Epilepsy in POLG related disease usually involves biallelic recessive mutations causing chronic neuronal loss and neuronal death. However, monoallelic POLG mutations have been reported in patients with neurological features such as seizures [1]. In these patients a second allele/gene was anticipated but not identified. The genetic etiology in epilepsy can contribute to better treatment strategies. For example, valproic acid (VPA) should be avoided in patients with POLG related epilepsy due to possible hepatotoxicity. We report a 12-year old boy with initially drug-resistant focal onset epilepsy, a mild developmental delay and behavioral issues. He carries potential pathogenic variants in the DNA polymerase gamma (POLG) gene (from asymptomatic mother) and in the liprin-alpha-4 (PPFIA4) gene (from asymptomatic father). This latter gene has never been related to (neurological) disorders, although its gene product interacts with several genes that play a role in excitatory neurotransmission and epileptogenesis. Hence, we hypothesize that the phenotype of our patient could be due to combination of detrimental effects to the neurons by the two aforementioned pathogenic variants. Nonetheless, we cannot exclude another undetected POLG mutation. In essence, genetic research should be aware that unexplained neurological disease can be caused by an oligogenic, rather than a monogenic, etiology.