Circulation: Genomic and Precision Medicine最新文献

{"title":"Polygenic Risk Scores of Coronary Heart Disease in Chronic Kidney Disease Population: The CRIC Study.","authors":"Quan Sun, Amarnath Marthi, Jia Wen, Bridget M Lin, Jiawen Du, Ana C Ricardo, Alan S Go, Panduranga S Rao, Mahboob Rahman, Jiang He, Yun Li, Nora Franceschini","doi":"10.1161/CIRCGEN.126.005684","DOIUrl":"10.1161/CIRCGEN.126.005684","url":null,"abstract":"<p><strong>Background: </strong>Cardiovascular disease is a major cause of death in individuals with chronic kidney disease; thus, improving its prediction is critical for cardiovascular disease risk reduction. Studies have not assessed whether a polygenic risk score (PRS) of coronary heart disease (CHD) developed from genetic studies in the general population can improve cardiovascular disease risk prediction in individuals with chronic kidney disease, especially when PRS is added to the American Heart Association Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) equations.</p><p><strong>Methods: </strong>Focusing on a 10-year composite CHD event, we applied PRSs of CHD obtained from the polygenic score catalog to the multi-center CRIC (Chronic Renal Insufficiency Cohort) participants, selected the best-performing PRS and evaluated the added value of the best PRS while accounting for PREVENT linear predictors. Three Cox proportional hazard models were fitted with PRS only, PREVENT predictors only, and PRS+PREVENT risk factors. We evaluated the prediction accuracy, discrimination, and calibration of the combined model compared with the PREVENT model.</p><p><strong>Results: </strong>A PRS of CHD was significantly associated with a 21% hazard of CHD in the PRS+PREVENT risk model (95% CI, [1.06-1.39], 2-sided Wald test <i>P</i>=5.5×10^-3). The PRS+PREVENT model demonstrated a higher area under the curve (72.4% [95% CI, 0.66-0.79] versus 70.8% [95% CI, 0.64-0.77]), better discrimination ability, and improved calibration compared with the PREVENT model predictors. Individuals were more correctly classified in prediction quartiles using the PRS+PREVENT model for the 10-year CHD event proportions.</p><p><strong>Conclusions: </strong>Our results demonstrate the added value of a CHD PRS to the PREVENT risk prediction models in individuals with chronic kidney disease. The combined PRS+PREVENT model has the potential to improve clinical decisions on disease prevention and treatment strategies.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005684"},"PeriodicalIF":6.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079719","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":"Homozygous TNNC1-A8V Causes Impaired Diastolic Function and Restrictive Cardiomyopathy in Children and Mice.","authors":"Paula Nieto Morales, Enya Dewars, Amanda M Mascarenhas, Mary Silzer, Minu-Tshyeto Bidzimou, Bo Sun, Brittany Balint, Sara Gregory, Michael Osei Assibey, Karissa Dieseldorff Jones, Rosemeire Kanashiro-Takeuchi, Juliana Lores, Milena Prada, Carmen E Ocampo, Carolyn Glass, P Bryant Chase, Vitold E Galkin, Stephen P Chelko, Andrew P Landstrom, Jose Renato Pinto","doi":"10.1161/CIRCGEN.125.005599","DOIUrl":"10.1161/CIRCGEN.125.005599","url":null,"abstract":"<p><strong>Background: </strong>Pathological variants in <i>TNNC1</i> are associated with the development of hypertrophic cardiomyopathy. Unlike other sarcomeric genes, <i>TNNC1</i> variants tend to cause early-onset disease, and the most common variant identified in the gene, TNNC1-A8V, may also lead to severe diastolic dysfunction and restrictive cardiomyopathy. Yet, this variant-disease association, and the mechanism of diastolic disease development remain poorly understood. To address this, we sought to determine whether the A8V variant was associated with the development of restrictive cardiomyopathy, and if so, to determine the frequency and age-specific spectrum of disease relative to hypertrophic cardiomyopathy.