Table 6. Defects in intrinsic and innate... | Rockefeller University Press

Table 6.

Defects in intrinsic and innate immunity

Disease	Genetic defect	Inheritance	OMIM	Affected cells	Affected function	Associated features
1. Mendelian susceptibility to mycobacterial disease (MSMD)
IL-12 and IL-23 receptor β1 chain deficiency	IL12RB1	AR	601604	L + NK+MAIT	IFN-γ secretion	Susceptibility to mycobacteria and Salmonella and CMC
IL-12p40 (IL-12 and IL-23) deficiency	IL12B	AR	161561	M
IL-12Rβ2 deficiency	IL12RB2	AR	601642	L + NK+MAIT
IL-23R deficiency	IL23R	AR	607562	L +NK+MAIT
IFN-γ receptor deficiency	IFNGR1	AR	209950	M + L	IFN-γ binding and signaling
	IFNGR1	AD	615978	M + L	IFN-γ binding and signaling
	IFNGR2	AR	147569	M + L	IFN-γ signaling
STAT1 deficiency	STAT1	AD LOF	614892	M + L	IFN-γ signaling
Macrophage gp91phox deficiency Q231P and T178P	CYBB	XL	300645	Macrophage only	Respiratory burst defect in monocytes (not in neutrophils)	Isolated susceptibility to mycobacteria
IRF8 deficiency	IRF8	AD	614893	M + L	Impaired development of cDCs and Th1* cells	Susceptibility to mycobacteria
IRF8 deficiency	IRF8	AR	226990	M	Lack of circulating monocytes and DCs, reduced NK cell numbers and function reported in some patients	Susceptibility to mycobacteria and multiple other infectious agents including EBV
SPPL2a deficiency	SPPL2A	AR	608238	M + L	Impaired development of cDCs and Th1* cells	Susceptibility to mycobacteria and Salmonella
TYK2 deficiency	TYK2	AR	611521	M + L	Impaired cellular responses to IL-10, IL-12, IL-23, and type I IFNs	Susceptibility to intracellular bacteria (mycobacteria, Salmonella) and viruses
P1104A TYK2 homozygosity	TYK2	AR	176941	L	Impaired cellular responses to IL-23	MSMD or tuberculosis
ISG15 deficiency	ISG15	AR	147571		IFN-γ production defect	Susceptibility to mycobacteria (BCG), brain calcification
RORγt deficiency	RORC	AR	602943	L + NK	Lack of functional RORγT protein, IFN-γ production defect, complete absence of IL-17A/F–producing T cells	Susceptibility to mycobacteria and candida
JAK1 deficiency	JAK1	AR LOF	147795	N + L	Reduced JAK1 activation to cytokines Reduced IFN-γ production	Susceptibility to mycobacteria and viruses, urothelial carcinoma
T-bet deficiency	TBX21	AR	619630	L	↓IFN-γ and TNF-α production by γδT cells, MAIT cells, iNKT cells, NK cells, and CD4⁺ T cells	Susceptibility to mycobacteria
IFN-γ deficiency	IFNG	AR	618963	L	No IFN-γ production by patient T and NK cells	Susceptibility to mycobacteria
IRF1 deficiency	*IRF1*	AR	620668	Lymphocytes, DCs, NK, ILCP, ILCP2	IRF1-dependent responses to IFN-γ are both quantitatively and qualitatively stronger than those to IFN-α/β. IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ, while IFN-α/β–dependent intrinsic immunity to viruses seems unaffected	Early-onset severe forms of MSMD due to BCG,M. avium complex. No history of severe viral illnesses. Histoplasmosis in 2 patients
MCTS1 deficiency	*MCTS1*	XLR	301115	Lymphocytes	Impaired cellular responses to IL-23 and partially IL-12, impaired IL-23dep IFN-γ induction by MAIT and γδT cells	Life-threatening early-onset BCG disease. Disease was multifocal or disseminated in several cases including osteomyelitis
2. Epidermodysplasia verruciformis (HPV)
EVER1 deficiency	TMC6	AR	605828	Keratinocytes	EVER1, EVER2, and CIB1 form a complex in keratinocytes	HPV (group B1) infections and cancer of the skin (typical EV)
EVER2 deficiency	TMC8		605829
CIB1 deficiency	CIB1		618267
WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome	CXCR4	AD GOF	162643	Leukocytes	Increased response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1)	Warts (HPV) infection, neutropenia, low B-cell number, hypogammaglobulinemia
3. Predisposition to severe viral infection
STAT1 deficiency	STAT1	AR LOF	600555	Leukocytes and other cells	STAT1-dependent IFN-α/β, INF-γ, and IFN-λ responses	Severe viral infections, mycobacterial infection
STAT2 deficiency	STAT2	AR	600556	Leukocytes and other cells	STAT2-dependent IFN-α/β, IFN-γ, and IFN-λ responses	Severe viral infections (disseminated vaccine-strain measles), influenza, HSV, enterovirus; atypical Kawasaki disease, HLH
IRF9 deficiency	IRF9	AR	618648	Leukocytes and other cells	IRF9- and ISGF3-dependent IFN-α/β and IFN-λ responses	Severe influenza disease
IRF7 deficiency	IRF7	AR	605047	Leukocytes, plasmacytoid DCs, nonhematopoietic cells	IFN-α, IFN-β, and IFN-γ production and IFN-l production	Severe influenza disease
IFNAR1 deficiency	IFNAR1	AR	619935	Leukocytes and other cells	IFNAR1-dependent responses to IFN-α/β	Severe viral infections (dissemination of yellow fever vaccine and measles vaccine)
IFNAR2 deficiency	IFNAR2	AR	602376	Broadly expressed	IFNAR2-dependent responses to IFN-α/β	Severe viral infections (disseminated vaccine-strain measles, HHV6)
CD16 deficiency	FCGR3A	AR	146740	NK cells	Altered NK cell function	Severe herpes viral infections, particularly VZV,EBV, and HPV
MDA5 deficiency	IFIH1	AR LOF	606951	Broadly expressed	Viral recognition and IFN induction	Rhinovirus and other RNA viruses
NOS2 deficiency	NOS2	AR	NA	Myeloid cells	Mutant NOS2 failed to induce nitrous oxide	Severe (fatal) susceptibility to CMV-induced disease; pneumocystis pneumonia secondary to CMV; intact responses to infection with other herpesviruses (EBV, VZV, HSV)
ZNFX1 deficiency	ZNFX1	AR	619644	Broadly expressed	↑ ISG in response to poly I/C	Severe infections by RNA/DNA viruses, mycobacteria; early-onset severe inflammation affecting liver, brain, kidneys, lungs; virally triggered inflammatory episodes, hepatosplenomegaly, lymphadenopathy
RNA polymerase III deficiency	POLR3A	AD	614258	Leukocytes and other cells	Impaired viral recognition and IFN induction in response to VZV or poly I:C	Severe VZV infection
	POLR3C	AD	617454
	POLR3F	AD	617455
MIS-C	*OAS1*	AR		Monocytic phagocytes	Excessive inflammatory cytokine production by monocytes	Multisystemic inflammatory syndrome in children (MIS-C) after SARS-CoV-2
	*OAS2*	AR		Monocytic phagocytes	Excessive inflammatory cytokine production by monocytes	MIS-C
	*RNASEL*	AR		Monocytic phagocytes	Excessive inflammatory cytokine production by monocytes	MIS-C
4. Herpes simplex encephalitis (HSE)
TLR3 deficiency	TLR3	AD	613002	CNS-resident cells and fibroblasts	TLR3-dependent IFN-α, IFN-β, and IFN-γ response	Herpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here); severe pulmonary influenza; VZV
TLR3 deficiency	TLR3	AR	613002		TLR3-dependent IFN-α, IFN-β, and IFN-γ response
UNC93B1 deficiency	UNC93B1	AR	608204		UNC-93B–dependent IFN-α, IFN-β, and IFN-γ response	Herpes simplex virus 1 encephalitis
TRAF3 deficiency	TRAF3	AD	601896		TRAF3-dependent IFN-α, IFN-β, and IFN-γ response
TRIF deficiency	TICAM1	AD	607601		TRIF-dependent IFN-α, IFN-β, and IFN-γ response
TRIF deficiency	TICAM1	AR	607601		TRIF-dependent IFN-α, IFN-β, and IFN-γ response
TBK1 deficiency	TBK1	AD	604834		TBK1-dependent IFN-α, IFN-β, and IFN-γ response
IRF3 deficiency	IRF3	AD	616532		Low IFN-α/β, production in response to HSV1 and decreased IRF3 phosphorylation
