Vagus nerve stimulation (VNS) is a neuromodulation therapy increasingly used for treating drug-resistant epilepsy. However, it remains to be determined which patients are best suited for the treatment, and it is difficult to predict the therapeutic effect before the implantation. Mutations in some genes could lead to epilepsy. Here we report two cases of pediatric patients with drug-resistant epilepsy treated by VNS therapy: Patient 1 with ARX mutation achieved good outcomes; Patient 2 with the CDKL5 mutation did not show improvement. Additionally, the therapeutic impact of VNS on brain networks was investigated, hoping to provide some empirical evidence for a better understanding of the mechanism of VNS treatment.