Circulation: Genomic and Precision Medicine最新文献

{"title":"Role of <i>TBX20</i> Truncating Variants in Dilated Cardiomyopathy and Left Ventricular Noncompaction.","authors":"Almudena Amor-Salamanca, Alfredo Santana Rodríguez, Hazhee Rasoul, José F Rodríguez-Palomares, Oana Moldovan, Thomas Morris Hey, María Gallego Delgado, David López Cuenca, Daniel de Castro Campos, María Teresa Basurte-Elorz, Rosa Macías-Ruiz, María Eugenia Fuentes Cañamero, Joseph Galvin, Raquel Bilbao Quesada, Luis de la Higuera Romero, Juan Pablo Trujillo-Quintero, Loida María García-Cruz, Ivonne Cárdenas-Reyes, Juan Jiménez-Jáimez, Soledad García-Hernández, María Valverde-Gómez, Iria Gómez-Díaz, Javier Limeres Freire, José M García-Pinilla, Juan R Gimeno-Blanes, Konstantinos Savattis, Pablo García-Pavía, Juan Pablo Ochoa","doi":"10.1161/CIRCGEN.123.004404","DOIUrl":"10.1161/CIRCGEN.123.004404","url":null,"abstract":"<p><strong>Background: </strong>Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. <i>TBX20</i> has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the <i>TBX20</i> truncating variant (<i>TBX20tv</i>) and DCM/LVNC.</p><p><strong>Methods: </strong><i>TBX20</i> was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124 098 external controls (individuals from the gnomAD database). Enrichment of <i>TBX20tv</i> in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers.</p><p><strong>Results: </strong><i>TBX20tv</i> was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22 773; 0.004%) and external comparison groups (4/124 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90-541.45; <i>P</i><0.0001) and 99.76 (95% CI, 34.60-287.62; <i>P</i><0.0001), respectively. <i>TBX20tv</i> was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with <i>TBX20tv</i> (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25-75:3.6-14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias.</p><p><strong>Conclusions: </strong><i>TBX20tv</i> is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. <i>TBX20tv</i>-associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. <i>TBX20</i> should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004404"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11019988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139729140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA Methylation-Based Biomarkers of Protein Levels and Cardiovascular Disease Risk: Opportunities and Challenges for Precision Cardiology.","authors":"Anne K Bozack, Ana Navas-Acien, Andres Cardenas","doi":"10.1161/CIRCGEN.124.004571","DOIUrl":"10.1161/CIRCGEN.124.004571","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004571"},"PeriodicalIF":6.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11021153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139721858","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":"Resource of Gene Expression Data From a Multiethnic Population Cohort of Induced Pluripotent Stem Cell-Derived Cardiomyocytes.","authors":"Wenjian Lv, Apoorva Babu, Michael P Morley, Kiran Musunuru, Marie A Guerraty","doi":"10.1161/CIRCGEN.123.004218","DOIUrl":"10.1161/CIRCGEN.123.004218","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004218"},"PeriodicalIF":6.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11021142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899500","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":"CYB5R3 T117S Genetic Mutation Is Associated With Major Adverse Cardiovascular and Cerebrovascular Events in Black Adults.","authors":"Rahul Chaudhary, Adam C Straub, Felix E Y Aggor, Ifeoluwa Onasanya, Jordan Richardson, Patrick J Strollo, Steven E Reis, Oladipupo Olafiranye","doi":"10.1161/CIRCGEN.123.004271","DOIUrl":"10.1161/CIRCGEN.123.004271","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004271"},"PeriodicalIF":6.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11021138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139729139","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":"Multiplexed Functional Assessments of <i>MYH7</i> Variants in Human Cardiomyocytes.","authors":"Clayton E Friedman, Shawn Fayer, Sriram Pendyala, Wei-Ming Chien, Alexander Loiben, Linda Tran, Leslie S Chao, Ashley McKinstry, Dania Ahmed, Stephen D Farris, April Stempien-Otero, Erica C Jonlin, Charles E Murry, Lea M Starita, Douglas M Fowler, Kai-Chun Yang","doi":"10.1161/CIRCGEN.123.004377","DOIUrl":"10.1161/CIRCGEN.123.004377","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic autosomal-dominant missense variants in <i>MYH7</i> (<i>myosin heavy chain 7</i>), which encodes the sarcomeric protein (β-MHC [beta myosin heavy chain]) expressed in cardiac and skeletal myocytes, are a leading cause of hypertrophic cardiomyopathy and are clinically actionable. However, ≈75% of <i>MYH7</i> missense variants are of unknown significance. While human-induced pluripotent stem cells (hiPSCs) can be differentiated into cardiomyocytes to enable the interrogation of <i>MYH7</i> variant effect in a disease-relevant context, deep mutational scanning has not been executed using diploid hiPSC derivates due to low hiPSC gene-editing efficiency. Moreover, multiplexable phenotypes enabling deep mutational scanning of <i>MYH7</i> variant hiPSC-derived cardiomyocytes are unknown.