DBR1 deficiency	DBR1	AR	607024		Impaired production of antiviral IFNs	HSE of the brainstem. Other viral infections of the brainstem
SNORA31 deficiency	SNORA31	AD	619396		Impaired production of antiviral IFNs	Forebrain HSV1 encephalitis
ATG4A deficiency	ATG4	AD	NA	CNS-resident cells and fibroblasts	Impaired HSV2-induced autophagy →increased viral replication and apoptosis of patient fibroblasts	Mollaret’s meningitis (recurrent lymphocytic meningitis) due to HSV2
MAP1LC3B2 deficiency	MAP1LC3B2	AD	NA	CNS-resident cells and fibroblasts
RIPK3 deficiency	*RIPK3*	AR	NA	Neurons	Impaired cellular apoptosis and necroptosis upon TLR3, TLR4, or TNFR1 stimulation and ZBP1/DAI-mediated necroptotic cell death after HSV-1 infection	Herpes simplex encephalitis recurrent in one patient. Otherwise, healthy
GTF3A deficiency	*GTF3A*	AR	NA	Fibroblasts	↓ RNA5SP141 expression results in abrogated RIG-I activation upon HSV-1 infection	CVID phenotype, low switched memory B cells, absent IgM. Defect in pneumococcal antibody response. T cells, mostly memory effector phenotype, low TFH and TH17 cells
IKBKE deficiency	*IKBKE*	AD	NA	Microglia	*Impaired induction of IFN-β1 (IFNB1) upon HSV-2 infection or dsDNA stimulation. Failure to induce phosphorylation of STING*	Recurrent HSV-2 meningitis
5. Predisposition to invasive fungal diseases
CARD9 deficiency	CARD9	AR	607212	Mononuclear phagocytes	CARD9 signaling pathway	Invasive candidiasis infection, deep dermatophytoses, other invasive fungal infections
6. Predisposition to mucocutaneous candidiasis
IL-17RA deficiency	IL17RA	AR	605461	Epithelial cells, fibroblasts, mononuclear phagocytes	IL-17RA signaling pathway, and fibroblasts fail to respond to IL-17A and IL-17F, and their T cells to IL-17E	CMC, folliculitis
IL-17RC deficiency	IL17RC	AR	610925	Epithelial cells, fibroblasts, mononuclear phagocytes	IL-17RC signaling pathway, fibroblasts fail to respond to IL-17A and IL-17F	CMC
IL-17F deficiency	IL17F	AD	606496	T cells	IL-17F–containing dimers	CMC
STAT1 GOF	STAT1	AD GOF	600555	T cells, B cells, NK, monocytes	Increased STAT1 phosphorylation Low Th17 cells	CMC, various fungal, bacterial, and viral (HSV) infections, autoimmunity (thyroiditis, diabetes, cytopenias), enteropathy
ACT1 deficiency	TRAF3IP2	AR	607043	T cells, fibroblasts	Fibroblasts fail to respond to IL-17A and IL-17F, and their T cells to IL-17E	CMC, blepharitis, folliculitis, and macroglossia
JNK1 haploinsufficiency	MAPK8	AD	NA	T cells, fibroblasts	↓ Th17 cells ex vivo, in vitro, ↓ responses of fibroblasts to IL-17A, IL-17F, ↓ c-Jun/ATF-2-dependent TGF-β signaling	CMC, connective tissue disorder (similar to Ehlers–Danlos syndrome)
7. TLR signaling pathway deficiency
IRAK4 deficiency	IRAK4	AR	606883	Lymphocytes + granulocytes + monocytes	TIR-IRAK4 signaling pathway	Pyogenic bacterial diseases, severe viral diseases
MyD88 deficiency	MYD88	AR	602170	Lymphocytes + granulocytes + monocytes	TIR-MyD88 signaling pathway	Pyogenic bacterial diseases, severe viral diseases
Systemic autoinflammation splenomegaly and anemia (NASA)	IRAK4	AR	607676	Lymphocytes	Loss of negative regulation of IRAK-4 and IRAK-1; dysregulation of myddosome assembly and disassembly; or kinase active site instability may drive dysregulated IL-6 and TNF production	Recurrent episodes of fever, massive splenomegaly, elevated inflammatory markers, and severe hypochromic microcytic anemia
IRAK1 deficiency	IRAK1	XL	300283	Lymphocytes + granulocytes + monocytes	TLR-IRAK1 signaling pathway in fibroblasts, TLR7- and TLR8-IRAK1 signaling pathway in EBV-B cells	Bacterial infections, X-linked MECP2 deficiency–related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1
