Circulation: Genomic and Precision Medicine最新文献

{"title":"Clonal Hematopoiesis of Indeterminate Potential in Chronic Coronary Disease: A Report From the ISCHEMIA Trials Biorepository.","authors":"Matthew Muller, Richard Liu, Farheen Shah, Jiyuan Hu, Claes Held, Iftikhar J Kullo, Bruce McManus, Lars Wallentin, L Kristin Newby, Mandeep S Sidhu, Sripal Bangalore, Harmony R Reynolds, Judith S Hochman, David J Maron, Kelly V Ruggles, Jeffrey S Berger, Jonathan D Newman","doi":"10.1161/CIRCGEN.124.004921","DOIUrl":"https://doi.org/10.1161/CIRCGEN.124.004921","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004921"},"PeriodicalIF":6.0,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984101","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":"Evaluating the Cardiometabolic Efficacy and Safety of Lipoprotein Lipase Pathway Targets in Combination With Approved Lipid-Lowering Targets: A Drug Target Mendelian Randomization Study.","authors":"Eloi Gagnon, Dipender Gill, Dominique Chabot, Héléne T Cronjé, Shuai Yuan, Stephen Brennan, Sébastien Thériault, Stephen Burgess, Benoit J Arsenault, Marie-Joe Dib","doi":"10.1161/CIRCGEN.124.004933","DOIUrl":"10.1161/CIRCGEN.124.004933","url":null,"abstract":"<p><strong>Background: </strong>Therapies targeting the LPL (lipoprotein lipase) pathway are under development for cardiometabolic disease. Insights into their efficacy-both alone and in combination with existing lipid-lowering therapies-modes of action, and safety of these agents are essential to inform clinical development. Using Mendelian randomization, we aimed to (1) evaluate efficacy, (2) explore shared mechanisms, (3) assess additive effects with approved lipid-lowering drugs, and (4) identify secondary indications and potential adverse effects.</p><p><strong>Methods: </strong>We selected triglyceride-lowering genetic variants located in the genes encoding ANGPTL3 (angiopoietin-like 3), ANGPTL4 (angiopoietin-like 4), APOC3 (apolipoprotein C3), and LPL and conducted drug target Mendelian randomization on primary outcomes including coronary artery disease and type 2 diabetes, and secondary outcomes, including apolipoprotein B, waist-to-hip ratio, body mass index, and 233 metabolic biomarkers. We conducted interaction Mendelian randomization analyses in 488 139 UK Biobank participants to test the effect of combination therapy targeting the LPL and LDLR (low-density lipoprotein receptor) pathways. Finally, we investigated potential secondary indications and adverse effects by leveraging genetic association data on 1204 disease end points.</p><p><strong>Results: </strong>Genetically predicted triglyceride lowering through the perturbation of LPL pathway activation targets ANGPTL4, APOC3, and LPL was associated with a lower risk of coronary artery disease and type 2 diabetes and lower apolipoprotein B. Genetically predicted triglyceride lowering through ANGPTL4 was associated with a lower waist-to-hip ratio, suggestive of a favorable body fat distribution. There was no evidence of a multiplicative interaction between genetically proxied perturbation of ANGPTL4, APOC3, and LPL and that of HMGCR (HMG-CoA reductase) and PCSK9 (proprotein convertase subtilisin/kexin type 9) on coronary artery disease and type 2 diabetes, consistent with additive effects. Finally, associations of genetically predicted LPL pathway targeting were supportive of the broad safety of these targets.</p><p><strong>Conclusions: </strong>Our findings provide genetic evidence supporting the efficacy and safety of LPL pathway activation therapies for the prevention of coronary artery disease and type 2 diabetes, alone or in combination with statins or PCSK9 inhibitors.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004933"},"PeriodicalIF":6.