Familial Frequent Premature Ventricular Contractions and the Relevance of Titin Mutations

Pathogenic variants in the Titin gene (TTN) are implicated in a range of cardiac and musculoskeletal disorders. Among these, Titin truncating variants (TTNtv) represent a major genetic cause of dilated cardiomyopathy (DCM) and are frequently associated with various types of arrhythmias.

We reviewed the medical records of a family presenting with frequent premature ventricular contractions (PVCs) as the primary clinical symptom. Clinical data included demographics, symptoms, 12-lead electrocardiograms (ECGs), transthoracic echocardiograms (TTEs), thyroid function tests, and 24-h Holter monitoring. For individuals exhibiting clinical phenotypes, cardiac magnetic resonance imaging (CMR) and late gadolinium enhancement (LGE) were also performed. Whole-exome sequencing was conducted for the proband and his daughter, and cascade screening of family members was performed via Sanger sequencing at an accredited genetic laboratory.

We report a family with frequent PVCs. The proband, a 68-year-old male, was diagnosed with frequent PVCs through ECG and 24-h Holter monitoring. Following radiofrequency ablation, the frequency of PVCs was significantly reduced. However, he gradually developed a reduced left ventricular ejection fraction and ventricular dyskinesia, suggesting the progression toward cardiomyopathy. Two younger brothers and one daughter of the proband also exhibited frequent PVCs, with one brother showing evidence of cardiomyopathy. Genetic testing of all living relatives revealed that individuals with frequent PVCs shared a heterozygous frameshift mutation in TTN, resulting in a truncating variant in the titin protein.

We hypothesize that frequent PVCs may represent a clinical phenotype of this TTN frameshift mutation and may be associated with titin-related cardiomyopathy.