Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee

Abstract

We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.

Inborn errors of immunity, also referred to as primary immunodeficiencies, manifest as increased susceptibility to infectious diseases, autoimmunity, autoinflammatory diseases, allergy, and/or malignancy. These conditions are caused by monogenic germline mutations that result in loss of expression, loss-of-function (LOF; amorphic/hypomorphic), or gain-of-function (GOF; hypermorphic) of the encoded protein [1, 2]. Heterozygous lesions may underlie autosomal dominant traits by GOF, haploinsufficiency, or negative dominance. Biallelic lesions typically cause autosomal recessive traits by LOF of the encoded protein (rarely GOF), while X-linked recessive traits arise from LOF of genes on the X chromosome, either in the hemizygous state in males or in the homozygous state in females. Rare X-linked dominant traits can also arise from LOF or GOF variants. This results in aberrant immunity due to the critical roles of these proteins in the development, maintenance and function of cells of the immune system, or cells other than leukocytes that contribute to immunity, during homeostasis and in response to external (e.g., infectious agents or environmental antigens) and internal (e.g., cytokines, self-antigens and cancer cells) stimuli [3–5]. Inborn errors of immunity were traditionally considered to be rare diseases, affecting ~ 1 in 10,000 to 1 in 50,000 births. However, with ongoing discovery of novel inborn errors of immunity (Fig. 1a) and improved definition of clinical phenotypes [6–8], the collective prevalence of these conditions is more likely to be at least 1/1000–1/5000 [9]. Indeed, more common inborn errors have recently been described [10]. Regardless of their exact incidence and prevalence, inborn errors of immunity represent an unprecedented model to link defined monogenic defects with clinical phenotypes of immune dysregulation, in a broad sense of the term. As a committee, we are aware that human immunity involves cells other than circulating or tissue leukocytes and that it can be scaled up from the immune system to the whole organism. Inborn errors of immunity have unequivocally revealed non-redundant roles of single genes and their products in immune function [3, 4, 6–8], formed the basis of improved mechanism-based therapies for the immunopathology underlying many diseases [8, 11], established immunological paradigms representing the foundations of basic, clinical and translational immunology [3–5, 9, 12–14], and provided insights into the molecular pathogenesis of more common diseases [9, 15]. Clear examples of these include:

• The initial description by Bruton of X-linked agammaglobulinemia (XLA) and the ability to treat this condition with antibody replacement therapy (the mainstay treatment for antibody deficiency diseases such as CVID) [16]

• The discovery of mutations in BTK [12] and the subsequent development of BTK-inhibitors such as ibrutinib for the treatment of B cell malignancies [14]

• Progressive CD4 T cell deficiency explains opportunistic infections secondary to HIV infection [9].

Fig. 1.

Rate of discovery of novel inborn errors of immunity: 1983–2019. a The number of genetic defects underlying monogenic immune disorders as reported by the IUIS/WHO committee in the indicated year. b The number of pathogenic gene variants listed in each table by the IUIS committee. Report published in 2017, and the number of new genes for each table contained in this report (red bars). The numbers in each column correspond to the number of genes reported in the 2017 IUIS update (blue bars) [1, 2], the number of new genes for each table contained in this report (red bars), and the total number of genes for each table. Note: only data for Tables 1, 2, 3, 4, 5, 6, 7, and 8 are shown, because Table 9 (bone marrow failure) is a new addition to the current report.

Thus, the study of inborn errors of immunity has provided profound advances in the practice of precision molecular medicine.

Since the early 1950s, when XLA was one of the first primary immune deficiencies to be described [16], clinical immunology has leveraged advances in the development of new methods to expedite the identification of defects of the immune system and the cellular, molecular, and genetic aberrations underlying these conditions. Indeed, the completion of the Human Genome Project in the early 2000s, coupled with rapid developments in next generation DNA sequencing (NGS) technologies, enabled the application of cost-effective and time-efficient sequencing of targeted gene panels, whole exomes, or whole genomes to cohorts of patients suspected of having a monogenic explanation for their disease. These platforms have led to a quantum leap in the identification and diagnosis of previously undefined genetically determined defects of the immune system (Fig. 1a, b; [6–8]).

The International Union of Immunological Societies Expert Committee of Inborn Errors of Immunity comprises pediatric and adult clinical immunologists, clinician/scientists and researchers in basic immunology from across the globe (https://iuis.org/committees/iei/). A major objective and responsibility of the committee is to provide the clinical and research communities with an update of genetic causes of immune deficiency and dysregulation. The committee has existed since 1970 and has published an updated report approximately every 2 years to inform the field of these advances (Fig. 1a). In March 2019, the committee met in New York to discuss and debate the inclusion of genetic variants published over the preceding 2 years (since June 2017) [1, 2], as well as gene mutations that had appeared in the literature earlier but, based on newly available evidence, were now substantiated (Fig. 1b).

Rather than simply including every gene variant reported, the committee applies very stringent criteria such that only those genes with convincing evidence of disease pathogenicity are classified as causes of novel inborn errors of immunity [17]. The Committee makes informed judgments for including new genetic causes of immunological conditions based on what we believe is most useful for practitioners caring for patients. Our current, and continuously evolving, practice is that criteria for inclusion can be met by several ways, for instance peer-reviewed publication of (1) multiple cases from unrelated kindreds, including detailed immunologic data, or (2) very few cases, or even a single case (see below), for whom compelling mechanistic/pathogenic data is also provided, generally from parallel studies in an animal or cell culture model.

Herein, we provide this latest update. The inborn errors of immunity are listed in 10 tables: Combined immunodeficiencies (Table 1), Combined immunodeficiencies with syndromic features (Table 2), Predominantly antibody deficiencies (Table 3), Diseases of immune dysregulation (Table 4), Congenital defects of phagocytes (Table 5), Defects in intrinsic and innate immunity (Table 6), Autoinflammatory diseases (Table 7), Complement deficiencies (Table 8), and Phenocopies of inborn errors of immunity (Table 10) (Fig. 1b). Since the last update (published January 2018) [1, 2], we have added a new table to consolidate genes that cause bone marrow failure (Table 9). Our division into phenotypes does not imply that the presentation is homogeneous. Rather, we recognize that substantial phenotypic and clinical heterogeneity exists within groups of patients with mutations in the same gene and even between individuals from the same pedigree with the identical gene mutation. To simplify the classification, each disorder has been listed only once, although distinct disorders due to mutations in the same gene, but with different modes of inheritance and pathogenic mechanisms are listed individually. Thus, several genes appear more than once in this update (some examples are listed below). Sub-divisions within each table segregate groups of disorders into coherent phenotypic sets. OMIM numbers are also provided within each table. If a OMIM number has not yet been issued for a particular genetic condition, then the number provided generally refers to the OMIM for that gene. Beneath each table, the new disorders added to this update are highlighted for easy reference.

Table 1.

