Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Observational Study
. 2025 Dec 22;46(48):5240-5257.
doi: 10.1093/eurheartj/ehaf380.

Titin-related familial dilated cardiomyopathy: factors associated with disease onset

Renee Johnson  1   2 , Robert A Fletcher  3   4   5 , Stacey Peters  6 , Monique Ohanian  1 , Magdalena Soka  1 , Andrei Smolnikov  7 , Katherine E Abihider  8 , Michael J Ackerman  9   10   11 , Flavie Ader  12 , Mohammed M Akhtar  13   14 , Ahmad S Amin  15   16 , Euan A Ashley  17   18   19 , John J Atherton  20   21 , Rachel Austin  22   23 , Annette F Baas  16   24 , Richard D Bagnall  25   26 , Samantha Barratt Ross  27 , Jean-Louis Blouin  28 , Emily E Brown  29 , Henning Bundgaard  16   30   31 , Douglas Cannie  13   32 , Przemyslaw Chmielewski  33 , Gemma Correnti  34 , Maria Generosa Crespo-Leiro  35 , Matteo Dal Ferro  16   36   37 , Lisa M Dellefave-Castillo  38   39 , Fernando Dominguez  16   40 , Dennis Dooijes  16   24 , Anne M Dybro  16   41 , Youssef Ed Demri  42 , Mohamed El Hachmi  43   44 , Luis Escobar-Lopez  16   40 , Sarah Jajesnica Foye  45 , Maria Franaszczyk  46   47 , Marta Gigli  16   36   37 , Esther Gonzalez Lopez  16   40 , Adeline Goudal  16   48 , Sharon Graw  49 , Michel Guipponi  28 , Eric Haan  50 , Jan Haas  51   52   53 , Daniel J Hammersley  14   54 , Frederikke G Hansen  55 , Christopher S Hayward  2   56   57 , Thomas Morris Hey  55 , Stephane Heymans  16   58   59 , Carolyn Y Ho  60 , Arjan C Houweling  61 , Jodie Ingles  2   62 , Angela Ingrey  63 , Andrew Jabbour  2   56   57 , Paul A James  64   65 , Joeri A Jansweijer  66   67 , Jan D H Jongbloed  68 , Anne M Keogh  2   56   57 , Jose M Larrañaga-Moreira  69 , Ronald H Lekanne Deprez  16   61 , Ivan Macciocca  70   71 , Peter S Macdonald  2   56   57 , Nicolas Mansencal  16   72 , Julia Mansour  73 , Cristina Martinez-Veira  74 , Barbara McDonough  75 , Julie McGaughran  22   76 , Kristen Medo  49 , Marco Merlo  16   36   37 , Ewa Michalak  33 , Lorenzo Monserrat  77 , Helen Mountain  78   79 , Steven A Muller  16   80 , Anne M Murphy  81 , Brittney Murray  29 , Emily C Oates  7   82 , Elizabeth Ormondroyd  83   84 , Nicholas Pachter  78   85   86 , Alessia Paldino  16   36   37 , Aurélien Palmyre  16   87 , Naveen L Pereira  9   11 , Kermshlise C Picard  60 , Nicola Poplawski  34   88 , Sanjay Prasad  54 , Julie Proukhnitzky  16   89 , Jean-Francois Pruny  16   90 , Patricia Reant  16   91   92 , Pascale Richard  12 , Anne Ronan  93   94 , Farbod Sedaghat-Hamedani  51   52   53 , Christopher Semsarian  26   95   27 , Garrett Storm  49 , Sophie Stroeks  16   59   96 , Petros Syrris  13 , Matthew R G Taylor  49 , Kate Thomson  83   97 , Tina Thompson  64   65 , J Peter van Tintelen  16   24 , Christoffer Rasmus Vissing  98   99 , Kathryn E Waddell-Smith  34 , Mathew Wallis  73   100 , Dominica Zentner  6   64   65 ; Australian Genomics Cardiac Flagship; Clare Arnott  27   101 , Ali J Marian  102 , Jaewon Oh  103 , Siv Fokstuen  28 , Cynthia A James  29 , Roberto Barriales-Villa  104 , Benjamin Meder  51   52   53 , Karim Wahbi  42   105 , John R Giudicessi  9   11 , Victoria N Parikh  106 , James S Ware  14   107 , Nicolas Piriou  16   108 , Caroline Rooryck  16   109   110 , Neal K Lakdawala  60   111 , Luisa Mestroni  49 , Gianfranco Sinagra  16   36   37 , Perry M Elliott  13   32 , Hugh Watkins  83 , Elizabeth M McNally  38   39 , Philippe Charron  16   87   90 , Karin Y van Spaendonck-Zwarts  22   61   68 , Pablo Garcia-Pavia  16   40   112 , Maria Luisa Peña-Peña  113 , Jens Mogensen  16   114 , Alex Hoerby Christensen  98 , Zofia T Bilińska  33 , Torsten B Rasmussen  16   41 , Jonathan G Seidman  75 , Christine E Seidman  60   75 , Anneline S J M Te Riele  16   80 , Job A J Verdonschot  16   59   96 , Yigal M Pinto  16   115 , Imke Christiaans  68 , Diane Fatkin  1   2   57
Collaborators, Affiliations
Observational Study

