Circulation: Genomic and Precision Medicine最新文献

{"title":"Rare Cardiac Genetic Variation Is Associated With Postoperative Atrial Fibrillation.","authors":"Zhanlin Chen, Anirudha S Chandrabhatla, Anna Pfenniger, Tom Liu, Patrick M McCarthy, James L Cox, Stephen F Chiu, Rod Passman, Philip Greenland, Adam Gordon, S Chris Malaisrie, Gregory Webster","doi":"10.1161/CIRCGEN.125.005688","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005688","url":null,"abstract":"<p><strong>Background: </strong>New-onset postoperative atrial fibrillation (POAF) is a common surgical complication, yet the contribution of rare genetic variants to POAF is poorly characterized.</p><p><strong>Methods: </strong>We conducted a cohort study including 49 913 adults who underwent surgery without a preoperative diagnosis of atrial fibrillation (AF). All participants had whole-genome sequencing linked to electronic health record data. Pathogenic or likely pathogenic (LP) variants were identified in 141 cardiac genes associated with early-onset AF. The primary outcome was POAF, defined as a new diagnosis of AF within 30 days of surgery; the secondary outcome was freedom from AF over 5 years. Multivariable regression and propensity-score matching were used to evaluate the associations between pathogenic/LP variants and POAF.</p><p><strong>Results: </strong>Among 49 913 participants, 2298 underwent cardiac surgery and 47 615 underwent noncardiac surgery. The prevalence of pathogenic/LP variants was 6.0% in the cardiac surgery group (138/2298) and 4.1% in the noncardiac surgery group (1947/47 615). Overall, carriers of ≥1 pathogenic/LP variant had higher odds of POAF than noncarriers (6.6% versus 4.0%; odds ratio [OR], 1.8 [95% CI, 1.4-2.1]). In cardiac surgery, 36.0% of pathogenic/LP carriers (78/216) developed POAF versus 23.4% of noncarriers (492/2082; OR, 2.3 [95% CI, 1.4-3.2]), and in noncardiac surgery, POAF occurred in 3.8% of carriers (74/1947) versus 2.5% of noncarriers (1465/45 668; OR, 1.5 [95% CI, 1.2-1.9]). Pathogenic/LP variants in cardiomyopathy-only genes (n=589; OR, 1.8 [95% CI, 1.3-2.6]) or in genes associated with both cardiomyopathy and arrhythmia (n=1059; OR, 1.8 [95% CI, 1.4-2.3]) were significantly associated with POAF, whereas variants in arrhythmia-only genes (n=454; OR, 1.3 [95% CI, 0.8-2.1]) were not. Five-year freedom from AF was lower among pathogenic/LP variant carriers in both cardiac surgery (53% versus 64%; <i>P</i>=0.010) and noncardiac surgery (92% versus 94%; <i>P</i>=0.002).</p><p><strong>Conclusions: </strong>Rare pathogenic/LP variants in cardiomyopathy genes were associated with risk of POAF and reduced AF-free survival over long-term follow-up across cardiac and noncardiac surgery.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005688"},"PeriodicalIF":6.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079704","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":"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":"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}

{"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":"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}