NEXN (nexilin F-actin binding protein) is an actin cytoskeleton-binding protein with dual roles in cardiac and vascular function. Primarily, NEXN maintains Z-disc and sarcomere structural integrity through F-actin binding 1, and regulates alternative splicing of sarcomeric genes including its own transcript through interactions with splicing machinery 2. The protein also protects against vascular calcification by promoting SERCA2 SUMOylation and stabilization in vascular smooth muscle cells 3. NEXN variants are associated with dilated cardiomyopathy (DCM), with moderate evidence strength 4. Monoallelic NEXN mutations account for approximately 0.33% of DCM cases, predominantly presenting with reduced ejection fraction that often improves with treatment, though some severe early-onset phenotypes occur 5. Biallelic variants cause fetal-onset DCM with variable severity 6. In incidental genetic screening, NEXN variants show higher DCM association likelihood compared to background populations 7. Gene replacement therapy via AAV-mediated NEXN delivery successfully rescues cardiac function and extends survival in Nexn knockout and disease-mutation mouse models 8, suggesting therapeutic potential for loss-of-function DCM variants.