Circulation: Genomic and Precision Medicine最新文献

{"title":"Imagenetics for Precision Medicine in Dilated Cardiomyopathy.","authors":"Alexios S Antonopoulos, Anastasia Xintarakou, Alexandros Protonotarios, George Lazaros, Antigoni Miliou, Konstantinos Tsioufis, Charalambos Vlachopoulos","doi":"10.1161/CIRCGEN.123.004301","DOIUrl":"10.1161/CIRCGEN.123.004301","url":null,"abstract":"<p><p>Dilated cardiomyopathy (DCM) is a common heart muscle disorder of nonischemic etiology associated with heart failure development and the risk of malignant ventricular arrhythmias and sudden cardiac death. A tailored approach to risk stratification and prevention of sudden cardiac death is required in genetic DCM given its variable presentation and phenotypic severity. Currently, advances in cardiogenetics have shed light on disease mechanisms, the complex genetic architecture of DCM, polygenic contributors to disease susceptibility and the role of environmental triggers. Parallel advances in imaging have also enhanced disease recognition and the identification of the wide spectrum of phenotypes falling under the DCM umbrella. Genotype-phenotype associations have been also established for specific subtypes of DCM, such as <i>DSP</i> (desmoplakin) or <i>FLNC</i> (filamin-C) cardiomyopathy but overall, they remain elusive and not readily identifiable. Also, despite the accumulated knowledge on disease mechanisms, certain aspects remain still unclear, such as which patients with DCM are at risk for disease progression or remission after treatment. Imagenetics, that is, the combination of imaging and genetics, is expected to further advance research in the field and contribute to precision medicine in DCM management and treatment. In the present article, we review the existing literature in the field, summarize the established knowledge and emerging data on the value of genetics and imaging in establishing genotype-phenotype associations in DCM and in clinical decision making for DCM patients.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004301"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139982462","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 Guideline for Preimplantation Genetic Testing in Inherited Cardiac Diseases.","authors":"Job A J Verdonschot, Debby M E I Hellebrekers, Vanessa P M van Empel, Malou Heijligers, Sonja de Munnik, Edith Coonen, Jos C M F Dreesen, Arthur van den Wijngaard, Han G Brunner, Masoud Zamani Esteki, Stephane R B Heymans, Christine E M de Die-Smulders, Aimée D C Paulussen","doi":"10.1161/CIRCGEN.123.004416","DOIUrl":"10.1161/CIRCGEN.123.004416","url":null,"abstract":"<p><strong>Background: </strong>Preimplantation genetic testing (PGT) is a reproductive technology that selects embryos without (familial) genetic variants. PGT has been applied in inherited cardiac disease and is included in the latest American Heart Association/American College of Cardiology guidelines. However, guidelines selecting eligible couples who will have the strongest risk reduction most from PGT are lacking. We developed an objective decision model to select eligibility for PGT and compared its results with those from a multidisciplinary team.</p><p><strong>Methods: </strong>All couples with an inherited cardiac disease referred to the national PGT center were included. A multidisciplinary team approved or rejected the indication based on clinical and genetic information. We developed a decision model based on published risk prediction models and literature, to evaluate the severity of the cardiac phenotype and the penetrance of the familial variant in referred patients. The outcomes of the model and the multidisciplinary team were compared in a blinded fashion.</p><p><strong>Results: </strong>Eighty-three couples were referred for PGT (1997-2022), comprising 19 different genes for 8 different inherited cardiac diseases (cardiomyopathies and arrhythmias). Using our model and proposed cutoff values, a definitive decision was reached for 76 (92%) couples, aligning with 95% of the multidisciplinary team decisions. In a prospective cohort of 11 couples, we showed the clinical applicability of the model to select couples most eligible for PGT.</p><p><strong>Conclusions: </strong>The number of PGT requests for inherited cardiac diseases increases rapidly, without the availability of specific guidelines. We propose a 2-step decision model that helps select couples with the highest risk reduction for cardiac disease in their offspring after PGT.