Circulation: Genomic and Precision Medicine最新文献

{"title":"Cardiovascular Genetic Counseling Is Associated With Improved Patient-Reported Outcomes Across Clinical Indications and Settings.","authors":"Brittney Murray, Catherine Gordon, Susan Christian, Tara Dzwiniel, Crystal Tichnell, Emily Brown, Gretchen MacCarrick, Rebecca McClellan, Chloe Reuter, Hannah Ison, Jennefer Carter, Tia Moscarello, Ryan Murtha, Mitchel Pariani, Julia Platt, Christina Rigelsky, Diane Clements, Paul Crawford, Joseph Liu, Elizabeth Jordan, Robyn J Hylind, Eugene K Wong, Sarah Wang, Zoe Lindsay-Mills, Megan Betts, Eric Tricou, Amy C Sturm, Adam H Buchanan, Sara Fitzgerald-Butt, Benjamin M Helm, Laura Yeates, Colleen Caleshu, Jodie Ingles, Lisa Yanek, Cynthia A James","doi":"10.1161/CIRCGEN.125.005514","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005514","url":null,"abstract":"<p><strong>Background: </strong>Contemporary guidelines recommend genetic counseling for potentially inherited cardiomyopathies, channelopathies, aortopathies, and dyslipidemias, but few small studies characterize cardiovascular genetic counseling (CVGC) outcomes, impeding efforts to improve CVGC service delivery. We aimed to (1) quantify psychosocial CVGC outcomes, (2) identify clinical, demographic, and service delivery characteristics associated with the extent of benefit from CVGC, and (3) determine how outcomes are associated with patient-reported quality of the genetic counselor:patient alliance.</p><p><strong>Methods: </strong>The MCVGC-GO (Multicenter Cardiovascular Genetic Counseling Outcomes Study) is a longitudinal survey-based study with pregenetic and postgenetic counseling data collection. Eight hundred ninety adults attending a first outpatient CVGC appointment at 8 United States and Canadian medical centers completed questionnaires assessing empowerment (Genetic Counseling Outcome Scale), worry (modified Cancer Worry Scale), cardiac anxiety (CAQ [Cardiac Anxiety Questionnaire]), and genetic counselor:patient alliance (Working Alliance Inventory-patient) before and up to 4 weeks post-CVGC, but before results of genetic tests ordered were returned to decouple CVGC and genetic test result impact.</p><p><strong>Results: </strong>Following CVGC, empowerment increased (Genetic Counseling Outcome Scale score change, +5.94±11.6; <i>P</i><0.001), worry decreased (Cancer Worry Scale score change, -0.40±3.55; <i>P</i>=0.002), and cardiac fear decreased (CAQ fear subscale change, -0.034±0.46; <i>P</i>=0.033) with no change in whole-scale CAQ (0.013±0.34; <i>P</i>=0.29). In linear regression, worry decreased most in patients with less formal education (<i>P</i>=0.0021), with an arrhythmia indication (<i>P</i>=0.013), and who were at-risk family members (<i>P</i>=0.016) although the strength of the genetic counselor:patient alliance had no impact. In contrast, the genetic counselor:patient alliance was strongly positively associated with change in empowerment (<i>P</i><0.001).</p><p><strong>Conclusions: </strong>This observational, multicenter, multiprovider study provides foundational evidence that CVGC is associated with increased empowerment and decreased worry in adults attending outpatient CVGC and suggests opportunities for optimizing CVGC services.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005514"},"PeriodicalIF":6.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149219975","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":"Standardization of Collected Biobank Data to Facilitate Cardiovascular Research: A Scientific Statement From the American Heart Association.","authors":"C Anwar A Chahal, Andrew P Landstrom, Selma F Mohammed, Nabila Bouatia-Naji, Iftikhar J Kullo, Christa Lese Martin, Steffen E Petersen, Riyaz S Patel, Malene E Lindholm, Nahla Afifi, J Michael Gaziano, Dan M Roden","doi":"10.1161/HCG.0000000000000102","DOIUrl":"https://doi.org/10.1161/HCG.0000000000000102","url":null,"abstract":"<p><p>Cardiovascular disease has been the focus of extensive biomedical research, yet it remains a leading cause of morbidity and mortality worldwide. One recent approach to support scientific discovery has been the development of large-scale population-based prospective studies that couple phenotypic data, including