Circulation: Genomic and Precision Medicine最新文献

{"title":"Circulating Blood Plasma Profiling Reveals Proteomic Signature and a Causal Role for SVEP1 in Sudden Cardiac Death.","authors":"ThuyVy Duong, Thomas R Austin, Jennifer A Brody, Ali Shojaie, Alexis Battle, Joel S Bader, Yun Soo Hong, Christie M Ballantyne, Josef Coresh, Robert E Gerszten, Russell P Tracy, Bruce M Psaty, Nona Sotoodehnia, Dan E Arking","doi":"10.1161/CIRCGEN.123.004494","DOIUrl":"10.1161/CIRCGEN.123.004494","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004494"},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11479847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132031","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":"Invasive Assessment of Coronary Artery Disease in Clonal Hematopoiesis of Indeterminate Potential.","authors":"J Brett Heimlich, Michael A Raddatz, John Wells, Caitlyn Vlasschaert, Sydney Olson, Marcus Threadcraft, Kristoff Foster, Emmanuel Boateng, Kelsey Umbarger, Yan Ru Su, Dan M Roden, Colin M Barker, Alexander G Bick","doi":"10.1161/CIRCGEN.123.004415","DOIUrl":"10.1161/CIRCGEN.123.004415","url":null,"abstract":"<p><strong>Background: </strong>Clonal hematopoiesis of indeterminate potential (CHIP) occurs due to acquired mutations in bone marrow progenitor cells. CHIP confers a 2-fold risk of atherosclerotic cardiovascular disease. However, there are limited data regarding specific cardiovascular phenotypes. The purpose of this study was to define the coronary artery disease phenotype of the CHIP population-based on coronary angiography.</p><p><strong>Methods: </strong>We recruited 1142 patients from the Vanderbilt University Medical Center cardiac catheterization laboratory and performed DNA sequencing to determine CHIP status. Multivariable logistic regression models and proportional odds models were used to assess the association between CHIP status and angiography phenotypes.</p><p><strong>Results: </strong>We found that 18.4% of patients undergoing coronary angiography had a CHIP mutation. Those with CHIP had a higher risk of having obstructive left main (odds ratio, 2.44 [95% CI, 1.40-4.27]; <i>P</i>=0.0018) and left anterior descending (odds ratio, 1.59 [1.12-2.24]; <i>P</i>=0.0092) coronary artery disease compared with non-CHIP carriers. We additionally found that a specific CHIP mutation, ten eleven translocase 2 <i>(TET2</i>), has a larger effect size on left main stenosis compared with other CHIP mutations.</p><p><strong>Conclusions: </strong>This is the first invasive assessment of coronary artery disease in CHIP and offers a description of a specific atherosclerotic phenotype in CHIP wherein there is an increased risk of obstructive left main and left anterior descending artery stenosis, especially among <i>TET2</i> mutation carriers. This serves as a basis for understanding enhanced morbidity and mortality in CHIP.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004415"},"PeriodicalIF":6.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11338040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466600","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":"Rapidly Progressive Peripheral Artery Disease: Importance of Oligogenic Inheritance and Functional Validation.","authors":"Lisa Dangreau, Yvonne Nitschke, Frank Rutsch, Olivier M Vanakker","doi":"10.1161/CIRCGEN.124.004574","DOIUrl":"10.1161/CIRCGEN.124.004574","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004574"},"PeriodicalIF":6.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare Variant in <i>MRC2</i> Associated With Familial Supraventricular Tachycardia and Wolff-Parkinson-White Syndrome.","authors":"Adam S Potter, Christina Y Miyake, Claudia Gonzaga-Jauregui, Yuriana Aguilar-Sanchez, Mohit M Hulsurkar, Satadru K Lahiri, Lucia M Moreira, Neelam Mehta, Mahshid S Azamian, James R Lupski, Svetlana Reilly, Seema R Lalani, Xander H T Wehrens","doi":"10.1161/CIRCGEN.124.004614","DOIUrl":"10.1161/CIRCGEN.124.004614","url":null,"abstract":"<p><strong>Background: </strong>Accessory pathways are a common cause of supraventricular tachycardia (SVT) and can lead to sudden cardiac death in otherwise healthy children and adults when associated with Wolff-Parkinson-White syndrome. The goal of this study was to identify genetic variants within a large family with structurally normal hearts affected by SVT and Wolff-Parkinson-White syndrome and determine causality of the gene deficit in a corresponding mouse model.