Homozygous TNNC1-A8V Causes Impaired Diastolic Function and Restrictive Cardiomyopathy in Children and Mice

BACKGROUND: variants tend to cause early-onset disease, and the most common variant identified in the gene, TNNC1-A8V, may also lead to severe diastolic dysfunction and restrictive cardiomyopathy. Yet, this variant-disease association, and the mechanism of diastolic disease development remain poorly understood. To address this, we sought to determine whether the A8V variant was associated with the development of restrictive cardiomyopathy, and if so, to determine the frequency and age-specific spectrum of disease relative to hypertrophic cardiomyopathy. METHODS: A pediatric proband was identified carrying the TNNC1-A8V variant. Sanger sequencing and cardiac evaluations were performed on several of the proband's family members. A literature search was performed to evaluate the cardiac penetrance of TNNC1-A8V. Additionally, we investigated cardiac contractility in a homozygous A8V mouse model. We assessed left ventricular function in 10- to 12-week-old mice via cardiac catheterization and left ventricular global and segmental myocardial strain analyses. Electrophysiological studies were conducted to evaluate arrhythmic predisposition. RESULTS: We report an 8-month-old female homozygous for p.A8V (c.C23T) who presented with bi-atrial enlargement, normal ventricular function, and ventricular tachycardia. Cardiac histology of the proband showed subendocardial vacuolization, endocardial fibrosis, and localized myocardial enhancement. The A8V mouse model showed an elevated end-diastolic pressure-volume relationship, prolonged relaxation time (tau), and impaired ventricular relaxation rate (dP/dt min) compared with controls, consistent with increased myocardial stiffness. Strain analyses further highlighted left ventricular dysfunction and dyssynchrony, and ECG analyses revealed atrial remodeling and enlargement at 10 weeks of age. CONCLUSIONS: Homozygous A8V mice recapitulate the severe diastolic dysfunction and early-onset restrictive cardiomyopathy observed in the pediatric proband carrying this pathogenic variant, underscoring the utility of this model for advancing translational research. Identifying myofilament-specific defects opens the door for precision therapies tailored to the underlying molecular disarray.