Table 2.

Inborn errors of immunity including primary immunodeficiency disorders and Mendelian/monogenic infection susceptibilities

Component of immune system affected	Example syndromes	Example genes involved	Inheritance	Infectious disease phenotype	Refs
Examples of primary immunodeficiency disorders
Combined humoral and cellular immunity deficiencies	Severe combined immunodeficiency	RAG1, RAG2, ADA, JAK3, PTPRC	AR, X-linked	Oral candidiasis, Pneumocystis jirovecii pneumonia, diarrhoea before 6 months	184
	Ataxia telangiectasia	ATM	AR	Recurrent sinopulmonary infections	185
Cellular immunity deficiencies	ZAP70 deficiency	ZAP70	AR	Common and opportunistic infections (including live-virus vaccine strains), Pneumocystis jirovecii infections	186
Humoral immunity deficiencies	Common variable immunodeficiency	TACI, ICOS, BAFFR, CD19, CD20	AD, AR	Recurrent sinopulmonary infections, bronchiectasis	187
	X-linked agammaglobulinaemia	BTK	X-linked	Recurrent sinopulmonary and skin infections during infancy Persistent central nervous system infections resulting from live attenuated oral polio vaccine, echoviruses or coxsackieviruses Increased risk of infectious arthritis, bronchiectasis	188
	Hyper-IgM syndrome	AID, UNG, CD40, CD40L	AR, X-linked	Similar to X-linked agammaglobulinaemia (recurrent pyogenic bacterial sinopulmonary infections) but greater frequency of Pneumocystis jirovecii pneumonia, cryptosporidiosis	189
Phagocytic cell defects	Chronic granulomatous disease	CYBA, NCF1, NCF2, NCF4	X-linked, AR	Granulomatous lesions, recurrent abscesses Infections by catalase-producing organisms (e.g. Staphylococcus aureus, Escherichia coli, Serratia, Klebsiella and Pseudomonas spp.) Aspergillus infections (leading cause of death)	190
	Leukocyte adhesion deficiency	ITGB2, SLC35C1, FERMT3	AR	Soft-tissue infections, periodontitis, no formation of pus	190
Complement deficiencies	C3 deficiency	C3	AR	Recurrent pyogenic infections with encapsulated bacteria beginning from birth	191
	C5–C9 deficiency	C5, C6, C7, C8, C9	AR	Recurrent and disseminated Neisseria infections	191
Examples of monogenic inborn errors of immunity with high/complete penetrancea
Viral restriction (keratinocyte)	Epidermodysplasia verruciformis	TMC6, TMC8, C1B1	AR	Human papillomaviruses infecting keratinocytes causing warts and non-melanoma skin cancer	9
IFNγ immunity (innate and adaptive lymphocytes)	Mendelian susceptibility to mycobacterial disease	IFNGR1, ISG15, TYK2, IRF8, SPPL2A	AR, AD	Severe bacillus Calmette–Guérin (BCG; a live attenuated strain of Mycobacterium bovis) or environmental non-tuberculous mycobacterial infection	91
Lymphocytes	X-lymphoproliferative disease	SH2D1A	X-linked	Haemophagocytosis during the course of Epstein–Barr virus infection, or hypogammaglobulinaemia or B cell lymphoma	192
Lymphocytes	Chronic mucocutaneous candidiasis	CARD9, IL17RA, STAT1, STAT3, IL17RC, IL17F, ACT1, JNK1, RORC, ZNF341	AD, AR	Cutaneous and mucosal lesions due to Candida albicans	193
Phagocytes	Invasive dermatophytic disease	CARD9	AR	Dermatophytes causing cutaneous and rarely invasive disease	194
Examples of monogenic inborn errors of immunity with low penetranceb
TLR3-mediated interferon-dependent immunity	Herpes simplex encephalitis	TLR3	AD	Encephalitis due to herpes simplex virus	74
TLR pathway	Invasive pneumococcal disease	NEMO, IRAK4, MYD88	X-linked	Invasive disease due to Streptococcus pneumoniae	75–78
Interferon-dependent immunity	Severe influenza pneumonitis	IRF7	X-linked	Severe lung infection due to influenza virus	87

This table lists inborn errors of immunity with genes and associated infectious disease phenotypes indicated. The classification for inborn errors of immunity underlying severe infectious disease follows that proposed by Casanova and Abel⁹. Primary immunodeficiencies (PIDs) comprise of a group of usually rare disorders involving partial or full dysfunction of one or more components of the immune system. The wide spectrum of PIDs leads to differing susceptibilities to infectious diseases depending on the part of the immune system affected. PIDs are associated with overt immunological abnormalities and have high/complete penetrance; they are often associated with other clinical phenotypes, such as autoimmunity, autoinflammation, cancer and allergy. Examples of other monogenic inborn errors of immunity are shown, which typically disrupt host defence against one or a few infectious agents, differentiated by penetrance. AD, autosomal dominant; AR, autosomal recessive; IFNγ, interferon-γ; TLR, Toll-like receptor. ^aHigh-penetrance/complete-penetrance inborn errors of immunity (‘Mendelian infections’) are usually familial. ^bLow-penetrance inborn errors of immunity are typically sporadic and rare.