MYH6</i> had the most recurrent variants in this cohort. Our data expand on the phenotypic spectrum of many established CHD genes, including the overlap between syndromic CHD genes and nonsyndromic presentation, and a potential link between aortopathy genes and conotruncal anomalies such as Tetralogy of Fallot. Variants were identified across the spectrum of CHD subtypes, with an increased yield in patients with atrioventricular septal defects and syndromic CHD, and a slight enrichment of P/LP variants in patients who died after CHD surgery. There were significantly fewer P/LP variants in patients who were of mixed ancestry.</p><p><strong>Conclusions: </strong>Together, these data confirm a role for rare deleterious variation in nonsyndromic CHD and demonstrate that a P/LP variant can be identified in 8% of patients from Southern Africa.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005463"},"PeriodicalIF":5.5,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-Term Efficacy and Safety of GLP-1R Agonist and SGLT2 Inhibitor Therapy in the General Population: A Mendelian Randomization Study.","authors":"Subbaramireddy Remala, Liming Liang, Amil M Shah, Leo F Buckley","doi":"10.1161/CIRCGEN.125.005535","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005535","url":null,"abstract":"<p><strong>Background: </strong>SGLT2 (sodium-glucose cotransporter-2) inhibitors and GLP-1R (glucagon-like peptide-1 receptor) agonists reduce the risk of major adverse cardiovascular and kidney events in individuals with various cardiometabolic conditions. The long-term efficacy and safety of these therapies, especially in low- and moderate-risk populations, remain uncertain.</p><p><strong>Methods: </strong>We conducted a biobank-scale analysis using genetic instruments derived from naturally occurring genetic variations in the genes encoding the targets of SGLT2 inhibitors (SLC5A2) and GLP-1R agonists (GLP1R) that are associated with glycated hemoglobin levels. This Mendelian randomization study utilized data from the All of Us Research Program, which includes whole genome sequencing and electronic health records of 633 547 participants.</p><p><strong>Results: </strong>Higher SGLT2 inhibitor genetic instrument scores were associated with a lower risk of heart failure (odds ratio [OR], 0.97 [95% CI, 0.96-0.99]) and chronic kidney disease (OR, 0.98 [95% CI, 0.96-0.99]). Higher GLP-1R agonist genetic instrument scores were linked to reduced risks of heart failure (OR, 0.97 [95% CI, 0.96-0.99]), chronic kidney disease (OR, 0.96 [95% CI, 0.95-0.98]), and coronary artery disease (OR, 0.98 [95% CI, 0.96-0.99]). We did not detect associations between the GLP-1R agonist instrument and multiple endocrine neoplasia or medullary thyroid carcinoma. PheWAS (Phenome-Wide Association Study) identified associations between the SGLT2 inhibitor and GLP-1R agonist genetic instruments and a lower risk of diabetes, but no other phenotypes.</p><p><strong>Conclusions: </strong>This study demonstrates the utility of biobank-scale health data for pharmacology research and suggests that, if feasible to implement in routine practice, long-term, primary prevention with an SGLT2 inhibitor or GLP-1R agonist would safely lower the risk of major adverse cardiovascular and kidney events in low- to moderate-risk adults.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005535"},"PeriodicalIF":5.5,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13120722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-Wide Association Study of Chronic Venous Insufficiency and Lymphedema in the Million Veteran Program.","authors":"Gina M Peloso, Nimish Adhikari, Melissa M Young, Kelly Cho, Scott Kinlay","doi":"10.1161/CIRCGEN.125.005442","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005442","url":null,"abstract":"<p><strong>Background: </strong>Lymphedema is a chronic condition characterized by the accumulation of fluid due to impaired lymphatic drainage, frequently occurring secondary to chronic venous insufficiency (CVI), malignancy, or obesity. Despite known environmental and clinical risk factors, the genetic contributors to lymphedema and CVI have been understudied.