PO96
Diving into Genetics: Dilated Cardiomyopathy with Left Ventricular Hypertrabeculation – Case Study and Familial Implications

Left ventricular hypertrabeculation is a heterogeneous phenotype that may overlap with dilated cardiomyopathy and conduction disease. We report a family with a pathogenic NKX2-5 variant, illustrating the role of genetic testing in diagnosis, risk stratification, and screening.

The clinical case describes a 39-year-old female with a personal history of atrial septal defect (ASD) surgically repaired at the age of 4. She was referred to our center with a diagnosis of dilated cardiomyopathy and mild left ventricular systolic dysfunction. At the time she was asymptomatic, and physical examination revealed no signs of congestion.

Initial investigations included: 12-lead electrocardiogram showing sinus rhythm, first-degree atrioventricular block (PR 335 ms), and complete left bundle branch block; transthoracic echocardiogram demonstrating a dilated left ventricle with trabeculation of the inferior, posterior and lateral walls, with an ejection fraction of 52%; Holter monitoring revealing episodes of second-degree atrioventricular block Mobitz I, nocturnal idioventricular rhythm and non-sustained ventricular tachycardia (NSVT); routine laboratory testing with NT-proBNP of 346 pg/mL.

Cardiac magnetic resonance imaging (MRI) was performed for morpho-functional assessment. It showed evident hypertrabeculation of the apical and lateral regions, but did not fulfil the formal criteria for non-compaction phenotype. No focal myocardial fibrosis or necrosis was identified.

Given the conduction disturbances, arrhythmic episodes, congenital heart disease and imaging findings, genetic testing was pursued. A likely pathogenic variant in the NKX2-5 gene was identified. Variants in this gene are well described in association with atrial septal and conduction defects, often accompanied by cardiomyopathies, including dilated cardiomyopathy and cardiomyopathy with left ventricular hypertrabeculation.

The diagnosis was therefore established as dilated cardiomyopathy with a phenotype of left ventricular hypertrabeculation, associated with congenital heart disease, conduction system disorder and ventricular arrhythmia. Prognostic-modifying therapy was initiated with an SGLT2 inhibitor and an MRA antagonist. After multidisciplinary discussion involving imaging cardiologists, electrophysiologists and geneticists, implantation of a subcutaneous implantable cardioverter-defibrillator (S-ICD) for primary prevention was performed, given the described risk of sudden death in patients carrying this mutation. Familial screening was conducted: one daughter tested positive for the same variant and already demonstrates a phenotype of left ventricular hypertrabeculation, documented by echocardiography and cardiac MRI fulfilling non-compaction criteria, as well as conduction abnormalities on Holter monitoring. Despite being asymptomatic, she is under specialized follow-up.

This case highlights the importance of genetic testing not only in diagnosing cardiomyopathies but also in guiding therapy and preventive strategies. The identification of a pathogenic NKX2-5 variant had direct implications for management, including the decision to implant an S-ICD for primary prevention and to initiate family screening, underlining the relevance of precision medicine in inherited cardiomyopathies.