TIRAP deficiency	TIRAP	AR	614382	Lymphocytes + granulocytes + monocytes	TIRAP signaling pathway, TLR1/2, TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes	Staphylococcal disease during childhood in the patient lacking lipoteichoic acid Abs
TLR7 deficiency	TLR7	XL	301051	Lymphocytes, myeloid cells	Impaired responses to TLR7 ligands; reduced production of type 1 IFN	Severe COVID-19 infection
TLR8 GOF	TLR8	XL/somatic mutations	301078	Myeloid cells	Elevated proinflammatory serum cytokines; increased proinflammatory responses of patient myeloid cells to TLR8 agonists; reduced ability of mutant TLR8 to attenuate TLR7 signaling	Early-onset, severe cytopenias, hepatosplenomegaly, lymphadenopathy; progressive autoinflammatory disease
MD2 deficiency	*LY96*	AR	NA	Myeloid cells	Decreased endocytosis of TLR4 leads to impaired NF-κB signaling and decreased cytokine production	Very early-onset inflammatory bowel disease and recurrent infections, pneumonia, and otitis media
TLR4 deficiency	*TLR4*	AR	NA		Impaired TLR4 signaling	Inflammatory bowel disease
8. Other IEIs related to nonhematopoietic tissues
Isolated congenital asplenia (ICA)	RPSA	AD	271400	No spleen	RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome	Bacteremia (encapsulated bacteria)
Isolated congenital asplenia (ICA)	HMOX	AR	141250	Macrophages	HO-1 regulates iron recycling, and heme-dependent damage occurs	Hemolysis, nephritis, inflammation
Trypanosomiasis	APOL1	AD	603743	Somatic	Pore-forming serum protein	Trypanosomiasis
Acute liver failure due to NBAS deficiency	NBAS	AR	608025	Somatic and hematopoietic	ER stress	Fever induces liver failure
Acute necrotizing encephalopathy	RANBP2	AD	601181	Ubiquitous expression	Nuclear pore	Fever induces acute encephalopathy
Osteopetrosis	CLCN7	AR/AD	602727	Osteoclasts	Secretory lysosomes	Osteopetrosis with hypocalcemia, neurological features
	SNX10	AR	614780			Osteopetrosis with visual impairment
	OSTM1	AR	607649			Osteopetrosis with hypocalcemia, neurological features
	PLEKHM1	AR	611466			Osteopetrosis
	TCIRG1	AR	604592			Osteopetrosis with hypocalcemia
	TNFRSF11A	AR	603499		Osteoclastogenesis	Osteopetrosis
	TNFSF11	AR	602642	Stromal	Osteoclastogenesis	Osteopetrosis with severe growth retardation
Hidradenitis suppurativa	NCSTN	AD	605254	Epidermis	Notch signaling/gamma-secretase in hair follicle regulates keratinization	Verneuil’s disease/hidradenitis suppurativa with acne
	PSEN	AD	613737			Verneuil’s disease/hidradenitis suppurativa with cutaneous hyperpigmentation
	PSENEN	AD	613736			Verneuil’s disease/hidradenitis suppurativa
9. Other IEIs related to leukocytes
IRF4 haploinsufficiency	IRF4	AD	601900	Lymphocytes and monocytes	IRF4 is a pleiotropic transcription factor	Whipple’s disease
IL-18BP deficiency	IL18BP	AR	604113	Leukocytes and other cells	IL-18BP neutralizes secreted IL-18	Fulminant viral hepatitis
GATA2 deficiency	GATA2	AD	137295	Monocytes + peripheral DC, NK cells	Multilineage cytopenia	Susceptibility to mycobacteria, HPV, histoplasmosis, alveolar proteinosis, MDS/AML/CMML, lymphedema

Disease	Genetic defect	Inheritance	OMIM	Affected cells	Affected function	Associated features
1. Mendelian susceptibility to mycobacterial disease (MSMD)
IL-12 and IL-23 receptor β1 chain deficiency	IL12RB1	AR	601604	L + NK+MAIT	IFN-γ secretion	Susceptibility to mycobacteria and Salmonella and CMC
IL-12p40 (IL-12 and IL-23) deficiency	IL12B	AR	161561	M
IL-12Rβ2 deficiency	IL12RB2	AR	601642	L + NK+MAIT