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572370","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":"Alcohol Exposure Among Patients With Dilated Cardiomyopathy and Their First-Degree Relatives: The DCM Precision Medicine Study.","authors":"Javier Jimenez, Hanyu Ni, Stuart D Katz, Garrie J Haas, Jinwen Cao, Muni Rubens, Sandra Chaparro, Anshul Saxena, Mark Hofmeyer, Evan Kransdorf, Gregory A Ewald, Alanna A Morris, Anjali Owens, Brian Lowes, Douglas Stoller, W H Wilson Tang, Palak Shah, Jane E Wilcox, Frank Smart, Jessica Wang, Stephen S Gottlieb, Daniel P Judge, Jonathan O Mead, Natalie Hurst, Patricia K Parker, Gordon S Huggins, Elizabeth Jordan, Daniel D Kinnamon, Ray E Hershberger","doi":"10.1161/CIRCGEN.124.004946","DOIUrl":"10.1161/CIRCGEN.124.004946","url":null,"abstract":"<p><strong>Background: </strong>Whether prolonged and excessive alcohol consumption contributes to dilated cardiomyopathy (DCM) remains uncertain. This study aimed to describe the prevalence of alcohol use in patients with DCM and their first-degree relatives (FDRs) and determine if cumulative alcohol exposure associates with DCM/partial DCM or modifies the association of DCM with DCM-relevant rare variants.</p><p><strong>Methods: </strong>All probands had DCM; FDRs were classified as with or without DCM or partial DCM. Alcohol exposure was measured with the Alcohol Use Disorder Identification Test-Consumption questionnaire and years of drinking. Rare variants in 36 DCM genes were classified as pathogenic, likely pathogenic, or variants of uncertain significance (pathogenic, likely pathogenic, variant of uncertain significance). Generalized linear mixed models were used to assess the association of DCM/partial DCM with alcohol use among FDRs.</p><p><strong>Results: </strong>DCM/partial DCM was found in 21.8% of 1373 FDRs of 1148 DCM probands. The prevalence of former or current alcohol use was 68% for probands and 70% for FDRs. About 30% of probands and 37% of FDRs had positive Alcohol Use Disorder Identification Test-Consumption scores, indicating moderate or heavy drinking. Among FDRs, DCM/partial DCM was associated with the presence of pathogenic/likely pathogenic variants in DCM genes (odds ratio, 3.51 [95% CI, 2.33-5.29]) but not with alcohol exposure. Cumulative alcohol exposure was not found to modify the association between DCM/partial DCM and these variants (<i>P</i>=0.55).</p><p><strong>Conclusions: </strong>Alcohol use was frequent among probands and FDRs. This study did not provide evidence supporting an association of cumulative alcohol exposure with DCM/partial DCM or a modifying effect of alcohol use on the association of DCM with DCM-relevant rare variants.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037632.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004946"},"PeriodicalIF":6.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12056839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729018","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":"On Penetrance Estimation in Family, Clinical, and Population Cohorts.","authors":"Marija Zaicenoka, Vasily E Ramensky, Anna V Kiseleva, Anna A Bukaeva, Anastasia V Blokhina, Alexandra I Ershova, Alexey N Meshkov, Oxana M Drapkina","doi":"10.1161/CIRCGEN.124.004816","DOIUrl":"10.1161/CIRCGEN.124.004816","url":null,"abstract":"<p><p>In recent years, there has been a considerable influx of publications assessing the penetrance of pathogenic variants associated with monogenic diseases with dominant inheritance. As large and diverse groups have been sequenced, it has become clear that incomplete penetrance is common to most hereditary diseases, as numerous molecular, genetic, or environmental factors can cause clinical diversity among the carriers of the same variant. In this review, we discuss some of these factors and focus on the existing approaches to estimating penetrance, depending on the data available and their application to different data sets. We also list some currently available large-scale data sets with penetrance estimates.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004816"},"PeriodicalIF":6.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729038","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":"Combined RNA Splicing and Patch-Clamp Analysis Reveal Pathogenicity of Splice-Altering Variants in <i>KCNH2</i>-Related LQTS.","authors":"Susan Clasper, Gunjan Trivedi, Kate L Thomson, Claire L S Turner, Smrithi Devaiah, Catherine L Mercer, Amnah Y Bdeir, Jumana Y Al-Aama, Khalid Dagriri, Alex R Hobson, Shankar N Sadagopan, Julian Ormerod, Eszter Szepesvary, Justin Phan, Diane Fatkin, Jamie I Vandenberg, Zahurul A Bhuiyan, Chai-Ann Ng","doi":"10.1161/CIRCGEN.124.004966","DOIUrl":"10.1161/CIRCGEN.124.004966","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004966"},"PeriodicalIF":6.