A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations

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(*557Gluext*46)), which encodes the IFN-alpha receptor signaling subunit. The IFNAR1(*557Gluext*46) resulted in replacement of the stop codon with 46 additional codons at the C-terminus. The level of IFNAR1(*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.