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Introduction A paradigm of host immunity is that an individual's susceptibility to pathogens indicates a specific molecular defect. Yet, there are apparent exceptions to this paradigm: individuals who develop infections [...], Primary immunodeficiencies are often monogenic disorders characterized by vulnerability to specific infectious pathogens. Here, we performed whole-exome sequencing of a patient with disseminated Mycobacterium abscessus, Streptococcus viridians bacteremia, and cytomegalovirus (CMV) viremia and identified mutations in 2 genes that regulate distinct IFN pathways. The patient had a homozygous frameshift deletion in IFNGR2, which encodes the signal transducing chain of the IFN-[gamma] receptor, that resulted in minimal protein expression and abolished downstream signaling. The patient also harbored a homozygous deletion in IFNAR1 ([IFNAR1.sup.*557Gluext*46]), which encodes the IFN-[alpha] receptor signaling subunit. The [IFNAR1.sup.*557Gluext*46] resulted in replacement of the stop codon with 46 additional codons at the C-terminus. The level of [IFNAR1.sup.*557Gluext*46] mutant protein expressed in patient fibroblasts was comparable to levels of WT IFNAR1 in control fibroblasts. IFN-[alpha]-induced signaling was impaired in the patient fibroblasts, as evidenced by decreased STAT1/STAT2 phosphorylation, nuclear translocation of STAT1, and expression of IFN-[alpha]-stimulated genes critical for CMV immunity. Pretreatment with IFN-[alpha] failed to suppress CMV protein expression in patient fibroblasts, whereas expression of WT IFNAR1 restored IFN-[alpha]-mediated suppression of CMV. This study identifies a human IFNAR1 mutation and describes a digenic immunodeficiency specific to type I and type II IFNs.