Microglia are tissue-resident macrophages playing essential roles in central nervous system (CNS) development and homeostasis [14, 17]. The importance of microglia for brain health in humans has been highlighted by the definition of Mendelian disorders associated with dysfunction of microglia-related proteins. These so-called microgliopathies [20] comprise a diverse set of neurological phenotypes including disease due to mutations in CSF1R [5, 8, 13], DAP12 and TYROBP/TREM2 [4, 7], USP18 [3, 11, 16, 18], and IRF8 [2, 6]. Here, we describe a novel early onset lethal encephalopathy due to mutations in the microglial-associated protein NRROS.