</p><p><strong>Methods: </strong>A pediatric proband was identified carrying the TNNC1-A8V variant. Sanger sequencing and cardiac evaluations were performed on several of the proband's family members. A literature search was performed to evaluate the cardiac penetrance of TNNC1-A8V. Additionally, we investigated cardiac contractility in a homozygous A8V mouse model. We assessed left ventricular function in 10- to 12-week-old mice via cardiac catheterization and left ventricular global and segmental myocardial strain analyses. Electrophysiological studies were conducted to evaluate arrhythmic predisposition.</p><p><strong>Results: </strong>We report an 8-month-old female homozygous for p.A8V (c.C23T) who presented with bi-atrial enlargement, normal ventricular function, and ventricular tachycardia. Cardiac histology of the proband showed subendocardial vacuolization, endocardial fibrosis, and localized myocardial enhancement. The A8V mouse model showed an elevated end-diastolic pressure-volume relationship, prolonged relaxation time (tau), and impaired ventricular relaxation rate (dP/dt min) compared with controls, consistent with increased myocardial stiffness. Strain analyses further highlighted left ventricular dysfunction and dyssynchrony, and ECG analyses revealed atrial remodeling and enlargement at 10 weeks of age.</p><p><strong>Conclusions: </strong>Homozygous A8V mice recapitulate the severe diastolic dysfunction and early-onset restrictive cardiomyopathy observed in the pediatric proband carrying this pathogenic variant, underscoring the utility of this model for advancing translational research. Identifying myofilament-specific defects opens the door for precision therapies tailored to the underlying molecular disarray.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005599"},"PeriodicalIF":6.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079656","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":"Genomic Readiness in Cardiology: Gaps in Awareness, Confidence, and Risk Literacy: Results From the PLATO Cross-Sectional Survey.","authors":"Ruofei Trophy Chen, Adam J Nelson, Stephen J Nicholls","doi":"10.1161/CIRCGEN.126.005831","DOIUrl":"https://doi.org/10.1161/CIRCGEN.126.005831","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005831"},"PeriodicalIF":6.1,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069182","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":"Gene-Corrected Human iPSC-Derived Cardiomyocytes and Skeletal Muscles Reveal Partial Dystrophin Dp427 Preservation and Cardiac Dp116 Expression in Duchenne Muscular Dystrophy Patient With a Splice-Site Mutation in Intron 68 (c.9975-1G>T).","authors":"Marta Białobrzeska, Marta Przymuszała, Paweł Ferdek, Iryna Viestia, Anna Potulska-Chromik, Anna Kostera-Pruszczyk, Katarzyna Łuczak-Woźniak, Jacek Stępniewski, Urszula Florczyk-Soluch, Józef Dulak","doi":"10.1161/CIRCGEN.125.005376","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005376","url":null,"abstract":"<p><strong>Background: </strong>Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disease caused by mutations in the <i>DMD</i> gene, leading to the absence or dysfunction of dystrophin. Although cardiac and skeletal muscles are both affected, tissue-specific differences in disease manifestation and dystrophin regulation remain poorly understood.</p><p><strong>Methods: </strong>To investigate these differences, we established a human induced pluripotent stem cell model of DMD from peripheral blood mononuclear cells of a patient (DMD patient with a point mutation in intron 68 (c.9975-1G>T) investigated in the study [DMB15]) carrying a splice-site mutation in intron 68 (c.9975-1G>T). An isogenic control line was generated via clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated protein 9 correction. Both repaired and DMD human induced pluripotent stem cells were differentiated into cardiomyocytes (DMB15-CMs) and skeletal muscle cells (DMB15-derived skeletal muscle cells); the skeletal muscle lineage included a myoblast (DMB15-derived myoblasts) stage. Transcript and protein analyses were performed, along with functional assessments using microelectrode array recordings and calcium handling analysis.