Three patients with defects in interferon gamma receptor signaling: a
challenging diagnosis


Background: Defects in IFN–gamma receptor (IFN-γR) signaling via STAT1
leads to susceptibility to infection by otherwise weak pathogenic
mycobacteria, resulting in mendelian susceptibility to mycobacterial
disease. We identified three patients presented with disseminated
mycobacterial infections caused by M. avium, M. persicum or M. bovis BCG
respectively. Whole-exome sequencing (WES) was used as the first line
diagnostic approach, however in all patients additional analysis was
crucial to make the definite diagnosis. Method: WES, SNP array and long
range PCR were performed to identify the genetic defects. Expression of
IFNGR1, STAT1, CD64, SOCS1 and phosphorylation of STAT1 were determined
after stimulation with IFN-α or IFN-γ. Results: In Patient 1, only one
heterozygous variant p.(Val63Gly) in the IFNGR1 gene was identified by
WES. Additional genetic analysis identified a second complex
Alu-insertion in IFNGR1. Patient 2 was compound heterozygous for the
null p.(Val68Lysfs*6) variant and the hypomorphic p.(Ile37Thr) variant
in IFNGR1. In Patient 3 a novel variant in the STAT1 gene p.(Asn460Ile)
was identified. Patients 1 and 2 had reduced expression of IFN-γR1. All
patients had reduced phosphorylation of STAT1 and absent induction of
SOCS1 after IFN-γ stimulation. While STAT1 phosphorylation was normal
after IFN–α stimulation in Patient 1 and 2, and mildly reduced in
Patient 3. Conclusion: We conclude that functional assays are crucial to
assess the extent of IFN-γR signaling defects when new combinations of
bi-allelic or non-conclusive genetic variants are found, which is
important in the determination of clinical treatment.

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