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699771","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":"Dysmorphology-Based Prediction Model for Genetic Disorders in Infants With Congenital Heart Disease.","authors":"Benjamin M Helm, Leah Wetherill, Benjamin J Landis, Stephanie M Ware","doi":"10.1161/CIRCGEN.124.004895","DOIUrl":"10.1161/CIRCGEN.124.004895","url":null,"abstract":"<p><strong>Background: </strong>Genetic disorders are prevalent in patients with congenital heart disease (CHD), but genetic evaluations are underutilized and nonstandardized. We sought to quantify a dysmorphology score and develop phenotype-based prediction models for genetic diagnoses in CHD.</p><p><strong>Methods: </strong>We used a test-negative case-control study of inpatient infants (<1 year) with CHD undergoing standardized genetic evaluations. We quantified a novel dysmorphology score and combined it with other clinical variables used in multivariable logistic regression models to predict genetic diagnoses identified by genetic testing.</p><p><strong>Results: </strong>Of 1008 patients, 24.1% (243/1008) had genetic diagnoses identified. About half of the cohort were either nondysmorphic or mildly dysmorphic with dysmorphology scores ≤2. There were higher dysmorphology scores according to CHD class (<i>P</i>=0.0007), extracardiac anomaly-positive status (<i>P</i><0.0001), female sex (<i>P</i>=0.05), and genetic diagnosis identified (<i>P</i><0.0001). Multivariable logistic regression models quantified this effect further: each +1 increase in the dysmorphology score was associated with a 17% to 20% increased risk of genetic diagnoses (odds ratios, 1.17-1.20, <i>P</i><0.0001). Extracardiac anomaly-positive status remained a stronger predictor of genetic diagnoses (odds ratios, 2.81-3.39). Nonetheless, about 10% of the cohort were minimally dysmorphic (dysmorphology scores ≤2), had isolated CHD, and were found to have genetic diagnoses, indicating that dysmorphology-based screening can be used to risk-stratify but not exclude genetic diagnoses.</p><p><strong>Conclusions: </strong>The dysmorphology score is a novel screen for patients with CHD at high risk of having genetic diagnoses identified by genetic testing, including disorders not easily recognized by clinicians. We used these results to develop predicted probability plots for genetic diagnoses in patients with CHD.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004895"},"PeriodicalIF":6.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11999770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729034","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":"DNA Damage Response and Repair Genes and Anthracycline-Induced Cardiomyopathy in Childhood Cancer Survivors: A Report From the Children's Oncology Group and the Childhood Cancer Survivor Study.","authors":"Xuexia Wang, Purnima Singh, Romina B Cejas, Liting Zhou, Noha Sharafeldin, Patrick J Trainor, Wendy Landier, Changde Cheng, Lindsey Hageman, Fan Wang, Yadav Sapkota, Yutaka Yasui, Melissa M Hudson, Eric J Chow, Saro H Armenian, Joseph P Neglia, Douglas S Hawkins, Jill P Ginsberg, Paul W Burridge, Gregory T Armstrong, Smita Bhatia","doi":"10.1161/CIRCGEN.124.004813","DOIUrl":"10.1161/CIRCGEN.124.004813","url":null,"abstract":"<p><strong>Background: </strong>Anthracyclines induce cardiotoxicity via DNA double-strand breaks and reactive oxygen species formation, resulting in cardiomyocyte dysfunction. The role of DNA damage response/repair (DDR) genes in anthracycline-induced cardiomyopathy remains unstudied.