ArticleScience translational medicine2015
Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.
Registry-linked trialAbstract read
In one paragraph
Article in Science translational medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05180188 (A Clinical Trial, Investigating the Effect of a Home-based Moderate Intensity Training Program on Oxidative Capacity and Hemodynamics in Patients With Truncating Genetic Variants in TTN.), which is not on this map. Cited by 275 papers, 4 of them syntheses that pooled it.
0numbers the graph read from it
0cells of the map it votes in
275citing papers in PubMed, 4 pooled it
28.7field-weighted citation impact, top 1% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Clinical Trial, Investigating the Effect of a Home-based Moderate Intensity Training Program on Oxidative Capacity and Hemodynamics in Patients With Truncating Genetic Variants in TTN.
Who cites it
275 citing papers in PubMed, 4 syntheses or guidelines pooled it, 489 citations in OpenAlex.
- A systematic review of GWAS on CMR imaging traits: genetic insights into cardiovascular structure, function, and diseases.EBioMedicine · 2025Pooled it
- Research landscape of genetics in dilated cardiomyopathy: insight from a bibliometric analysis.Frontiers in cardiovascular medicine · 2024Pooled it
- ACMG SF v3.2 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG).Genetics in medicine : official journal of the American College of Medical Genetics · 2023Guideline
- Pooled it
- Effects of SGLT2 inhibition on incident heart failure in carriers of cardiomyopathy-associated genetic variants.Nature medicine · 2026Trial
- Contribution of Noncanonical Splice Variants toCirculation. Genomic and precision medicine · 2021Trial
- Pathogenic Variants Associated With Dilated Cardiomyopathy Predict Outcome in Pediatric Myocarditis.Circulation. Genomic and precision medicine · 2021Trial
- Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.Lancet (London, England) · 2019Trial
- Functional analysis ofMolecular therapy. Nucleic acids · 2026Article
- Pangenomes aid accurate detection of large insertions and deletions from targeted sequencing: the case of cardiomyopathies.Genome medicine · 2026Article
- Extended Germline Profiling of Cancer Predisposition and Homologous Recombination Repair Genes in 275 Russian Patients with Triple-Negative Breast Cancer.Biomedicines · 2026Article
- Variant Site-Specific Natural History of Titin-Induced Cardiomyopathy: An International Multicenter Registry.Circulation. Genomic and precision medicine · 2026Article
- The Role of Next-Generation Sequencing in the Management of Asymptomatic, Young Slovenian Athletes for Distinction Between Athlete's Heart and Cardiomyopathy.Biomedicines · 2026Article
- Prenatal-Onset Recessive Titinopathies: Clinical Spectrum, Genotype-Phenotype Correlations, and Outcomes.Diagnostics (Basel, Switzerland) · 2026Article
- Epidemiology of non-ischaemic dilated cardiomyopathy.Nature reviews. Cardiology · 2026Review
- Prevalence of deleterious variants in cardiomyopathy genes in early-onset atrial fibrillation.European journal of human genetics : EJHG · 2026Article
- Population-scale genomic screening reveals high frequency of actionable secondary findings in Chinese newborns.NPJ genomic medicine · 2026Article
- Genetic evaluation of early-onset atrial fibrillation: impact on patient management.European heart journal · 2026Article
- Genotype-phenotype correlations in patients with pathogenic/likely pathogenic titin variants from the Swiss Arrhythmogenic Cardiomyopathy Registry.Open heart · 2026Observational
- Quantitative Histological Insights Into Sudden Arrhythmic Death Syndrome: Findings From a Forensic Autopsy Cohort.APMIS : acta pathologica, microbiologica, et immunologica Scandinavica · 2026Article
215 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
42 authors at 15 institutions in 5 countries.
Angharad M RobertsClinical Sciences Centre, Medical Research Council (MRC), Imperial College London, London W12 0NN, UK. National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK.
James S WareNational Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK. National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Daniel S HermanDepartment of Genetics, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
Sebastian SchaferCardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
John BaksiNational Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK.
Alexander G BickDepartment of Genetics, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Rachel J BuchanNational Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK.
Roddy WalshNational Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK.
Shibu JohnNational Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK.
Samuel WilkinsonNational Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK.
Francesco MazzarottoNational Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK. National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
Leanne E FelkinNational Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK. National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
Sungsam GongNational Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK.
Jacqueline A L MacArthurEuropean Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
Fiona CunninghamEuropean Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
Jason FlannickBroad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Stacey B GabrielBroad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
David M AltshulerBroad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
Peter S MacdonaldCardiology Department, St Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia. Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia. Faculty of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia.
Matthias HeinigCardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
Anne M KeoghCardiology Department, St Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia. Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia. Faculty of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia.
