De novo pathogenic CSF1R variant implicates microglial dysfunction in pathogenesis of febrile infection-related epilepsy syndrome

Abstract

Febrile infection-related epilepsy syndrome (FIRES) is a rare presentation of refractory status epilepticus following a febrile illness with resulting refractory epilepsy. Evidence supports the presence of immune dysregulation in patients with FIRES, but a monogenic basis for FIRES has not been identified in most cases. We present a case of a previously healthy 16-year-old male with FIRES who was found to have a de novo predicted damaging missense variant in CSF1R on clinical whole genome sequencing, a gene encoding a critical regulator of microglial homeostasis in which pathogenic variants cause adult onset leukoencephalopathy. Molecular modeling demonstrates that the CSF1R variant likely destabilizes the critical ATP-binding domain of the CSF1 receptor. Furthermore, the variant was shown to disrupt CSF1R autophosphorylation in response to CSF1 treatment, thereby establishing its pathogenicity. This case proposes a role of microglial dysfunction in the pathogenesis of FIRES, contributing to the existing literature proposing innate immune dysregulation as an etiology of FIRES. These findings may suggest consideration of interventions targeting microglia specifically in the treatment of patients with FIRES.