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TTN:c.12478del in proximal I-band of titin represents a common molecular cause of dilated cardiomyopathy in Slovenian patients
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TTN:c.12478del in proximal I-band of titin represents a common molecular cause of dilated cardiomyopathy in Slovenian patients
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TTN:c.12478del in proximal I-band of titin represents a common molecular cause of dilated cardiomyopathy in Slovenian patients
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Journal Article
TTN:c.12478del in proximal I-band of titin represents a common molecular cause of dilated cardiomyopathy in Slovenian patients
2025
Overview
Background
Titin truncating variants (
TTN
tv-s) are the most common genetic cause of dilated cardiomyopathy (DCM). Only rare
TTN
tv-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
TTN
tv-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
TTN
tv-s in Slovenian patients with cardiomyopathy and to clinically characterise the most recurrent
TTN
tv.
Results
We collected all
TTN
tv-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
TTN
tv-s in constitutively expressed exons of the I-band as (likely) pathogenic. Therefore, 33 (78.6%)
TTN
tv-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
TTN
tv-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
TTN
tv-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
TTN
tv-s in the constitutively expressed exons of the I-band and for
TTN
:c.12478del in patients with DCM in this geographical region.
