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
. 2025 Apr;107(4):425-433.
doi: 10.1111/cge.14679. Epub 2025 Jan 22.

Exploring the Familial Phenotypic Variability Associated With TTN Truncating Variants in Cardiomyopathies: Variant Spectrum, Genotype-Phenotype Correlation and Consequences in Genetic Counseling

Marie Massier  1   2 , Pascal de Groote  3 , Erwan Donal  4 , Isabelle Magnin-Poull  5 , Christine Coubes  6 , Xavier Le Guillou Horn  7 , Caroline Rooryck  8 , Patricia Réant  9 , Yann Troadec  10 , Anne-Claire Bréhin  11 , Julie Proukhnitzky  12 , Estelle Gandjbakhch  12   13 , Philippe Charron  12   13 , Pascale Richard  1   13 , Flavie Ader  1   13   14
Affiliations

Exploring the Familial Phenotypic Variability Associated With TTN Truncating Variants in Cardiomyopathies: Variant Spectrum, Genotype-Phenotype Correlation and Consequences in Genetic Counseling

Marie Massier et al. Clin Genet. 2025 Apr.

Abstract

Titin truncating variants (TTNtv) are the main genetic cause of dilated cardiomyopathies (DCMs). The phenotype and prognosis of probands have been evaluated in several large cohorts. However, few data are available on intrafamilial expressivity. To evaluate the phenotypical variability, we selected probands and family members carrying a unique TTN variant and recorded cardiac and genetic information. The cohort included 332 probands (314 TTNtv probands and 18 probands with in silico predicted in-frame exon skipping probands) and 191 relatives of TTNtv probands including 98 affected family members. Within TTNtv families, 96% of the affected relatives presented the same cardiomyopathy subtype as the proband, and 60% shared severity criteria (heart transplantation, implantable cardioverter-defibrillator, personal sudden death). Furthermore, we reported 18 probands that carry predicted in-frame exon skipping variants; they presented DCM (84%) as TTNtv patients but lower rate of rhythm disorders (0% vs. 29% respectively). In this work, we extend the genetic spectrum of TTNtv associated with DCM and show that within a family, and the cardiomyopathy phenotype is homogenous but the expressivity could vary. Such results are helpful for appropriate genetic counseling to better predict and manage the phenotype of mutation carriers.

Keywords: Titin cardiomyopathy; dilated cardiomyopathy; genetic counseling; phenotype genotype correlation.

PubMed Disclaimer

References

    1. B. Gerull, M. Gramlich, J. Atherton, et al., “Mutations of TTN, Encoding the Giant Muscle Filament Titin, Cause Familial Dilated Cardiomyopathy,” Nature Genetics 30, no. 2 (2002): 201–204.
    1. M. L. Bang, T. Centner, F. Fornoff, et al., “The Complete Gene Sequence of Titin, Expression of an Unusual Approximately 700‐kDa Titin Isoform, and Its Interaction With Obscurin Identify a Novel Z‐Line to I‐Band Linking System,” Circulation Research 89 (2001): 1065–1072.
    1. D. S. Herman, L. Lam, M. R. Taylor, et al., “Truncations of Titin Causing Dilated Cardiomyopathy,” New England Journal of Medicine 366, no. 7 (2012): 619–628.
    1. J. S. Ware and S. A. Cook, “Role of Titin in Cardiomyopathy: From DNA Variants to Patient Stratification,” Nature Reviews. Cardiology 15, no. 4 (2018): 241–252, https://doi.org/10.1038/nrcardio.2017.190.
    1. M. M. Akhtar, M. Lorenzini, M. Cicerchia, et al., “Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the TTN Gene,” Circulation. Heart Failure 13, no. 10 (2020): e006832, https://doi.org/10.1161/CIRCHEARTFAILURE.119.006832.

LinkOut - more resources