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Three patients with defects in interferon gamma receptor signaling: a challenging diagnosis
  • +11
  • Zijun Zhou,
  • Iris Hollink,
  • Arjan Bouman,
  • Mirthe Lourens,
  • Rik Brooimans,
  • Tjakko van Ham,
  • Peter Fraaij,
  • Annemarie van Rossum,
  • Eline Zijtregtop,
  • Willem Dik,
  • Virgil van Dalm,
  • Martin van Hagen,
  • Hanna Ijspeert,
  • Clementien Vermont
Zijun Zhou
Erasmus MC

Corresponding Author:z.zhou.1@erasmusmc.nl

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Iris Hollink
Erasmus MC
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Arjan Bouman
Erasmus MC
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Mirthe Lourens
Erasmus MC
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Rik Brooimans
Erasmus MC
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Tjakko van Ham
Erasmus MC
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Peter Fraaij
Erasmus MC
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Annemarie van Rossum
Sophia Children's Hospital of the Erasmus University Medical Center in Rotterdam
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Eline Zijtregtop
Sophia Children's Hospital of the Erasmus University Medical Center in Rotterdam
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Willem Dik
Erasmus MC
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Virgil van Dalm
Erasmus MC
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Martin van Hagen
Erasmus MC, University Medical Center Rotterdam
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Hanna Ijspeert
Erasmus MC
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Clementien Vermont
Erasmus MC
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Abstract

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.
29 Sep 2021Submitted to Pediatric Allergy and Immunology
31 Oct 2021Reviewer(s) Assigned
19 Nov 2021Review(s) Completed, Editorial Evaluation Pending
24 Nov 2021Editorial Decision: Revise Major
16 Feb 20221st Revision Received
17 Feb 2022Review(s) Completed, Editorial Evaluation Pending
21 Feb 2022Reviewer(s) Assigned
18 Mar 2022Editorial Decision: Accept
Apr 2022Published in Pediatric Allergy and Immunology volume 33 issue 4. 10.1111/pai.13768