Immunodeficiencies affecting cellular and humoral immunity

Disease	Genetic defect	Inheritance	OMIM	T cells	B cells	Ig	Associated features
1. T-B+ severe combined immune deficiency (SCID)
γc deficiency (common gamma chain SCID, CD132 deficiency)	IL2RG	XL	308380	Very low	Normal to high	Low	Low NK
JAK3 deficiency	JAK3	AR	600173	Very low	Normal to high	Low	Low NK
IL7Rα deficiency	IL7R	AR	146661	Very low	Normal to high	Low	Normal NK
CD45 deficiency	PTPRC	AR	151460	Very low	Normal	Low	Normal γ/δ Τ cells
CD3δ deficiency	CD3D	AR	186790	Very low	Normal	Low	Normal NK, no γ/δ T cells
CD3ε deficiency	CD3E	AR	186830	Very low	Normal	Low	Normal NK, no γ/δ T cells
CD3ζ deficiency	CD3Z	AR	186780	Very low	Normal	Low	Normal NK, no γ/δ T cells
Coronin-1A deficiency	CORO1A	AR	605000	Very low	Normal	Low	Detectable thymus
LAT deficiency	LAT	AR	602354	Normal to low	Normal to low	High	Typical SCID or combined immunodeficiency, the latter with adenopathy, splenomegaly, recurrent infections, autoimmunity
2. T-B- SCID
RAG deficiency	RAG1 RAG2	AR	179615 179616	Very low	Very low	Decreased	Normal NK cell number, but increased risk of graft rejection, possibly due to activated NK cells
DCLRE1C (Artemis) deficiency	DCLRE1C	AR	605988	Very low	Very low	Decreased	Normal NK cell number, but increased risk of graft rejection, possibly due to activated NK cells, radiation sensitivity
DNA PKcs deficiency	PRKDC	AR	615966	Very low	Very low	Variable	Normal NK, radiation sensitivity, microcephaly
Cernunnos/XLF deficiency	NHEJ1	AR	611290	Very low	Very low	Decreased	Normal NK, radiation sensitivity, microcephaly
DNA ligase IV deficiency	LIG4	AR	601837	Very low	Very low	Decreased	Normal NK, radiation sensitivity, microcephaly
Adenosine deaminase (ADA) deficiency	ADA	AR	608958	Very low	Low, decreasing	Low, decreasing	Low NK, bone defects, may have pulmonary alveolar proteinosis, cognitive defects
AK2 defect	AK2	AR	103020	Very low	Very Low	Decreased	Reticular dysgenesis with neutropenia; deafness
Activated RAC2 defect	RAC2	AD GOF	602049	Very low	Very Low	Low, poor specific antibody responses	Recurrent bacterial and viral infections, lymphoproliferation; neutropenia
3. Combined immunodeficiency (CID), generally less profound than SCID
CD40 ligand (CD154) deficiency	CD40LG	XL	308230	Normal to low	sIgM+IgD+ naïve B cells present; IgG+, IgA+, IgE+ memory B cells absent	IgM normal or high, other Ig isotypes low	Severe and opportunistic infections, idiopathic neutropenia; hepatitis and cholangitis, Cryptosporidium infections, cholangiocarcinoma; autoimmune blood cytopenias; peripheral neuroectodermal tumors
CD40 deficiency	CD40	AR	606843	Normal			Neutropenia, opportunistic infections, gastrointestinal and biliary tract and liver disease, Cryptosporidium infections
ICOS deficiency	ICOS	AR	604558	Normal	Normal	Low	Recurrent infections, autoimmunity, gastroenteritis, granulomas
ICOSL deficiency	ICOSLG	AR	605717	Low	Low	Low	Recurrent bacterial and viral infections, neutropenia
CD3γ deficiency	CD3G	AR	186740	Normal number, but low TCR expression	Normal	Normal	Immune deficiency and autoimmunity of variable severity
CD8 deficiency	CD8A	AR	186910	Absent CD8, Normal CD4	Normal	Normal	Recurrent infections, may be asymptomatic
ZAP-70 deficiency (ZAP70 LOF)	ZAP70	AR	269840	Low CD8 number, normal CD4 number but with poor function	Normal	Normal	May have immune dysregulation, autoimmunity
ZAP-70 combined hypomorphic and activating mutations	ZAP70	AR (LOF/GOF)	617006	Decreased CD8, normal or decreased CD4 cells	Normal or decreased	Normal IgA, low IgM, low/normal IgG; protective Ab responses to vaccines	Severe autoimmunity (bullous pemphigoid, inflammatory colitis
MHC class I deficiency	TAP1	AR	170260	Low CD8, normal CD4, absent MHC I on lymphocytes	Normal	Normal	Vasculitis, pyoderma gangrenosum
	TAP2	AR	170261
	TAPBP	AR	601962
	B2M	AR	109700				Sinopulmonary infections, cutaneous granulomas. Absent β2m associated proteins MHC-I, CD1a, CD1b, and CD1c
MHC class II deficiency group A, B, C, D	CIITA	AR	600005	Low CD4+ T cells, reduced MHC II expression on lymphocytes	Normal	Normal to low	Failure to thrive, respiratory and gastrointestinal infections, liver/biliary tract disease
	RFXANK	AR	603200
	RFX5	AR	601863
	RFXAP	AR	601861
IKAROS deficiency	IKZF1	AD DN	603023	no memory T cells	no memory B cells	Low Ig,	recurrent sinopulmonary infections, pneumocystis early CID onset
DOCK8 deficiency	DOCK8	AR	243700	T cell lymphopenia, reduced naïve CD8 T cells, increased exhausted CD8+ TEM cells, reduced MAIT, NKT cells, increased γδ T cells; poor proliferation; few Treg with poor function	increased total B cells, reduced memory B cells Poor peripheral B cell tolerance.	Low IgM, normal/high IgG and IgA, very high IgE, poor antibody responses	Low NK cells with poor function. Eosinophilia, recurrent infections, cutaneous viral, fungal and staphylococcal infections, severe atopy/allergic disease, cancer diathesis
DOCK2 deficiency	DOCK2	AR	603122	Low	Normal	IgG normal or low, poor antibody responses	Early invasive herpes viral, bacterial infections, Normal NK cell number, but defective function. Poor interferon responses in hematopoietic and non-hematopoietic cells
Polymerase and deficiency	POLD1 POLD2	AR	174761 600815	Low CD4 T cells	Low B cells but normal maturation	Low igG	Recurrent respiratory tract infections, skin infections, warts and molluscum, short stature, intellectual disability
RHOH deficiency	RHOH	AR	602037	Normal, few naïve T cells, restricted repertoire, poor proliferation to CD3	Normal	Normal	HPV infection, lung granulomas, molluscum contagiosum, lymphoma
STK4 deficiency	STK4	AR	614868	CD4 lymphopenia, reduced naïve T cells, increased TEM and TEMRA cells, poor proliferation	Reduced memory B cells	Reduced IgM, increased IgG, IgA, IgE; impaired Ab responses	Intermittent neutropenia, bacterial, viral (HPV, EBV, molluscum), candidal infections, lymphoproliferation, autoimmune cytopenias, lymphoma, congenital heart disease
TCRα deficiency	TRAC	AR	615387	Absent TCRαβ except for a minor CD3-dim TCRαβ population; most T cells γδ; poor proliferation	Normal	Normal	Recurrent viral, bacterial, fungal infections, immune dysregulation and autoimmunity, diarrhea
LCK deficiency	LCK	AR	615758	Low CD4+, low Treg, restricted T cell repertoire, poor TCR signaling	Normal	Normal IgG and IgA, high IgM	Recurrent infections, immune dysregulation, autoimmunity
ITK deficiency	ITK	AR	186973	Progressive CD4 T cell lymphopenia; reduced T cell activation	Normal	Normal to low serum Ig	EBV associated B cell lymphoproliferation, lymphoma, immune dysregulation
MALT1 deficiency	MALT1	AR	615468	Normal number, poor proliferation	Normal	Normal levels, poor specific antibody response	Bacterial, fungal and viral infections
CARD11 deficiency	CARD11	AR LOF	615206	Normal number, predominantly naïve T cells, poor proliferation	Normal, transitional B cell predominance	Absent/low	Pneumocystis jirovecii pneumonia, bacterial and viral infections
BCL10 deficiency	BCL10	AR	616098	Normal number, few memory T and Treg cells, poor antigen and anti-CD3 proliferation	Normal number, decreased memory and switched B cells	Low	Recurrent bacterial and viral infections, candidiasis, gastroenteritis
IL-21 deficiency	IL21	AR	615767	Normal number, normal/low function	Low, decreased memory and switched B cells	Hypogammaglobulinemia, poor specific antibody responses; increased IgE	Severe early onset colitis, recurrent sinopulmonary infections
IL-21R deficiency	IL21R	AR	615207	Normal number, low cytokine production, poor antigen proliferation	Normal, decreased memory and switched B cells		Recurrent infections, Pneumocystis jiroveci, Cryptosporidium infections, liver disease
OX40 deficiency	TNFRSF4	AR	615593	Normal numbers, low antigen specific memory CD4+	Normal numbers, low memory B cells	Normal	Impaired immunity to HHV8, Kaposi’s sarcoma
IKBKB deficiency	IKBKB	AR	615592	Normal number, absent Treg and γ/δ T cells, impaired TCR activation	Normal number, poor function	Low	Recurrent bacterial, viral, fungal infections, opportunistic infections
NIK deficiency	MAP 3 K14	AR	604655	Normal number, poor proliferation to antigen	Low, low switched memory B cells	Low Ig’s	Low NK number and function, recurrent bacterial, viral and Cryptosporidium infections
RelB deficiency	RELB	AR	604758	Normal number, poor diversity, reduced proliferation to mitogens; no response to Ag	Marked increase in B cell number	Normal Ig levels but Impaired specific antibody responses	Recurrent infections
RelA haploinsufficiency	RELA	AD	618287	Normal/increased	Normal	Normal	Chronic mucocutaneous ulceration, Impaired NFkB activation; reduced production of inflammatory cytokines
Moesin deficiency	MSN	XL	300988	Normal number, defective migration, proliferation	Low number	Low Ig’s over time	Recurrent infections with bacteria, varicella, neutropenia
TFRC deficiency	TFRC	AR	616740	Normal number, poor proliferation	Normal number, low memory B cells	Low	Recurrent infections, neutropenia, thrombocytopenia
c-Rel deficiency	REL	AR	164910	Normal, decreased memory CD4, poor proliferation	Low, mostly naïve; few switched memory B cells, impaired proliferation	Low, poor specific antibody responses	Recurrent infections with bacteria, mycobacteria, salmonella and opportunistic organisms. Defective innate immunity
FCHO1 deficiency	FCHO1	AR	613437	Low, poor proliferation	Normal number	Normal	Recurrent infections (viral, mycobacteria, bacterial, fungal), lymphoproliferation, failure to thrive, increased activation-induced T cell death, defective clathrin-mediated endocytosis

SCID/CID spectrum: Infants with SCID who have maternal T cell engraftment may have T cells in normal numbers that do not function normally; these cells may cause autoimmune cytopenias or graft versus host disease. Hypomorphic mutations in several of the genes that cause SCID may result in Omenn syndrome (OS), or “leaky” SCID, or still less profound combined immunodeficiency (CID) phenotypes. Both OS and leaky SCID can be associated with > 300 autologous T cells/μL of peripheral blood and reduced, rather than absent, proliferative responses when compared with typical SCID caused by null mutations. A spectrum of clinical findings including typical SCID, OS, leaky SCID, CID, granulomas with T lymphopenia, autoimmunity and CD4 T lymphopenia can be found in an allelic series of RAG1/2 and other SCID-associated genes. There can be clinical overlap between some genes listed here and those listed in Table 7

Total number of disorders in Table 1: 50

Total number of mutant genes: 58

New inborn errors of immunity: 8; New inborn errors of immunity: 8; RAC2 GOF [18–21]; ICOSLG [22]; AD DN IKZF1 [23]; POLD1 [24, 25]; POLD2 [24]; RELA [26, 27]; REL [28]; FCHO1 [29]

SCID severe combined immunodeficiency, CID combined immunodeficiency, EBV Epstein-Barr virus, MHC major histocompatibility complex, HPV human papillomavirus, Treg T regulatory cell, XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, LOF loss-of-function, GOF gain-of-function

Table 2.

