Circulation: Genomic and Precision Medicine最新文献

{"title":"Potential Diagnostic Role for a Combined Postmortem DNA and RNA Sequencing for Brugada Syndrome.","authors":"Carlos Bueno-Beti, David C Johnson, Chris Miles, Joseph Westaby, Mary N Sheppard, Elijah R Behr, Angeliki Asimaki","doi":"10.1161/CIRCGEN.122.004251","DOIUrl":"10.1161/CIRCGEN.122.004251","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004251"},"PeriodicalIF":6.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10729895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41112761","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":"Genotype-Phenotype Taxonomy of Hypertrophic Cardiomyopathy.","authors":"Lara Curran, Antonio de Marvao, Paolo Inglese, Kathryn A McGurk, Pierre-Raphaël Schiratti, Adam Clement, Sean L Zheng, Surui Li, Chee Jian Pua, Mit Shah, Mina Jafari, Pantazis Theotokis, Rachel J Buchan, Sean J Jurgens, Claire E Raphael, Arun John Baksi, Antonis Pantazis, Brian P Halliday, Dudley J Pennell, Wenjia Bai, Calvin W L Chin, Rafik Tadros, Connie R Bezzina, Hugh Watkins, Stuart A Cook, Sanjay K Prasad, James S Ware, Declan P O'Regan","doi":"10.1161/CIRCGEN.123.004200","DOIUrl":"10.1161/CIRCGEN.123.004200","url":null,"abstract":"<p><strong>Background: </strong>Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression.</p><p><strong>Methods: </strong>We enrolled 436 patients with HCM (median age, 60 years; 28.8% women) with clinical, genetic, and imaging data. An independent cohort of 60 patients with HCM from Singapore (median age, 59 years; 11% women) and a reference population from the UK Biobank (n=16 691; mean age, 55 years; 52.5% women) were also recruited. We used machine learning to analyze the 3-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree.</p><p><strong>Results: </strong>Carriers of pathogenic or likely pathogenic variants for HCM had lower left ventricular mass, but greater basal septal hypertrophy, with reduced life span (mean follow-up, 9.9 years) compared with genotype negative individuals (hazard ratio, 2.66 [95% CI, 1.42-4.96]; <i>P</i><0.002). Four main phenotypic branches were identified using unsupervised learning of 3-dimensional shape: (1) nonsarcomeric hypertrophy with coexisting hypertension; (2) diffuse and basal asymmetrical hypertrophy associated with outflow tract obstruction; (3) isolated basal hypertrophy; and (4) milder nonobstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for pathogenic or likely pathogenic variants, 2.18 [95% CI, 1.93-2.28]; <i>P</i>=0.0001). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalizable to an independent cohort (trustworthiness, M₁: 0.86-0.88).</p><p><strong>Conclusions: </strong>We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk, and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004200"},"PeriodicalIF":6.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10729901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138444116","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":"Compound Heterozygous Truncating Variants in the <i>BAG5</i> Gene As a Cause of Early-Onset Dilated Cardiomyopathy.","authors":"Shunsuke Inoue, Toshiyuki Ko, Seitaro Nomura, Takanobu Yamada, Bo Zhang, Zhehao Dai, Takahiro Jimba, Manami Katoh, Junichi Ishida, Eisuke Amiya, Masaru Hatano, Norifumi Takeda, Hiroyuki Morita, Minoru Ono, Issei Komuro","doi":"10.1161/CIRCGEN.123.004282","DOIUrl":"10.1161/CIRCGEN.123.004282","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004282"},"PeriodicalIF":6.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49688958","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":"Hypertrophic Cardiomyopathy Secondary to <i>RAF1</i> Cysteine-Rich Domain Variants.","authors":"Dominic E Fullenkamp, Ryan M Jorgensen, Desiree F Leach, Arjun Sinha, Isabella M Salamone, Jamie R Johnston, Lisa M Dellefave-Castillo, Lubna Choudhury, Elizabeth M McNally, Lisa D Wilsbacher","doi":"10.1161/CIRCGEN.123.004262","DOIUrl":"10.1161/CIRCGEN.123.004262","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004262"},"PeriodicalIF":6.