</p><p><strong>Results: </strong>Transcript analysis revealed an in-frame deletion of 2 amino acids (Tyr3325 and Arg3326) due to skipping of the first 6 nucleotides of exon 69. Despite this, near full-length Dp427 (full-length dystrophin isoform of 427 kDa) was detected by Western blot, along with expression of Dp116 (dystrophin isoform of 116 kDa) in DMB15-CMs. Dystrophin levels were preserved in DMD DMB15-CMs but markedly reduced in DMB15-derived skeletal muscle cells, suggesting tissue-specific regulation. Analysis of DMB15-derived myoblasts demonstrated possible changes in myogenic program activation, alongside inconsistent expression of utrophin, the dystrophin paralogue. Functional analysis showed altered β-adrenergic responsiveness in DMD DMB15-CMs, with increased beating frequency and accelerated repolarization on isoproterenol stimulation. DMB15-CMs showed largely preserved basal Ca²⁺ cycling but failed to maintain a normal amplitude response under β-adrenergic stimulation.</p><p><strong>Conclusions: </strong>Our study identifies a splice-site <i>DMD</i> gene mutation that preserves high levels of dystrophin expression in cardiac muscle but reduced in skeletal muscle and reveals Dp116 expression in cardiomyocytes. These findings highlight the importance of tissue context in DMD and demonstrate the power of human induced pluripotent stem cell-based systems for dissecting mutation-specific effects.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005376"},"PeriodicalIF":6.1,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036794","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":"Comparing Cardiac Genetic Testing Pathways: Impacts on Access, Informed Choice, and Decisional Satisfaction.","authors":"Susan Christian, Tallia C Belcher, Marc Benoit, Alicia Chan, Tara Dzwiniel, Erkan Ilhan, Shailly Jain Ghai, Karen Katchmer, Omid Kiamanesh, Margaret Lilley, Julien Marcadier, Skylar Moreau, Andrew Muranyi, Ashley J Nicolas, Priyana Sharma, Xi Zhao, Cathleen Huculak","doi":"10.1161/CIRCGEN.126.005829","DOIUrl":"https://doi.org/10.1161/CIRCGEN.126.005829","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005829"},"PeriodicalIF":6.1,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029871","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":"Effects of Polygenic Risk Scores and Physical Activity on Blood Pressure Trajectories in Childhood, Adolescence, and Young Adulthood.","authors":"Tian Xie, Shili Luo, Chris H L Thio, Marloes Cardol, Eva Corpeleijn, Gerton Lunter, Harold Snieder","doi":"10.1161/CIRCGEN.125.004307","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.004307","url":null,"abstract":"<p><strong>Background: </strong>Understanding the effects of genetics and lifestyle habits such as physical activity on blood pressure (BP) trajectories at an early age helps to improve understanding of the pathogenesis of hypertension over the life course.</p><p><strong>Methods: </strong>BP was assessed twice (at baseline and follow-up) in prepuberty (n=1063; age 5-6 years; median follow-up, 4.72 years), puberty (n=2494; age 8-14 years; median follow-up, 3.00 years), and postpuberty (n=2549; age 15-20 years; median follow-up, 3.00 years). We calculated polygenic risk scores (PRSs) for BP based on the largest BP genome-wide association study and examined the associations of PRSs with BP trajectories in the 3 age epochs, using linear mixed models.</p><p><strong>Results: </strong>One SD of PRSs was positively associated with 1.70, 1.65, and 2.92 mm Hg SBP level and 1.68, 0.85, and 1.18 mm Hg diastolic blood pressure (DBP) level at ages 5, 8, and 15 years, respectively. There was evidence of associations between PRSs and rates of change in SBP during puberty and DBP during postpuberty. During puberty, individuals in the highest quartile of systolic blood pressure (SBP)-PRS showed a 0.32 (95% CI, 0.02-0.63) mm Hg greater increase in SBP per year compared with those in the lowest quartile, while in postpuberty, those in the highest quartile of the DBP-PRS exhibited a 0.24 (95% CI, 0.02-0.45) mm Hg/y greater increase in DBP. Children who were physically active had, on average, 1.90 (95% CI, -3.77 to -0.03) mm Hg lower initial SBP than inactive children in puberty. No evidence was found for interactions of physical activity with PRS on BP levels or changes.