Studies of MSMD in the mid-1990s used a forward genetic analysis of the pathophysiology of mycobacterial disease in humans (6, 8–13) and identified a core mechanism of MSMD in patients with most genetic etiologies appears to involve an impairment of IFN-γ production (IFNG, IL12B, IL12RB1, IL12RB2, IL23R, TYK2, ISG15, RORC, TBX21, and MCTS1), the cellular response to IFN-γ (IFNGR1, IFNGR2, STAT1, JAK1, CYBB, and CCR2), or both (IKBKG, IRF1, IRF8, and SPPL2A) (14–18). This evidence concerns the gene ISG15 and Mendelian susceptibility to mycobacterial diseases.