Inherited IFNAR1 Deficiency in a Child with Both Critical COVID-19 Pneumonia and Multisystem Inflammatory Syndrome

Abstract

Background: Inborn errors of immunity (IEI) and autoantibodies to type I interferons (IFNs) underlie critical COVID-19 pneumonia in at least 15% of the patients, while the causes of multisystem inflammatory syndrome in children (MIS-C) remain elusive.

Objectives: To detect causal genetic variants in very rare cases with concomitant critical COVID-19 pneumonia and MIS-C.

Methods: Whole exome sequencing was performed, and the impact of candidate gene variants was investigated. Plasma levels of cytokines, specific antibodies against the virus, and autoantibodies against type I IFNs were also measured.

Results: We report a 3-year-old child who died on day 56 of SARS-CoV-2 infection with an unusual clinical presentation, combining both critical COVID-19 pneumonia and MIS-C. We identified a large, homozygous loss-of-function deletion in IFNAR1, underlying autosomal recessive IFNAR1 deficiency.

Conclusions: Our findings confirm that impaired type I IFN immunity can underlie critical COVID-19 pneumonia, while suggesting that it can also unexpectedly underlie concomitant MIS-C. Our report further raises the possibility that inherited or acquired dysregulation of type I IFN immunity might contribute to MIS-C in other patients.

Keywords: COVID-19; IFNAR1; critical pneumonia; inborn errors of immunity (IEI); multisystem inflammatory syndrome in children (MIS-C); primary immunodeficiency (PID).

Fig. 1

Clinical and genetic evaluation of a patient with IFNAR1 deficiency associated with both critical COVID-19 pneumonia and MIS-C. Panel A shows the pedigree of the index patient; Panel B shows computed tomography (CT) scan revealing right sinus affected by mucormycosis at age 2; Panel C shows chest CT scan day 8 after the onset of the disease, with ground-glass opacification and dense consolidation on air bronchograms; Panel D shows chronological clinical complications in a patient; Panel E depicts a schematic illustration of the localization of the large deletion identified in this report and mutations identified in previously reported cases with IFNAR1 deficiency. IEI inborn errors of immunity. Panels F–G represent the confirmation of large deletion in the index patient by integrative genomics viewer of the whole-exome sequencing, PCR, and Sanger sequencing

Fig. 2

The patient’s IFNAR1 variant (H263fs*) is not expressed at the cell surface and is a loss-of-function variant. Overexpression experiments that were performed in HEK293T cells showed normal mRNA expression except when using a probe spanning exons 6–7 (Panel A), and truncated protein expression detected by western blotting (WB, Panel B) and a very low level of cell surface IFNAR1 expression by fluorescence-activated cell sorting (FACS, Panel C) in the H263fs*mutant compared to the wild type (WT) protein. Panel D depicts IFN-sensitive response element (ISRE) activity induction upon stimulations with IFN-α2, IFN-ω, or IFN-β in IFNAR1^−/− cells where different WT or mutant IFNAR1 plasmids were transiently transfected and the H263fs* mutant does rescue the response in contrast to the WT variant. NT nontransfected cell lines, EV empty vector, MFI mean fluorescent intensity, KO knockout