IL-23R deficiency	IL23R	AR	607562	L +NK+MAIT
IFN-γ receptor deficiency	IFNGR1	AR	209950	M + L	IFN-γ binding and signaling
	IFNGR1	AD	615978	M + L	IFN-γ binding and signaling
	IFNGR2	AR	147569	M + L	IFN-γ signaling
STAT1 deficiency	STAT1	AD LOF	614892	M + L	IFN-γ signaling
Macrophage gp91phox deficiency Q231P and T178P	CYBB	XL	300645	Macrophage only	Respiratory burst defect in monocytes (not in neutrophils)	Isolated susceptibility to mycobacteria
IRF8 deficiency	IRF8	AD	614893	M + L	Impaired development of cDCs and Th1* cells	Susceptibility to mycobacteria
IRF8 deficiency	IRF8	AR	226990	M	Lack of circulating monocytes and DCs, reduced NK cell numbers and function reported in some patients	Susceptibility to mycobacteria and multiple other infectious agents including EBV
SPPL2a deficiency	SPPL2A	AR	608238	M + L	Impaired development of cDCs and Th1* cells	Susceptibility to mycobacteria and Salmonella
TYK2 deficiency	TYK2	AR	611521	M + L	Impaired cellular responses to IL-10, IL-12, IL-23, and type I IFNs	Susceptibility to intracellular bacteria (mycobacteria, Salmonella) and viruses
P1104A TYK2 homozygosity	TYK2	AR	176941	L	Impaired cellular responses to IL-23	MSMD or tuberculosis
ISG15 deficiency	ISG15	AR	147571		IFN-γ production defect	Susceptibility to mycobacteria (BCG), brain calcification
RORγt deficiency	RORC	AR	602943	L + NK	Lack of functional RORγT protein, IFN-γ production defect, complete absence of IL-17A/F–producing T cells	Susceptibility to mycobacteria and candida
JAK1 deficiency	JAK1	AR LOF	147795	N + L	Reduced JAK1 activation to cytokines Reduced IFN-γ production	Susceptibility to mycobacteria and viruses, urothelial carcinoma
T-bet deficiency	TBX21	AR	619630	L	↓IFN-γ and TNF-α production by γδT cells, MAIT cells, iNKT cells, NK cells, and CD4⁺ T cells	Susceptibility to mycobacteria
IFN-γ deficiency	IFNG	AR	618963	L	No IFN-γ production by patient T and NK cells	Susceptibility to mycobacteria
IRF1 deficiency	*IRF1*	AR	620668	Lymphocytes, DCs, NK, ILCP, ILCP2	IRF1-dependent responses to IFN-γ are both quantitatively and qualitatively stronger than those to IFN-α/β. IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ, while IFN-α/β–dependent intrinsic immunity to viruses seems unaffected	Early-onset severe forms of MSMD due to BCG,M. avium complex. No history of severe viral illnesses. Histoplasmosis in 2 patients
MCTS1 deficiency	*MCTS1*	XLR	301115	Lymphocytes	Impaired cellular responses to IL-23 and partially IL-12, impaired IL-23dep IFN-γ induction by MAIT and γδT cells	Life-threatening early-onset BCG disease. Disease was multifocal or disseminated in several cases including osteomyelitis
2. Epidermodysplasia verruciformis (HPV)
EVER1 deficiency	TMC6	AR	605828	Keratinocytes	EVER1, EVER2, and CIB1 form a complex in keratinocytes	HPV (group B1) infections and cancer of the skin (typical EV)
EVER2 deficiency	TMC8		605829
CIB1 deficiency	CIB1		618267
WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome	CXCR4	AD GOF	162643	Leukocytes	Increased response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1)	Warts (HPV) infection, neutropenia, low B-cell number, hypogammaglobulinemia
3. Predisposition to severe viral infection
STAT1 deficiency	STAT1	AR LOF	600555	Leukocytes and other cells	STAT1-dependent IFN-α/β, INF-γ, and IFN-λ responses	Severe viral infections, mycobacterial infection
STAT2 deficiency	STAT2	AR	600556	Leukocytes and other cells	STAT2-dependent IFN-α/β, IFN-γ, and IFN-λ responses	Severe viral infections (disseminated vaccine-strain measles), influenza, HSV, enterovirus; atypical Kawasaki disease, HLH
