Background: The coexistence of a metabolic or genetic disease can complicate the course of an atrial septal defect device closure. Methods: The database of our hospital was searched for patients who had undergone atrial septal defect (ASD) device closure and had concurrent metabolic and genetic diseases. Out of 188 such patients, 11 were identified. Results: This cohort study included 11 patients with type 1 diabetes mellitus, insulin resistance, mitochondrial diseases, rickets, Seckel syndrome, Alagille syndrome, cystic fibrosis, Down syndrome, and Crigler-Najjar syndrome type II. The patients were followed for a median of 4 years. Two patients experienced thromboembolic events. One procedure failed as the device was embolized. Large devices with a waist circumference greater than 1.5 times the body weight were used in 3 patients. One patient died 19 days after the procedure due to multi-organ failure, which was not related to device closure. Conclusions: In patients with metabolic or genetic diseases, this procedure may be complicated by factors such as small patient size, hypercoagulation, organ failure (cardiac, renal, or hepatic), vascular abnormalities, and issues with anesthesia or transesophageal echocardiography. It is recommended that careful attention be given to the specific challenges associated with each disease. The utilization of large devices can be considered safe, particularly in patients beyond 4 years of age.