</p><p><strong>Conclusions: </strong>Our study suggests that genetic influences on BP are evident as early as age 5 and extend to dynamic changes in SBP during puberty and DBP during postpuberty. Higher physical activity may reduce SBP levels in puberty independent of genetic susceptibility.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004307"},"PeriodicalIF":6.1,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029891","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":"Clinical Characteristics and Outcomes of Hypertrophic Cardiomyopathy Associated With Thin Filament Variants: Insights From the SHaRe Registry.","authors":"Alessia Argirò, Joshua Meisner, Eric Adler, Edoardo Bertero, Niccolò Maurizi, Brian Claggett, Neal K Lakdawala, Anjali Owens, Thomas D Ryan, Erin M Miller, Sara Saberi, Henning Bundgaard, Anna Axelsson Raja, Joseph W Rossano, Kimberly Lin, Francesca Girolami, Michelle Michels, Peter Paul Zwetsloot, Dominic Abrams, Rachel Lampert, John C Stendahl, James Ware, Victoria N Parikh, Euan Ashley, Jodie Ingles, Belinda Gray, Romi L Castillo, Jil Tardiff, Lia Crotti, Alexandre Pereira, Carolyn Y Ho, Sharlene Day, Adam Helms, Iacopo Olivotto","doi":"10.1161/CIRCGEN.126.005696","DOIUrl":"https://doi.org/10.1161/CIRCGEN.126.005696","url":null,"abstract":"<p><strong>Background: </strong>Conflicting evidence exists about whether sarcomeric hypertrophic cardiomyopathy (HCM) caused by genes encoding thin filament proteins (<i>TNNT2, TNNI3, ACTC, TPM1</i>, <i>TNNC1</i>; thin filament HCM) has a distinct clinical presentation and natural history from disease caused by the more commonly involved thick filament genes (<i>MYH7</i>, <i>MYBPC3</i>, <i>MYL2</i>, <i>MYL3</i>; thick filament HCM).</p><p><strong>Methods: </strong>Retrospective analysis of the Sarcomeric Human Cardiomyopathy Registry.</p><p><strong>Results: </strong>Four hundred eighty-eight patients with thin filament HCM were compared with 3494 patients with thick filament HCM. After controlling for age at diagnosis, sex, and proband status, thin filament HCM was associated with a higher risk of composite ventricular arrhythmias (hazard ratio, 1.48 [95% CI, 1.09-2.01]), cardiac arrest (hazard ratio, 2.02 [95% CI, 1.33-3.06]), and heart transplant or left ventricular assist device implantation (hazard ratio, 2.18 [95% CI, 1.3-3.65]). Younger age at diagnosis was associated with an increased risk for the ventricular arrhythmia composite outcome in thin and thick filament HCM (hazard ratio, 0.93 [95% CI, 0.91-0.94]; hazard ratio, 0.93 [95% CI, 0.93-0.94]; age reported as 5-year increment). Within specific thin filament genes, an increased risk of arrhythmic events or heart transplant/left ventricular assist device implantation was evident for variants in <i>TNNT2</i> amino acids 92 to 94 (odds ratio versus other <i>TNNT2</i> variants; odds ratio, 3.02 [95% CI, 1.17-7.49]) and <i>TNNI3</i> amino acids 191 to 210 (odds ratio versus other <i>TNNI3</i> variants; odds ratio, 3.5 [95% CI, 1.58-8.02]).</p><p><strong>Conclusions: </strong>Thin filament HCM seems to carry a higher risk for ventricular arrhythmias and advanced heart failure compared with thick filament HCM. Integrating gene-level and intragene-level information may improve risk stratification in patients with HCM.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005696"},"PeriodicalIF":6.1,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029863","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":"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":"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}