Combined immunodeficiencies with associated or syndromic features

Disease	Genetic defect	Inheritance	OMIM	T cells	B cells	Ig	Associated features
1. Immunodeficiency with congenital thrombocytopenia
Wiskott-Aldrich syndrome (WAS LOF)	WAS	XL	300392	Progressive decrease in numbers, abnormal lymphocyte responses to anti-CD3	Normal numbers	Low IgM and antibody responses to polysaccharides, often high IgA and IgE	Thrombocytopenia with small platelets, eczema, recurrent bacterial/viral infections, bloody diarrhea, lymphoma, autoimmune disease, IgA- nephropathy. Patients with XL-thrombocytopenia have later onset of complications and more favourable life expectancy but eventually develop similar complications as observed in WAS
WIP deficiency	WIPF1	AR	602357	Reduced, defective lymphocyte responses to anti-CD3	Normal or low	Normal, except for high IgE	Thrombocytopenia with or without small platelets, recurrent bacterial and viral infections, eczema, bloody diarrhea; WAS protein absent
Arp2/3-mediated filament branching defect	ARPC1B	AR	604223	Normal	Normal numbers	Normal except for high IgA and IgE	Mild thrombocytopenia with normal sized platelets, recurrent invasive infections; colitis, vasculitis, autoantibodies (ANA, ANCA), eosinophilia; defective Arp2/3 filament branching
2. DNA repair defects other than those listed in Table 1
Ataxia-telangiectasia	ATM	AR	607585	Progressive decrease, poor proliferation to mitogens; may have low TRECs and T cells by newborn screening (NBS)	Normal	Often low IgA, IgE and IgG subclasses, increased IgM monomers; antibodies variably decreased	Ataxia, telangiectasia especially of sclerae; pulmonary infections; lymphoreticular and other malignancies; increased alpha fetoprotein; increased radiosensitivity, chromosomal instability and chromosomal translocations
Nijmegen breakage syndrome	NBS1	AR	602667	Progressive decrease; may have low TRECs and T cells by NBS	Variably reduced	Often low IgA, IgE, and IgG subclasses, increased IgM; antibodies variably decreased	Microcephaly, dysmorphic facies; lymphomas and solid tumors; increased radiosensitivity;, chromosomal instability
Bloom syndrome	BLM	AR	604610	Normal	Normal	Low	Short stature, dysmorphic facies sun-sensitive erythema; marrow failure; leukemia, lymphoma; chromosomal instability
Immunodeficiency with centromeric instability and facial anomalies (ICF types 1, 2, 3, 4)	DNMT3B	AR	602900	Decreased or normal, responses to PHA may be decreased	Decreased or normal	Hypogammaglobulinemia or agammaglobulinemia, variable antibody deficiency	Facial dysmorphic features, developmental delay, macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16
	ZBTB24	AR	614064	Decreased or normal			Facial dysmorphic features, macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16
	CDCA7	AR	609937	Decreased or normal; responses to PHA may be decreased
	HELLS	AR	603946	Decreased or normal
PMS2 deficiency	PMS2	AR	600259	Normal	Low B cells, switched and non-switched	Low IgG and IgA, high IgM, abnormal antibody responses	Recurrent infections; café-au-lait spots; lymphoma, colorectal carcinoma, brain tumors
RNF168 deficiency (Radiosensitivity, Immune Deficiency, Dysmorphic features, Learning difficulties [RIDDLE] syndrome)	RNF168	AR	612688	Normal	Normal	Low IgG or IgA	Short stature, mild defect of motor control to ataxia; normal intelligence to learning difficulties; mild facial dysmorphism to microcephaly; increased radiosensitivity
MCM4 deficiency	MCM4	AR	602638	Normal	Normal	Normal	NK cells: low number and function; viral infections (EBV, HSV, VZV); short stature; B cell lymphoma; adrenal failure
X-linked reticulate pigmentary disorder (POLA1 deficiency)	POLA1	XL	301220	Not assessed	Not assessed	Not assessed	Hyperpigmentation, characteristic facies, lung and GI involvement
POLE1 (Polymerase ε subunit 1) deficiency (FILS syndrome)	POLE1	AR	174762	Normal; decreased T cell proliferation	Low memory B cells	Low IgG2 and IgM, lack of antibody to PPS	Recurrent respiratory infections, meningitis; facial dysmorphism, livido, short stature
POLE2 (Polymerase ε subunit 2) deficiency	POLE2	AR	602670	Lymphopenia, lack of TRECS at NBS, absent proliferation in response to antigens	Very low	Hypogammaglobulinemia	Recurrent infections, disseminated BCG infections; autoimmunity (type 1 diabetes), hypothyroidism, facial dysmorphism
Ligase I deficiency	LIG1	AR	126391	Lymphopenia, increased γδ T cells, decreased mitogen response	Normal	Hypogammaglobulinemia, Reduced antibody responses	Recurrent bacterial and viral infections; growth retardation; sun sensitivity, radiation sensitivity; macrocytic red blood cells
NSMCE3 deficiency	NSMCE3	AR	608243	Decreased number, poor responses to mitogens and antigens	Normal	Normal IgG, IgA, normal to elevated IgM; decreased antibody responses to PPS	Severe lung disease (possibly viral); thymic hypoplasia; chromosomal breakage, radiation sensitivity
ERCC6L2 (Hebo deficiency)	ERCC6L2	AR	615667	Lymphopenia	Low	Normal	Facial dysmorphism, microcephaly; bone marrow failure
GINS1 deficiency	GINS1	AR	610608	Low or normal	Low or normal	High IgA, low IgM and IgG	Neutropenia; IUGR; NK cells very low
3. Thymic defects with additional congenital anomalies
DiGeorge/velocardio-facial syndrome Chromosome 22q11.2 deletion syndrome (22q11.2DS)	Large deletion (3 Mb) typically in chromosome 22 (TBX1)	AD	602054	Decreased or normal, 5% have low TRECs at NBS and < 1500 CD3T cells/μL in neonatal period	Normal	Normal or decreased	Hypoparathyroidism; conotruncal cardiac malformation, velopalatal insufficiency; abnormal facies; intellectual disability
DiGeorge/velocardio-facial syndrome	Unknown	Sporadic		Decreased or normal
TBX1 deficiency	TBX1	AD	602054	Decreased or normal, may have low TRECs at NBS
CHARGE syndrome	CHD7	AD	608892	Decreased or normal, may have low TRECs at NBS; response to PHA may be decreased	Normal	Normal or decreased	Coloboma of eye; heart anomaly; choanal atresia; intellectual disability; genital and ear anomalies, CNS malformation; some are SCID-like
	SEMA3E	AD	608166
	Unknown
Winged helix nude FOXN1 deficiency	FOXN1	AR	601705	Very low	Normal	Decreased	Severe infections; abnormal thymic epithelium, immunodeficiency; congenital alopecia, nail dystrophy; neural tube defect
FOXN1 haploinsufficiency	FOXN1	AD	600838	Severe T cell lymphopenia at birth, normalised by adulthood	Normal/low	Not assessed	Recurrent, viral and bacterial respiratory tract infections; skin involvement (eczema, dermatitis), nail dystrophy
Chromosome 10p13-p14 deletion syndrome (10p13-p14DS)	Del10p13-p14	AD	601362	Normal, rarely lymphopenia and decreased lymphoproliferation to mitogens and antigens; hypoplastic thymus may be present	Normal	Normal	Hypoparathyroidism; renal disease; deafness; growth retardation; facial dysmorphism; cardiac defects may be present; recurrent infections ±
Chromosome 11q deletion syndrome (Jacobsen syndrome)	11q23del	AD	147791	Lymphopenia; low NK cells	Decreased B cells and switched memory B cells	Hypogammaglobulinemia, decreased antibody responses	Recurrent respiratory infections; multiple warts; facial dysmorphism, growth retardation
4. Immuno-osseous dysplasias
Cartilage hair hypoplasia (CHH)	RMRP	AR	157660	Varies from severely decreased (SCID) to normal; impaired lymphocyte proliferation	Normal	Normal or reduced, antibodies variably decreased	Short-limbed dwarfism with metaphyseal dysostosis; sparse hair; bone marrow failure; autoimmunity; susceptibility to lymphoma and other cancers; impaired spermatogenesis; neuronal dysplasia of the intestine
Schimke immuno-osseous dysplasia	SMARCAL1	AR	606622	Decreased	Normal	Normal	Short stature, spondiloepiphyseal dysplasia, intrauterine growth retardation; nephropathy; bacterial, viral, fungal infections; may present as SCID; bone marrow failure
MYSM1 deficiency	MYSM1	AR	612176	T cell lymphopenia, reduced naïve T cells, low NK cells	B cell deficiency	Hypogammaglobulinemia	Short stature; recurrent infections; congenital bone marrow failure, myelodysplasia; immunodeficiency affecting B cells and granulocytes; skeletal anomalies; cataracts; developmental delay
MOPD1 deficiency (Roifman syndrome)	RNU4ATAC	AR	601428	Decreased NK cell function	Decreased total and memory B cells	Hypogammaglobulinemia, variably decreased specific antibodies	Recurrent bacterial infections; lymphadenopathy; spondyloepiphyseal dysplasia, extreme intrauterine growth retardation; retinal dystrophy; facial dysmorphism; may present with microcephaly; short stature
Immunoskeletal dysplasia with neurodevelopmental abnormalities (EXTL3 deficiency)	EXTL3	AR	617425	Decreased	Normal	Decreased to normal	Short stature; cervical spinal stenosis, neurodevelopmental impairment; eosinophilia; may have early infant mortality
5. Hyper IgE syndromes (HIES)
AD-HIES STAT3 deficiency (Job syndrome)	STAT3	AD LOF (dominant negative)	147060	Normal overall; Th17, T follicular helper, MAIT, NKT cells decreased, Tregs may be increased; impaired responses to STAT3-activatng cytokines	Normal, reduced memory B cells, BAFF expression increased, impaired responses to STAT3-activating cytokines	Very high IgE, specific antibody production decreased	Distinctive facial features (broad nasal bridge); bacterial infections (boils, pulmonary abscesses, pneumatoceles) due to S. aureus, pulmonary aspergillus, Pneumocystis jirovecii; eczema, mucocutaneous candidiasis; hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms
IL6 receptor deficiency	IL6R	AR	147880	Normal/increased; normal responses to mitogens	Normal total and memory B; reduced switched memory B	Normal/low serum IgM, G, A. Very high IgE; specific antibody production low	Recurrent pyogenic infections, cold abscesses; high circulating IL-6 levels
IL6 signal transducer (IL6ST) deficiency	IL6ST	AR	618523	Decreased Th17 cells	Reduced switched and non-switched memory B cells	High IgE, specific antibody production variably affected	Bacterial infections, boils, eczema, pulmonary abscesses, pneumatoceles; bone fractures; scoliosis; retention of primary teeth; craniosynostosis
ZNF341 deficiency AR-HIES	ZNF341	AR	618282	Decreased Th17 and NK cells	Normal, reduced memory B cells, impaired responses to STAT3-activaitng cytokines	High IgE and IgG, specific antibody production decreased	Phenocopy of AD-HIES; mild facial dysmorphism; early onset eczema, MCC, bacterial skin infections, abscesses, recurrent bacterial respiratory infections (S. aureus), lung abscesses and pneumatoceles; hyperextensible joints; bone fractures and retention of primary teeth
ERBIN deficiency	ERBB2IP	AD	606944	Increased circulating Treg	Normal	Moderately increased IgE	Recurrent respiratory infections, susceptibility to S. aureus, eczema; hyperextensible joints, scoliosis; arterial dilatation in some patients
Loeys-Dietz syndrome (TGFBR deficiency)	TGFBR1	AD	609192	Normal	Normal	Elevated IgE	Recurrent respiratory infectons; eczema, food allergies; hyper-extensible joints, scoliosis, retention of primary teeths; aortic aneurisms.
	TGFBR2		610168
Comel-Netherton syndrome	SPINK5	AR	605010	Normal	Low switched and non-switched B cells	High IgE and IgA, Antibody variably decreased	Congenital ichthyosis, bamboo hair, atopic diathesis; increased bacterial infections; failure to thrive
PGM3 deficiency	PGM3	AR	172100	CD8 and CD4 T cells may be decreased	Low B and memory B cells	Normal or elevated IgG and IgA, most with high IgE, eosinophilia	Severe atopy; autoimmunity; bacterial and viral infections; skeletal anomalies/dysplasia: short stature, brachydactyly, dysmorphic facial features; intellectual disability and cognitive impairment, delayed CNS myelination in some affected individuals
CARD11 deficiency (heterozygous DN)	CARD11	AD LOF	617638	Normal overall, but defective T cell activation and proliferation; skewing toward Th2	Normal to low	High IgE, poor specific antibody production; impaired activation of both NF-κB and mTORC1 pathways	Variable atopy, eczema, food allergies, eosinophilia; cutaneous viral infections, recurrent respiratory infections; lymphoma; CID
6. Defects of vitamin B12 and folate metabolism
Transcobalamin 2 deficiency	TCN2	AR	613441	Normal	Variable	Decreased	Megaloblastic anemia, pancytopenia; if untreated (B12) for prolonged periods results in intellectual disability
SLC46A1/PCFT deficiency causing hereditary folate malabsorption	SLC46A1	AR	229050	Variable numbers and activation profile	Variable	Decreased	Megaloblastic anemia, failure to thrive; if untreated for prolonged periods results in intellectual disability
Methylene-tetrahydrofolate dehydrogenase 1 (MTHFD1) deficiency	MTHFD1	AR	172460	Low thymic output, normal in vitro proliferation	Low	Decreased/poor antibody responses to conjugated polysaccharide antigens	Recurrent bacterial infection, Pneumocystis jirovecii; megaloblastic anemia; failure to thrive; neutropenia; seizures, intellectual disability; folate-responsive
7. Anhidrotic ectodermodysplasia with immunodeficiency (EDA-ID)
EDA-ID due to NEMO/IKBKG deficiency (ectodermal dysplasia, immune deficiency)	IKBKG	XL	300248	Normal or decreased, TCR activation impaired	Normal; Low memory and isotype switched B cells	Decreased, some with elevated IgA, IgM, poor specific antibody responses, absent antibodies to polysaccharide antigens	Anhidrotic ectodermal dysplasia (in some); various infections (bacteria, mycobacteria, viruses, fungi); colitis; conical teeth, variable defects of skin, hair and teeth; monocyte dysfunction
EDA-ID due to IKBA GOF mutation	NFKBIA	AD GOF	164008	Normal total T cells, TCR activation impaired	Normal B cell numbers, impaired BCR activation, low memory and isotype switched B cells	Decreased IgG and IgA, elevated IgM, poor specific antibody responses, absent antibody to polysaccharide antigens	Anhidrotic ectodermal dysplasia; various infections (bacteria, mycobacteria, viruses, fungi); colitis; variable defects of skin, hair and teeth; T cell and monocyte dysfunction
EDA-ID due to IKBKB GOF mutation	IKBKB	AD GOF	618204	Decreased T cells, impaired TCR activation	Normal number, poor function	Reduced	Recurrent bacterial, viral, fungal infections; variable ectodermal defects
8. Calcium channel defects
ORAI-1 deficiency	ORAI1	AR	610277	Normal, defective TCR mediated activation	Normal	Normal	Autoimmunity; EDA; non-progressive myopathy
STIM1 deficiency	STIM1	AR	605921
9. Other defects
Purine nucleoside phosphorylase (PNP) deficiency	PNP	AR	164050	Progressive decrease	Normal	Normal or low	Autoimmune hemolytic anemia; neurological impairment
Immunodeficiency with multiple intestinal atresias	TTC7A	AR	609332	Variable, but sometimes absent or low TRECs at NBS; may have SCID phenotype at birth	Normal or low	Markedly decreased IgG, IgM, IgA	Bacterial (sepsis), fungal, viral infections; multiple intestinal atresias, often with intrauterine polyhydramnios and early demise
Tricho-Hepato-Enteric Syndrome (THES)	TTC37	AR	222470	Impaired IFNγ production	Variably low numbers of switched memory B cells	Hypogammaglobulinemia, may have low antibody responses	Respiratory infections; IUGR; facial dysmorphic features, wooly hair; early onset intractable diarrhea, liver cirrhosis; platelet abnormalities
	SKIV2L		614602
Hepatic veno-occlusive disease with immunodeficiency (VODI)	SP110	AR	604457	Normal (decreased memory T cells)	Normal (decreased memory B cells)	Decreased IgG, IgA, IgM, absent germinal center and tissue plasma cells	Hepatic veno-occlusive disease; susceptibility to Pneumocystis jirovecii pneumonia, CMV, candida; thrombocytopenia; hepatosplenomegaly; cerebrospinal leukodystrophy
BCL11B deficiency	BCL11B	AD	617237	Low, poor proliferation	Normal	Normal	Congenital abnormalities, neonatal teeth, dysmorphic facies; absent corpus callosum, neurocognitive deficits
EPG5 deficiency (Vici syndrome)	EPG5	AR	615068	Profound depletion of CD4+ cells	Defective	Decreased (particularly IgG2)	Agenesis of the corpus callosum; cataracts; cardiomyopathy; skin hypopigmentation; intellectual disability; microcephaly; recurrent infections, chronic mucocutaneous candidiasis
HOIL1 deficiency	RBCK1	AR	610924	Normal numbers	Normal, decreased memory B cells	Poor antibody responses to polysaccharides	Bacterial infections; autoinflammation; amylopectinosis
HOIP deficiency	RNF31	AR	612487	Normal numbers	Normal, decreased memory B cells	decreased	Bacterial infections; autoinflammation; amylopectinosis; lymphangiectasia
Hennekam-lymphangiectasia-lymphedema syndrome	CCBE1	AR	612753	Low/variable	Low/variable	decreased	Lymphangiectasia and lymphedema with facial abnormalities and other dysmorphic features
	FAT4	AR	612411	Low/variable	Low/variable	decreased	Lymphangiectasia and lymphedema with facial abnormalities and other dysmorphic features
Activating de novo mutations in nuclear factor, erythroid 2- like (NFE2L2)	NFE2L2	AD	617744	Not reported	Decreased switched memory B cells	Hypogammaglobulinemia, decreased antibody responses	Recurrent respiratory and skin infections; growth retardation, developmental delay; white matter cerebral lesions; increased level of homocysteine; increased expression of stress response genes
STAT5b deficiency	STAT5B	AR	245590	Modestly decreased, reduced Treg number and function	Normal	hypergammaglobulinemia, increased IgE	Growth-hormone insensitive dwarfism; dysmorphic features; eczema; lymphocytic interstitial pneumonitis; prominent autoimmunity
STAT5b deficiency	STAT5B	AD (dominant negative)	604260	Normal	Normal	Increased IgE	Growth-failure; eczema (no immune defects compared to AR STAT5 deficiency)
Kabuki syndrome (type 1 and 2)	KMT2D	AD	602113	Normal	Normal	Low IgA and occasionally low IgG	Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature; intellectual disability; congenital heart defects; recurrent infections (otitis media, pneumonia) in 50% of patients; autoimmunity may be present
	KDM6A	XL (females may be affected)	300128
KMT2A deficiency (Wiedemann-Steiner syndrome)	KMT2A	AD	605130	Normal	Decreased switched and non-switched memory B cells	Hypogammaglobulinemia, decreased antibody responses	Respiratory infections; short stature; hypertelorism; hairy elbows; developmental delay, intellectual disability

