The major finding of the present study is the description of a novel predisposition to severe viral infection involving abnormal AMFR-mediated polyubiquitination and decreased activation of STING in a child with a cellular phenotype showing impaired VZV-induced type I IFN responses and increased VZV replication and a clinical presentation with severe VZV infection and HLH. Here, AMFR is linked to viral infectious disease.