Cardiomyopathy prevalence exceeds 30% in individuals with TTN variants and early atrial fibrillation

Open AccessPublished:January 09, 2023DOI:
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      Truncating variants in TTN (TTNtvs) represent the largest known genetic cause of dilated cardiomyopathies (DCM), but their penetrance for DCM in general populations is low. More broadly, patients with cardiomyopathies (CM) often exhibit other cardiac conditions, such as atrial fibrillation (Afib), which has also been linked to TTNtvs. This retrospective analysis aims to characterize the relationship between different cardiac conditions in those with TTNtvs and identify individuals with the highest risk of DCM.


      In this work we leverage longitudinal EHR and exome sequencing data from ∼450,000 individuals in two health systems to statistically confirm and pinpoint the genetic footprint of TTN-related diagnoses aside from CM, such as Afib, and determine if vetting additional significantly-associated phenotypes better stratifies CM risk across those with TTNtvs. We focus on TTNtvs in exons with a “percentage spliced in” index > 90 (hiPSI TTNtvs), a representation of constitutive cardiac expression.


      Controlling for CM and Afib, other cardiac conditions retain only nominal association with TTNtvs. A sliding window analysis of TTNtvs across the locus confirms the association is specific to hiPSI exons for both CM and Afib, with no meaningful associations in loPSI exons. The combination of hiPSI TTNtv status and early Afib diagnosis (before age 60) finds a subset of TTNtv individuals at high risk for CM. The prevalence of CM in this subset is 33%, a rate that is 3.5 fold higher than individuals with hiPSI TTNtvs (9% prevalence), 5-fold higher than those without TTNtvs with early Afib (6% prevalence), and 80-fold higher than the general population.


      Our retrospective analyses reveal that those with hiPSI TTNtvs and early Afib (∼1/2900) have a high prevalence of CM (33%), far exceeding that of other individuals with TTNtvs and of those without TTNtvs with an early Afib diagnosis. These results show that combining phenotypic information along with genomic population screening can identify patients at higher risk for progressing to symptomatic heart failure.

      Graphical abstract



      PPV (positive predictive value), TTNtvs (TTN truncating variants), LoF (loss of function), hiPSI (percent spliced in >90%), loPSI (percent spliced in <=90%), DCM (dilated cardiomyopathy), CM (cardiomyopathy), Afib (atrial fibrillation), ACMG (American College of Medical Genetics), PVS1 (pathogenic very strong criteria 1 from the ACMG variant interpretation rubric), LOFTEE (Loss-Of-Function Transcript Effect Estimator), MIM (Mendelian Inheritance in Man), CDS (Coding sequence)