Total number of disorders in Table 2: 58

Total number of mutant genes in Table 2: 62

New inborn errors of immunity: 12; LIG1 [30]; FOXN1 haploinsufficiency [31]; IL6R [32, 33]; IL6ST [34, 35]; ZNF341 [36, 37]; ERBB2IP [38]; TGFBR1 [39]; TGFBR2 [39]; AD LOF CARD11 [40, 41]; AD GOF IKBKB [42]; SKIV2L [43]; NFE2L2 [44]

Unknown cause of DiGeorge syndrome, unknown cause of CHARGE syndrome, unknown gene(s) within 10p13–14 deletion responsible for phenotype

EDA ectodermal dysplasia anhydrotic, HSV herpes simplex virus, VZV varicella zoster virus, BCG Bacillus Calmette-Guerin, NBS newborn screen, TREC T cell receptor excision circle (biomarker for low T cells used in NBS), IUGR interuterine growth retardation

Table 3.

Predominantly antibody deficiencies

Disease	Genetic defect	Inheritance	OMIM	Ig	Associated features
1. Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells, agammaglobulinemia
BTK deficiency, X-linked agammaglobulinemia (XLA)	BTK	XL	300300	All isotypes decreased in majority of patients, some patients have detectable immunoglobulins	Severe bacterial infections, normal numbers of pro-B cells
μ heavy chain deficiency	IGHM	AR	147020	All isotypes decreased	Severe bacterial infections, normal numbers of pro-B cells
λ5 deficiency	IGLL1	AR	146770
Igα deficiency	CD79A	AR	112205
Igβ deficiency	CD79B	AR	147245
BLNK deficiency	BLNK	AR	604515
p110δ deficiency	PIK3CD	AR	602839		Severe bacterial infections; autoimmune complications (IBD)
p85 deficiency	PIK3R1	AR	615214		Severe bacterial infections, cytopenias, decreased or absent pro-B cells
E47 transcription factor deficiency	TCF3	AD	616941		Recurrent bacterial infections
	TCF3	AR	147141		Severe, recurrent bacterial infections, failure to thrive
SLC39A7 (ZIP7) deficiency	SLC39A7	AR	601416		Early onset infections, blistering dermatosis, failure to thrive, thrombocytopenia
Hoffman syndrome/TOP2B deficiency	TOP2B	AD	126431		Recurrent infections, facial dysmorphism, limb anomalies
2. Severe reduction in at least 2 serum immunoglobulin isotypes with normal or low number of B cells, CVID phenotype
Common variable immune deficiency with no gene defect specified (CVID)	Unknown	Variable		Low IgG and IgA and/or IgM	Clinical phenotypes vary: most have recurrent infections, some have polyclonal lymphoproliferation, autoimmune cytopenias and/or granulomatous disease
Activated p110δ syndrome (APDS)	PIK3CD GOF	AD	615513 (APDS1)	Normal/increased IgM, reduced IgG and IgA	Severe bacterial infections; reduced memory B cells and increased transitional B cells, EBV ± CMV viremia, lymphadenopathy/splenomegaly, autoimmunity, lymphoproliferation, lymphoma
	PIK3R1	AD	616005 (APDS2)		Severe bacterial infections, reduced memory B cells and increased transitional B cells, lymphadenopathy/splenomegaly, lymphoproliferation, lymphoma; developmental delay
PTEN deficiency (LOF)	PTEN	AD	158350	Normal/Decreased	Recurrent infections, Lymphoproliferation, Autoimmunity; developmental delay
CD19 deficiency	CD19	AR	107265	Low IgG and IgA and/or IgM	Recurrent infections, may have glomerulonephritis (CD81 mutation abolishes expression of CD19, thereby phenocopying CD19 mutations)
CD81 deficiency	CD81	AR	186845	Low IgG, low or normal IgA and IgM
CD20 deficiency	CD20	AR	112210	Low IgG, normal or elevated IgM and IgA	Recurrent infections
CD21 deficiency	CD21	AR	120650	Low IgG, impaired anti-pneumococcal response	Recurrent infections
TACI deficiency#	TNFRSF13B	AR or AD	604907	Low IgG and IgA and/or IgM	Variable clinical expression and penetrance for monoallelic variants
BAFF receptor deficiency	TNFRSF13C	AR	606269	Low IgG and IgM,	Variable clinical expression
TWEAK deficiency	TNFSF12	AD	602695	Low IgM and A, lack of anti-pneumococcal antibody	Pneumonia, bacterial infections, warts, thrombocytopenia. Neutropenia
TRNT1 deficiency	TRNT1	AR	612907	B cell deficiency and hypogammaglobulinemia	congenital sideroblastic anemia, deafness, developmental delay
NFKB1 deficiency	NFKB1	AD	164011	Normal or low IgG, IgA, IgM, low or normal B cells, low memory B cells	Recurrent sinopulmonary infections, COPD, EBV proliferation, autoimmune cytopenias, alopecia and autoimmune thyroiditis
NFKB2 deficiency	NFKB2	AD	615577	Low serum IgG, A and M; low B cell numbers	Recurrent sinopulmonary infections, alopecia and endocrinopathies
IKAROS deficiency	IKZF1	AD (haploinsufficiency)	603023	Low IgG, IgA, IgM, low or normal B cells; B cells and Ig levels reduce with age	Decreased pro-B cells, recurrent sinopulmonary infections; increased risk of ALL, autoimmunity, CVID phenotype
IRF2BP2 deficiency	IRF2BP2	AD	615332	Hypogammaglobulinemia, absent IgA	Recurrent infections, possible autoimmunity and inflammatory disease
ATP6AP1 deficiency	ATP6AP1	XL	300972	Variable immunoglobulin findings	Hepatopathy, leukopenia, low copper
ARHGEF1 deficiency	ARHGEF1	AR	618459	Hypogammaglobulinemia; lack of antibody	Recurrent infections, bronchiectasis
SH3KBP1 (CIN85) deficiency	SH3KBP1	XL	300310	IgM, IgG deficiency; loss of antibody	Severe bacterial infections
SEC61A1 deficiency	SEC61A1	AD	609213	Hypogammaglobulinemia	Severe recurrent respiratory tract infections
RAC2 deficiency	RAC2	AR	602049	Low IgG, IgA, IgM, low or normal B cells; reduced Ab responses following vaccination	Recurrent sinopulmonary infections, selective IgA deficiency; poststreptococcal glomerulonephritis; urticaria
Mannosyl-oligosaccharide glucosidase deficiency	MOGS	AR	601336	Low IgG, IgA, IgM, increased B cells; poor Ab responses following vaccination	Bacterial and viral infections; severe neurologic disease; also known as congenital disorder of glycosylation type IIb (CDG-IIb)
3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells, hyper IgM
AID deficiency	AICDA	AR	6055258	IgG and IgA decreased, IgM increased; normal memory B cells but lacking somatic hypermutation	Bacterial infections, enlarged lymph nodes and germinal centers; autoimmunity
		AD	605257	IgG absent or decreased, IgA undetected, IgM increased; normal memory B cells with intact somatic hypermutation	Bacterial infections, enlarged lymph nodes and germinal centers. Mutations uniquely localize to the nuclear export signal.
UNG deficiency	UNG	AR	191525	IgG and IgA decreased, IgM increased	Enlarged lymph nodes and germinal centers
INO80 deficiency	INO80	AR	610169	IgG and IgA decreased, IgM increased	Severe bacterial infections
MSH6 deficiency	MSH6	AR	600678	Variable IgG, defects, increased IgM in some, normal B cells, low switched memory B cells, Ig class switch recombination and somatic hypermutation defects	Family or personal history of cancer
4. Isotype, light chain, or functional deficiencies with generally normal numbers of B cells
Ig heavy chain mutations and deletions	Mutation or chromosomal deletion at 14q32	AR		One or more IgG and/or IgA subclasses as well as IgE may be absent	May be asymptomatic
Kappa chain deficiency	IGKC	AR	147200	All immunoglobulins have lambda light chain	Asymptomatic
Isolated IgG subclass deficiency	Unknown	?		Reduction in one or more IgG subclass	Usually asymptomatic, a minority may have poor antibody response to specific antigens and recurrent viral/bacterial infections
IgG subclass deficiency with IgA deficiency	Unknown	?		Reduced IgA with decrease in one or more IgG subclass	Recurrent bacterial infections
May be asymptomatic
Selective IgA deficiency	Unknown	?		Absent IgA with other isotypes normal, normal subclasses and specific antibodies	May be asymptomatic Bacterial infections, autoimmunity mildly increased
Specific antibody deficiency with normal Ig levels and normal B cells	Unknown	?		Normal	Reduced ability to produce antibodies to specific antigens
Transient hypogammaglobulinemia of infancy	Unknown	?		IgG and IgA decreased	Normal ability to produce antibodies to vaccine antigens, usually not associated with significant infections
CARD11 GOF	CARD11	AD GOF	616452	Polyclonal B cell lymphocytosis due to constitutive NF-κB activation	Splenomegaly, lymphadenopathy, poor vaccine response
Selective IgM deficiency	Unknown	?		Absent serum IgM	Pneumococcal/bacterial

