Immunodeficiency, whether primary or secondary, results in the disruption of normal immune response and function. Typical presentations of immune deficiency are increased susceptibility to infection, usually in a specific class depending on the immune pathway or cell affected. [1,2] The phenotype is broad, and autoimmunity, immune dysregulation and increased risk for malignancy may also be hallmarks of the immunodeficiency. [2,3] In the absence of secondary immunodeficiency, severe infections in otherwise healthy children can alert clinicians to single-gene inborn errors of immunity or primary immunodeficiency disorders (PIDDs). [1,4] In tuberculosis (TB)-hyperendemic settings such as South Africa (SA), the risk for infection with TB cumulates with exposure, which provides an interesting context for the study of PIDD, in particular Mendelian susceptibility to mycobacterial disease (MSMD). [5][6][7][8] MSMD is molecularly characterised by errors in the interleukin 12 (IL-12) and interferon gamma (IFN-γ) pathway. [9] IFN-γ is a key cytokine in both innate and adaptive responses against viruses and intracellular bacteria, namely mycobacteria. [9][10][11] There is a dynamic balance between the host and the organism that determines the course of TB infection. [4,[12][13][14][15] The risk of progression to active disease is highest in infants aged <12 months and lowest in children aged 5 -10 years, the 'wonder years' . [6] Severe disease implies that there is either poor host control of the infection, i.e. dissemination, or a complex disease manifestation, often with severe sequelae such as TB empyema or pericarditis. [15] Non-severe disease implies that the host has managed to control the pathogen, resulting in contained disease. [15] Impaired response to IFN-γ is caused by mutations in the IFNGR1, IFNGR2, STAT1, CYBB, IRF8 and NEMO genes. [9,10] Deficient production of IFN-γ is associated with mutations in IL12B, IL12RB1, IL12RB2, TYK2, SPPL2a and ISG15. [9,10] MSMD is a PIDD characterised by selective predisposition to infections, typically with BCG or poorly pathogenic mycobacteria (e.g. Mycobacterium avium complex, M. kansasii, M. ghodii). [10,12] Individuals with MSMD are also predisposed to infection with M. tuberculosis complex (MTBC), Salmonella species, Listeria, Candida species, Toxoplasma species, and This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

While individual primary immunodeficiency diseases (PIDs) are rare, collectively they represent a significant burden of disease. Recent estimates show that about one million people in Africa suffer from a PID. However, data from African PID registries reflect only a small percentage of the estimated prevalence. This disparity is partly due to the lack of PID awareness and the masking of PIDs by the endemic pathogens. Over three million tuberculosis (TB) cases were reported in Africa in 2016, with many of these from southern Africa. Despite concerted efforts to address this high burden of disease, the underlying genetic correlates of susceptibility to TB remain poorly understood. High penetrance mutations in immune system genes can cause PIDs that selectively predispose individuals to TB and other mycobacterial diseases. Additionally, the identification of individuals at a heightened risk of developing TB or of presenting with severe or disseminated TB due to their genetic ancestry is crucial to promote a positive treatment outcome. The screening for and identification of PID mutations in TB-endemic regions by next-generation sequencing (NGS) represents a promising approach to improve the understanding of what constitutes an effective immune response to TB, as well as the range of associated PIDs and phenotypes.