</p><p><strong>Methods: </strong>We conducted a multipopulation genome-wide association study in participants of the Million Veteran Program without cancer to identify genetic variants associated with CVI, lymphedema, and their cooccurrence. Individuals were categorized into 3 case groups: CVI only (n=34 664), lymphedema only (n=2452), and lymphedema+CVI (n=3283) and were compared with 367 684 controls.</p><p><strong>Results: </strong>We identified 11 genome-wide significant variants (<i>P</i><5×10^-⁸) in the multipopulation analysis, including 8 for CVI only, 1 for lymphedema only, and 2 for lymphedema+CVI, and 2 population-specific genetic variants. Three independent variants replicated in the UK Biobank for CVI only near <i>CASZ1</i>, <i>SLC12A2</i>, and <i>NDP</i>. Polygenic risk scores derived from the Million Veteran Program were associated with CVI in the UK Biobank and phenome-wide associations of CVI-associated variants revealed pleiotropic associations with cardiometabolic traits.</p><p><strong>Conclusions: </strong>These findings enhance our understanding of the genetic architecture of lymphatic dysfunction.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005442"},"PeriodicalIF":5.5,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare <i>KDR</i> Variants Define a Distinct Genetic Contribution to Congenital Heart Disease.","authors":"Feria A Ladha, Paul Avillach, Alexander R Opotowsky, Aldweib Nael, Martina Brueckner, Wendy K Chung, James F Cnota, Bruce D Gelb, Matthew Lewis, Cong Liu, Amy E Roberts, Christine E Seidman, J G Seidman, Martin Tristani-Firouzi, Michael Wagner, Jane W Newburger, Yuri Kim, Sarah U Morton","doi":"10.1161/CIRCGEN.125.005659","DOIUrl":"10.1161/CIRCGEN.125.005659","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005659"},"PeriodicalIF":5.5,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scalable System-Wide CYP2C19 Pharmacogenomic Testing Reveals 38% Excess Incidence of Adverse Events in Metabolizers Receiving Inappropriate Prescriptions.","authors":"Natalie Telis, Douglas Stoller, Christopher N Chapman, C Anwar A Chahal, Daniel P Judge, Douglas A Olson, Joseph J Grzymski, Catherine Hajek, Teresa Kruisselbrink, Nicole L Washington, Elizabeth T Cirulli","doi":"10.1161/CIRCGEN.125.005363","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005363","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005363"},"PeriodicalIF":5.5,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biobank-Scale Plasma Proteomics Identifies Novel Biomarkers in Hypertrophic Cardiomyopathy.","authors":"Jonathan H Chan, Christopher Grace, Mohsen Mazidi, Robert Clarke, Carolyn Y Ho, Stefan Neubauer, Christopher M Kramer, Hugh Watkins, Anuj Goel","doi":"10.1161/CIRCGEN.125.005325","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005325","url":null,"abstract":"<p><strong>Background: </strong>Hypertrophic cardiomyopathy (HCM) is characterized by substantial heterogeneity in both clinical phenotype and risk of adverse outcomes, including heart failure and sudden cardiac death. This highlights the need for robust biomarkers for risk stratification, and while previous studies have identified the role of select plasma proteins, comprehensive large-scale proteomic analyses have been limited in HCM.</p><p><strong>Methods: </strong>We performed a case-control analysis of 2922 plasma proteins in 49 588 UK Biobank participants (100 HCM cases) to identify proteins associated with HCM. External replication analyses were performed in the deCODE Genetics Icelandic study (51 cases/38 904 controls) and All of Us (546 cases/41 049 controls) data sets. Associations with adverse clinical outcomes and cardiac endophenotypes of disease severity were further identified, and causal relationships were evaluated using Mendelian randomization. Relative biomarker importance was also assessed by joint modeling via machine learning.