Circulation: Genomic and Precision Medicine最新文献

{"title":"Metabolomic and Proteomic Signatures of Cardiorespiratory Fitness for Predicting All-Cause Mortality and Non-Communicable Disease Risk: A Prospective Study in the UK Biobank.","authors":"Sergio Miras-Moreno, Álvaro Torres-Martos, Jonatan R Ruiz, Jennifer Carter, Carolina Abreu de Carvalho, Concepción M Aguilera, Carmen Piernas, Borja Martinez-Tellez","doi":"10.1161/CIRCGEN.125.005736","DOIUrl":"10.1161/CIRCGEN.125.005736","url":null,"abstract":"<p><strong>Background: </strong>Cardiorespiratory fitness (CRF) is a strong predictor of mortality and noncommunicable disease risk, but its underlying molecular mechanisms are poorly understood. In this study, we identified 2 signatures of CRF (1 metabolomic and 1 proteomic) from UK Biobank participants who completed a risk-stratified submaximal cycle ergometer test, with CRF estimated from the heart rate response to incremental workload.</p><p><strong>Methods: </strong>These signatures were validated in an independent sample of UK participants with data on metabolomics (n=354 222) and proteomics (n=29 961) to investigate prospective associations with all-cause mortality and noncommunicable diseases. Prospective associations were evaluated using Cox proportional hazards models adjusted for age, sex, ethnicity, socioeconomic status, lifestyle factors (including smoking, alcohol intake, diet, and body mass index), and relevant medical history.</p><p><strong>Results: </strong>Our findings reveal that higher CRF is characterized by downregulation of pathways related to inflammation, triglyceride metabolism, glycolysis, and vascular dysfunction, and upregulation of pathways related to cholesterol transport, apolipoprotein particle size, and cytoskeletal remodeling. Leveraging these insights, we developed 2 novel signatures of CRF (1 metabolomic and 1 proteomic) that robustly reflect CRF levels (R²: 0.50-0.60). Over an average of 9 years of follow-up, we observed 27 659 cases of all-cause mortality. Across the discovery and validation cohorts, we found that the metabolomic signature of CRF was strongly associated with a 39% to 54% lower risk of all-cause mortality and markedly reduced risk of type 2 diabetes (90% in both), cardiovascular disease (42%-47%), and colorectal cancer (33%-39%). Additionally, the proteomic signature of CRF was associated with a 17% lower risk of all-cause mortality, and with a 22% to 39% lower risk of type 2 diabetes and cardiovascular disease.</p><p><strong>Conclusions: </strong>Together, these findings indicate that circulating metabolites and proteins are associated with CRF and with subsequent risk of mortality and noncommunicable diseases.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005736"},"PeriodicalIF":6.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13489766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374893","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":"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":"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":6.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13489771/pdf/","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":"OA","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":"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":6.1,"publicationDate":"2026-08-01","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":"Functional and Molecular Characterization of Novel <i>GDF2</i> (<i>BMP9</i>) and <i>BMP10</i> Variants From the French PAH and HHT Cohorts.","authors":"Agnès Desroches-Castan, Léa Beurier-Soulat, Maud Tusseau, Florence Coulet, Valentin Azemard, Delphine Logeart-Avramoglou, Hélène Maillard, Fanny Laffargue, Caroline Nachury-Janel, Sophie Giraud, Gaëtan Lesca, Julien Grynblat, Alexandre Guilhem, Emmanuelle Tillet, Sophie Dupuis-Girod, David Montani, Sabine Bailly","doi":"10.1161/CIRCGEN.125.005626","DOIUrl":"10.1161/CIRCGEN.125.005626","url":null,"abstract":"<p><strong>Background: </strong><i>GDF2</i> (encoding BMP9) variants have been described in pulmonary arterial hypertension (PAH) and hereditary hemorrhagic telangiectasia (HHT), as well as a few <i>BMP10</i> variants in PAH. The purpose of the present study was to develop a functional assay capable of discriminating benign from pathogenic variants and to characterize the underlying molecular mechanisms responsible for their loss of function.</p><p><strong>Methods: </strong>We developed a single-step functional assay in which C2C12 cells stably expressing a BMP (bone morphogenetic protein)-responsive element upstream of a firefly luciferase reporter would be stimulated by the autocrine secretion of BMP9 or BMP10 variants produced by transfected expression plasmids.</p><p><strong>Results: </strong>Using this functional assay, we reclassified all <i>GDF2</i> variants and 2 out of 5 <i>BMP10</i> variants identified in patients with PAH as likely pathogenic. In contrast, only 2 of the 4 <i>GDF2</i> variants identified in suspected patients with HHT were found to be likely pathogenic; nevertheless, none of the patients met the diagnostic criteria for hereditary hemorrhagic telangiectasia. We also showed, using ELISAs and Western blots, that the loss of function of <i>GDF2</i> and <i>BMP10</i> variants was mostly due to altered processing (folding/stability defects). Moreover, we found that loss-of-function <i>GDF2</i> variants impaired the secretion of BMP10, suggesting a potential dominant-negative mechanism.