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10841507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71410959","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":"Combining Polygenic and Proteomic Risk Scores With Clinical Risk Factors to Improve Performance for Diagnosing Absence of Coronary Artery Disease in Patients With de novo Chest Pain.","authors":"Peter Loof Møller,&nbsp;Palle Duun Rohde,&nbsp;Jonathan Nørtoft Dahl,&nbsp;Laust Dupont Rasmussen,&nbsp;Samuel Emil Schmidt,&nbsp;Louise Nissen,&nbsp;Victoria McGilligan,&nbsp;Jacob F Bentzon,&nbsp;Daniel F Gudbjartsson,&nbsp;Kari Stefansson,&nbsp;Hilma Holm,&nbsp;Simon Winther,&nbsp;Morten Bøttcher,&nbsp;Mette Nyegaard","doi":"10.1161/CIRCGEN.123.004053","DOIUrl":"10.1161/CIRCGEN.123.004053","url":null,"abstract":"<p><strong>Background: </strong>Patients with de novo chest pain, referred for evaluation of possible coronary artery disease (CAD), frequently have an absence of CAD resulting in millions of tests not having any clinical impact. The objective of this study was to investigate whether polygenic risk scores and targeted proteomics improve the prediction of absence of CAD in patients with suspected CAD, when added to the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) minimal risk score (PMRS).</p><p><strong>Methods: </strong>Genotyping and targeted plasma proteomics (N=368 proteins) were performed in 1440 patients with symptoms suspected to be caused by CAD undergoing coronary computed tomography angiography. Based on individual genotypes, a polygenic risk score for CAD (PRS_CAD) was calculated. The prediction was performed using combinations of PRS_CAD, proteins, and PMRS as features in models using stability selection and machine learning.</p><p><strong>Results: </strong>Prediction of absence of CAD yielded an area under the curve of PRS_CAD-model, 0.64±0.03; proteomic-model, 0.58±0.03; and PMRS model, 0.76±0.02. No significant correlation was found between the genetic and proteomic risk scores (Pearson correlation coefficient, -0.04; <i>P</i>=0.13). Optimal predictive ability was achieved by the full model (PRS_CAD+protein+PMRS) yielding an area under the curve of 0.80±0.02 for absence of CAD, significantly better than the PMRS model alone (<i>P</i><0.001). For reclassification purpose, the full model enabled down-classification of 49% (324 of 661) of the 5% to 15% pretest probability patients and 18% (113 of 611) of >15% pretest probability patients.</p><p><strong>Conclusions: </strong>For patients with chest pain and low-intermediate CAD risk, incorporating targeted proteomics and polygenic risk scores into the risk assessment substantially improved the ability to predict the absence of CAD. Genetics and proteomics seem to add complementary information to the clinical risk factors and improve risk stratification in this large patient group.</p><p><strong>Registration: </strong>URL: https://www.</p><p><strong>Clinicaltrials: </strong>gov; Unique identifier: NCT02264717.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"442-451"},"PeriodicalIF":7.4,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41117441","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":"Novel Insights Into DMD-Associated Dilated Cardiomyopathy.","authors":"Teresa Wang,&nbsp;Jessica Chowns,&nbsp;Sharlene M Day","doi":"10.1161/CIRCGEN.123.004384","DOIUrl":"10.1161/CIRCGEN.123.004384","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"431-433"},"PeriodicalIF":7.4,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41113673","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":"Cardiac Sarcoidosis Mimickers: Genetic Testing in Undifferentiated Inflammatory Cardiomyopathies.","authors":"Matteo Castrichini,&nbsp;Kolade M Agboola,&nbsp;Hridyanshu Vyas,&nbsp;Omar F Abou Ezzeddine,&nbsp;Konstantinos C Siontis,&nbsp;John R Giudicessi,&nbsp;Andrew N Rosenbaum,&nbsp;Naveen L Pereira","doi":"10.1161/CIRCGEN.123.004099","DOIUrl":"10.1161/CIRCGEN.123.004099","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"478-479"},"PeriodicalIF":7.4,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9746813","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":"Contemporary Polygenic Scores of Low-Density Lipoprotein Cholesterol and Coronary Artery Disease Predict Coronary Atherosclerosis in Adolescents and Young Adults.","authors":"Rodrigo Guarischi-Sousa, Elias Salfati, Pik Fang Kho, Kruthika R Iyer, Austin T Hilliard, David M Herrington, Philip S Tsao, Shoa L Clarke, Themistocles L Assimes","doi":"10.1161/CIRCGEN.122.004047","DOIUrl":"10.1161/CIRCGEN.122.004047","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"480-482"},"PeriodicalIF":7.4,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/06/30/hcg-16-480.PMC10581412.