</p><p><strong>Results: </strong>We identified novel associations of ANGPT2 (angiopoietin-2) and LTBP2 (latent transforming growth factor-beta binding protein 2) with HCM, with both also showing prognostic utility for heart failure-related outcomes in HCM cases. We also confirmed the associations of established biomarkers (eg, NT-proBNP [N-terminal pro-B-type natriuretic peptide], troponins I and T) with HCM cases, cardiac imaging markers of disease severity, and adverse outcomes. Mendelian randomization analyses supported a causal effect of HCM on increasing NT-proBNP and troponin T levels.</p><p><strong>Conclusions: </strong>This biobank-scale plasma proteomic study in HCM identified ANGPT2 and LTBP2 as novel HCM biomarkers with potential diagnostic and prognostic utility. These findings highlight the potential for plasma proteomics to improve risk prediction and provide insight into HCM pathobiology.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005325"},"PeriodicalIF":5.5,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting PPAR-γ Reduces Fibrosis and Arrhythmogenic Remodeling in DSG2-Linked Arrhythmogenic Cardiomyopathy.","authors":"Yung-Hsin Yeh, Yu-Shien Ko, Yi-Hsin Chan, Ying-Ju Lai, Gwo-Jyh Chang, Chi-Jen Chang, Lung-An Hsu","doi":"10.1161/CIRCGEN.125.005434","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005434","url":null,"abstract":"<p><strong>Background: </strong>Arrhythmogenic cardiomyopathy is an inherited disorder characterized by fibro-fatty myocardial replacement and ventricular arrhythmias. Although desmosomal mutations such as desmoglein-2 (<i>DSG2</i>) are well-established causes, the pathogenic mechanisms of specific missense variants remain incompletely defined.</p><p><strong>Methods: </strong>We generated a physiologically relevant <i>Dsg2^F536C/F536C</i> knock-in mouse model using CRISPR/Cas9 to mimic the human <i>DSG2</i> p.Phe531Cys mutation. Comprehensive phenotyping included histopathology, immunostaining, transcriptomic profiling, in vitro cardiomyocyte and fibroblast assays, in vivo imaging and ECG analysis, and ex vivo optical mapping. Therapeutic potential was assessed using the PPAR-γ (peroxisome proliferator-activated receptor gamma) antagonist GW9662.</p><p><strong>Results: </strong><i>Dsg2</i>^{<i>F536C/F536C</i>} mice developed progressive cardiac hypertrophy, interstitial fibrosis, lipid accumulation, and inducible ventricular arrhythmias following isoproterenol infusion and programmed electrical stimulation. These changes led to severe cardiac dysfunction and reduced survival. Mechanistically, the mutation caused reduced DSG2 and nuclear accumulation of β-catenin and PPAR-γ, promoting triacylglycerol biosynthesis, oxidative stress, cardiomyocyte death, and calcium-handling abnormalities. We also identified activation of epicardial epithelial-to-mesenchymal transition and paracrine fibroblast activation via IL-6 (interleukin-6) and PDGF-BB (platelet-derived growth factor-BB) as key contributors to fibrotic remodeling. Optical mapping revealed prolonged and heterogeneous action potential duration, with both reentrant and focal ectopic mechanisms of ventricular tachycardia. Treatment with GW9662 attenuated lipid accumulation, fibrosis, reactive oxygen species production, and arrhythmogenic susceptibility.</p><p><strong>Conclusions: </strong>The <i>Dsg2</i>^{<i>F536C/F536C</i>} knock-in mouse is a genotype-specific arrhythmogenic cardiomyopathy model that links desmosomal dysfunction to metabolic remodeling, epicardial epithelial-to-mesenchymal transition, and electrophysiological instability. PPAR-γ inhibition ameliorated structural and arrhythmogenic remodeling, supporting PPAR-γ as a potential therapeutic target and advancing precision strategies for desmosome-related cardiomyopathies.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005434"},"PeriodicalIF":5.5,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147688494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}