Nexilin mutations, a cause of chronic heart failure: A state-of-the-art review starting from a clinical case

Heart failure (HF) is a medical condition associated with high morbidity and mortality, despite ongoing advances in diagnosis and treatment. Among the various causes of HF, cardiomyopathies are particularly significant and must be thoroughly diagnosed and characterized from the outset. In this review, we aim to present a brief overview of cardiomyopathies as a driver of HF, with a specific focus on the genetic causes, particularly nexilin (NEXN) cardiomyopathy, illustrated by a clinical case. The case involves a 63-year-old male who presented with HF symptoms at moderate exertion. Six months prior, he had been asymptomatic, and a routine transthoracic echocardiography had shown a preserved left ventricular ejection fraction (LVEF). However, during the current evaluation, transthoracic echocardiography revealed a dilated left ventricle with a severely reduced LVEF of 30%. Subsequent coronary angiography ruled out ischemic heart disease, while cardiac magnetic resonance imaging indicated a non-inflammatory, non-infiltrative dilated cardiomyopathy with extensive LV fibrosis. Genetic testing identified a heterozygous in-frame deletion variant in the NEXN gene [c.1949_1951del, p.(Gly650del)], classified as likely pathogenic. State-of-the-art HF treatment was initiated, including cardiac resynchronization therapy with defibrillator support. Following treatment, the patient’s symptoms resolved, and LVEF improved to 42%. Interestingly, this patient experienced the onset of symptoms and left ventricular dysfunction within just six months, a much faster progression compared to previously documented cases where the G650del NEXN variant is typically linked to a more gradual development of dilated cardiomyopathy. Current literature offers limited data on patients with NEXN mutations, and the connection between this gene and both dilated and hypertrophic cardiomyopathies remains an area of active research.