outcomes, to collection and analysis of biological samples. Large, data-dense biobanks, particularly those linked to electronic health records (including laboratory, electrocardiographic, imaging, and therapeutic data) and genomic data, have demonstrated value for interdisciplinary research into the epidemiology, cause, treatment, and prevention of disease and yield increasingly refined insights into monogenic and complex traits. One limitation to wider use of these resources is that they may collect phenotypic and biological data in a nonuniform fashion, limiting data harmonization, analysis, and validation. The purpose of this scientific statement is to discuss the current state of available biobanks, endorse biobanks for discovery and implementation science, and propose opportunities for future harmonization to increase the potential for novel studies aimed at understanding mechanisms and developing novel therapies for cardiovascular disease treatment and prevention.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e000102"},"PeriodicalIF":6.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149219939","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":"Pyrophosphatase 2 Deficiency: Clinical Presentation, Diagnosis and Management.","authors":"Hayley Nehoff, Ian Crozier, Hilary Vernon, Christine James, Ana I Fernández-Ávila, Michael Bowes, Esther Gomez-Gonzalez, Colin Phoon, Kristy DiLoreto, Martin E Matsumura, Désirée Y van Haaften-Visser, Cameron Seaman, Matthew R Edwards, Deborah J Morris-Rosendahl, Kathleen Simonetti, Alyssa L Rippert, Rebecca C Ahrens-Nicklas, Cassandra Tormey, Emily Bogush, Aaina Kochhar, Johan L K Van Hove, Alicia M Kamsheh, Bridget A Leone, Saskia B Wortmann, Robert G Weintraub, W Reid Thompson, Eric S Silver, Warren A Zuckerman, John Pearson, Jan Till, Kathryn Chatfield, Amy Goldstein, Robert McFarland, Johannes A Mayr, Kit Doudney","doi":"10.1161/CIRCGEN.125.005673","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005673","url":null,"abstract":"<p><strong>Background: </strong>PPA2 (pyrophosphatase 2) deficiency is a relatively newly recognized condition caused by biallelic variants in the <i>PPA2</i> gene. The gene encodes the mitochondrial enzyme PPA2, involved in the production of orthophosphate in the mitochondrial matrix. Affected individuals typically present with sudden cardiac death or acute heart failure following common viral illnesses in infants and toddlers, or following exposure to small amounts of alcohol as teenagers. The condition has a high mortality rate in these situations. Here, we explore the clinical presentations and current management of these patients with a view to guiding future emergency clinical management of cases.</p><p><strong>Methods: </strong>Case records from published and unpublished affected individuals diagnosed with PPA2 deficiency were compiled in a retrospective cohort study of genotypes, phenotypes and clinical management protocols in individuals with biallelic (likely) pathogenic <i>PPA2</i> variants.</p><p><strong>Results: </strong>We collated 93 affected individuals from 53 families, 14 of which have not previously been reported. Patient presentation is invariably acute, often associated with fatigue, vomiting, seizures and collapse. Generally, presenting individuals received standard emergency management with cardiopulmonary resuscitation and appropriate management of arrhythmia, and here we present compiled clinical management protocols for emergency and ongoing treatment of PPA2-deficient patients. A pronounced inheritance rate of pathogenic alleles from carrier parents is noted, and further research is warranted to confirm and investigate any selective advantage for gametes carrying pathogenic <i>PPA2</i> variants.</p><p><strong>Conclusions: </strong>PPA2 deficiency has a high mortality rate following exposure to common childhood viruses in children around and under the age of 3 and in teenagers exposed to ethanol. We have presented current therapeutic approaches gathered from a worldwide survey of clinicians treating their patients, possible pathogenic mechanisms and inheritance peculiarities of the condition and provide a comprehensive review of the current recommendations surrounding patients' clinical management.