Caregivers of children with developmental and epileptic encephalopathies (DEEs) often face uncertainty regarding their child’s medical condition. DEEs are defined as a group of rare neurologic conditions that occur during early childhood. Children with DEEs often experience severe epilepsy and require aggressive treatments. Technologic advances in next-generation sequencing (NGS), commonly used for gene panel testing and whole exome sequencing (WES), have significantly improved the diagnostic yield to ~30% for those with DEEs. At the same time, NGS can find variants of unknown significance (VUS), for which the impact of an identified genetic variation is uncertain; these results can complicate the clinical picture without offering a clear answer. In this scenario, further interpretation of whether a VUS may be causative of an individual child’s phenotype may not be possible given insufficient knowledge of a gene or disease to date, limiting the understanding of an illness. In this manner, NGS can provide information with uncertain interpretation that can add to the diagnostic odyssey for both caregivers and those with a DEE with an unknown cause.