Christopher S HaywardCardiology Department, St Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia. Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia. Faculty of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia.
Nicholas R BannerNational Heart & Lung Institute, Imperial College London, London SW3 6NP, UK. Royal Brompton & Harefield NHS Foundation Trust, Harefield Hospital, Hill End Road, Harefield, Middlesex UB9 6JH, UK.
Dudley J PennellNational Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK. National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
Declan P O'ReganClinical Sciences Centre, Medical Research Council (MRC), Imperial College London, London W12 0NN, UK.
Tan Ru SanNational Heart Centre Singapore, Singapore 169609, Singapore.
Antonio de MarvaoClinical Sciences Centre, Medical Research Council (MRC), Imperial College London, London W12 0NN, UK.
Timothy J W DawesClinical Sciences Centre, Medical Research Council (MRC), Imperial College London, London W12 0NN, UK.
Ankur GulatiNational Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK.
Emma J BirksNational Heart & Lung Institute, Imperial College London, London SW3 6NP, UK. Department of Medicine, University of Louisville and Jewish Hospital, Louisville, KY 40202, USA.
Magdi H YacoubNational Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
Michael RadkeNeuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany.
Michael GotthardtNeuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany. German Centre for Cardiovascular Research, 13347 Berlin, Germany.
James G WilsonDepartment of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Christopher J O'DonnellNational Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA 01702, USA. Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
Sanjay K PrasadNational Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK.
Paul J R BartonNational Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK. National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
Diane FatkinCardiology Department, St Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia. Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia. Faculty of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia.
Norbert HubnerCardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany. German Centre for Cardiovascular Research, 13347 Berlin, Germany. Charité-Universitätsmedizin, 10117 Berlin, Germany.
Jonathan G SeidmanDepartment of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Christine E SeidmanDepartment of Genetics, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. stuart.cook@nhcs.com.sg cseidman@genetics.med.harvard.edu.
Stuart A CookClinical Sciences Centre, Medical Research Council (MRC), Imperial College London, London W12 0NN, UK. National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK. National Heart Centre Singapore, Singapore 169609, Singapore. Duke-National University of Singapore, Singapore 169857, Singapore. stuart.cook@nhcs.com.sg cseidman@genetics.med.harvard.edu.
Broad Institute · USHarvard University · USMassachusetts Institute of Technology · USMax Delbrück Center · DENational Heart Centre Singapore · SGUNSW Sydney · AUCharité - Universitätsmedizin Berlin · DEEuropean Bioinformatics Institute · GBMassachusetts General Hospital · USNational Heart Lung and Blood Institute · USSt Vincent's Hospital Sydney · AUUniversity of Mississippi Medical Center · USUniversity of Washington · USVictor Chang Cardiac Research Institute · AUWellcome Trust · GB
Funding
Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6MMedical Scientist Training ProgramT32GM007753 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI WALENSKY, LOREN DAVID · 1985 to 2021
$50.0MPRECURSORS OF STROKE INCIDENCE AND PROGNOSISR01NS017950 · NINDS · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI Hugo Javier Aparicio, Jose Rafael Romero · 1985 to 2026
$22.9MTRAINING GRANT IN GENETICST32GM007748 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI Anne O'Donnell-Luria, Louise Wilkins-Haug · 1985 to 2026
$12.0MDefining Pathways from Gene Mutation to Heart FailureR01HL080494 · NHLBI · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI CHEN, CHRISTOPHER S, SEIDMAN, CHRISTINE E · 2005 to 2024
$9.4MGenomic Epidemiology of Cardiovascular DiseaseZIAHL006002 · NHLBI · NATIONAL HEART, LUNG, AND BLOOD INSTITUTE · PI O'DONNELL, CHRISTOPHER · 2009 to 2015