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005673"},"PeriodicalIF":6.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149219932","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":"Bioactive Lipids of Cardiorespiratory Fitness Insights From Exercise Models in Humans, Mice, and Burmese Pythons.","authors":"J Sawalla Guseh, Athar Roshandelpoor, Mona Alotaibi, Shahrooz Zarbafian, Emily S Lau, Alexandra Kuznetsov, Anthony Rosenzweig, Nima Saeidi, Amit Choudhary, Mohit Jain, Susan Cheng, Gregory D Lewis, Jennifer E Ho","doi":"10.1161/CIRCGEN.126.005720","DOIUrl":"https://doi.org/10.1161/CIRCGEN.126.005720","url":null,"abstract":"<p><strong>Background: </strong>Cardiorespiratory fitness, commonly measured as peak oxygen consumption (peak VO₂, is a strong predictor of cardiovascular health. Circulating lipids have been linked to exercise responses and metabolic adaptation, but the bioactive lipid species associated with objectively measured aerobic capacity and their dynamic regulation during exercise remain incompletely defined.</p><p><strong>Methods: </strong>We performed directed, nontargeted liquid chromatography-mass spectrometry profiling of circulating bioactive lipids in adults undergoing clinically indicated cardiopulmonary exercise testing, relating resting lipid levels and acute exercise-induced lipid changes to peak VO₂. We then examined fitness-associated lipid species across complementary models of physiological stress, including marathon running, chronic voluntary wheel running in mice, and the postprandial Burmese python model.</p><p><strong>Results: </strong>Among 1896 detected lipid species in the primary human cohort, 47 were associated with peak VO₂ after false-discovery rate correction, including 16 metabolites with known molecular identities. Higher levels of several eicosanoids and free fatty acids were associated with greater peak VO₂, including docosahexaenoic acid, arachidic acid, and 12,13-dihydroxy-9Z-octadecenoic acid. In paired rest and peak exercise samples, 37 of 47 fitness-associated lipid species changed acutely with exercise. Among metabolites with known identities, exercise-induced changes in 12,13-dihydroxy-9Z-octadecenoic acid, 8-hydroxyicosa-9,11,14-trienoic acid, 11,12-epoxy-5Z,8Z,14Z-eicosatrienoic acid, and 8,9-dihydroxy-5Z,11Z,14Z-eicosatrienoic acid were associated with peak VO₂. In marathon runners, 43 of 47 fitness-associated lipid species changed after prolonged endurance exercise. Exploratory animal analyses demonstrated overlapping lipid regulation in chronic voluntary wheel-running mice and in the postprandial Burmese python model.</p><p><strong>Conclusions: </strong>Circulating bioactive lipids, particularly eicosanoids and free fatty acids, are associated with human cardiorespiratory fitness and are dynamically regulated during exercise. Overlapping lipid responses across complementary human and animal models identify candidate lipid pathways that may merit future mechanistic study.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005720"},"PeriodicalIF":6.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126900","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":"Personalized Nutrition for Hypertension: Current Evidence and Future Directions.","authors":"Phoebe Cheong, Cass Mangan, Erin D Clarke, Jordan Stanford, Murray J Cairns, Clare E Collins, Francine Z Marques, Matthew Snelson","doi":"10.1161/CIRCGEN.125.005566","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005566","url":null,"abstract":"<p><p>Hypertension is a leading risk factor for cardiovascular disease, with lifestyle interventions, particularly diet, playing a pivotal role in its management. Recent advancements in personalized nutrition that tailor dietary recommendations based on an individual's unique biology (eg, genetics, microbiome) and lifestyle factors can potentially improve blood pressure control. Indeed, emerging evidence suggests that personalized nutrition can result in more effective and sustained blood pressure reductions than general dietary guidelines. This review explores the current evidence supporting personalized nutrition as a novel strategy for managing hypertension, while leveraging established approaches for