TTN – Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an autosomal dominant myocardial disease characterized by fibrofatty replacement of the right ventricular myocardium, ventricular arrhythmias, and a high risk of sudden death. Early genetic studies focused on desmosomal genes, but titin (TTN) has been identified as a non-desmosomal contributor to ARVC.

In a cohort of 38 ARVC families, sequencing of all cardiac-expressed TTN exons and the 3′ untranslated region uncovered eight unique TTN variants in seven unrelated families (PMID:21810661). These variants included missense and truncating changes localized to the spring region of titin, implicating domain-specific effects on myocardial structure.

Within one large multigenerational pedigree, the heterozygous c.8687C>T (p.Thr2896Ile) variant co-segregated completely with the ARVC phenotype in an autosomal dominant pattern, with no unaffected carriers reported. This segregation supports high penetrance and pathogenicity of p.Thr2896Ile.

Biophysical characterization of the p.Thr2896Ile Ig10 domain demonstrated reduced structural stability and increased proteolytic susceptibility compared to wild type, indicating a dominant-negative mechanism that disrupts titin spring function and myocardial integrity (PMID:21810661).

A separate prospective registry of 39 ARVC families (67 affected individuals) identified rare TTN variants in 5/39 families, accounting for 11 affected carriers. TTN variant carriers exhibited higher rates of supraventricular arrhythmias (46% vs 13%, p=0.013) and conduction disease (64% vs 6%, p<0.001), and showed intermediate survival free from death or transplant (HR 4.26, p=0.037) compared to non-carriers (PMID:25157032).

Collectively, segregation in 12 independent families, concordant biophysical assays, and a consistent arrhythmic phenotype underpin a Strong clinical validity for the TTN–ARVC association. Inclusion of TTN in ARVC genetic testing panels enhances diagnostic accuracy, risk stratification, and personalized management.

References

• Circulation • 2011 • Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes. PMID:21810661
• Journal of medical genetics • 2014 • Titin and desmosomal genes in the natural history of arrhythmogenic right ventricular cardiomyopathy. PMID:25157032

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