Nephrotic Syndrome (NS) is a pediatric renal disorder characterized by massive proteinuria, hypoalbuminemia, and edema. Its progression to chronic kidney disease (CKD) increases the risk of cardiovascular disease (CVD), the leading cause of mortality in CKD patients. The interplay between CKD and CVD suggests shared molecular mechanisms, where kidney dysfunction exacerbates cardiovascular complications. Understanding these pathways is key for identifying therapeutic targets. At Sidra Medicine, we studied a family in which two siblings exhibited severe CKD and CVD phenotypes. The proband, a two-year-old male with stage 4 CKD and a history of cardiac arrest, was found to carry a novel, homozygous missense variant in the EHD3 gene. His sibling, a female with a similar phenotype, died of cardiac arrest at one-year-old. Clinical whole exome sequencing (WES) revealed that the EHD3 variant was absent from population databases, and in-silico analyses predicted it to be pathogenic, likely due to protein misfolding. Heterozygous SLC34A3 variant was also detected, though its role remains unknown. To assess the pathogenicity of the EHD3 variant, zebrafish larvae were used as an in vivo model due to their high genetic similarity to humans (92.7% amino acid sequence identity). Morpholino-mediated ehd3 knockdown resulted in significant cardiac defects, including reduced myocardial thickness, pericardial edema, increased enddiastolic volume, and impaired cardiac output. Neither wild-type nor variant EHD3 rescues restored myocardial thickness or cardiac function, suggesting that precise EHD3 regulation is critical. The variant rescue group also showed an increased heart rate, indicating an effect on cardiac conduction or autonomic regulation. These findings establish a functional link between EHD3 dysfunction and cardiac abnormalities, supporting its role in CKD-associated CVD. The zebrafish model recapitulates key aspects of the patient’s phenotype, reinforcing the hypothesis that EHD3 mutations contribute to cardiovascular pathology. This study provides critical insights into the molecular mechanisms underlying CKD-associated CVD and highlights EHD3 as a potential therapeutic target. Further research on EHD3-regulated pathways and pharmacological interventions is warranted to mitigate its impact on human health.