IRF9 deficiency	IRF9	AR	618648	Leukocytes and other cells	IRF9- and ISGF3-dependent IFN-α/β and IFN-λ responses	Severe influenza disease
IRF7 deficiency	IRF7	AR	605047	Leukocytes, plasmacytoid DCs, nonhematopoietic cells	IFN-α, IFN-β, and IFN-γ production and IFN-l production	Severe influenza disease
IFNAR1 deficiency	IFNAR1	AR	619935	Leukocytes and other cells	IFNAR1-dependent responses to IFN-α/β	Severe viral infections (dissemination of yellow fever vaccine and measles vaccine)
IFNAR2 deficiency	IFNAR2	AR	602376	Broadly expressed	IFNAR2-dependent responses to IFN-α/β	Severe viral infections (disseminated vaccine-strain measles, HHV6)
CD16 deficiency	FCGR3A	AR	146740	NK cells	Altered NK cell function	Severe herpes viral infections, particularly VZV,EBV, and HPV
MDA5 deficiency	IFIH1	AR LOF	606951	Broadly expressed	Viral recognition and IFN induction	Rhinovirus and other RNA viruses
NOS2 deficiency	NOS2	AR	NA	Myeloid cells	Mutant NOS2 failed to induce nitrous oxide	Severe (fatal) susceptibility to CMV-induced disease; pneumocystis pneumonia secondary to CMV; intact responses to infection with other herpesviruses (EBV, VZV, HSV)
ZNFX1 deficiency	ZNFX1	AR	619644	Broadly expressed	↑ ISG in response to poly I/C	Severe infections by RNA/DNA viruses, mycobacteria; early-onset severe inflammation affecting liver, brain, kidneys, lungs; virally triggered inflammatory episodes, hepatosplenomegaly, lymphadenopathy
RNA polymerase III deficiency	POLR3A	AD	614258	Leukocytes and other cells	Impaired viral recognition and IFN induction in response to VZV or poly I:C	Severe VZV infection
	POLR3C	AD	617454
	POLR3F	AD	617455
MIS-C	*OAS1*	AR		Monocytic phagocytes	Excessive inflammatory cytokine production by monocytes	Multisystemic inflammatory syndrome in children (MIS-C) after SARS-CoV-2
	*OAS2*	AR		Monocytic phagocytes	Excessive inflammatory cytokine production by monocytes	MIS-C
	*RNASEL*	AR		Monocytic phagocytes	Excessive inflammatory cytokine production by monocytes	MIS-C
4. Herpes simplex encephalitis (HSE)
TLR3 deficiency	TLR3	AD	613002	CNS-resident cells and fibroblasts	TLR3-dependent IFN-α, IFN-β, and IFN-γ response	Herpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here); severe pulmonary influenza; VZV
TLR3 deficiency	TLR3	AR	613002		TLR3-dependent IFN-α, IFN-β, and IFN-γ response
UNC93B1 deficiency	UNC93B1	AR	608204		UNC-93B–dependent IFN-α, IFN-β, and IFN-γ response	Herpes simplex virus 1 encephalitis
TRAF3 deficiency	TRAF3	AD	601896		TRAF3-dependent IFN-α, IFN-β, and IFN-γ response
TRIF deficiency	TICAM1	AD	607601		TRIF-dependent IFN-α, IFN-β, and IFN-γ response
TRIF deficiency	TICAM1	AR	607601		TRIF-dependent IFN-α, IFN-β, and IFN-γ response
TBK1 deficiency	TBK1	AD	604834		TBK1-dependent IFN-α, IFN-β, and IFN-γ response
IRF3 deficiency	IRF3	AD	616532		Low IFN-α/β, production in response to HSV1 and decreased IRF3 phosphorylation
DBR1 deficiency	DBR1	AR	607024		Impaired production of antiviral IFNs	HSE of the brainstem. Other viral infections of the brainstem
SNORA31 deficiency	SNORA31	AD	619396		Impaired production of antiviral IFNs	Forebrain HSV1 encephalitis
ATG4A deficiency	ATG4	AD	NA	CNS-resident cells and fibroblasts	Impaired HSV2-induced autophagy →increased viral replication and apoptosis of patient fibroblasts	Mollaret’s meningitis (recurrent lymphocytic meningitis) due to HSV2
MAP1LC3B2 deficiency	MAP1LC3B2	AD	NA	CNS-resident cells and fibroblasts