Common variable immunodeficiency disorders (CVID) include several clinical and laboratory phenotypes that may be caused by distinct genetic and/or environmental factors. Some patients with CVID and no known genetic defect have markedly reduced numbers of B cells as well as hypogammaglobulinemia. Identification of causal variants can assist in defining treatment. In addition to monogenic causes on this table, a small minority of patients with XLP (Table 4), WHIM syndrome (Table 6), ICF (Table 2), VODI (Table 2), thymoma with immunodeficiency (Good syndrome), or myelodysplasia are first seen by an immunologist because of recurrent infections, hypogammaglobulinemia, and normal or reduced numbers of B cells

Total number of disorders in Table 3: 46

Total number of mutant genes in Table 3: 39

New disorders: 9: AR PIK3CD [46–48]; AR TCF3 [49, 50]; SLC39A7 [51]; TOP2B [52]; ARHGEF1 [53]; SH3KBP1 [54]; SEC61A1 [55]; AR LOF RAC2 [56]; AD AICDA

EBV Epstein-Barr virus, COPD chronic obstructive pulmonary disease

^#Heterozygous variants in TNFRSF13B have been detected in healthy individuals, thus such variants are likely to be disease-modifying rather than disease-causing

Table 4.

Diseases of immune dysregulation

Disease	Genetic defect	Inheritance	OMIM	Circulating T cells	Circulating B cells	Functional defect	Associated features
1. Familial hemophagocytic lymphohistiocytosis (FHL syndromes)
Perforin deficiency (FHL2)	PRF1	AR	170280	Increased activated T cells	Normal	Decreased to absent NK and CTL activities cytotoxicity	Fever, HSM, hemophagocytic lymphohistiocytosis (HLH), cytopenias
UNC13D/Munc13–4 deficiency (FHL3)	UNC13D	AR	608897	Increased activated T cells	Normal	Decreased to absent NK and CTL activities (cytotoxicity and/or degranulation)	Fever, HSM, HLH, cytopenias,
Syntaxin 11 deficiency (FHL4)	STX11	AR	605014
STXBP2/Munc18–2 deficiency (FHL5)	STXBP2	AR or AD	601717
FAAP24 deficiency	FAAP24	AR	610884	Increased activated T cells	Normal	Failure to kill autologous EBV transformed B cells. Normal NK cell function	EBV-driven lymphoproliferative disease
SLC7A7 deficiency	SLC7A7	AR	222700	Normal	Normal	Hyper-inflammatory response of macrophages Normal NK cell function	Lysinuric protein intolerance, bleeding tendency, alveolar proteinosis
2. FHL syndromes with hypopigmentation
Chediak-Higashi syndrome	LYST	AR	606897	Increased activated T cells	Normal	Decreased NK and CTL activities (cytotoxicity and/or degranulation)	Partial albinism, recurrent infections, fever, HSM, HLH, giant lysosomes, neutropenia, cytopenias, bleeding tendency, progressive neurological dysfunction
Griscelli syndrome, type 2	RAB27A	AR	603868	Normal	Normal	Decreased NK and CTL activities (cytotoxicity and/or degranulation)	Partial albinism, fever, HSM, HLH, cytopenias
Hermansky-Pudlak syndrome, type 2	AP3B1	AR	603401	Normal	Normal	Decreased NK and CTL activities (cytotoxicity and/or degranulation)	Partial albinism, recurrent infections, pulmonary fibrosis, increased bleeding, neutropenia, HLH
Hermansky-Pudlak syndrome, type 10	AP3D1	AR	617050	Normal	Normal	Decreased NK and CTL activities (cytotoxicity and/or degranulation)	Oculocutaneous albinism, severe neutropenia, recurrent infections, seizures, hearing loss and neurodevelopmental delay
3. Regulatory T cell defects
IPEX, immune dysregulation, polyendocrinopathy, enteropathy X-linked	FOXP3	XL	300292	Normal	Normal	Lack of (and/or impaired function of) CD4+ CD25+ FOXP3+ regulatory T cells (Tregs)	Autoimmune enteropathy, early onset diabetes, thyroiditis hemolytic anemia, thrombocytopenia, eczema, elevated IgE and IgA
CD25 deficiency	IL2RA	AR	147730	Normal to decreased	Normal	No CD4 + C25+ cells with impaired function of Tregs cells	Lymphoproliferation, autoimmunity, impaired T cell proliferation in vitro
CD122 deficiency	IL2RB	AR	618495	Increased memory CD8 T cells, decreased Tregs	Increased memory B cells	Diminished IL2Rβ expression, dysregulated signaling in response to IL-2/IL-15; increased immature NK cells	Lymphoproliferation, lymphadenopathy, hepatosplenomegaly, autoimmune hemolytic anemia, dermatitis, enteropathy, hypergammaglobulinemia, recurrent viral (EBV, CMV) infections
CTLA4 haploinsufficiency (ALPS-V)	CTLA4	AD	123890	Decreased	Decreased	Impaired function of Tregs.	Autoimmune cytopenias, enteropathy, interstitial lung disease, extra-lymphoid lymphocytic infiltration, recurrent infections
LRBA deficiency	LRBA	AR	606453	Normal or decreased CD4 numbers T cell dysregulation	Low or normal numbers of B cells	Reduced IgG and IgA in most	Recurrent infections, inflammatory bowel disease, autoimmunity
DEF6 deficiency	DEF6	AR	610094	Mild CD4 and CD8 lymphopenia	Low or normal numbers of B cells	Impaired Treg function	Enteropathy, hepatosplenomegaly, cardiomyopathy, recurrent infections
STAT3 GOF mutation	STAT3	AD GOF	102582	Decreased	Decreased	Enhanced STAT3 signaling, leading to increased Th17 cell differentiation, lymphoproliferation and autoimmunity. Decreased Tregs and impaired function	Lymphoproliferation, solid organ autoimmunity, recurrent infections
BACH2 deficiency	BACH2	AD	605394	Progressive T cell lymphopenia	Impaired memory B cell development	Haploinsufficiency for a critical lineage specification transcription factor	Lymphocytic colitis, sinopulmonary infections
FERMT1 deficiency	FERMT1	AR	173650	Normal	Normal	Intracellular accumulation of IgG, IgM, IgA, and C3 in colloid bodies under the basement membrane	Dermatosis characterized by congenital blistering, skin atrophy, photosensitivity, skin fragility, and scaling
4. Autoimmunity with or without lymphoproliferation
APECED (APS-1), autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy	AIRE	AR or AD	240300	Normal	Normal	AIRE serves as check-point in the thymus for negative selection of autoreactive T cells and for generation of Tregs	Autoimmunity: hypoparathyroidism, hypothyroidism, adrenal insufficiency, diabetes, gonadal dysfunction and other endocrine abnormalities; dental enamel hypoplasia, alopecia areata enteropathy, pernicious anemia; chronic mucocutaneous candidiasis
ITCH deficiency	ITCH	AR	606409	Not assessed	Not assessed	Itch deficiency may cause immune dysregulation by affecting both anergy induction in auto-reactive effector T cells and generation of Tregs	Early-onset chronic lung disease (interstitial pneumonitis), autoimmunity (thyroiditis, type I diabetes, chronic diarrhea/enteropathy, and hepatitis), failure to thrive, developmental delay, dysmorphic facial features
Tripeptidyl-peptidase II deficiency	TPP2	AR	190470	Decreased	Decreased	TPP2 deficiency results in premature immunosenescence and immune dysregulation	Variable lymphoproliferation, severe autoimmune cytopenias, hypergammaglobulinemia, recurrent infections
JAK1 GOF	JAK1	AD GOF	147795	Not assessed	Not assessed	Hyperactive JAK1	HSM, eosinophilia, eosinophilic enteritis, thyroid disease, poor growth, viral infections
Prolidase deficiency	PEPD	AR	613230	Normal	Normal	Peptidase D	Autoantibodies common, chronic skin ulcers, eczema, infections
5. Immune dysregulation with colitis
IL-10 deficiency	IL10	AR	124092	Normal	Normal	No functional IL-10 secretion	Inflammatory bowel disease (IBD), folliculitis, recurrent respiratory diseases, arthritis,
IL-10R deficiency	IL10RA	AR	146933	Normal	Normal	Leukocytes unresponsive to IL-10	IBD, folliculitis, recurrent respiratory diseases, arthritis, lymphoma
	IL10RB	AR	123889	Normal	Normal	Leukocytes unresponsive to IL-10, and IL-22, IL-26, IL-28A, IL-28B and IL-29
NFAT5 haploinsufficiency	NFAT5	AD	604708	Normal	Normal	Decreased memory B cells and plasmablasts	IBD, recurrent sinopulmonary infections
TGFB1 deficiency	TGFB1	AR	618213	Normal	Normal	Decreased T cell proliferation in response to anti-CD3	IBD, immunodeficiency, recurrent viral infections, microcephaly, and encephalopathy
RIPK1	RIPK1	AR	618108	Reduced	Normal/reduced	Reduced activation of MAPK, NFkB pathways to	Recurrent infections, early-onset IBD, progressive polyarthritis
6. Autoimmune lymphoproliferative syndrome (ALPS, Canale-Smith syndrome)
ALPS-FAS	TNFRSF6	AD AR	134637	Increased TCR α/β+CD4−CD8− double negative (DN) T cells	Normal, low memory B cells	Apoptosis defect FAS mediated	Splenomegaly, adenopathies, autoimmune cytopenias, increased lymphoma risk, IgG and A normal or increased, elevated serum FasL, IL-10, vitamin B12
ALPS-FASLG	TNFSF6	AR	134638	Increased DN T cells	Normal	Apoptosis defect FASL mediated	Splenomegaly, adenopathies, autoimmune cytopenias, SLE, soluble FasL is not elevated
ALPS-Caspase10	CASP10	AD	601762	Increased DN T cells	Normal	Defective lymphocyte apoptosis	Adenopathies, splenomegaly, autoimmunity
ALPS-Caspase 8	CASP8	AR	601763	Slightly increased DN T cells	Normal	Defective lymphocyte apoptosis and activation	Adenopathies, splenomegaly, bacterial and viral infections, hypogammaglobulinemia
FADD deficiency	FADD	AR	602457	Increased DN T cells	Normal	Defective lymphocyte apoptosis	Functional hyposplenism, bacterial and viral infections, recurrent episodes of encephalopathy and liver dysfunction
7. Susceptibility to EBV and lymphoproliferative conditions
SAP deficiency (XLP1)	SH2D1A	XL	300490	Normal or Increased activated T cells	Reduced Memory B cells	Reduced NK cell and CTL cytotoxic activity	Clinical and immunologic features triggered by EBV infection: HLH, Lymphoproliferation, Aplastic anemia, Lymphoma. Hypogammaglobulinemia, Absent iNKT cells
XIAP deficiency (XLP2)	XIAP	XL	300079	Normal or Increased activated T cells; low/normal iNK T cells	Normal or reduced Memory B cells	Increased T cells susceptibility to apoptosis to CD95 and enhanced activation-induced cell death (AICD)	EBV infection, Splenomegaly, lymphoproliferation HLH, Colitis, IBD, hepatitis Low iNKT cells
CD27 deficiency	CD27	AR	615122	Normal	No memory B cells	hypogammaglobulinemia; poor Ab responses to some vaccines/infections	Features triggered by EBV infection, HLH, aplastic anemia, low iNKT cells, B-lymphoma
CD70 deficiency	CD70	AR	602840	Normal number, low Treg, poor activation and function	Decreased memory B cells	hypogammaglobulinemia; poor Ab responses to some vaccines/infections	EBV susceptibility, Hodgkin lymphoma; autoimmunity in some patients
CTPS1 deficiency	CTPS1	AR	615897	Normal to low, but reduced activation, proliferation	Decreased memory B cells	Normal/high IgG poor proliferation to antigen	Recurrent/chronic bacterial and viral infections (EBV, VZV), EBV lymphoproliferation, B cell non-Hodgkin lymphoma
CD137 deficiency (41BB)	TNFRSF9	AR	602250	Normal	Normal	Low IgG, low IgA, poor responses to T cell-dependent and T cell independent antigens, decreased T cell proliferation, IFNγ secretion, cytotoxicity	EBV lymphoproliferation, B cell lymphoma, chronic active EBV infection
RASGRP1 deficiency	RASGRP1	AR	603962	Poor activation, proliferation, motility. Reduced naïve T cells	Poor activation, proliferation, motility	Normal IgM, IgG, increased IgA	Recurrent pneumonia, herpesvirus infections, EBV associated lymphoma Decreased NK cell function
RLTPR deficiency	CARMIL2	AR	610859	Normal number, high CD4, increased naïve CD4+ and CD8+ T cells, low Treg and MAIT, poor CD28-induced function	Normal B cell numbers, reduced memory B cells	Normal to low, poor T dependent antibody response	Recurrent bacterial, fungal and mycobacterial infections, viral warts, molluscum and EBV lymphoproliferative and other malignancy, atopy
X-linked magnesium EBV and neoplasia (XMEN)	MAGT1	XL	300853	Low CD4 Low recent thymic emigrant cels, inverted CD4/CD8 ratio, reduced MAIT cells, poor proliferation to CD3	Normal but decreased memory B cells	Progressive hypogammaglobulinemia Reduced NK cell and CTL cytotoxic activity due to impaired expression of NKG2D	EBV infection, lymphoma, viral infections, respiratory and GI infections Glycosylation defects
PRKCD deficiency	PRKCD	AR	615559	Normal	Low memory B cells, high CD5 B cells	Apoptotic defect in B cells	Recurrent infections, EBV chronic infection, lymphoproliferation, SLE-like autoimmunity (nephrotic and antiphospholipid syndromes), low IgG