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004416"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11019983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140183881","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":"Development and Implementation of an Integrated Preclinical Atherosclerosis Database.","authors":"Rachel R Xiang, Yihua Wang, Megan M Shuey, Brigett V Carvajal, Quinn S Wells, Joshua A Beckman, Iris Z Jaffe","doi":"10.1161/CIRCGEN.123.004397","DOIUrl":"10.1161/CIRCGEN.123.004397","url":null,"abstract":"<p><strong>Background: </strong>Basic scientists have used preclinical animal models to explore mechanisms driving human diseases for decades, resulting in thousands of publications, each supporting causative inferences. Despite substantial advances in the mechanistic construct of disease, there has been limited translation from individual studies to advances in clinical care. An integrated approach to these individual studies has the potential to improve translational success.</p><p><strong>Methods: </strong>Using atherosclerosis as a test case, we extracted data from the 2 most common mouse models of atherosclerosis (ApoE [apolipoprotein E]-knockout and LDLR [low-density lipoprotein receptor]-knockout). We restricted analyses to manuscripts published in 2 well-established journals, <i>Arteriosclerosis, Thrombosis, and Vascular Biology</i> and <i>Circulation</i>, as of query in 2021. Predefined variables including experimental conditions, intervention, and outcomes were extracted from each publication to produce a preclinical atherosclerosis database.</p><p><strong>Results: </strong>Extracted data include animal sex, diet, intervention type, and distinct plaque pathologies (size, inflammation, and lipid content). Procedures are provided to standardize data extraction, attribute interventions to specific genes, and transform the database for use with available transcriptomics software. The database integrates hundreds of genes, each directly tested in vivo for causation in a murine atherosclerosis model. The database is provided to allow the research community to perform integrated analyses that reflect the global impact of decades of atherosclerosis investigation.</p><p><strong>Conclusions: </strong>This database is provided as a resource for future interrogation of sub-data sets associated with distinct plaque pathologies, cell type, or sex. We also provide the methods and software needed to expand this data set and apply this approach to the extensive repository of peer-reviewed data utilizing preclinical models to interrogate mechanisms of diverse human diseases.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004397"},"PeriodicalIF":6.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11021141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140334912","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":"Reproductive Carrier Screening: Identifying Families at Risk for Familial Hypercholesterolemia in the United States","authors":"Vivienne Souter, Emily Becraft, Samantha Brummit, Bryan Gall, Brittany Prigmore, Yang Wang, Peter Benn","doi":"10.1161/circgen.123.004457","DOIUrl":"https://doi.org/10.1161/circgen.123.004457","url":null,"abstract":"BACKGROUND:Familial hypercholesterolemia is a treatable genetic condition but remains underdiagnosed. We reviewed the frequency of pathogenic or likely pathogenic (P/LP) variants in the <i>LDLR</i> gene in female individuals receiving reproductive carrier screening.METHODS:This retrospective observational study included samples from female patients (aged 18–55 years) receiving a 274-gene carrier screening panel from January 2020 to September 2022. <i>LDLR</i> exons and their 10 base pairs flanking regions were sequenced. Carrier frequency for P/LP variants was calculated for the entire population and by race/ethnicity. The most common variants and their likely functional effects were evaluated.RESULTS:A total of 91 637 tests were performed on women identifying as Asian (8.8%), Black (6.1%), Hispanic (8.5%), White (29.0%), multiple or other race/ethnicity (15.0%), and missing (33.0%). Median age was 32.8 years with 83 728 (91%) &lt;40 years. P/LP <i>LDLR</i> variants were identified in 283 samples (1 in 324). No patients were identified with &gt;1 P/LP variant. <i>LDLR</i> carrier frequency