Genetic heterogeneity of Mendelian susceptibility to mycobacterial infection

Mendelian susceptibility to poorly virulent mycobacterial species, such as bacillus Calmette-Guérin (BCG) and environmental nontuberculous mycobacteria (NTM), is a phenotypically heterogeneous syndrome. It has therefore long been suspected to be genetically heterogeneous. In the past 5 years, this prediction has been confirmed and different types of mutations (dominant or recessive, nonfunctional or hypofunctional) in four genes (IFNGR1, IFNGR2, IL12B, IL12RB1) have revealed both allelic and nonallelic heterogeneity. The eight disorders resulting from these mutations are genetically different but immunologically related, as impaired IFN-gamma-mediated immunity is the common pathogenic mechanism accounting for mycobacterial infection in all patients. The severity of the phenotype depends on the genotype. Complete IFN-gammaR1 and IFN-gammaR2 deficiencies predispose patients to a more severe clinical course than partial IFN-gammaR1 and IFN-gammaR2 deficiencies and complete IL-12 p40 and IL-12Rbeta1 deficiencies.