</p><p><strong>Methods: </strong>Whole exome sequencing performed on 2 distant members of a 3-generation family in which multiple members were affected by SVT or Wolff-Parkinson-White pattern (preexcitation) on ECG identified <i>MRC2</i> as a candidate gene. Serial electrocardiograms, intracardiac electrophysiology studies, echocardiography, optical mapping studies, and histology were performed on both <i>Mrc2</i> mutant and WT (wild-type) mice.</p><p><strong>Results: </strong>A rare HET (heterozygous) missense variant c.2969A>G;p.Glu990Gly (E990G) in <i>MRC2</i> was identified as the leading candidate gene variant segregating with the cardiac phenotype following an autosomal-dominant Mendelian trait segregation pattern with variable expressivity. In vivo electrophysiology studies revealed reentrant SVT in E990G mice. Optical mapping studies in E990G mice demonstrated abnormal retrograde conduction, suggesting the presence of an accessory pathway. Histological analysis of E990G mouse hearts showed a disordered ECM (extracellular matrix) in the annulus fibrosus. Finally, <i>Mrc2</i> knockdown in human cardiac fibroblasts enhanced accelerated cell migration.</p><p><strong>Conclusions: </strong>This study identified a rare nonsynonymous variant in the <i>MRC2</i> gene in individuals with familial reentrant SVT, Wolff-Parkinson-White ECG pattern, and structurally normal hearts. Furthermore, <i>Mrc2</i> knock-in mice revealed an increased incidence of reentrant SVT and bypass tract formation in the setting of preserved cardiac structure and function.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004614"},"PeriodicalIF":6.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476000","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":"High-Risk Nonclassical Long-QT Syndrome Genotypes: Spectrum of Genetic and Phenotypic Features.","authors":"Abdulkarim Abdulrahman, Brianna Davies, Habib Khan, Shubhayan Sanatani, Rafik Tadros, Mario Talajic, Julia Cadrin-Tourigny, Joseph Atallah, David Lee, Martin Gardner, Christian Steinberg, Simon Hansom, Martin Green, Anne Fournier, Laura Arbour, Richard Leather, Shane Kimber, Jason Roberts, Jeffrey Healey, Paul Angaran, Christopher Simpson, Colette Seifer, Erkan Ilhan, Jacqueline Joza, Andrew Krahn, Zachary Laksman","doi":"10.1161/CIRCGEN.124.004554","DOIUrl":"10.1161/CIRCGEN.124.004554","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004554"},"PeriodicalIF":6.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787431","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":"Multisite Validation of a Functional Assay to Adjudicate <i>SCN5A</i> Brugada Syndrome-Associated Variants.","authors":"Joanne G Ma, Matthew J O'Neill, Ebony Richardson, Kate L Thomson, Jodie Ingles, Ayesha Muhammad, Joseph F Solus, Giovanni Davogustto, Katherine C Anderson, M Benjamin Shoemaker, Andrew B Stergachis, Brendan J Floyd, Kyla Dunn, Victoria N Parikh, Henry Chubb, Mark J Perrin, Dan M Roden, Jamie I Vandenberg, Chai-Ann Ng, Andrew M Glazer","doi":"10.1161/CIRCGEN.124.004569","DOIUrl":"10.1161/CIRCGEN.124.004569","url":null,"abstract":"<p><strong>Background: </strong>Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in <i>SCN5A</i>. Interpreting the pathogenicity of <i>SCN5A</i> missense variants is challenging, and ≈79% of <i>SCN5A</i> missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification.</p><p><strong>Methods: </strong>An in vitro <i>SCN5A</i>-Brugada syndrome automated patch clamp assay was independently performed at Vanderbilt University Medical Center and Victor Chang Cardiac Research Institute. The assay was calibrated according to ClinGen Sequence Variant Interpretation recommendations using high-confidence variant controls (n=49). Normal and abnormal ranges of function were established based on the distribution of benign variant assay results. Odds of pathogenicity values were derived from the experimental results according to ClinGen Sequence Variant Interpretation recommendations. The calibrated assay was then used to study <i>SCN5A</i> variants of uncertain significance observed in 4 families with Brugada syndrome and other arrhythmia phenotypes associated with <i>SCN5A</i> loss-of-function.</p><p><strong>Results: </strong>Variant channel parameters generated independently at the 2 research sites showed strong correlations, including peak <i>I</i>_Na density (<i>R</i>²=0.86). The assay accurately distinguished benign controls (24/25 concordant variants) from pathogenic controls (23/24 concordant variants). Odds of pathogenicity values were 0.042 for normal function and 24.0 for abnormal function, corresponding to strong evidence for both American College of Medical Genetics and Genomics/Association for Molecular Pathology benign and pathogenic functional criteria (BS3 and PS3, respectively). Application of the assay to 4 clinical <i>SCN5A</i> variants of uncertain significance revealed loss-of-function for 3/4 variants, enabling reclassification to likely pathogenic.</p><p><strong>Conclusions: </strong>This validated high-throughput assay provides clinical-grade functional evidence to aid the classification of current and future <i>SCN5A</i>-Brugada syndrome variants of uncertain significance.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004569"},"PeriodicalIF":6.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475999","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":"Loss of Function Variant in <i>SMAD6</i> Is Associated With a Novel Phenotype of Internal Carotid Artery Dissection.","authors":"Malak A Alghamdi, Wael Alqarawi, Essa Alharbi, Reham M Balahmar, Haya Alruqi, Nisserin Jadu, Majid Alhomidan, Mohammed Hussien Alghamdi, Naif A M Almontashiri","doi":"10.1161/CIRCGEN.124.004686","DOIUrl":"10.1161/CIRCGEN.124.004686","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004686"},"PeriodicalIF":6.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787432","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":"Circulating Metabolite Profiles and Risk of Coronary Heart Disease Among Racially and Geographically Diverse Populations.","authors":"Kui Deng, Deepak K Gupta, Xiao-Ou Shu, Loren Lipworth, Wei Zheng, Hui Cai, Qiuyin Cai, Danxia Yu","doi":"10.1161/CIRCGEN.123.004437","DOIUrl":"10.1161/CIRCGEN.123.004437","url":null,"abstract":"<p><strong>Background: </strong>Metabolomics may reveal novel biomarkers for coronary heart disease (CHD). We aimed to identify circulating metabolites and construct a metabolite risk score (MRS) associated with incident CHD among racially and geographically diverse populations.</p><p><strong>Methods: </strong>Untargeted metabolomics was conducted using baseline plasma samples from 900 incident CHD cases and 900 age-/sex-/race-matched controls (300 pairs of Black Americans, White Americans, and Chinese adults, respectively), which detected 927 metabolites with known identities among ≥80% of samples. After quality control, 896 case-control pairs remained and were randomly divided into discovery (70%) and validation (30%) sets within each race. In the discovery set, conditional logistic regression and least absolute shrinkage and selection operator over 100 subsamples were applied to identify metabolites robustly associated with CHD risk and construct the MRS. The MRS-CHD association was evaluated using conditional logistic regression and the C-index. Mediation analysis was performed to examine if MRS mediated associations between conventional risk factors and incident CHD. The results from the validation set were presented as the main findings.