</p><p><strong>Methods: </strong>We conducted a gene-based and pathway-based analysis to examine the main effect and gene-anthracycline interaction effect between DDR genes and anthracycline-induced cardiomyopathy. A discovery analysis performed with a matched case-control set of anthracycline-exposed non-Hispanic White childhood cancer survivors from Children's Oncology Group-ALTE03N1 (113 cases; 226 controls) was replicated using a cohort of anthracycline-exposed non-Hispanic White childhood cancer survivors from the Childhood Cancer Survivor Study cohort (n=1658; 97 cases). Functional analyses were performed by examining the response to doxorubicin of human-induced pluripotent stem cell-derived cardiomyocytes with CRISPR/Cas9-mediated knockout of prioritized genes.</p><p><strong>Results: </strong>Successfully replicated DDR genes demonstrating main-effect association included <i>FANCC</i> (<i>P</i>=0.037) and <i>XRCC5</i> (<i>P</i>=0.001) and demonstrated gene-anthracycline interaction included <i>MGMT</i> (<i>P</i>=0.041). Knockouts of <i>FANCC</i> and <i>MGMT</i> in human-induced pluripotent stem cell-derived cardiomyocytes demonstrated significant resistance to doxorubicin, suggesting that these genes play a role in anthracycline-induced cardiotoxicity. Successfully replicated DDR pathways demonstrating main-effect association included base excision repair (<i>P</i>=2.7×10^-4); role of <i>BRCA1</i> in DDR (<i>P</i>=9.2×10^-5); p53 signaling (<i>P</i><1×10^-16); role of checkpoint kinases proteins in cell cycle checkpoint control (<i>P</i><1×10^-16); mismatch repair (<i>P</i><10^-16); and double-strand break repair by homologous recombination (<i>P</i><1×10^-16). Successfully replicated DDR pathways demonstrating significant interaction effects included role of <i>BRCA1</i> in DDR (<i>P</i>=1.4×10^-4); p53 signaling (<i>P<</i>1×10^-16); the role of checkpoint kinases proteins in cell cycle checkpoint control (<i>P</i><1×10^-16); mismatch repair (<i>P</i><1×10^-16); cell cycle: G2/M DNA damage checkpoint regulation (<i>P</i>=0.002); double-strand break repair by homologous recombination (<i>P</i>=0.009); <i>GADD45</i> signaling (<i>P</i>=4.8×10^-4); and cell cycle control of chromosomal replication (<i>P</i>=4.5×10^-4).</p><p><strong>Conclusions: </strong>These findings provide evidence for the role of DDR genes and pathways in anthracycline-induced cardiomyopathy and provide a framework for targeted therapeutic interventions.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004813"},"PeriodicalIF":6.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11999796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729031","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":"Many Journeys Originating at the Same Source to Arrive at Solutions to the Common Problem of High Lipoprotein(a).","authors":"Jean Woody Luxama, Joshua W Knowles","doi":"10.1161/CIRCGEN.125.005126","DOIUrl":"10.1161/CIRCGEN.125.005126","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005126"},"PeriodicalIF":6.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11999797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699772","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":"Analysis of <i>TTN</i> Truncating Variants in >74 000 Cases Reveals New Clinically Relevant Gene Regions.","authors":"Matteo Vatta, Ellen Regalado, Michael Parfenov, Dan Swartzlander, Andrea Nagl, Meghan Mannello, Rachel Lewis, Daniel Clemens, John Garcia, Rachel E Ellsworth, Ana Morales, Yi-Lee Ting, Swaroop Aradhya","doi":"10.1161/CIRCGEN.124.004982","DOIUrl":"10.1161/CIRCGEN.124.004982","url":null,"abstract":"<p><strong>Background: </strong>Truncating variants (TTNtvs) in the titin (<i>TTN</i>) gene have been associated with cardiomyopathies or arrhythmias (C/A) and autosomal recessive neuromuscular diseases (NM). However, the clinical significance of TTNtvs across the entire coding sequence of <i>TTN</i> has not been comprehensively assessed. The purpose of this study was to examine the burden of TTNtvs in C/A and NM cases compared with controls in the genome aggregation database.</p><p><strong>Methods: </strong>This was a retrospective study of probands who underwent multigene testing (49 740 C/A panel, 24 514 NM panel) that included <i>TTN</i> from November 2017 to October 2021. Burden testing was performed using controls in the genome aggregation database v3.1.2 database, and the analysis was stratified by exon/band location and exon usage in cardiac or skeletal muscle. Frequency and odds ratio of TTNtv alleles in C/A or NM cases and genome aggregation database controls were measured.