RIPK3 deficiency	*RIPK3*	AR	NA	Neurons	Impaired cellular apoptosis and necroptosis upon TLR3, TLR4, or TNFR1 stimulation and ZBP1/DAI-mediated necroptotic cell death after HSV-1 infection	Herpes simplex encephalitis recurrent in one patient. Otherwise, healthy
GTF3A deficiency	*GTF3A*	AR	NA	Fibroblasts	↓ RNA5SP141 expression results in abrogated RIG-I activation upon HSV-1 infection	CVID phenotype, low switched memory B cells, absent IgM. Defect in pneumococcal antibody response. T cells, mostly memory effector phenotype, low TFH and TH17 cells
IKBKE deficiency	*IKBKE*	AD	NA	Microglia	*Impaired induction of IFN-β1 (IFNB1) upon HSV-2 infection or dsDNA stimulation. Failure to induce phosphorylation of STING*	Recurrent HSV-2 meningitis
5. Predisposition to invasive fungal diseases
CARD9 deficiency	CARD9	AR	607212	Mononuclear phagocytes	CARD9 signaling pathway	Invasive candidiasis infection, deep dermatophytoses, other invasive fungal infections
6. Predisposition to mucocutaneous candidiasis
IL-17RA deficiency	IL17RA	AR	605461	Epithelial cells, fibroblasts, mononuclear phagocytes	IL-17RA signaling pathway, and fibroblasts fail to respond to IL-17A and IL-17F, and their T cells to IL-17E	CMC, folliculitis
IL-17RC deficiency	IL17RC	AR	610925	Epithelial cells, fibroblasts, mononuclear phagocytes	IL-17RC signaling pathway, fibroblasts fail to respond to IL-17A and IL-17F	CMC
IL-17F deficiency	IL17F	AD	606496	T cells	IL-17F–containing dimers	CMC
STAT1 GOF	STAT1	AD GOF	600555	T cells, B cells, NK, monocytes	Increased STAT1 phosphorylation Low Th17 cells	CMC, various fungal, bacterial, and viral (HSV) infections, autoimmunity (thyroiditis, diabetes, cytopenias), enteropathy
ACT1 deficiency	TRAF3IP2	AR	607043	T cells, fibroblasts	Fibroblasts fail to respond to IL-17A and IL-17F, and their T cells to IL-17E	CMC, blepharitis, folliculitis, and macroglossia
JNK1 haploinsufficiency	MAPK8	AD	NA	T cells, fibroblasts	↓ Th17 cells ex vivo, in vitro, ↓ responses of fibroblasts to IL-17A, IL-17F, ↓ c-Jun/ATF-2-dependent TGF-β signaling	CMC, connective tissue disorder (similar to Ehlers–Danlos syndrome)
7. TLR signaling pathway deficiency
IRAK4 deficiency	IRAK4	AR	606883	Lymphocytes + granulocytes + monocytes	TIR-IRAK4 signaling pathway	Pyogenic bacterial diseases, severe viral diseases
MyD88 deficiency	MYD88	AR	602170	Lymphocytes + granulocytes + monocytes	TIR-MyD88 signaling pathway	Pyogenic bacterial diseases, severe viral diseases
Systemic autoinflammation splenomegaly and anemia (NASA)	IRAK4	AR	607676	Lymphocytes	Loss of negative regulation of IRAK-4 and IRAK-1; dysregulation of myddosome assembly and disassembly; or kinase active site instability may drive dysregulated IL-6 and TNF production	Recurrent episodes of fever, massive splenomegaly, elevated inflammatory markers, and severe hypochromic microcytic anemia
IRAK1 deficiency	IRAK1	XL	300283	Lymphocytes + granulocytes + monocytes	TLR-IRAK1 signaling pathway in fibroblasts, TLR7- and TLR8-IRAK1 signaling pathway in EBV-B cells	Bacterial infections, X-linked MECP2 deficiency–related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1
TIRAP deficiency	TIRAP	AR	614382	Lymphocytes + granulocytes + monocytes	TIRAP signaling pathway, TLR1/2, TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes	Staphylococcal disease during childhood in the patient lacking lipoteichoic acid Abs
TLR7 deficiency	TLR7	XL	301051	Lymphocytes, myeloid cells	Impaired responses to TLR7 ligands; reduced production of type 1 IFN	Severe COVID-19 infection