</p><p><strong>Conclusions: </strong>We developed a functional assay for <i>GDF2</i> and <i>BMP10</i> variants, enabling the reclassification of variants of unknown significance. Together, this study further supports the involvement of <i>GDF2</i> and <i>BMP10</i> as predisposing genes in PAH. This single-step assay will be transferable to clinical genetic laboratories and will improve diagnosis of patients with PAH and HHT.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005626"},"PeriodicalIF":6.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204279","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":"Cardiomyopathy and Sudden Cardiac Death as a Rare Presentation of Mucolipidosis Type III in a Family With Compound Heterozygous Variants in <i>GNPTAB</i>.","authors":"Natalie Stewart, Natasha Henden, Carlos C Smith-Díaz, Jennifer Rigby, Alexandra Butters, Amy Baker, Laura Catto, Inuli Subasinghe, Laura Yeates, Lucy Geraghty, Jasmine Follett, David Sillence, Leah Kemp, Ira W Deveson, Muayad Alasady, Sharon Wilson, Cas Simons, Daniel G MacArthur, Belinda Gray, Johan Duflou, Mary-Louise Freckmann, Ebony Richardson, Andreas Zankl, Jodie Ingles","doi":"10.1161/CIRCGEN.126.005703","DOIUrl":"10.1161/CIRCGEN.126.005703","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005703"},"PeriodicalIF":6.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142806","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":"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":"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":6.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13489775/pdf/","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":"OA","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":6.1,"publicationDate":"2026-08-01","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":"Machine Learning Reveals the Contribution of Rare Genetic Variants and Enhances Risk Prediction for Coronary Artery Disease in the Japanese Population.","authors":"Hirotaka Ieki, Sai Zhang, Satoshi Koyama, Martin Kjellberg, Hiroki Yoshida, Ryo Kurosawa, Hiroshi Matsunaga, Kazuo Miyazawa, Nobuyuki Enzan, Changhoon Kim, Jeong-Sun Seo, Koichiro Higasa, Kouichi Ozaki, Yoshihiro Onouchi, Koichi Matsuda, Yoichiro Kamatani, Chikashi Terao, Fumihiko Matsuda, Michael P Snyder, Issei Komuro, Kaoru Ito","doi":"10.1161/CIRCGEN.125.005341","DOIUrl":"10.1161/CIRCGEN.125.005341","url":null,"abstract":"<p><strong>Background: </strong>GWASs (genome-wide association studies) have advanced our understanding of coronary artery disease (CAD) genetics and enabled the development of polygenic risk scores (PRSs) for estimating genetic risk based on common variant burden. However, GWASs have limitations in analyzing rare variants due to insufficient statistical power, thereby constraining PRS performance.</p><p><strong>Methods: </strong>We conducted whole-genome sequencing of 1752 Japanese patients with CAD and 3019 controls. A machine learning-based analytical framework was applied to identify and interpret rare genetic variants associated with CAD pathogenesis.</p><p><strong>Results: </strong>This approach identified 59 CAD-related genes, including known causal genes such as <i>LDLR</i> and those not previously captured by GWASs. A rare variant-based risk score derived from the framework demonstrated distinct clinical characteristics compared with a conventional common variant-based PRS. The rare variant-based risk score significantly discriminated CAD cases and predicted cardiovascular mortality in an independent cohort. Furthermore, combining the rare variant-based risk score with the traditional PRS improved CAD prediction compared with the PRS alone (area under the curve, 0.66 versus 0.61; <i>P</i>=0.007).</p><p><strong>Conclusions: </strong>These findings underscore the distinct and complementary value of the rare variant-based risk score compared with the conventional PRS, highlighting the enhanced predictive power achieved through their integration. This comprehensive approach proposes broader genetic profiling, offering substantial potential for improved clinical risk stratification and personalized prevention strategies.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005341"},"PeriodicalIF":6.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13310176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148155521","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":"Metabolic Task Analysis Reveals Distinct Metabotypes in End-Stage Dilated Cardiomyopathy.","authors":"Bastien S C Nihant, Job A J Verdonschot, Sonia Bălan, Eva Thielecke, Joost J F P Luiken, Miranda Nabben, Stephane Heymans, Marian Breuer, Michiel E Adriaens","doi":"10.1161/CIRCGEN.125.005366","DOIUrl":"10.1161/CIRCGEN.125.005366","url":null,"abstract":"<p><strong>Background: </strong>Dilated cardiomyopathy (DCM) is associated with shifts in cardiac metabolism. However, those shifts vary widely across patients, likely reflecting the diverse underlying causes of the disease. Identifying metabolic subtypes, or metabotypes, in DCM patients could help tailor treatments to patient needs. Hence, having a practical approach to identify these metabotypes would be a significant advance toward precision medicine in DCM.