TTN – Titin-Related Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is a common cause of heart failure characterized by ventricular dilatation and systolic dysfunction. Truncating variants in the TTN gene, encoding the giant sarcomeric protein titin, are enriched in DCM cohorts compared with controls, supporting a pathogenic role for TTN loss-of-function in cardiomyocyte mechanics and structure (PMID:22335739; PMID:28045975). Clinical genetic testing has revealed TTN truncating variants in approximately 25–30% of familial and 18–27% of sporadic DCM cases, with hotspots in the A-band region and incomplete penetrance influenced by sex and age (PMID:22335739; PMID:28045975).

Multiple families show cosegregation of TTN truncating variants with DCM, with an aggregate of 29 mutation carriers and 17 affected relatives in segregation studies, yielding combined LOD scores exceeding 11 for A-band truncations in independent kindreds (PMID:22335739; PMID:28045975). The inheritance pattern is consistent with autosomal dominant transmission, and there is robust recurrence of protein-truncating variants (TTNtv) in unrelated European, Asian, and American cohorts.

The TTN variant spectrum is dominated by nonsense, frameshift, and splice-site mutations. For example, the recurrent A-band truncation c.31735A>T (p.Lys10579Ter) has been reported in a DCM patient and lies in a region critical for sarcomere stability (PMID:22335739). Deep-intronic and structural variants also contribute to the mutational landscape, though missense variants appear at similar frequencies in cases and controls and require cautious interpretation (PMID:27886618).

Functional studies demonstrate that TTNtv disrupt sarcomere assembly, increase passive stiffness, and impair excitation–contraction coupling in patient-derived cardiomyocytes and animal models. Antisense-mediated exon skipping restores reading frame and rescues contractile function in induced pluripotent stem cell-derived cardiomyocytes and knock-in mice carrying a frameshift in exon 326, highlighting a potential therapeutic strategy (PMID:25759365). Calcium-dependent binding of titin N2A domains to F-actin further implicates titin in active force regulation (PMID:30275509).

Despite definitive evidence for TTN truncations, the role of missense variants remains disputed; one large sequencing study found no excess of rare TTN missense changes in DCM versus healthy individuals, questioning their pathogenicity without segregation or functional data (PMID:27886618). Ongoing ClinGen curation is refining variant classification.

Integrating genetic and experimental data establishes a definitive association between TTN truncating variants and DCM. Autosomal dominant TTNtv confer significant risk, and inclusion of TTN in diagnostic gene panels enhances test sensitivity. Key Take-home: TTN truncations are a major monogenic cause of DCM with clear clinical utility for genetic diagnosis and management.

References

• The New England Journal of Medicine • 2012 • Truncations of titin causing dilated cardiomyopathy PMID:22335739
• PLoS One • 2017 • Titin Truncating Variants in Dilated Cardiomyopathy - Prevalence and Genotype-Phenotype Correlations PMID:28045975
• EMBO molecular medicine • 2015 • Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy PMID:25759365
• Scientific Reports • 2018 • Calcium increases titin N2A binding to F-actin and regulated thin filaments PMID:30275509
• International Journal of Cardiology • 2017 • Massive parallel sequencing questions the pathogenic role of missense variants in dilated cardiomyopathy PMID:27886618

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