was higher in Asian (1 in 191 [95% CI, 1 in 142–258]) compared with White (1 in 417 [95% CI, 1 in 326–533]; <i>P</i>&lt;0.001) or Black groups (1 in 508 [95% CI, 1 in 284–910]; <i>P</i>=0.004). The most common variants differed between populations. Of all variants, at least 25.0% were predicted as null variants.CONCLUSIONS:P/LP variants in <i>LDLR</i> are common. Expanding the use of reproductive carrier screening to include genes associated with FH presents another opportunity to identify people predisposed to cardiovascular disease.","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":"23 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140167682","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":"Real-World Genetic Testing Utilization Among Patients With Cardiomyopathy.","authors":"Ana Morales, Chad Moretz, Sheng Ren, Elizabeth Smith, Thomas E Callis, Taryn Hall, Kathryn E Hatchell, Robert L Nussbaum, Ellen Regalado, Susan Rojahn, Matteo Vatta, Edward D Esplin, Jaime Murillo","doi":"10.1161/CIRCGEN.122.004028","DOIUrl":"10.1161/CIRCGEN.122.004028","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004028"},"PeriodicalIF":7.4,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138799730","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":"A Promoter Deletion Confirms That <i>MYBPC3</i> Haploinsufficiency Is Sufficient to Cause Hypertrophic Cardiomyopathy in Humans.","authors":"Jesse B G Hayesmoore, Michael Bowman, Nora Shannon, Edward Blair, Hugh Watkins, Kate L Thomson","doi":"10.1161/CIRCGEN.123.004134","DOIUrl":"10.1161/CIRCGEN.123.004134","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004134"},"PeriodicalIF":6.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139519292","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":"Evaluating the Cardiovascular Impact of Genetically Proxied PCSK9 and HMGCR Inhibition in East Asian and European Populations: A Drug-Target Mendelian Randomization Study.","authors":"Daniel B Rosoff, Andrew S Bell, Lucas A Mavromatis, Ali Hamandi, Lauren Park, Jeesun Jung, Josephin Wagner, Pal Pacher, David Ray, George Davey Smith, Falk W Lohoff","doi":"10.1161/CIRCGEN.122.004224","DOIUrl":"10.1161/CIRCGEN.122.004224","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004224"},"PeriodicalIF":7.4,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139519066","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":"NEXN Gene in Cardiomyopathies and Sudden Cardiac Deaths: Prevalence, Phenotypic Expression, and Prognosis.","authors":"Alexis Hermida, Flavie Ader, Gilles Millat, Guillaume Jedraszak, Phillipe Maury, Romain Cador, Pierre-Antoine Catalan, Gaël Clerici, Nicolas Combes, Pascal De Groote, Delphine Dupin-Deguine, Romain Eschalier, Laurence Faivre, Patricia Garcia, Benoit Guillon, Alexandre Janin, Beatrice Kugener, Marylin Lackmy, Mikael Laredo, Xavier Le Guillou, François Lesaffre, Hugues Lucron, Antoine Milhem, Gwenaël Nadeau, Karine Nguyen, Aurélien Palmyre, Elodie Perdreau, François Picard, Nicolas Rebotier, Pascale Richard, Caroline Rooryck, Julien Seitz, Alain Verloes, Agathe Vernier, Pierre Winum, Grace-A-Dieu Yabeta, Océane Bouchot, Philippe Chevalier, Philippe Charron, Estelle Gandjbakhch","doi":"10.1161/CIRCGEN.123.004285","DOIUrl":"10.1161/CIRCGEN.123.004285","url":null,"abstract":"<p><strong>Background: </strong>Few clinical data are available on <i>NEXN</i> mutation carriers, and the gene's involvement in cardiomyopathies or sudden death has not been fully established. Our objectives were to assess the prevalence of putative pathogenic variants in <i>NEXN</i> and to describe the phenotype and prognosis of patients carrying the variants.</p><p><strong>Methods: </strong>DNA samples from consecutive patients with cardiomyopathy or sudden cardiac death/sudden infant death syndrome/idiopathic ventricular fibrillation were sequenced with a custom panel of genes. Index cases carrying at least one putative pathogenic variant in the <i>NEXN</i> gene were selected.</p><p><strong>Results: </strong>Of the 9516 index patients sequenced, 31 were carriers of a putative pathogenic variant in <i>NEXN</i> only, including 2 with double variants and 29 with a single variant. Of the 29 unrelated probands with a single variant (16 males; median age at diagnosis, 32.0 [26.0-49.0] years), 21 presented with dilated cardiomyopathy (prevalence, 0.33%), and 3 presented with hypertrophic cardiomyopathy (prevalence, 0.14%). Three patients had idiopathic ventricular fibrillation, and there were 2 cases of sudden infant death syndrome (prevalence, 0.46%). For patients with dilated cardiomyopathy, the median left ventricle ejection fraction was 37.5% (26.25-50.0) at diagnosis and improved with treatment in 13 (61.9%). Over a median follow-up period of 6.0 years, we recorded 3 severe arrhythmic events and 2 severe hemodynamic events.