CRELD1 (Cysteine-Rich with EGF-Like Domains 1) is a multifunctional protein essential for cardiac development and immune homeostasis. As a protein disulfide isomerase, CRELD1 promotes acetylcholine receptor (AChR) assembly and surface localization by physically interacting with AChR subunits in the endoplasmic reticulum 1. CRELD1 regulates cardiac development through activation of calcineurin/NFATc1 signaling, controlling endocardial cell proliferation and valve formation 2. Myocardial CRELD1 function is critical for proper extracellular matrix remodeling and trabeculation through Notch1 signaling modulation 3. Beyond cardiac tissue, CRELD1 modulates immune system homeostasis by maintaining CD4+ T cell homeostasis through Wnt signaling interactions 4. Biallelic CRELD1 variants cause a multisystem syndrome featuring developmental delay, early-onset epilepsy, cardiac arrhythmias, and increased seizure susceptibility, with missense variants reducing protein function 5. CRELD1 variants are implicated in atrioventricular septal defects, particularly in Down syndrome, where calcium-binding domain alterations disrupt calcineurin/NFATc1 regulation 6. These findings establish CRELD1 as a pleiotropic regulator coordinating cardiac morphogenesis, neurodevelopment, and immune function.