Pedigrees of patients with mycobacterial disease due to monogenic lesions. Patients with clinical disease caused by the BCG vaccine (black) or the agent of tuberculosis (gray) are represented. M. tuberculosis is ∼1,000 times more virulent than BCG, as it triggers disease in about 5% of infected individuals, whereas BCG causes disease in only about 0.005% (5/100,000) of infected individuals. Patients with mycobacterial disease due to autoantibodies neutralizing type II IFN are not represented; most, if not all, cases are sporadic. HLA DRB1* 15:02 or 16:02 is found in most, if not all, patients, but most carriers of these HLA DRB1 alleles do not develop these autoantibodies (see text and Fig. 6). Patients with severe combined immunodeficiency (SCID) are vulnerable to many infections, including BCGosis; they are very sick in the first few months of life and die before the age of 1 year in the absence of hematopoietic stem cell transplantation. This accounts for the rarity of reported cases of tuberculosis, to which these patients are also prone. The first genetic etiology was reported in 1985, with mutations of ADA (85). Patients with MSMD are selectively prone to clinical disease triggered by BCG, environmental mycobacteria, or other intramacrophagic pathogens, such as Salmonella. Their genetic etiologies have been deciphered since 1996, with up to 46 inborn errors of type II IFN involving 22 loci. It was rapidly realized that most etiologies of MSMD are not Mendelian, with incomplete penetrance for BCG and environmental mycobacteriosis, as illustrated by the most common genetic etiology of MSMD, autosomal recessive IL-12Rβ1 deficiency, which blocks cellular responses to IL-12 and IL-23. This led to reports of patients with known etiologies of MSMD who did not have MSMD but did have tuberculosis, not only in families with MSMD index cases (in 2001), but also in families with no history of MSMD in 2003 (87, 88, 89). These genetic defects being rare, they underlie only a small proportion of cases of tuberculosis. Nevertheless, they paved the way for the discovery of monogenic etiologies of tuberculosis due to common variants, initially P1104A TYK2 in 2018 (30) and then common variants of IL-23R (90). The P1104A TYK2 variant underlies about 1% of cases of tuberculosis in populations of European descent, with high penetrance. Its frequency in Europeans has slowly declined over the last 3,000 years due to purging. It selectively impairs the induction of type II IFN by IL-23. Homozygotes for this variant can display MSMD, albeit very rarely, as penetrance is very low and this genetic lesion is unlikely to be the main determinant of vulnerability to BCG or environmental mycobacteriosis.