CELF4 is an RNA-binding protein that regulates pre-mRNA alternative splicing through recognition of muscle-specific splicing enhancer (MSE) intronic elements 1. Its N-terminal RNA recognition motifs (RRM1 and RRM2) are necessary and sufficient for RNA binding, while RRM2 plus adjacent divergent domain sequences are required for splicing activation 1. CELF4 promotes exon inclusion in cardiac troponin T (TNNT2) during heart development and regulates alternative splicing in other genes including actinin and tau [UniProt annotations]. CELF4 has emerging clinical significance in multiple disease contexts. Genome-wide association studies identified CELF4 variants associated with anthracycline-induced cardiotoxicity (AIC) in cancer patients 2. The CELF4 rs1786814 GG variant increases susceptibility to cardiotoxicity in childhood cancer survivors exposed to high-dose anthracycline, detectable via speckle-tracking echocardiography 3. Beyond cardiology, CELF4 variants are pleiotropic loci linking neuroticism with gastrointestinal diseases including irritable bowel syndrome and gastroesophageal reflux disease 4. In neurodevelopment, CELF4 controls mRNA translation underlying synaptic development in the prenatal neocortex, with expression enriched in the marginal zone and subplate 5. Heterozygous CELF4 variants in the N-terminal RNA-binding region cause neurodevelopmental disorders with global developmental delay, seizures, and early-onset obesity 6. CELF4 regulates dendritic spine formation and is implicated in depression, with reduced expression associated with decreased spine density and depression-like behaviors 7. Genome-wide association studies of structural connectivity implicate CELF4 in neural cell proliferation and differentiation affecting white-matter organization 8.