TLR8 GOF	TLR8	XL/somatic mutations	301078	Myeloid cells	Elevated proinflammatory serum cytokines; increased proinflammatory responses of patient myeloid cells to TLR8 agonists; reduced ability of mutant TLR8 to attenuate TLR7 signaling	Early-onset, severe cytopenias, hepatosplenomegaly, lymphadenopathy; progressive autoinflammatory disease
MD2 deficiency	*LY96*	AR	NA	Myeloid cells	Decreased endocytosis of TLR4 leads to impaired NF-κB signaling and decreased cytokine production	Very early-onset inflammatory bowel disease and recurrent infections, pneumonia, and otitis media
TLR4 deficiency	*TLR4*	AR	NA		Impaired TLR4 signaling	Inflammatory bowel disease
8. Other IEIs related to nonhematopoietic tissues
Isolated congenital asplenia (ICA)	RPSA	AD	271400	No spleen	RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome	Bacteremia (encapsulated bacteria)
Isolated congenital asplenia (ICA)	HMOX	AR	141250	Macrophages	HO-1 regulates iron recycling, and heme-dependent damage occurs	Hemolysis, nephritis, inflammation
Trypanosomiasis	APOL1	AD	603743	Somatic	Pore-forming serum protein	Trypanosomiasis
Acute liver failure due to NBAS deficiency	NBAS	AR	608025	Somatic and hematopoietic	ER stress	Fever induces liver failure
Acute necrotizing encephalopathy	RANBP2	AD	601181	Ubiquitous expression	Nuclear pore	Fever induces acute encephalopathy
Osteopetrosis	CLCN7	AR/AD	602727	Osteoclasts	Secretory lysosomes	Osteopetrosis with hypocalcemia, neurological features
	SNX10	AR	614780			Osteopetrosis with visual impairment
	OSTM1	AR	607649			Osteopetrosis with hypocalcemia, neurological features
	PLEKHM1	AR	611466			Osteopetrosis
	TCIRG1	AR	604592			Osteopetrosis with hypocalcemia
	TNFRSF11A	AR	603499		Osteoclastogenesis	Osteopetrosis
	TNFSF11	AR	602642	Stromal	Osteoclastogenesis	Osteopetrosis with severe growth retardation
Hidradenitis suppurativa	NCSTN	AD	605254	Epidermis	Notch signaling/gamma-secretase in hair follicle regulates keratinization	Verneuil’s disease/hidradenitis suppurativa with acne
	PSEN	AD	613737			Verneuil’s disease/hidradenitis suppurativa with cutaneous hyperpigmentation
	PSENEN	AD	613736			Verneuil’s disease/hidradenitis suppurativa
9. Other IEIs related to leukocytes
IRF4 haploinsufficiency	IRF4	AD	601900	Lymphocytes and monocytes	IRF4 is a pleiotropic transcription factor	Whipple’s disease
IL-18BP deficiency	IL18BP	AR	604113	Leukocytes and other cells	IL-18BP neutralizes secreted IL-18	Fulminant viral hepatitis
GATA2 deficiency	GATA2	AD	137295	Monocytes + peripheral DC, NK cells	Multilineage cytopenia	Susceptibility to mycobacteria, HPV, histoplasmosis, alveolar proteinosis, MDS/AML/CMML, lymphedema

NF-κB, nuclear factor kappa B; TIR, Toll and interleukin-1 receptor; IFN, interferon; TLR, Toll-like receptor; MDC, myeloid dendritic cell; CNS, central nervous system; CMC, chronic mucocutaneous candidiasis; HPV, human papillomavirus; VZV, varicella zoster virus; EBV, Epstein-Barr virus; CVID, common variable immunodeficiency; Abs, antibodies.

Total number of mutant genes in Table 6: 86 diseases with 2 entries for IRAK4 counted separately as they constitute different genetic mechanisms and associated phenotypes. GATA2 was moved from nonlymphoid disease table to Table 6, subtable 9.

New IEIs: 10, IRF1, MCTS1, OAS1, OAS2, RNASEL, RIPK3, MD2, TLR4, GTF3A, and IKBKE (76, 77, 78, 79, 80, 81, 82, 83).

* after Th1 refers to Th1 cells, which are a specificsubset of human CD4+ T cells and are specifically affected by the indicatedgene mutations i.e. IRF8, SPPL2A.

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