$8.0MMolecular Signaling in Hypertrophic CardiomyopathyR01HL084553 · NHLBI · HARVARD MEDICAL SCHOOL · PI SEIDMAN, JONATHAN G · 2007 to 2022
$5.9MJACKSON HEART STUDY--EXAM CENTERN01HC095171 · HC · UNIVERSITY OF MISSISSIPPI MEDICAL CENTER · PI JONES, DANIEL W · 1999 to 2001
$4.6MWHI Sequencing Project (WHISP)UC2HL102924 · NHLBI · OHIO STATE UNIVERSITY · PI CARLSON, CHRISTOPHER S, JACKSON, REBECCA D · 2010 to 2010
$2.4MGene Expression for Functional Genomics in Human PopulationsZIAHL006175 · NHLBI · NATIONAL HEART, LUNG, AND BLOOD INSTITUTE · PI O'DONNELL, CHRISTOPHER · 2013 to 2015
$2.2MCLIN CTR CLIN TRIAL/OBSERVATIONAL STUDY OF WHIN01WH042119 · WH · YESHIVA UNIVERSITY · PI WASSERTHEIL-SMOLLER, SYLVIA · 1994 to 2001
$2.2MWHI Sequencing Project (WHISP)RC2HL102924 · NHLBI · OHIO STATE UNIVERSITY · PI CARLSON, CHRISTOPHER S, JACKSON, REBECCA D · 2009 to 2009
$2.1MArthritis Research UKBritish Heart Foundation FS/13/13/29819British Heart Foundation FS/15/29/31492British Heart Foundation PG/12/27/29489British Heart Foundation SP/10/10/28431Howard Hughes Medical InstituteMedical Research Council MC_U120085815NHGRI NIH HHS U54 HG003067NHLBI NIH HHS HL080494NHLBI NIH HHS HL-102924NHLBI NIH HHS N01 HC025195NHLBI NIH HHS N01 HC095170NHLBI NIH HHS N01 HC095171NHLBI NIH HHS N01 HC095172NHLBI NIH HHS N01-HC-25195NHLBI NIH HHS N01-HC-95170NHLBI NIH HHS N01-HC-95171NHLBI NIH HHS N01-HC-95172NHLBI NIH HHS N02-HL-6-4278NHLBI NIH HHS R01 HL080494NHLBI NIH HHS R01 HL084553NHLBI NIH HHS RC2 HL102924NHLBI NIH HHS UC2 HL102924NIGMS NIH HHS 5-T32-GM007748-33NIGMS NIH HHS T32 GM007748NIGMS NIH HHS T32 GM007753NINDS NIH HHS 6R01-NS 17950NINDS NIH HHS R01 NS017950Wellcome TrustWellcome Trust 087183/Z/08/ZWellcome Trust 092854/Z/10/ZWellcome Trust WT095908WHI NIH HHS N01 WH022110WHI NIH HHS N01WH24152WHI NIH HHS N01WH32100WHI NIH HHS N01WH32101WHI NIH HHS N01WH32102WHI NIH HHS N01WH32105WHI NIH HHS N01WH32106WHI NIH HHS N01WH32108WHI NIH HHS N01WH32109WHI NIH HHS N01WH32111WHI NIH HHS N01WH32112WHI NIH HHS N01WH32113WHI NIH HHS N01WH32115WHI NIH HHS N01WH32118WHI NIH HHS N01WH32119WHI NIH HHS N01WH32122WHI NIH HHS N01WH42107WHI NIH HHS N01WH42108WHI NIH HHS N01WH42109WHI NIH HHS N01WH42110WHI NIH HHS N01WH42111WHI NIH HHS N01WH42112WHI NIH HHS N01WH42113WHI NIH HHS N01WH42114WHI NIH HHS N01WH42115WHI NIH HHS N01WH42116WHI NIH HHS N01WH42117WHI NIH HHS N01WH42118WHI NIH HHS N01WH42119WHI NIH HHS N01WH42120WHI NIH HHS N01WH42121WHI NIH HHS N01WH42122WHI NIH HHS N01WH42123WHI NIH HHS N01WH42124WHI NIH HHS N01WH42125WHI NIH HHS N01WH42126WHI NIH HHS N01WH42129WHI NIH HHS N01WH42130WHI NIH HHS N01WH42131WHI NIH HHS N01WH42132WHI NIH HHS N01WH44211
Abstract
The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN-truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effects of TTNtv, we coupled TTN gene sequencing with cardiac phenotyping in 5267 individuals across the spectrum of cardiac physiology and integrated these data with RNA and protein analyses of human heart tissues. We report diversity of TTN isoform expression in the heart, define the relative inclusion of TTN exons in different isoforms (using the TTN transcript annotations available at http://cardiodb.org/titin), and demonstrate that these data, coupled with the position of the TTNtv, provide a robust strategy to discriminate pathogenic from benign TTNtv. We show that TTNtv is the most common genetic cause of DCM in ambulant patients in the community, identify clinically important manifestations of TTNtv-positive DCM, and define the penetrance and outcomes of TTNtv in the general population. By integrating genetic, transcriptome, and protein analyses, we provide evidence for a length-dependent mechanism of disease. These data inform diagnostic criteria and management strategies for TTNtv-positive DCM patients and for TTNtv that are identified as incidental findings.
Indexed as
AllelesMutationTranscription, GeneticAdolescentAdultAgedCardiomyopathy, DilatedCohort StudiesConnectinExonsGenetic VariationHealthy VolunteersHeartHeart FailureHumansImmunoglobulinsConnectinImmunoglobulinsProtein IsoformsTTN protein, human
Identifiers
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Registered trials
NCT05180188ClinicalTrials.gov
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.