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9756486","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":"Implementation of Rapid Genome Sequencing for Critically Ill Infants With Complex Congenital Heart Disease.","authors":"Thomas Hays,&nbsp;Rebecca Hernan,&nbsp;Michele Disco,&nbsp;Emily L Griffin,&nbsp;Nimrod Goldshtrom,&nbsp;Diana Vargas,&nbsp;Ganga Krishnamurthy,&nbsp;Miles Bomback,&nbsp;Atteeq U Rehman,&nbsp;Amanda T Wilson,&nbsp;Saurav Guha,&nbsp;Shruti Phadke,&nbsp;Volkan Okur,&nbsp;Dino Robinson,&nbsp;Vanessa Felice,&nbsp;Avinash Abhyankar,&nbsp;Vaidehi Jobanputra,&nbsp;Wendy K Chung","doi":"10.1161/CIRCGEN.122.004050","DOIUrl":"10.1161/CIRCGEN.122.004050","url":null,"abstract":"<p><strong>Background: </strong>Rapid genome sequencing (rGS) has been shown to improve care of critically ill infants. Congenital heart disease (CHD) is a leading cause of infant mortality and is often caused by genetic disorders, yet the utility of rGS has not been prospectively studied in this population.</p><p><strong>Methods: </strong>We conducted a prospective evaluation of rGS to improve the care of infants with complex CHD in our cardiac neonatal intensive care unit.</p><p><strong>Results: </strong>In a cohort of 48 infants with complex CHD, rGS diagnosed 14 genetic disorders in 13 (27%) individuals and led to changes in clinical management in 8 (62%) cases with diagnostic results. These included 2 cases in whom genetic diagnoses helped avert intensive, futile interventions before cardiac neonatal intensive care unit discharge, and 3 cases in whom eye disease was diagnosed and treated in early childhood.</p><p><strong>Conclusions: </strong>Our study provides the first prospective evaluation of rGS for infants with complex CHD to our knowledge. We found that rGS diagnosed genetic disorders in 27% of cases and led to changes in management in 62% of cases with diagnostic results. Our model of care depended on coordination between neonatologists, cardiologists, surgeons, geneticists, and genetic counselors. These findings highlight the important role of rGS in CHD and demonstrate the need for expanded study of how to implement this resource to a broader population of infants with CHD.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"415-420"},"PeriodicalIF":7.4,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10117567","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":"Risks of Ventricular Arrhythmia and Heart Failure in Carriers of <i>RBM20</i> Variants.","authors":"Douglas E Cannie, Alexandros Protonotarios, Athanasios Bakalakos, Petros Syrris, Massimiliano Lorenzini, Bianca De Stavola, Louise Bjerregaard, Anne M Dybro, Thomas M Hey, Frederikke G Hansen, Marina Navarro Peñalver, Maria G Crespo-Leiro, Jose M Larrañaga-Moreira, Fernando de Frutos, Renee Johnson, Thomas A Slater, Lorenzo Monserrat, Anshuman Sengupta, Luisa Mestroni, Matthew R G Taylor, Gianfranco Sinagra, Zofia Bilinska, Itziar Solla-Ruiz, Xabier Arana Achaga, Roberto Barriales-Villa, Pablo Garcia-Pavia, Juan R Gimeno, Matteo Dal Ferro, Marco Merlo, Karim Wahbi, Diane Fatkin, Jens Mogensen, Torsten B Rasmussen, Perry M Elliott","doi":"10.1161/CIRCGEN.123.004059","DOIUrl":"10.1161/CIRCGEN.123.004059","url":null,"abstract":"<p><strong>Background: </strong>Variants in <i>RBM20</i> are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in <i>RBM20</i> variant carriers and the impact of sex on outcomes.</p><p><strong>Methods: </strong>Consecutive probands and relatives carrying <i>RBM20</i> variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and men and women compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. <i>RBM20</i> variant carriers with left ventricular systolic dysfunction (<i>RBM20</i>_LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction.</p><p><strong>Results: </strong>Longitudinal follow-up data were available for 143 <i>RBM20</i> variant carriers (71 men; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between men and women (log-rank <i>P</i>=0.07 and <i>P</i>=0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 men and 3 women; log-rank <i>P</i><0.001). Four of 10 variant carriers with available LVEF contemporary to MVA had an LVEF >35%. At 5 years, 15 of 67 (22.4%) <i>RBM20</i>_LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank <i>P</i><0.001). <i>RBM20</i> variant carriage conferred a 6.0-fold increase in risk of the primary end point.</p><p><strong>Conclusions: </strong><i>RBM20</i> variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female <i>RBM20</i> variant carriers is similar, but male sex is strongly associated with ESHF.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"434-441"},"PeriodicalIF":7.4,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10581410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10375155","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}