</p><p><strong>Methods: </strong>To overcome these obstacles, we used CRISPRa On-Target Editing Retrieval enrichment to generate an hiPSC library containing 113 <i>MYH7</i> codon variants suitable for deep mutational scanning. We first established that β-MHC protein loss occurs in a hypertrophic cardiomyopathy human heart with a pathogenic <i>MYH7</i> variant. We then differentiated the <i>MYH7</i> missense variant hiPSC library to cardiomyocytes for multiplexed assessment of β-MHC variant abundance by massively parallel sequencing and hiPSC-derived cardiomyocyte survival.</p><p><strong>Results: </strong>Both the multiplexed assessment of β-MHC abundance and hiPSC-derived cardiomyocyte survival accurately segregated all known pathogenic variants from synonymous variants. Functional data were generated for 4 variants of unknown significance and 58 additional <i>MYH7</i> missense variants not yet detected in patients.</p><p><strong>Conclusions: </strong>This study leveraged hiPSC differentiation into disease-relevant cardiomyocytes to enable multiplexed assessments of <i>MYH7</i> missense variants for the first time. Phenotyping strategies used here enable the application of deep mutational scanning to clinically actionable genes, which should reduce the burden of variants of unknown significance on patients and clinicians.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004377"},"PeriodicalIF":6.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11196868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139740576","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":"Incremental Value of a Metabolic Risk Score for Heart Failure Mortality: A Population-Based Study.","authors":"Jungnam Joo, Joseph J Shearer, Anna Wolska, Alan T Remaley, James D Otvos, Margery A Connelly, Maureen Sampson, Suzette J Bielinski, Nicholas B Larson, Hoyoung Park, Katherine M Conners, Sarah Turecamo, Véronique L Roger","doi":"10.1161/CIRCGEN.123.004312","DOIUrl":"10.1161/CIRCGEN.123.004312","url":null,"abstract":"<p><strong>Background: </strong>Heart failure is heterogeneous syndrome with persistently high mortality. Nuclear magnetic resonance spectroscopy enables high-throughput metabolomics, suitable for precision phenotyping. We aimed to use targeted metabolomics to derive a metabolic risk score (MRS) that improved mortality risk stratification in heart failure.</p><p><strong>Methods: </strong>Nuclear magnetic resonance was used to measure 21 metabolites (lipoprotein subspecies, branched-chain amino acids, alanine, GlycA (glycoprotein acetylation), ketone bodies, glucose, and citrate) in plasma collected from a heart failure community cohort. The MRS was derived using least absolute shrinkage and selection operator penalized Cox regression and temporal validation. The association between the MRS and mortality and whether risk stratification was improved over the Meta-Analysis Global Group in Chronic Heart Failure clinical risk score and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels were assessed.</p><p><strong>Results: </strong>The study included 1382 patients (median age, 78 years, 52% men, 43% reduced ejection fraction) with a 5-year survival rate of 48% (95% CI, 46%-51%). The MRS included 9 metabolites measured. In the validation data set, a 1 standard deviation increase in the MRS was associated with a large increased rate of death (hazard ratio, 2.2 [95% CI, 1.9-2.5]) that remained after adjustment for Meta-Analysis Global Group in Chronic Heart Failure score and NT-proBNP (hazard ratio, 1.6 [95% CI, 1.3-1.9]). These associations did not differ by ejection fraction. The integrated discrimination and net reclassification indices, and Uno's C statistic, indicated that the addition of the MRS improved discrimination over Meta-Analysis Global Group in Chronic Heart Failure and NT-proBNP.