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July 10, 2026Circulation Genomic and Precision MedicineOpen Access

M-band TTNtv linked to ~45% risk of SCD or major ventricular arrhythmias versus other bands.

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Why the study?

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 titin truncating variants, 81%…

Comparison

Titin truncating variant location vs Comparison between variant locations and…

Design

Cohort

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

MPMaria PerottoCRCinzia RadesichAPAlessia Paldino

Discussion

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Overview

TTNtv location should not guide DCM risk stratification; leaves open whether position influences outcomes beyond molecular mechanisms.

Key Points

  • This research aims to explore how the location of titin truncating variants affects clinical phenotype and prognosis in dilated cardiomyopathy.
  • Established an international multicenter registry for carriers of pathogenic TTN variants.
  • Classified patients based on variant location: A-band, Z/I-band, M-band.
  • Conducted a case-control study to assess enrichment of TTN variants across gene regions.
  • 467 patients were included, with the majority having A-band TTN variants (80%).
  • Higher risk of sudden cardiac death/major ventricular arrhythmias was observed in M-band carriers (45%) compared to A-band (12%).
  • Location of the TTN variant independently predicted the risk of sudden cardiac death.

Study Design

Type

Observational (n=467)

Multicenter

Yes

Structured PICO

Does the location of titin truncating variants affect clinical phenotype and prognosis in patients with TTN-induced cardiomyopathy?

P
Population
467 phenotypically affected carriers of pathogenic or likely pathogenic TTN truncating variants (median age 47, 27% female), followed for a median of 83 months.
E
Exposure
Titin truncating variant (TTNtv) location (A-band, Z/I-band, M-band)
C
Comparator
Comparison between variant locations (A-band vs Z/I-band vs M-band) and comparison with GnomAD for enrichment
O
Outcome
Composite of all-cause mortality and heart transplantationcomposite

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.

Cite This Study

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).

synapsesocial.com/papers/6a508d536eeac72a437a0db4https://doi.org/10.1161/circgen.125.005422
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Phenotypic spectrum of cardiac conduction disturbance and cardiomyopathy linked to titin canonical splice-site variants2025 · 2 citations
  2. 2Location-Dependent Differences in Cardiac and Skeletal Muscle Dysfunction Associated With Truncating Titin ( <i>ttn.2</i> ) Variants2026
  3. 3Titin Cardiomyopathy, Emerging Evidence: More Than A Big Heart2025 · 3 citations
  4. 4Titin-related familial dilated cardiomyopathy: factors associated with disease onset2025
  5. 5Bridging the cardio-oncology gap with insights from a functional TTN-truncating variant model2025