Among 310 TTN variant carriers, 24.9% showed phenotype progression over 4 years with pre-clinical, NDLVC, and DCM stages identified, indicating need for longitudinal follow-up.
What is the phenotypic spectrum and rate of progression in individuals with TTN variants from families affected by dilated cardiomyopathy?
TTN variant carriers exhibit a broad spectrum of cardiomyopathy including pre-clinical and non-dilated left ventricular phenotypes, with nearly 25% showing disease progression over 4 years, highlighting the need for longitudinal follow-up.
Absolute Event Rate: 0% vs 0%
Abstract Background Variants in the titin, TTN gene are commonly linked to dilated cardiomyopathy (DCM), however, the phenotypic spectrum of pre-clinical and early-stage cardiomyopathy, including the under-recognised non-dilated left ventricular cardiomyopathy (NDLVC) phenotype, is not well described. This is an important area, especially with increased genetic testing identifying more asymptomatic or minimally symptomatic carriers. Purpose To characterise the phenotypic spectrum and progression of cardiomyopathy associated with TTN variants in families affected by dilated cardiomyopathy Methods Probands (TTN proband) were identified following genetic evaluation of dilated cardiomyopathy between January 2008 and November 2024. Relatives (TTN relative) were identified through cascade family testing. TTN variants were classified as pathogenic or likely pathogenic according to ACMG criteria Cardiomyopathy phenotype was assessed at baseline and during follow-up. Phenotype categories included: 1) DCM, 2) NDLVC (both defined by ESC guidelines) 3) Pre-clinical (defined by ECG or imaging abnormalities which did not meet cardiomyopathy diagnostic criteria) and 4) Normal (no ECG or imaging abnormality). ECG and echocardiography were performed in all patients and cardiac MRI and Holter monitoring at the discretion of the clinician. Phenotype progression was defined as change from one or more phenotype category during follow-up. Results 310 individuals were included, 122 (39.4%) TTN probands and 188 (60.6%) TTN relatives. 118 distinct TTN variants were identified. The c.49648+2del splice variant occurred in 45 individuals, 14.3%), from 14 families (9.9%). Three individuals had 2 TTN variants. TTN probands were more likely to be male (80 v 42 p=0.005) and were older (57 (47, 62) years) than TTN relatives (42 (30, 62) years, p 0.001). Cardiac MRI was performed in 137 (44.2%) patients. At baseline, 96 (51.1%) TTN relatives had a normal phenotype, 47 had pre-clinical phenotype, 12 (6.4%) had NDLVC, and 33 (17.6%) had DCM. Median follow-up was 4 years (2, 6). Phenotype progression was observed in all groups with 44 (24.9 %) patients progressing 1 or more phenotype stage during follow. Conclusions The spectrum of TTN related cardiomyopathy includes pre-clinical and NDLVC phenotypes in addition to DCM with age and sex related penetrance. Phenotype progression is common, and carriers warrant longitudinal follow-up.Table 1 Figure 1
Goldie et al. (Sat,) reported a other. Among 310 TTN variant carriers, 24.9% showed phenotype progression over 4 years with pre-clinical, NDLVC, and DCM stages identified, indicating need for longitudinal follow-up.