Total number of disorders in Table 4: 44

Total number of mutant genes in Table 4: 45

New disorders: 8; SLC7A7 [57]; IL2RB [58, 59]; DEF6 [60]; FERMT1 [61]; TGFB1 [62]; RIPK1 [63, 64]; TNFRSF9 [46, 65, 66]; STAT5B AD DN []

FHL familial hemophagocytic lymphohistiocytosis, HLH hemophagocytic lymphohistiocytosis, HSM hepatosplenomegaly, DN double-negative, SLE systemic lupus erythematous, IBD Inflammatory bowel disease

Table 5.

Congenital defects of phagocyte number or function

Disease	Genetic defect	Inheritance	OMIM	Affected cells	Affected function	Associated features
1. Congenital neutropenias
Elastase deficiency (Severe congential neutropenia [SCN] 1)	ELANE	AD	130130	N	Myeloid differentiation	Susceptibility to MDS/leukemia Severe congenital neutropenia or cyclic neutropenia
GFI 1 deficiency (SCN2)	GFI1	AD	600871	N	Myeloid differentiation	B/T lymphopenia
HAX1 deficiency (Kostmann Disease) (SCN3)	HAX1	AR	605998	N	Myeloid differentiation	Cognitive and neurological defects in patients with defects in both HAX1 isoforms, susceptibility to MDS/leukemia
G6PC3 deficiency (SCN4)	G6PC3	AR	611045	N	Myeloid differentiation, chemotaxis, O2− production	Structural heart defects, urogenital abnormalities, inner ear deafness, and venous angiectasias of trunks and limbs
VPS45 deficiency (SCN5)	VPS45	AR	610035	N	Myeloid differentiation, migration	Extramedullary hematopoiesis, bone marrow fibrosis, nephromegaly
Glycogen storage disease type 1b	G6PT1	AR	602671	N + M	Myeloid differentiation, chemotaxis, O2− production	Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly
X-linked neutropenia/myelodysplasia	WAS	XL GOF	300299	N	Differentiation, mitosis. Results from GOF mutations in GTPase binding domain of WASp	Neutropenia, myeloid maturation arrest, monocytopenia, variable lymphoid anomalies
P14/LAMTOR2 deficiency	LAMTOR2	AR	610389	N + M	Endosomal biogenesis	Neutropenia Hypogammaglobulinemia ↓CD8 cytotoxicity, partial albinism, growth failure
Barth Syndrome (3-Methylglutaconic aciduria type II)	TAZ	XL	300394	N + L Mel	Mitochondrial function	Cardiomyopathy, myopathy, growth retardation, neutropenia
Cohen syndrome	VPS13B	AR	607817	N	Myeloid differentiation	Dysmorphism, mental retardation, obesity, deafness, neutropenia
Clericuzio syndrome (Poikiloderma with neutropenia)	USB1	AR	613276	N	Myeloid differentiation	Retinopathy, developmental delay, facial dysmorphisms, poikiloderma
JAGN1 deficiency	JAGN1	AR	616012	N	Myeloid differentiation	Myeloid maturation arrest, osteopenia
3-Methylglutaconic aciduria	CLPB	AR	616254	N	Myeloid differentiation Mitochondrial protein	Neurocognitive developmental aberrations, microcephaly, hypoglycemia, hypotonia, ataxia, seizures, cataracts, IUGR
G-CSF receptor deficiency	CSF3R	AR	138971	N	Stress granulopoiesis disturbed
SMARCD2 deficiency	SMARCD2	AR	601736	N	Chromatin remodeling, Myeloid differentiation and neutrophil functional defect	Neutropenia, developmental aberrations, bones, hematopoietic stem cells, myelodysplasia
Specific granule deficiency	CEBPE	AR	189965	N	Terminal maturation and global dysfunction	Neutropenia, Neutrophils with bilobed nuclei
Shwachman-Diamond Syndrome	SBDS	AR	607444	N	Neutrophil maturation, chemotaxis, ribosomal biogenesis	Pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia
	DNAJC21	AR	617052	N + HSC		Pancytopenia, exocrine pancreatic insufficiency
	EFL1	AR	617941	N + HSC
HYOU1 deficiency	HYOU1	AR	601746	N	Unfolded protein response	Hypoglycemia, inflammatory complications
SRP54 deficiency	SRP54	AD	604857	N	Protein translocation to ER, myeloid differentiation and neutrophil functional defect	Neutropenia, exocrine pancreatic insufficiency
2. Defects of motility
Leukocyte adhesion deficiency type 1 (LAD1)	ITGB2	AR	600065	N + M + L + NK	Adherence, chemotaxis, endocytosis, T/NK cytotoxicity	Delayed cord separation, skin ulcers, periodontitis, leukocytosis
Leukocyte adhesion deficiency type 2 (LAD2)	SLC35C1	AR	605881	N + M	Rolling, chemotaxis	Mild LAD type 1 features with hh-blood group, growth retardation, developmental delay
Leukocyte adhesion deficiency type 3 (LAD3)	FERMT3	AR	607901	N + M + L + NK	Adherence, chemotaxis	LAD type 1 plus bleeding tendency
Rac2 deficiency	RAC2	AD LOF	608203	N	Adherence, chemotaxis O2− production	Poor wound healing, leukocytosis
β actin deficiency	ACTB	AD	102630	N + M	Motility	Mental retardation, short stature
Localized juvenile periodontitis	FPR1	AR	136537	N	Formylpeptide induced chemotaxis	Periodontitis only
Papillon-Lefèvre syndrome	CTSC	AR	602365	N + M	Chemotaxis	Periodontitis, palmoplantar hyperkeratosis in some patients
WDR1 deficiency	WDR1	AR	604734	N	Spreading, survival, chemotaxis	Mild neutropenia, poor wound healing, severe stomatitis, neutrophil nuclei herniate
Cystic fibrosis	CFTR	AR	602421	M only	Chemotaxis	Respiratory infections, pancreatic insufficiency, elevated sweat chloride
Neutropenia with combined immune deficiency due to MKL1 deficiency	MKL1	AR	606078	N + M + L + NK	Impaired expression of cytoskeletal genes	Mild thrombocytopenia
3. Defects of respiratory burst
X-linked chronic granulomatous disease (CGD), gp91phox	CYBB	XL	306400	N + M	Killing (faulty O2− production)	Infections, autoinflammatory phenotype, IBD McLeod phenotype in patients with deletions extending into the contiguous Kell locus
Autosomal recessive CGD	CYBA	AR	608508			Infections, autoinflammatory phenotype
	CYBC1		618334
	NCF1		608512
	NCF2		608515
	NCF4		613960
G6PD deficiency class I	G6PD	XL	305900	N	Reduced O2− production	Infections
4. Other non-lymphoid defects
GATA2 deficiency	GATA2	AD	137295	Monocytes + peripheral DC	Multi lineage cytopenias	Susceptibility to mycobacteria, HPV, histoplasmosis, alveolar proteinosis, MDS/AML/CMML, lymphedema
Pulmonary alveolar proteinosis	CSF2RA	XL (Biallelic mutations in pseudo-autosomal gene)	300770	Alveolar macrophages	GM-CSF signaling	Alveolar proteinosis
	CSFR2B	AR	614370

