Adult Onset of MSMD Caused by IL-12Rβ1 Variants: Report of a Young Woman with NTM Infection Lacking Bacille Calmette-Guérin (BCG)-induced Diseases.

Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by increased susceptibility to infections caused by weakly virulent mycobacteria (such as nontuberculous mycobacteria (NTM) or the Bacillus Calmette–Guérin (BCG) vaccine) in otherwise healthy individuals. In this study, we described a 29-year-old patient with MSMD due to NTM infection identified using metagenomic next-generation sequencing (mNGS) testing. The patient showed a poor response to standard antimycobacterial treatment. Therefore, we performed whole-exome sequencing (WES) and identified three heterozygous variants in IL-12Rβ1 (Ala131Thr, Arg323* and Arg561*). The two deleterious IL-12RB1 variants, Arg323* and Arg561*,were shown to be in trans (paternal and maternal, respectively). Further investigation revealed that two of these variants (Arg323* and Arg561*) could affect the binding between IL-12Rβ1 and IL-12Rβ2, leading to a weakened response of CD4+ T cells to stimulation with IL-12 plus tuberculosis antigen (TbAg), with reduced expression levels of IFN-γ and its downstream target p-STAT4. However, these variants did not affect the CD4+ T-cell response to glucan stimulation, as the three heterozygous variant loci do not interfere with the aggregation of IL-12Rβ1 and IL-23R. This autosomal recessive, partial IL-12Rβ1 deficiency ultimately resulted in the patient developing disseminated NTM infection. In clinical treatment, we combined IFN-γ with standard antimycobacterial therapy. The patient showed only a partial response to therapy. Therefore, as detection techniques continue to advance, it is important for clinicians to increase their understanding of MSMD to enable faster and more accurate diagnosis and treatment.