Titin-related familial dilated cardiomyopathy: factors associated with disease onset

Renee Johnson et al. Eur Heart J. .

Abstract

Background and aims: Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv.

Methods: An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM.

Results: A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80-30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06-5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27-3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35-9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08-.23).

Conclusions: Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

Keywords: Dilated cardiomyopathy; Genetics; Prevention; Risk factors; Titin.

PubMed Disclaimer

Figures

Structured Graphical Abstract
Structured Graphical Abstract
Factors associated with disease onset in titin-related familial dilated cardiomyopathy and implications for management.
Figure 1
Figure 1
Distribution of DCM-associated TTNtv. TTNtv identified in families with DCM are plotted with respect to the gnomAD population database and their location in the inferred complete titin protein (meta-transcript NM_001267550.2): Z-disk (red), I-band (blue), A-band (green) and M-band (purple). TTNtv are denoted by vertical bars; consequences of splice-site variants are shown: frameshift (red), in-frame (green), mixed effects (orange). Differences in exon usage across the various titin isoforms are indicated by percent spliced-in (PSI) scores. TTNtv in exons with PSI scores >.75 (green) were included in this study
Figure 2
Figure 2
Association of TTNtv with DCM. Curves show the cumulative incidence of DCM over time adjusted for sex and family relatedness in genotype-positive (TTNtv+) and genotype-negative (TTNtv-) subjects
Figure 3
Figure 3
Associations of factors with DCM penetrance in TTNtv-positive subjects. Survival curves show associations of proband vs family member status (panel A), sex (panel B), and variant characteristics (panels C–F). The latter includes the three main types of TTNtv (nonsense, frameshift insertion/deletion, and canonical splice-site change; panel C), a comparison of splice-altering variants in canonical and non-canonical sites (panel D), predicted downstream consequences of splice-altering variants (out-of-frame, in-frame, mixed effects; panel E), and titin domain location (panel F)
Figure 4
Figure 4
Associations of clinical risk factors with DCM penetrance in TTNtv-positive subjects. Forest plots show odds ratios and corresponding 95% confidence intervals (CI) for DCM associated with single risk factors (panel A), or combinations of risk factors (panel B). See text for definitions of risk factor combinations. Odds ratios and 95% CIs were estimated across ten imputed datasets generated using multiple imputations by chained equations and pooled using Rubin's Rules. BB/RAS, beta-adrenergic receptor or renin-angiotensin system-blocking drugs
Figure 5
Figure 5
Comparison of risk factor prevalence in different age groups. Forest plot shows odds ratios and corresponding 95% confidence intervals of risk factor combinations with DCM according to age at DCM diagnosis (<30 years, 30 to <60 years, ≥60 years). Odds ratios and 95% CIs were estimated across ten imputed datasets generated using multiple imputations by chained equations and pooled using Rubin's Rules
See this image and copyright information in PMC

References

    1. Fatkin D, Huttner IG, Kovacic JC, Seidman JG, Seidman CE. Precision medicine in the management of dilated cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol 2019;74:2921–38. 10.1016/j.jacc.2019.10.011 - DOI - PubMed
    1. Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med 2012;366:619–28. 10.1056/NEJMoa1110186 - DOI - PMC - PubMed
    1. Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, et al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med 2015;7:270ra6. 10.1126/scitranslmed.3010134 - DOI - PMC - PubMed
    1. Fatkin D, Huttner IG. Titin-truncating mutations in dilated cardiomyopathy: the long and short of it. Curr Opin Cardiol 2017;32:232–8. 10.1097/HCO.0000000000000382 - DOI - PubMed
    1. Akhtar MM, Lorenzini M, Cicerchia M, Ochoa JP, Hey TM, Sabater Molina M, et al. Clinical phenotypes and prognosis of dilated cardiomyopathy caused by truncating variants in the TTN gene. Circ Heart Fail 2020;13:e006832. 10.1161/CIRCHEARTFAILURE.119.006832 - DOI - PubMed

Publication types

Supplementary concepts

Grants and funding