Abstract
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-γ 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-α 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-α–induced signaling was impaired in the patient fibroblasts, as evidenced by decreased STAT1/STAT2 phosphorylation, nuclear translocation of STAT1, and expression of IFN-α–stimulated genes critical for CMV immunity. Pretreatment with IFN-α failed to suppress CMV protein expression in patient fibroblasts, whereas expression of WT IFNAR1 restored IFN-α–mediated suppression of CMV. This study identifies a human
IFNAR1
mutation and describes a digenic immunodeficiency specific to type I and type II IFNs.