</p><p><strong>Results: </strong>Twenty-four metabolites selected in ≥90% of subsamples comprised the MRS, which was significantly associated with incident CHD (odds ratio per 1 SD, 2.21 [95% CI, 1.62-3.00] after adjusting for sociodemographics, lifestyles, family history, and metabolic health status). MRS could distinguish incident CHD cases from matched controls (C-index, 0.69 [95% CI, 0.63-0.74]) and improve CHD risk prediction when adding to conventional risk factors (C-index, 0.71 [95% CI, 0.65-0.76] versus 0.67 [95% CI, 0.61-0.73]; <i>P</i><0.001). The odds ratios and C-index were similar across subgroups defined by race, sex, socioeconomic status, lifestyles, metabolic health, family history, and follow-up duration. The MRS mediated large portions (46.0%-74.2%) of the associations for body mass index, smoking, diabetes, hypertension, and dyslipidemia with incident CHD.</p><p><strong>Conclusions: </strong>In a diverse study sample, we identified 24 circulating metabolites that, when combined into an MRS, were robustly associated with incident CHD and modestly improved CHD risk prediction beyond conventional risk factors.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004437"},"PeriodicalIF":6.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475998","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":"Phenotypic Spectrum of Subclinical Sarcomere-Related Hypertrophic Cardiomyopathy and Transition to Overt Disease.","authors":"Constantin-Cristian Topriceanu, James C Moon, Anna Axelsson Raja, Gabriella Captur, Carolyn Y Ho","doi":"10.1161/CIRCGEN.124.004580","DOIUrl":"10.1161/CIRCGEN.124.004580","url":null,"abstract":"<p><p>Genetic hypertrophic cardiomyopathy (HCM) is classically caused by pathogenic/likely pathogenic variants in sarcomere genes (G+). Currently, HCM is diagnosed if there is unexplained left ventricular (LV) hypertrophy with LV wall thickness ≥15 mm in probands or ≥13 mm in at-risk relatives. Although LV hypertrophy is a key feature, this binary metric does not encompass the full constellation of phenotypic features, particularly in the subclinical stage of the disease. Subtle phenotypic manifestations can be identified in sarcomere variant carriers with normal LV wall thickness, before diagnosis with HCM (G+/LV hypertrophy-; subclinical HCM). We conducted a systematic review to summarize current knowledge about the phenotypic spectrum of subclinical HCM and factors influencing penetrance and expressivity. Although the mechanisms driving the development of LV hypertrophy are yet to be elucidated, activation of profibrotic pathways, impaired relaxation, abnormal Ca²⁺ signaling, altered myocardial energetics, and microvascular dysfunction have all been identified in subclinical HCM. Progression from subclinical to clinically overt HCM may be more likely if early phenotypic manifestations are present, including ECG abnormalities, longer mitral valve leaflets, lower global E' velocities on Doppler echocardiography, and higher serum N-terminal propeptide of B-type natriuretic peptide. Longitudinal studies of variant carriers are critically needed to improve our understanding of penetrance, characterize the transition to disease, identify risk predictors of phenotypic evolution, and guide the development of novel treatment strategies aimed at influencing disease trajectory.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004580"},"PeriodicalIF":6.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141442192","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":"Prediction of Positive Genetic Testing for Arrhythmogenic Left Ventricular Cardiomyopathy.","authors":"Youssef Ed Demri, Clarisse Billon, Mohamed El Hachmi, Mohamed Dembélé, Albert Hagège, Pascale Richard, Flavie Ader, Diala Khraiche, Damien Bonnet, Xavier Jeunemaitre, Karim Wahbi","doi":"10.1161/CIRCGEN.124.004612","DOIUrl":"10.1161/CIRCGEN.124.004612","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004612"},"PeriodicalIF":6.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787433","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}