Mendelian susceptibility to mycobacterial disease: Clinical, immunological, and genetic study in India

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare syndrome characterized by increased and selective susceptibility to weakly virulent mycobacteria and other intramacrophagic pathogens. This study emphasizes the utility of immunological and functional assays in diagnosing MSMD by analyzing clinical, immunological, and genetic features in 50 Indian patients. Immunological workup included lymphocyte subset analysis, nitroblue tetrazolium test (NBT), and flow cytometric assessment of IFN-γR1 (CD119), IL-12Rβ1 (CD212), and phosphorylated STAT1/STAT4 following cytokine stimulation. Functional assays measured IFN-γ and IL-12p70 production. Genetic evaluation was performed using whole-exome or Sanger sequencing. The median age at onset was 3 mo. BCG complications were the most common presentation (96%), while 4% had non-tuberculous mycobacterial infections. Additional infections included Mycobacterium tuberculosis, Salmonella spp., Candida spp., and multiple types of viruses. IL-12Rβ1 deficiency was the most frequent diagnosis, with 10 novel variants in the IL12RB1 gene identified. These results demonstrate that combining flow cytometry with functional and genetic analyses enables accurate and timely MSMD diagnosis.