| Title: | TTN:c.12478del in proximal I-band of titin represents a common molecular cause of dilated cardiomyopathy in Slovenian patients |
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| Authors: | ID Vodnjov, Nina (Author)
ID Cerar, Andraž (Author)
ID Maver, Aleš (Author)
ID Peterlin, Borut (Author)
ID Writzl, Karin (Author) |
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| Files: |  PDF - Presentation file, download (1,14 MB)
MD5: B146323FD5F92D0D2BDD2CFD2AE14428
 URL - Source URL, visit https://ojrd.biomedcentral.com/articles/10.1186/s13023-025-03613-7
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| Language: | English |
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| Typology: | 1.01 - Original Scientific Article |
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| Organization: |  UKC LJ - Ljubljana University Medical Centre
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| Abstract: | Background Titin truncating variants (TTNtv-s) are the most common genetic cause of dilated cardiomyopathy (DCM). Only rare TTNtv-s in the constitutively expressed exons of the A-band of the protein titin are associated with DCM according to the guidelines, however, studies in large cohorts of patients with DCM suggest that the region where TTNtv-s are associated with DCM is wider, extending at least into the I-band. The aim of this study was to describe the molecular pathology of TTNtv-s in Slovenian patients with cardiomyopathy and to clinically characterise the most recurrent TTNtv. Results We collected all TTNtv-s identified in patients with cardiomyopathy using next-generation sequencing genetic testing between 2010 and July 2024, resulting in 42 unique variants identified in 54 patients. The TTN:c.12478del variant, affecting not the A-band but the proximal I-band, specifically the cardiac-specific N2Bus region, was found to be the most recurrent variant, present in seven (11.6%) probands with DCM. Genetic characterisation revealed a probable founder origin of the variant. Clinical characterisation of these probands revealed a phenotype consistent with DCM and severely reduced left ventricular ejection fraction in all probands. Three (43%) of the probands had atrial fibrillation and/or non-sustained ventricular tachycardia. Based on literature reports and evidence supporting the pathogenicity of the TTN:c.12478del variant affecting the proximal I-band, we classified all rare TTNtv-s in constitutively expressed exons of the I-band as (likely) pathogenic. Therefore, 33 (78.6%) TTNtv-s were classified as (likely) pathogenic (13 in the I-band, affecting 19 probands and 20 in the A-band affecting 25 probands), meaning that TTNtv-s were identified in 44 genotype-positive Slovenian probands with DCM, explaining 73.3% of the molecular pathology of DCM. Conclusion We report an almost threefold higher diagnostic yield of TTNtv-s in probands with DCM compared to previously reported findings in cohorts of patients with DCM from other populations. We also highlight the need for screening for rare TTNtv-s in the constitutively expressed exons of the I-band and for TTN:c.12478del in patients with DCM in this geographical region. |
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| Keywords: | Titin, TTNtv, I-band, TTN:c.12478del, dilated cardiomyopathy, DCM |
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| Publication status: | Published |
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| Publication version: | Version of Record |
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| Year of publishing: | 2025 |
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| Number of pages: | str. 1-9 |
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| Numbering: | Vol. 20, [article no.] 92 |
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| PID: | 20.500.12556/DiRROS-24498  |
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| UDC: | 616.1:557.2 |
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| ISSN on article: | 1750-1172 |
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| DOI: | 10.1186/s13023-025-03613-7 |
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| COBISS.SI-ID: | 231896835 |
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| Note: | Nasl. z nasl. zaslona;
Opis vira z dne 8. 4. 2025;
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| Publication date in DiRROS: | 02.12.2025 |
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| Views: | 127 |
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| Downloads: | 59 |
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