</p><p><strong>Conclusions: </strong>Putative pathogenic <i>NEXN</i> variants were mainly associated with dilated cardiomyopathy; in these individuals, the prognosis appeared to be relatively good. However, severe and early onset phenotypes were also observed-especially in patients with double <i>NEXN</i> variants. We also detected <i>NEXN</i> variants in patients with hypertrophic cardiomyopathy and sudden infant death syndrome/idiopathic ventricular fibrillation, although a causal link could not be established.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004285"},"PeriodicalIF":7.4,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138497962","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":"AAV-Mediated Delivery of Plakophilin-2a Arrests Progression of Arrhythmogenic Right Ventricular Cardiomyopathy in Murine Hearts: Preclinical Evidence Supporting Gene Therapy in Humans.","authors":"Chantal J M van Opbergen, Bitha Narayanan, Chester B Sacramento, Katie M Stiles, Vartika Mishra, Esther Frenk, David Ricks, Grace Chen, Mingliang Zhang, Paul Yarabe, Jonathan Schwartz, Mario Delmar, Chris D Herzog, Marina Cerrone","doi":"10.1161/CIRCGEN.123.004305","DOIUrl":"10.1161/CIRCGEN.123.004305","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic variants in PKP2 (plakophilin-2) cause arrhythmogenic right ventricular cardiomyopathy, a disease characterized by life-threatening arrhythmias and progressive cardiomyopathy leading to heart failure. No effective medical therapy is available to prevent or arrest the disease. We tested the hypothesis that adeno-associated virus vector-mediated delivery of the human <i>PKP2</i> gene to an adult mammalian heart deficient in PKP2 can arrest disease progression and significantly prolong survival.</p><p><strong>Methods: </strong>Experiments were performed using a PKP2-cKO (cardiac-specific, tamoxifen-activated PKP2 knockout murine model). The potential therapeutic, adeno-associated virus vector of serotype rh.74 (AAVrh.74)-PKP2a (PKP2 variant A; RP-A601) is a recombinant AAVrh.74 gene therapy viral vector encoding the human PKP2 variant A. AAVrh.74-PKP2a was delivered to adult mice by a single tail vein injection either before or after tamoxifen-activated PKP2-cKO. PKP2 expression was confirmed by molecular and histopathologic analyses. Cardiac function and disease progression were monitored by survival analyses, echocardiography, and electrocardiography.</p><p><strong>Results: </strong>Consistent with prior findings, loss of PKP2 expression caused 100% mortality within 50 days after tamoxifen injection. In contrast, AAVrh.74-PKP2a-mediated PKP2a expression resulted in 100% survival for >5 months (at study termination). Echocardiographic analysis revealed that AAVrh.74-PKP2a prevented right ventricle dilation, arrested left ventricle functional decline, and mitigated arrhythmia burden. Molecular and histological analyses showed AAVrh.74-PKP2a-mediated transgene mRNA and protein expression and appropriate PKP2 localization at the cardiomyocyte intercalated disc. Importantly, the therapeutic benefit was shown in mice receiving AAVrh.74-PKP2a after disease onset.</p><p><strong>Conclusions: </strong>These preclinical data demonstrate the potential for AAVrh.74-PKP2a (RP-A601) as a therapeutic for PKP2-related arrhythmogenic right ventricular cardiomyopathy in both early and more advanced stages of the disease.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004305"},"PeriodicalIF":6.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10923105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139575334","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":"Editors and Editorial Board.","authors":"","doi":"10.1161/HCG.0000000000000096","DOIUrl":"10.1161/HCG.0000000000000096","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":"17 1","pages":"e000096"},"PeriodicalIF":7.4,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139912171","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}