Why the study?
Titin truncating variants show incomplete penetrance and phenotypic variability, and emerging molecular evidence suggests variant location may influence disease mechanisms, prompting investigation into its effect on clinical phenotype and prognosis.
Does the location of titin truncating variants affect clinical phenotype and prognosis in patients with TTN-induced cardiomyopathy?
Population
467 phenotypically affected carriers of pathogenic or likely pathogenic TTNtv
Comparison
TTNtv location across 3 groups: A-band vs Z/I-band vs M-band
Design
International multicenter registry and case-control study
Follow-up
Median 83 months
Key result
M-band TTN truncating variants were associated with a higher risk of sudden cardiac death or major ventricular arrhythmias compared to Z/I-band and A-band variants (45% vs 23% vs 12%; P=0.001).
Authors
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TTNtv location should not guide DCM risk stratification; leaves open whether position influences outcomes beyond molecular mechanisms.
Observational (n=467)
Yes
Does the location of titin truncating variants affect clinical phenotype and prognosis in patients with TTN-induced cardiomyopathy?
The location of titin truncating variants independently predicts the risk of sudden cardiac death and major ventricular arrhythmias, with M-band variants carrying the highest risk, suggesting variant location should guide personalized risk stratification.
Perotto et al. (2026) conducted an observational in Titin-Induced Cardiomyopathy (n=467). TTN truncating variant location (M-band, Z/I-band, A-band) vs. Between-group comparison of variant locations was evaluated on Composite of all-cause mortality and heart transplantation. M-band TTN truncating variants were associated with a higher risk of sudden cardiac death or major ventricular arrhythmias compared to Z/I-band and A-band variants (45% vs 23% vs 12%; P=0.001).