controlling glycemia. We evaluate studies integrating genetic markers and genomics, gut microbiome profiles, and metabolic phenotypes to design personalized dietary interventions to reduce blood pressure. Specifically, we discuss how nutritional factors, including sodium and fiber intake and diets such as the Dietary Approaches to Stop Hypertension, interact with an individual's genetic predisposition and gut microbiota composition to influence blood pressure outcomes. However, challenges remain in translation to clinical practice, including the need for larger, long-term trials in real-world settings, accessibility of advanced dietary assessments, considerations of patient adherence, and equity. We highlight the potential of personalized nutrition to refine hypertension treatment and call for further research to optimize its implementation at the public health and clinical practice levels. Particularly in low- and middle-income countries, where hypertension prevalence is higher, cost is an important consideration for successful implementation. However, some personalized treatments focusing on diet are cost-effective and should be prioritized. Ultimately, a personalized nutrition approach may offer a powerful tool for mitigating the global burden of hypertension through targeted, individualized dietary strategies.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005566"},"PeriodicalIF":6.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104934","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":"<i>FLNC</i>-Related Cardiomyopathies in an Admixed Population: Expanding the Genotype-Phenotype Spectrum and Clinical Correlates.","authors":"Natalia Quintella Sangiorgi Olivetti, Luciana Sacilotto, Julia de Barros Negri Ferreira, Silas Furquim, Márya Pagotti, Bruno Moreira Santos, Marjorie Mizuta, Paula de Mendonça Senra, Giovanna Napolitano, Kelvin Vilalva, Fernanda Andrade, Mariana Lombardi Peres de Carvalho, Emanuelle Leonília Marques, Jose Salvatore Leister Patane, Lucas Vieira Lacerda Pires, Angelica Nakagawa Lima, Alexandre C Pereira, Francisco da Costa Darrieux, Mauricio Scanavacca, Fábio Fernandes, Jose E Krieger","doi":"10.1161/CIRCGEN.126.005733","DOIUrl":"https://doi.org/10.1161/CIRCGEN.126.005733","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic and likely pathogenic variants in filamin C (<i>FLNC</i>) cause a broad spectrum of cardiomyopathies. However, available genotype-phenotype data are derived predominantly from European and North American populations, with limited representation of admixed populations.</p><p><strong>Methods: </strong>We characterized carriers of pathogenic/likely pathogenic <i>FLNC</i> variants identified among 2654 unrelated probands undergoing exome sequencing for suspected inherited cardiomyopathy and their relatives identified through cascade screening. Clinical, electrocardiographic, imaging, genetic, and longitudinal data were analyzed according to cardiomyopathy phenotype and variant class. Genetic ancestry was evaluated. Associations with arrhythmic, heart failure, and composite outcomes were examined in exploratory analyses.</p><p><strong>Results: </strong>The cohort included 97 carriers (58 probands, 39 relatives), of whom 72 had cardiomyopathy and 25 were phenotype-negative at evaluation. Truncating variants predominated among patients with arrhythmogenic cardiomyopathy and dilated cardiomyopathy, whereas missense variants were concentrated among those with hypertrophic cardiomyopathy and restrictive cardiomyopathy. Arrhythmogenic cardiomyopathy and dilated cardiomyopathy were characterized by a greater burden of ventricular arrhythmias, low QRS voltage, systolic dysfunction, and myocardial fibrosis, whereas hypertrophic cardiomyopathy and restrictive cardiomyopathy showed greater wall thickness and more atrial arrhythmias. Twelve pathogenic/likely pathogenic variants absent from gnomAD and ClinVar were identified. Ancestry analysis confirmed heterogeneous genetic backgrounds but detected no ancestry-related differences in variant class or phenotype. In exploratory outcome analyses, nonsustained ventricular tachycardia, low QRS voltage, and late gadolinium enhancement were associated with outcomes.