# Case Report: A patient with a novel heterozygous IRF8 variant with repeated infection and immune-mediated organ disease, but without disseminated mycobacterial disease despite BCG immunization

## TL;DR

A patient with a new IRF8 gene variant shows immune issues and organ disease but not severe mycobacterial infection, despite BCG vaccination.

## Contribution

This case report expands understanding of mono-allelic IRF8 variants and their variable clinical manifestations.

## Key findings

- The first patient had a novel IRF8 variant and immune dysfunction, including low pDCs and poor cytokine production.
- The second patient with a different IRF8 variant had milder symptoms and normal immune cell function.
- Altered dendritic cell subsets and cytokine deficiencies may help interpret IRF8 variants of unknown significance.

## Abstract

We describe a patient with a novel, de novo heterozygous IRF8 variant (c.1182dup) who presented with viral and bacterial susceptibility, lymphoproliferation, and liver and lung diseases characteristically seen in patients with underlying inborn errors of immunity, but without disseminated mycobacterial disease, despite vaccination with Bacillus Calmette-Guérin (BCG), the live attenuated vaccine form of Mycobacterium bovis. Laboratory evaluation revealed an absence of circulating plasmacytoid dendritic cells (pDC) with poor IL-12p70 and IFN-γ secretion upon LPS stimulation, and poor IFN-γ secretion upon PHA stimulation. In contrast, another patient with a different novel, de novo heterozygous IRF8 variant (c.10C>T) had milder early life infection susceptibility, but no lymphoproliferation, nor immune-mediated organ disease, and no prior exposure to BCG vaccine. They had a normal number of circulating pDC, and IL-12p70 production upon LPS stimulation that was no different compared to the mother who did not possess the IRF8 variant, and with normal IFN-γ secretion upon PHA stimulation. Our findings support impaired IRF8 function in the first patient, but less for the second patient. We propose that altered DC subsets and deficient cytokine production can assist with IRF8 VUS (variant of unknown significance) interrogation. This report expands current knowledge of mono-allelic human IRF8 variants.