Total number of disorders in Table 5: 34

Total number of mutant genes in Table 5: 41

New disorders: 3; SRP54 [67, 68]; DNAJC21 [69]; CYBC1 [70, 71]

Removed: Cyclic neutropenia was merged with elastase deficiency

MDS myelodysplastic syndrome, IUGR intrauterine growth retardation, LAD leukocyte adhesion deficiency, AML acute myelogenous leukemia, CMML chronic myelomonocytic leukemia, N neutrophil, M monocyte, MEL melanocyte, L lymphocyte, NK natural killer

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	IFN-γ secretion	Susceptibility to mycobacteria and Salmonella
IL-12p40 (IL-12 and IL-23) deficiency	IL12B	AR	161561	M
IL-12Rβ2 deficiency	IL12RB2	AR	601642	L + NK
IL-23R deficiency	IL23R	AR	607562	L + NK
IFN-γ receptor 1 deficiency	IFNGR1	AR	209950	M + L	IFN-γ binding and signaling
		AD	615978	M + L
IFN-γ receptor 2 deficiency	IFNGR2	AR	147569	M + L	IFN-γ signaling
STAT1 deficiency	STAT1	AD LOF	614892	M + L
Macrophage gp91 phox deficiency	CYBB	XL	300645	Macrophage only	Killing (faulty O2− production)	Isolated susceptibility to mycobacteria
IRF8 deficiency	IRF8	AD	614893	M + L	Impaired development of cDCs and Th1* cells	Susceptibility to mycobacteria
		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		IFNγ production defect	Susceptibility to mycobacteria (BCG), brain calcification
RORγt deficiency	RORC	AR	602943	L + NK	Lack of functional RORγT protein, IFNγ 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 IFNγ production	Susceptibility to mycobacteria and viruses, urothelial carcinoma
2. Epidermodysplasia verruciformis (HPV)
EVER1 deficiency	TMC6	AR	605828	Keratinocytes	EVER1, EVER2 and CIB1 form a complex in keratinocytes	Human papillomavirus (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, γ and λ responses	Severe viral infections, mycobacterial infection
STAT2 deficiency	STAT2	AR	600556	Leukocytes and other cells	STAT2-dependent IFN-α/β and λ response	Severe viral infections (disseminated vaccine-strain measles)
IRF9 deficiency	IRF9	AR	147574*	Leukocytes and other cells	IRF9- and ISGF3-dependent IFN-α/β and λ responses	Severe influenza disease
IRF7 deficiency	IRF7	AR	605047	Leukocytes, plasmacytoid dendritic cells, non-hematopoietic cells	IFN-α, β and γ production and IFN-λ production
IFNAR1 deficiency	IFNAR1	AR	107450*	Leukocytes and other cells	IFNAR1-dependent responses to IFN-α/β	Severe disease caused by 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 cells function	Severe herpes viral infections, particularly VZV, Epstein-Barr virus (EBV), and (HPV)
MDA5 deficiency	IFIH1	AR LOF	606951	Broadly expressed	Viral recognition and IFN induction	Rhinovirus and other RNA viruses
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
4. Herpes simplex encephalitis (HSE)
TLR3 deficiency	TLR3	AD	613002	Central nervous system (CNS) resident cells and fibroblasts	TLR3-dependent IFN-α, β and γ response	Herpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here); severe pulmonary influenza; VZV
		AR
UNC93B1 deficiency	UNC93B1	AR	608204		UNC-93B-dependent IFN-α, β and γ response	Herpes simplex virus 1 encephalitis
TRAF3 deficiency	TRAF3	AD	601896		TRAF3-dependent IFN-α, β and γ response
TRIF deficiency	TICAM1	AD	607601		TRIF-dependent IFN-α, β and γ response
		AR
TBK1 deficiency	TBK1	AD	604834		TBK1-dependent IFN-α, β and 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 anti-viral IFNs	HSE of the brainstem. Other viral infections of the brainstem.
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	CMC, folliculitis
IL-17RC deficiency	IL17RC	AR	610925		IL-17RC signaling pathway	CMC
IL-17F deficiency	IL17F	AD	606496	T cells	IL-17F-containing dimers	CMC, folliculitis
STAT1 GOF	STAT1	AD GOF	600555	T cells, B cells, monocytes	Gain-of-function STAT1 mutations that impair the development of IL-17-producing T cells	CMC, various fungal, bacterial and viral (HSV) infections, auto-immunity (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
7. TLR signaling pathway deficiency with bacterial susceptibility
IRAK4 deficiency	IRAK4	AR	606883	Lymphocytes + granulocytes+ monocytes	TIR-IRAK4 signaling pathway	Bacterial infections (pyogens)
MyD88 deficiency	MYD88	AR	602170	Lymphocytes + granulocytes + monocytes	TIR-MyD88 signaling pathway
IRAK1 deficiency	IRAK1	XL	300283	Lymphocytes + granulocytes + monocytes	TIR-IRAK1 signaling pathway	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
8. Other inborn errors of immunity related to non-hematopoietic 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)
	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   Osteopetrosis	RANBP2	AR	601181	Ubiquitous expression	Nuclear pore	Fever induces acute encephalopathy
	CLCN7	AR	602727	Osteoclasts	Secretory lysosomes	Osteopetrosis with hypocalcemia, neurologic features
	SNX10	AR	614780			Osteopetrosis with visual impairment
	OSTM1	AR	607649			Osteopetrosis with hypocalcemia, neurologic 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 suppurative with cutaneous hyperpigmentation
	PSENEN	AD	613736			Verneuil’s disease/Hidradenitis suppurativa
9. Other inborn errors of immunity related to leukocytes
IRF4 haploinsufficiency	IRF4	AD	601900	L + M	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

Total number of disorders in Table 6: 53

Total number of mutant genes in Table 6: 64

New genes: 13, IL12RB2 [72]; IL23R [72]; SPPL2A [73]; TYK2 P1104A allele [10]; CIB1 [74]; IRF9 [75]; IFNAR1 [76]; POLR3A [77]; POLR3C [77]; POLR3F [78]; DBR1 [79]; IRF4 [80]; IL18BP [81]

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

Table 7.