</p><p><strong>Conclusions: </strong>This deeply phenotyped Brazilian cohort expands the <i>FLNC</i> variant spectrum and supports broad genotype-phenotype associations across an admixed population. Exploratory findings suggest that markers of ventricular arrhythmia and myocardial fibrosis may complement left ventricular ejection fraction in future risk-stratification strategies, although validation in larger, independent cohorts is required.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005733"},"PeriodicalIF":6.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104960","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":"Decoding Long Noncoding RNAs in Cardiac Development and Congenital Heart Disease: Recent Advances and Clinical Perspectives.","authors":"Ying Zhang, Aldons J Lusis, Marlin Touma","doi":"10.1161/CIRCGEN.125.005691","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005691","url":null,"abstract":"<p><p>Long noncoding RNAs (lncRNAs) have emerged as crucial regulators in cardiac development and congenital heart disease. With advances in high-throughput sequencing, single-cell omics, and epigenetic profiling, accumulating evidence suggests that lncRNAs participate in transcriptional, posttranscriptional, and structural remodeling processes underlying cardiac morphogenesis. This in-depth review summarizes recent progress in elucidating the roles of lncRNAs in heart development and congenital heart disease pathogenesis. Specifically, we discuss how lncRNAs modulate key developmental signaling pathways, including Notch, Wnt/β-catenin, BMP, and TGF-β, through interactions with chromatin modifiers, transcription factors, and microRNAs. Representative cardiac-enriched lncRNAs, such as <i>Braveheart</i>, <i>Fendrr</i>, <i>CARMEN</i>, <i>H19</i>, <i>MALAT1</i>, and <i>TBX5-AS1,</i> are highlighted for their roles in cardiomyocyte lineage commitment, endothelial-to-mesenchymal transition, endocardial-myocardial interactions, and structural morphogenesis. In various congenital heart disease subtypes, including ventricular septal defect, atrial septal defect, tetralogy of Fallot, and hypoplastic left heart syndrome, lncRNAs exhibit disease-specific expression patterns and participate in regulatory networks involving alternative splicing, competing endogenous RNA interactions, and genomic structural variations. Moreover, circulating and exosomal lncRNAs detected in maternal plasma and amniotic fluid have shown promise as candidate biomarkers for prenatal diagnoses. Collectively, these findings reveal that lncRNAs function as multilayered regulators, linking genetic, epigenetic, and environmental factors during cardiac development. A deeper understanding of lncRNA-mediated mechanisms may provide novel molecular targets, biomarkers, and diagnostic strategies for precision prevention and management of newborn infants with congenital heart disease.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005691"},"PeriodicalIF":6.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104972","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":"Cardiologist-Delivered Genetic Testing in 482 Patients With Cardiomyopathy: The Infrastructure Needed for Mainstream Testing at Scale.","authors":"Omid Kiamanesh, Susan Christian, Robert Miller, Kristin Lyons, Jonathan Howlett, Lea Harper, Lauren Archer, Noelle Mahon, Julien Marcadier, Kim McBride","doi":"10.1161/CIRCGEN.126.005782","DOIUrl":"https://doi.org/10.1161/CIRCGEN.126.005782","url":null,"abstract":"<p><strong>Background: </strong>Mainstream cardiac genetic testing, in which the treating cardiologist orders and returns multigene panel results without a traditional genetic counseling session, may expand access, but no mainstream program has quantified the operational burden. We quantified high-risk genotypes, variant reclassification, and carrier findings in a mainstream cardiomyopathy testing program to characterize the infrastructure required for safe scale-up.</p><p><strong>Methods: </strong>We retrospectively analyzed 482 consecutive patients with dilated cardiomyopathy (n=338), nondilated left ventricular cardiomyopathy (n=84), or hypertrophic cardiomyopathy (n=60) who underwent multigene panel testing ordered by cardiologists at the Broderick Cardiomyopathy Program (January 2022 to February 2026). Variant classifications used each laboratory's most current interpretation.