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Interferon gamma pathway defects causing Mendelian susceptibility to mycobacterial diseases

Gene	Inheritance	Defect	Infections	Treatment*	Diagnostic issues
IFNGR1	AR	Complete	Severe, often fatal Disseminated BCG, NTM Salmonella Listeria Viruses (CMV, HHV8, RSV, PRV-3, VZV)	Antibiotics Possible adjuvant IFN-alpha HCT recommended	No response to IFN-gamma
IFNGR1	AR	Partial	Disseminated BCG, NTM Salmonella Viruses (respiratory, herpes family)	Antibiotics Long-term secondary prophylaxis Consider adjuvant IFN-gamma and/or IFN-alpha	Diminished response to IFN-gamma
IFNGR1	AD	Partial	Recurrent, moderately severe, disseminated infections with BCG, NTM, Salmonella, endemic mycoses (Coccidioides spp, Histoplasma) Osteomyelitis is common	Antibiotics Long-term secondary prophylaxis Adjuvant IFN-gamma	Diminished response to IFN-gamma
IFNGR2	AR	Complete	Severe, often fatal Disseminated BCG, NTM Salmonella Viral infections (herpes family)	Antibiotics Possible adjuvant IFN-alpha HCT recommended	No response to IFN-gamma
IFNGR2	AR	Partial	Disseminated BCG, NTM infections	Antibiotics Long-term secondary prophylaxis Adjuvant IFN-gamma	Diminished response to IFN-gamma
IFNGR2	AD	Partial	Disseminated BCG, NTM infections	Antibiotics Long-term secondary prophylaxis Adjuvant IFN-gamma	Diminished response to IFN-gamma
STAT1	AR	Complete	Severe, often fatal Disseminated bacterial and viral infections	Antibiotics HCT recommended	Absent cellular responses to IFN-alpha and IFN-gamma
STAT1	AR	Partial	Disseminated infections with BCG, NTM, Salmonella, and viruses (EBV, CMV, and VZV)	Antibiotics Consider HCT	Diminished response to IFN-gamma, IFN-alpha/beta, IFN-lambda 1, and IL-27
STAT1	AD	Dominant negative	Disseminated BCG, NTM infections Multifocal osteomyelitis	Antibiotics Adjuvant IFN-gamma	Diminished response to IFN-gamma
STAT1	AD	Dominant gain of function	Mucocutaneous candidiasis Endemic fungi, viruses Mycobacterial infections PML Aneurysms Autoimmunity	Antifungals JAK inhibitors may help with autoimmunity HCT may be considered	Elevated STAT1 phosphorylation in response to IFN-gamma
IL12B (IL-12p40)	AR	Complete	BCG and NTM infections Salmonella Severe TB	Antibiotics Adjuvant IFN-gamma	Diminished IFN-gamma production but retained response
IL12RB1	AR	Complete	Recurrent, moderately severe, disseminated infections with BCG, NTM, Salmonella, endemic mycoses (Coccidioides spp, Histoplasma) Incomplete penetrance	Antibiotics Consider adjuvant IFN-gamma	No response to IL-12
IL12RB2	AR	Complete	BCG, NTM, and tuberculosis Incomplete penetrance	Antibiotics	Diminished STAT4 response to IL-12 stimulation
IL23R	AR	Complete	BCG, NTM	Antibiotics	Diminished STAT3 phosphorylation after IL-12 stimulation
TYK2	AR	Complete	Mycobacterial, intracellular bacterial infections, and viral infection	Antibiotics	Diminished responses to IL-12 and IFN-alpha/beta
IRF8	AR	Complete	Disseminated BCG disease, oral candidiasis, and severe respiratory infection Myeloproliferation	Antibiotics HCT	Lack of dendritic cells
IRF8	AD	Partial	Disseminated BCG disease	Antibiotics	Diminished CD1c+ myeloid dendritic cells
GATA2	AD	Haploinsufficiency	NTM, not BCG Disseminated histoplasmosis HPV infections Molluscum EBV CMV	Antibiotics Consider HCT	In symptomatic cases, low monocytes, NK cells, B cells, dendritic cells
ISG15	AR	Complete	BCG NTM	Antibiotics	Diminished IFN-gamma production Enhanced IFN-alpha/beta
IKBKG (NEMO)	X linked	Recessive	Pyogenic bacteria, mycobacteria, viruses PJP	Antibiotics Consider HCT	Diminished IFN-gamma and IL-12 production Diminished TLR signaling Diminished CD40 signaling
NFKBIA	AD	Gain of function	NTM Mucocutaneous candidiasis Bacteria	Antibiotics Consider HCT	Diminished IFN-gamma and IL-12 production Diminished TLR signaling Diminished CD40 signaling
CYBB	X linked	Recessive	BCG	Antibiotics	Abnormal macrophage superoxide production
SPPL2A	AR	Complete	BCG	Antibiotics	Diminished IL-12 and IFN-gamma production, signaling
RORC (RORgamma and RORgammaT isotypes)	AR	Complete	Mucocutaneous candidiasis NTM BCG	Antibiotics	Diminished IFN-gamma and IL-12 production Decreased Th17 cells
JAK1	AR	Partial	NTM Viral infections (HPV, Zoster) Fungal infections	Antimicrobials	Decreased STAT1 phosphorylation

IFNGR1: interferon gamma receptor 1; AR: autosomal recessive; BCG: Bacillus-Calmette Guérin; NTM: nontuberculous mycobacteria; CMV: cytomegalovirus; HHV8: human herpesvirus 8; RSV: respiratory syncytial virus; PRV-3: pseudorabies virus 3; VZV: varicella-zoster virus; IFN: interferon; HCT: hematopoietic cell transplantation; AD: autosomal dominant; IFNGR2: interferon gamma receptor 2; STAT: signal transducer and activator of transcription; EBV: Epstein-Barr virus; IL: interleukin; PML: progressive multifocal leukoencephalopathy; JAK: Janus kinase; IL12B: interleukin 12B; TB: tuberculosis; IL12RB1: interleukin 12 receptor beta 1; IL12RB2: interleukin 12 receptor beta 2; IL23R: interleukin 23 receptor; TYK2: tyrosine kinase 2; IRF8: interferon regulatory factor 8; GATA2: GATA-binding protein 2; HPV: human papillomavirus; NK: natural killer; ISG15: ISG15 ubiquitin-like modifier; IKBKG: inhibitor of nuclear factor-kappa-B kinase regulatory subunit gamma; NEMO: nuclear factor-kappa-B essential modulator; PJP: Pneumocystis jirovecii pneumonia; TLR: Toll-like receptor; NFKBIA: NF kappa B inhibitor alpha; CYBB: cytochrome b-245 beta chain; SPPL2A: signal peptide peptidase-like 2A; RORC: RAR-related orphan receptor C; Th17: T helper cell type 17.
* For many defects, the role of HCT remains unknown.

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