</p><p><strong>Results: </strong>There were 2446 (4.9%) C/A and 482 (2.0%) NM cases with 2446 and 528 TTNtv alleles, respectively. TTNtvs in all bands were significantly enriched in both C/A and NM cases compared with controls. A significant enrichment of TTNtvs in C/A was observed for exon 358 of the M-band (odds ratio, 2.55 [95% CI, 1.85-3.54]) but not the other M-band exons.</p><p><strong>Conclusions: </strong>In the largest single-site cohort of C/A and NM cases with TTNtvs, an enrichment of TTNtvs across <i>TTN</i> was observed. These findings expand the clinically relevant regions of <i>TTN</i>.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004982"},"PeriodicalIF":6.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11999099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448159","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":"Natural History, Phenotype Spectrum, and Clinical Outcomes of Desmin (<i>DES</i>)-Associated Cardiomyopathy.","authors":"Babken Asatryan, Marina Rieder, Brittney Murray, Steven A Muller, Crystal Tichnell, Alessio Gasperetti, Richard T Carrick, Emily Joseph, Doris G Leung, Anneline S J M Te Riele, Stefan L Zimmerman, Hugh Calkins, Cynthia A James, Andreas S Barth","doi":"10.1161/CIRCGEN.124.004878","DOIUrl":"10.1161/CIRCGEN.124.004878","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic/likely pathogenic (LP) desmin (<i>DES</i>) variants cause heterogeneous cardiomyopathy and skeletal myopathy phenotypes. Limited data suggest a high incidence of major adverse cardiac events (MACEs), including cardiac conduction disease, sustained ventricular arrhythmias (VA), and heart failure (HF) events (HF hospitalization, left ventricular assist device/cardiac transplant, HF-related death) in patients with pathogenic/LP <i>DES</i> variants. However, pleiotropic presentation and small cohort sizes have limited clinical phenotype and outcome characterization. We aimed to describe the natural history, phenotype spectrum, familial penetrance and outcomes in patients with pathogenic/LP <i>DES</i> variants through a systematic review and individual patient data meta-analysis using published reports.</p><p><strong>Methods: </strong>We searched Medline (PubMed) and Embase for studies that evaluated cardiac phenotypes in patients with pathogenic/LP <i>DES</i> variants. Cardiomyopathy diagnosis or occurrence of MACE was considered evidence of cardiac involvement/penetrance. Lifetime event-free survival from cardiac conduction disease, sustained VA, HF events, and composite MACE was assessed.</p><p><strong>Results: </strong>Of the 4212 screened publications, 71 met the inclusion criteria. A total of 230 patients were included (52.6% men, 52.2% probands, median age: 31 years [22.0-42.8] at first evaluation, median follow-up: 3 years [0-11.0]). Overall, 124 (53.9%) patients were diagnosed with cardiomyopathy, predominantly dilated cardiomyopathy (14.8%), followed by restrictive cardiomyopathy (13.5%), whereas other forms were less common: arrhythmogenic cardiomyopathy (7.0%), hypertrophic cardiomyopathy (6.1%), arrhythmogenic right ventricular cardiomyopathy (5.2%), and other forms (7.4%). Overall, 132 (57.4%) patients developed MACE, with 96 (41.7%) having cardiac conduction disease, 36 (15.7%) sustained VA, and 43 (18.7%) HF events. Familial penetrance of cardiac disease was 63.6% among relatives with pathogenic/LP <i>DES</i> variants. Male sex was associated with an increased risk of sustained VA (hazard ratio, 2.28; <i>P</i>=0.02) and HF events (hazard ratio, 2.45; <i>P</i>=0.008).</p><p><strong>Conclusions: </strong><i>DES</i> cardiomyopathy exhibits heterogeneous phenotypes and a distinct natural history, characterized by high familial penetrance and a substantial MACE burden. Male patients face a higher risk of sustained VA events.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004878"},"PeriodicalIF":6.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11999772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448161","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}