</p><p><strong>Methods: </strong>We present a systems biology approach to uncover metabotypes directly from widely available transcriptomic data. We use in silico metabolic modeling methods that we have optimized for cardiac research to predict metabolic function activities from enzyme expression, followed by a hierarchical clustering approach. To demonstrate its power, we applied our method to publicly available cardiac data from end-stage DCM patients (N=164) and nonfailing controls (N=160).</p><p><strong>Results: </strong>We identified 2 distinct metabotypes in end-stage DCM patients. These metabotypes are characterized by unique metabolic changes, notably in calcium handling, amino acid oxidation, and the pentose phosphate pathway. Strikingly, 1 DCM metabotype showed greater metabolic divergence from healthy controls, suggesting a greater metabolic contribution to its underlying etiology-even though disease severity was similar between the 2 identified DCM metabotypes. Further transcriptome-wide analysis revealed immune-related differences between metabotypes, suggesting an underlying interplay between inflammation, the immune response, and metabolism.</p><p><strong>Conclusions: </strong>Our results imply the presence of distinct metabotypes in end-stage DCM. Our systems biology approach offers an exciting opportunity to uncover novel insights into DCM, paving the way for a deeper understanding of its progression and heterogeneity.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005366"},"PeriodicalIF":6.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13489769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374767","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":"Cardiomyopathy-Associated Mutations in a Hotspot Region at the C-Terminal Part of Desmin Coil-2 Domain Impair the Intermediate Filament Assembly.","authors":"Jonas Reckmann, Hendrik Milting, Sabrina Voß, Marco T Radukic, Franziska Klag, Franziska Flottmann, Alexander Lütkemeyer, Joline Groß, Anna Gärtner, Sandra Landwehr, Dario Anselmetti, Annika Hoyer, Kristian M Müller, Jan Gummert, Volker Walhorn, Andreas Brodehl","doi":"10.1161/CIRCGEN.125.005653","DOIUrl":"10.1161/CIRCGEN.125.005653","url":null,"abstract":"<p><strong>Background: </strong>The <i>DES</i> gene encodes the IF (intermediate filament) protein desmin, which connects different multiprotein complexes, such as the cardiac desmosomes, and is highly important for the structural integrity of cardiomyocytes. Pathogenic <i>DES</i> mutations cause filament assembly defects leading to cardiomyopathies. However, most <i>DES</i> variants listed in genetic disease databases are currently classified as variants of unknown significance. Here, we characterized 21 different <i>DES</i> variants of unknown significance and 18 additional proline variants, localized in a highly conserved stretch at the C terminus of the desmin coil-2 subdomain.</p><p><strong>Methods: </strong>We inserted desmin variants via site-directed mutagenesis and investigated the filament assembly in transfected cell lines and cardiomyocytes derived from induced pluripotent stem cells by confocal microscopy. In addition, we purified recombinant wild-type and mutant desmin and analyzed the filament formation by atomic force microscopy. Coexpression with wild-type desmin delivered by adeno-associated virus was used to model the heterozygous status of cardiomyopathy patients.</p><p><strong>Results: </strong>Twelve <i>DES</i> variants of unknown significance formed cytoplasmic aggregates, which were likewise verified by atomic force microscopy. Of note, these 12 variants disturb the filament assembly even when coexpressed with wild-type desmin. Using a proline screen, we showed that proline residues localized at nearly each of the positions in this stretch cause filament assembly defects. By modeling the tetrameric structure of desmin, we demonstrated that specific heptad positions, as well as positions of intramolecular and intermolecular ion bridge sites, are particularly susceptible to mutations that promote desmin aggregation.</p><p><strong>Conclusions: </strong>In summary, our study demonstrated that the highly conserved stretch at the C terminus of the coil-2 subdomain is a hotspot region, where several pathogenic <i>DES</i> mutations cause an aberrant desmin aggregation. Based on our molecular data, we suggest reclassifying the aggregate-forming variants as likely pathogenic mutations rather than variants of unknown significance. Our study may have relevance for the genetic counseling of cardiomyopathy patients with similar <i>DES</i> variants.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005653"},"PeriodicalIF":6.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359663","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}