</p><p><strong>Conclusions: </strong>This MRS developed in a heart failure community cohort was associated with a large excess risk of death and improved risk stratification beyond an established risk score and clinical markers.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004312"},"PeriodicalIF":6.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11021175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140183882","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":"Sex Differences in the Association of Multiethnic Genome-Wide Blood Pressure Polygenic Risk Score With Population-Level Systolic Blood Pressure Trajectories.","authors":"Naman S Shetty, Akhil Pampana, Nirav Patel, Krishin Yerabolu, Gnyata Patel, Marguerite R Irvin, Pradeep Natarajan, Henry J Lin, Xiuqing Guo, Stephen S Rich, Jerome I Rotter, Peng Li, Garima Arora, Pankaj Arora","doi":"10.1161/CIRCGEN.123.004515","DOIUrl":"10.1161/CIRCGEN.123.004515","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004515"},"PeriodicalIF":6.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11021155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899501","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":"Pooled Genetic Screenings to Identify Likely Pathogenic Variants in Hypertrophic Cardiomyopathy.","authors":"Adrien Georges, Choudhary Anwar A Chahal","doi":"10.1161/CIRCGEN.124.004599","DOIUrl":"10.1161/CIRCGEN.124.004599","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004599"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140142910","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":"Regional Variation in Cardiovascular Genes Enables a Tractable Genome Editing Strategy.","authors":"Vikki A Krysov, Rachel H Wilson, Nicholas S Ten, Nathan Youlton, Hannah N De Jong, Shirley Sutton, Yong Huang, Chloe M Reuter, Megan E Grove, Matthew T Wheeler, Euan A Ashley, Victoria N Parikh","doi":"10.1161/CIRCGEN.123.004370","DOIUrl":"10.1161/CIRCGEN.123.004370","url":null,"abstract":"<p><strong>Background: </strong>To realize the potential of genome engineering therapeutics, tractable strategies must be identified that balance personalized therapy with the need for off-the-shelf availability. We hypothesized that regional clustering of pathogenic variants can inform the design of rational prime editing therapeutics to treat the majority of genetic cardiovascular diseases with a limited number of reagents.</p><p><strong>Methods: </strong>We collated 2435 high-confidence pathogenic/likely pathogenic (P/LP) variants in 82 cardiovascular disease genes from ClinVar. We assessed the regional density of these variants by defining a regional clustering index. We then combined a highly active base editor with prime editing to demonstrate the feasibility of a P/LP hotspot-directed genome engineering therapeutic strategy in vitro.</p><p><strong>Results: </strong>P/LP variants in cardiovascular disease genes display higher regional density than rare variants found in the general population. P/LP missense variants displayed higher average regional density than P/LP truncating variants. Following hypermutagenesis at a pathogenic hotspot, mean prime editing efficiency across introduced variants was 57±27%.</p><p><strong>Conclusions: </strong>Designing therapeutics that target pathogenic hotspots will not only address known missense P/LP variants but also novel P/LP variants identified in these hotspots as well. Moreover, the clustering of P/LP missense rather than truncating variants in these hotspots suggests that prime editing technology is particularly valuable for dominant negative disease. Although prime editing technology in relation to cardiac health continues to improve, this study presents an approach to targeting the most impactful regions of the genome for inherited cardiovascular disease.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004370"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11020015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140173906","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":"Dilated Cardiomyopathy With Concomitant Salt-Losing Renal Tubulopathy Caused by Heterozygous <i>RRAGD</i> Gene Variant.","authors":"Fernando de Frutos, Carles Diez-Lopez, Elena García-Romero, Leire Gondra, Leire Madariaga, Gema Ariceta, Alejandro García-Castaño, Edoardo Melilli, Lorena Herrador, Laura Triguero-Llonch, Ferran Gran, Laia Rosenfeld, Roger Llatjos, Josep Comin-Colet, José González-Costello","doi":"10.1161/CIRCGEN.123.004336","DOIUrl":"10.1161/CIRCGEN.123.004336","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004336"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899499","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}