TTN Truncating Variant Risk Stratifier

TTN Truncating Variant Risk Stratifier: Rationale, Interpretation & Clinical Context Truncating variants in the TTN gene (TTNtv) are among the most common genetic contributors to dilated cardiomyopathy (DCM) and have been associated with increased risk of heart failure, atrial fibrillation, and adverse cardiac events in multiple cohort studies. Risk modifiers identified across the literature include whether the TTNtv lies in exons with high proportion spliced-in (hiPSI), the degree of left ventricular systolic dysfunction (LVEF), symptomatic status (NYHA class), presence of atrial fibrillation, family history of cardiomyopathy or sudden death, age, and male sex which has been associated with higher penetrance in some series. This tool combines those evidence-informed modifiers into a simple points-based stratifier to provide an exploratory estimate of relative risk (Low / Intermediate / High).

How to interpret: treat the result as hypothesis-generating. A higher score suggests greater likelihood of near-term adverse outcomes based on published associations; this should prompt review for guideline-directed medical therapy optimization, targeted imaging (e.g., CMR), consideration of arrhythmia risk assessment, and familial cascade testing as appropriate. Do not use this calculator alone to make decisions about device therapy (ICD) or withholding/initiating therapies without specialist input.

Reference (key sources used to design this exploratory stratifier): Akhtar MM, et al. Clinical phenotypes and prognosis of dilated cardiomyopathy related to TTN truncating variants. Circulation: Heart Failure.

2020. Schafer S, et al. Titin-truncating variants affect heart function in disease models and humans.

Science Translational Medicine. 2016. Shetty NS, et al.

Titin truncating variants, cardiovascular risk factors and the risk of atrial fibrillation and heart failure. Nature Cardiovascular Research. 2024.

Cannatà A, et al. Association of Titin Variations With Late-Onset Dilated Cardiomyopathy. JAMA Cardiology.

2022. Limitations: This tool implements an evidence-informed points system rather than a statistically-validated multivariable model. There are important nuances in variant interpretation (transcript used, exon PSI, population frequency, ACMG classification) that require clinical molecular genetics input.

Predictive performance of this exact points map has not been prospectively validated; use clinical correlation and specialist genetic counselling.