</p><p><strong>Results: </strong>Diagnostic pathogenic/likely pathogenic variants were identified in 95 of 482 patients (yield, 19.7% [95% CI, 16.4%-23.5%]) across 21 genes. Three categories of results required program-level infrastructure: (1) 18 of 95 genotype-positive patients (18.9%) had high-risk genotypes (<i>DSP</i>, <i>LMNA</i>, <i>FLNC</i> [truncating], <i>RBM20</i>, <i>DES</i>) requiring genotype-specific management; (2) 8 of 12 reclassified variants (12/743 total, 1.6%) crossed the pathogenic/likely pathogenic threshold, including 7 variant of uncertain significance-to- pathogenic/likely pathogenic upgrades converting nondiagnostic patients to genotype-positive; and (3) carrier findings comprised 26 of 121 pathogenic/likely pathogenic variants (21.5%), inflating apparent yield to 23.7% if carrier findings were not distinguished from diagnostic results based on gene inheritance pattern. Variants of uncertain significance were reported in 295 patients (61.2%).</p><p><strong>Conclusions: </strong>These data identify 5 capabilities that support safe mainstream scale-up: high-risk genotype pathways for the 1 in 5 diagnostic patients with a high-risk variant, variant surveillance with recontact capacity for the 1 in 60 patients affected by actionable reclassification, recognition of gene inheritance pattern for the 1 in 19 patients with a carrier finding, a defined referral pathway to medical genetics, and standardized family screening infrastructure for all result categories.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005782"},"PeriodicalIF":6.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104987","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":"Genomic Yield of Long-Read Sequencing in Congenital Heart Disease.","authors":"Robert Lesurf, Anjali Jain, Nour Hanafi, Aleksandra Mitina, Yue Yin, Venkat A Kolla, Jade Wilson, Tanya Papaz, Erwin Oechslin, Ryan K C Yuen, Seema Mital","doi":"10.1161/CIRCGEN.125.005305","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005305","url":null,"abstract":"<p><strong>Background: </strong>Congenital heart disease (CHD) is the most common birth defect. Ninety percent of isolated cases remain genotype-elusive despite short-read genome sequencing (GS). Our goal was to assess genomic yield with long-read GS compared with short-read GS in CHD.</p><p><strong>Methods: </strong>We performed Illumina short-read GS on 1101 CHD probands. In a subset of 46 genotype-elusive probands, we performed additional PacBio long-read GS as well as parental sequencing of 7 complete trios. We compared variant calls genome-wide, including across dark and CHD genes in samples with paired short-read and long-read GS.</p><p><strong>Results: </strong>Paired analysis of the 46 probands revealed that genome-wide, long-read GS had 1.01- to 7.93-fold higher call rates of single nucleotide variants, deletions, duplications, and insertions but fewer indels and inversions compared with short-read GS. With a genome-wide sequencing depth of 18.3×, long-read GS had higher coverage for 10 Tier 1 CHD genes and dark genes, but nonuniform and low sequencing depth (<10×) in intragenic regions of 4 of these genes. Long-read GS was better able to resolve complex structural variants and the size of large repeat expansions in 59 known disease-causing regions. For example, long-read GS accurately characterized a complex de novo structural variant upstream of <i>ZEB2</i> in a CHD proband who had an extracardiac phenotype overlapping with Mowat-Wilson syndrome.</p><p><strong>Conclusions: </strong>Long-read GS demonstrated higher genome-wide variant call yield compared with short-read GS, better coverage of several cardiac-relevant genes, and better resolution of complex structural variants, including tandem repeat expansions. Long-read GS may provide an option for a subset of patients with CHD who remain genotype-elusive on short-read GS.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005305"},"PeriodicalIF":6.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079700","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 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}