Autoinflammatory disorders

Disease	Genetic defect	Inheritance	OMIM	T cells	B cells	Functional defect	Associated features
1. Type 1 interferonopathies
STING-associated vasculopathy, infantile-onset (SAVI)	TMEM173	AR	612374	Not assessed	Not assessed	STING activates both the NF-kappa-B and IRF3 transcription pathways to induce expression of IFN	Skin vasculopathy, inflammatory lung disease, systemic autoinflammation and ICC, FCL
ADA2 deficiency	ADA2	AR	607575	Not assessed	Not assessed	ADAs deactivate extracellular adenosine and terminate signaling through adenosine receptors	Polyarteritis nodosa, childhood-onset, early-onset recurrent ischemic stroke and fever; some patients develop hypogammaglobulinemia
TREX1 deficiency, Aicardi-Goutieres syndrome 1 (AGS1)	TREX1	AR	606609	Not assessed	Not assessed	Intracellular accumulation of abnormal ss DNA species leading to increased type I IFN production	Classical AGS, SLE, FCL
RNASEH2B deficiency, AGS2	RNASEH2B	AR	610326	Not assessed	Not assessed	Intracellular accumulation of abnormal RNA-DNA hybrid species leading to increased type I IFN production	Classical AGS, SP
RNASEH2C deficiency, AGS3	RNASEH2C	AR	610330	Not assessed	Not assessed		Classical AGS
RNASEH2A deficiency, AGS4	RNASEH2A	AR	606034	Not assessed	Not assessed		Classical AGS
SAMHD1 deficiency, AGS5	SAMHD1	AR	606754	Not assessed	Not assessed	Controls dNTPs in the cytosol, failure of which leads to increased type I IFN production	Classical AGS, FCL
ADAR1 deficiency, AGS6	ADAR1	AR	146920	Not assessed	Not assessed	Catalyzes the deamination of adenosine to inosine in dsRNA substrates, failure of which leads to increased type I IFN production	Classical AGS, BSN, SP
Aicardi-Goutieres syndrome 7 (AGS7)	IFIH1	AD GOF	615846	Not assessed	Not assessed	IFIH1 gene encodes a cytoplasmic viral RNA receptor that activates type I interferon signaling through the MAVS adaptor molecule	Classical AGS, SLE, SP, SMS
DNAse II deficiency	DNASE2	AR	126350	Not assessed	Not assessed	DNAse II degrades and eliminates DNA. Loss of DNase II activity induces type I interferon signaling	AGS
Pediatric systemic lupus erythematosus due to DNASE1L3 deficiency	DNASE1L3	AR	614420			DNASE1L3 is an endonuclease that degrades extracellular DNA. DNASE1L3 deficiency decreases clearance of apoptotic cells	Very early onset SLE, reduced complement levels, autoantibodies (dsDNA, ANCA), lupus nephritis, hypocomplementemic urticarial vasculitis syndrome
Spondyloenchondro-dysplasia with immune dysregulation (SPENCD)	ACP5	AR	171640	Not assessed	Not assessed	Upregulation of IFN through mechanism possibly relating to pDCS	Short stature, SP, ICC, SLE, thrombocytopenia and autoimmune hemolytic anemia, possibly recurrent bacterial and viral infections
X-linked reticulate pigmentary disorder	POLA1	XL	301220	Not assessed	Not assessed	POLA1 is required for synthesis of cytosolic RNA:DNA and its deficiency leads to increase production of type I interferon	Hyperpigmentation, characteristic facies, lung and GI involvement
USP18 deficiency	USP18	AR	607057	Not assessed	Not assessed	Defective negative regulation of ISG15 leading to increased IFN	TORCH-like syndrome
OAS1 deficiency	OAS1	AD GOF	164350		Low	Increased interferon from recognition of RNA	Pulmonary alveolar proteinosis, skin rash
2. Defects affecting the inflammasome
Familial Mediterranean fever	MEFV	AR LOF	249100	Mature granulocytes, cytokine-activated monocytes.	Increased inflammasome-mediated induction of IL1β.	Recurrent fever, serositis and inflammation responsive to colchicine. Predisposes to vasculitis and inflammatory bowel disease.
		AD	134610	Mature granulocytes, cytokine-activated monocytes.	Usually M694del variant.
Mevalonate kinase deficiency (Hyper IgD syndrome)	MVK	AR	260920	Somatic and hemaotpoietic	affecting cholesterol synthesis, pathogenesis of disease unclear	Periodic fever and leukocytosis with high IgD levels
Muckle-Wells syndrome	NLRP3	AD GOF	191900	PMNs Monocytes	Defect in cryopyrin, involved in leukocyte apoptosis and NFkB signaling and IL-1 processing	Urticaria, SNHL, amyloidosis.
Familial cold autoinflammatory syndrome 1		AD GOF	120100	PMNs, monocytes		Non-pruritic urticaria, arthritis, chills, fever and leukocytosis after cold exposure.
Neonatal onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA)		AD GOF	607115	PMNs, chondrocytes		Neonatal onset rash, chronic meningitis, and arthropathy with fever and inflammation.
Familial cold autoinflammatory syndrome 2	NLRP12	AD GOF	611762	PMNs, monocytes		Non-pruritic urticaria, arthritis, chills, fever and leukocytosis after cold exposure.
NLRC4-MAS (macrophage activating syndrome)	NLRC4	AD GOF	616050	PMNs monocytes macrophages	Gain of function mutation in NLRC4 results in elevated secretion of IL-1β and IL-18 as well as macrophage activation	Severe enterocolitis and macrophage activation syndrome
Familial cold autoinflammatory syndrome 4			616115
PLAID (PLCγ2 associated antibody deficiency and immune dysregulation)	PLCG2	AD GOF	614878	B cells, NK, Mast cells	Mutations activate IL-1 pathways	Cold urticaria hypogammaglobulinemia, impaired humoral immunity, autoinflammation
Familial cold autoinflammatory syndrome 3 or APLAID (c2120A > C)			614468
NLRP1 deficiency	NLRP1	AR	617388	leukocytes	Systemic elevation of IL-18 and caspase 1, suggesting involvement of NLRP1 inflammasome	Dyskeratosis, autoimmunity and arthritis
NLRP1 GOF	NLRP1	AD GOF	615225	Keratinocytes	Increased IL1β	Palmoplantar carcinoma, corneal scarring; recurrent respiratory papillomatosis
3. Non-inflammasome-related conditions
TNF receptor-associated periodic syndrome (TRAPS)	TNFRSF1A	AD	142680	PMNs, monocytes	Mutations of 55-kD TNF receptor leading to intracellular receptor retention or diminished soluble cytokine receptor available to bind TNF	Recurrent fever, serositis, rash, and ocular or joint inflammation
Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome, hyperzincemia and hypercalprotectinemia	PSTPIP1	AD	604416	Hematopoietic tissues, upregulated in activated T cells	Disordered actin reorganization leading to compromised physiologic signaling during inflammatory response	Destructive arthritis, inflammatory skin rash, myositis
Blau syndrome	NOD2	AD	186580	Monocytes	Mutations in nucleotide binding site of CARD15, possibly disrupting interactions with lipopolysaccharides and NF-kB signaling	Uveitis, granulomatous synovitis, camptodactyly, rash and cranial neuropathies, 30% develop Crohn colitis
ADAM17 deficiency	ADAM17	AR	614328	Leukocytes and epithelial cells	Defective TNFα production	Early onset diarrhea and skin lesions
Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)	LPIN2	AR	609628	Neutrophils, bone marrow cells	Undefined	Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders
DIRA (Deficiency of the Interleukin 1 Receptor Antagonist)	IL1RN	AR	612852	PMNs, Monocytes	Mutations in the IL1 receptor antagonist allow unopposed action of Interleukin 1	Neonatal onset of sterile multifocal osteomyelitis, periostitis and pustulosis.
DITRA (Deficiency of IL-36 receptor antagonist)	IL36RN	AR	614204	Keratinocytes, leukocytes	Mutations in IL-36RN leads to increase IL-8 production	Pustular psoriasis
SLC29A3 mutation	SLC29A3	AR	602782	Leukocytes, bone cells	–	Hyperpigmentation hypertrichosis, histiocytosis-lymphadenopathy plus syndrome
CAMPS (CARD14 mediated psoriasis)	CARD14	AD	602723	Mainly in keratinocytes	Mutations in CARD14 activate the NF-kB pathway and production of IL-8	Psoriasis
Cherubism	SH3BP2	AD	118400	Stroma cells, bone cells	Hyperactived macrophage and increase NF-kB	Bone degeneration in jaws
CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy)	PSMB8*	AR and AD	256040	Keratinocytes, B cell adipose cells	Mutations cause increased IFN signaling through an undefined mechanism	Contractures, panniculitis, ICC, fevers
	PSMG2	AR	609702	Lymphocytes		Panniculitis, lipodystrophy, autoimmune hemolytic anemia
COPA defect	COPA	AD	6011924	PMN and tissue specific cells	Defective intracellular transport via the coat protein complex I (COPI)	Autoimmune inflammatory arthritis and interstitial lung disease with Th17 dysregulation and autoantibody production
Otulipenia/ORAS	OTULIN	AR	615712	Leukocytes	Increase LUBAC induction of NF-KB activation leading to high proinflamatory cytokines levels.	Fever, diarrhea, dermatitis
A20 deficiency	TNFAIP3	AD	616744	Lymphocytes	Defective inhibition of NF-KB signaling pathway	Arthralgia, mucosal ulcers, ocular inflammation
AP1S3 deficiency	AP1S3	AR	615781	Keratinocytes	Disrupted TLR3 translocation	Pustular psoriasis
ALPI deficiency	ALPI	AR	171740	Intestinal epithelial cells	Deficient inhibition of LPS in intestine	Inflammatory bowel disease
TRIM22	TRIM22	AR	606559	Macrophages, intestinal epithelial cells	Granulomatous colitis	Inflammatory bowel disease
T cell lymphoma subcutaneous panniculitis-like (TIM3 deficiency)	HAVCR2	AR	618398	Leukocytes	Increased inflammasome activity due to defective checkpoint signaling	Panniculitis, HLH, polyclonal cutaneous T cell infiltrates or T cell lymphoma

Total number of disorders in Table 7: 45

Total number of mutant genes in Table 7: 42

New disorders: 9; DNASE2 [82]; DNASE1L3 [83–85]; OAS1 [86]; AD MEFV; NLRP1 GOF [87, 88]; ALPI [89]; TRIM22 [90]; PSMG2 [91]; HAVCR2 [92, 93]

IFN interferon, HSM hepatosplenomegaly, CSF cerebrospinal fluid, SLE systemic lupus erythematosus, TORCH toxoplasmosis, other, rubella, cytomegalovirus, and herpes infections, SNHL sensorineural hearing loss, AGS Aicardi-Goutières syndrome, BSN bilateral striatal necrosis, FCL familial chilblain lupus, ICC intracranial calcification, IFN interferon type I, pDCs plasmacytoid dendritic cells, SP spastic paraparesis, SMS Singleton-Merten syndrome, ss single-stranded DNA

*Variants in PSMB4, PSMB9, PSMA3, and POMP have been proposed to cause a similar CANDLE phenotype in compound heterozygous monogenic (PSMB4), digenic (PSMA3/PSMB8, PSMB9/PSMB4, PSMB4/PSMB8) and AD monogenic (POMP) models [94]

Table 8.

Complement deficiencies

Disease	Genetic defect	Inheritance	Gene OMIM	Laboratory features	Associated features
Complement deficiencies
C1q deficiency due to defects	C1QA	AR	120550	Absent CH50 hemolytic activity, defective activation of the classical pathway, diminished clearance of apoptotic cells	SLE, infections with encapsulated organisms
	C1QB	AR	120570
	C1QC	AR	120575
C1r deficiency	C1R	AR	613785	Absent CH50 hemolytic activity, defective activation of the classical pathway	SLE, infections with encapsulated organisms, Ehlers-Danlos phenotype
C1r Periodontal Ehlers-Danlos	C1R	AD GOF	613785	Normal CH50	Hyperpigmentation, skin fragility
C1s deficiency	C1S	AR	613785	Absent CH50 hemolytic activity, defective activation of the classical pathway	SLE, infections with encapsulated organisms, Ehlers-Danlos phenotype
C1s Periodontal Ehlers-Danlos	C1S	AD GOF	613785	Normal CH50	Hyperpigmentation, skin fragility
Complete C4 deficiency	C4A + C4B	AR	120810	Absent CH50 hemolytic activity, defective activation of the classical pathway, complete deficiency requires biallelic mutations/deletions/conversions of both C4A and C4B	SLE, infections with encapsulated organisms, partial deficiency is common (either C4A or C4B) and appears to have a modest effect on host defense
C2 deficiency	C2	AR	217000	Absent CH50 hemolytic activity, defective activation of the classical pathway	SLE, infections with encapsulated organisms, atherosclerosis
C3 deficiency (LOF)	C3	AR	120700	Absent CH50 and AH50 hemolytic activity, defective opsonization, defective humoral immune response	Infections, glomerulonephritis, atypical hemolytic-uremic syndrome with GOF mutations.
C3 GOF	C3	AD GOF	120700	Increased activation of complement	Atypical hemolytic-uremic syndrome
C5 deficiency	C5	AR	120900	Absent CH50 and AH50 hemolytic activity Defective bactericidal activity	Disseminated neisserial infections
C6 deficiency	C6	AR	217050	Absent CH50 and AH50 hemolytic activity, defective bactericidal activity
C7 deficiency	C7	AR	217070
C8α deficiency	C8A	AR	120950
C8 γ deficiency	C8G	AR	120930
C8 β deficiency	C8B	AR	120960
C9 deficiency	C9	AR	120940	Reduced CH50 and AP50 hemolytic activity, deficient bactericidal activity	Mild susceptibility to disseminated neisserial infections
MASP2 deficiency	MASP2	AR	605102	Deficient activation of the lectin activation pathway	Pyogenic infections, inflammatory lung disease, autoimmunity
Ficolin 3 deficiency	FCN3	AR	604973	Absence of complement activation by the Ficolin 3 pathway.	Respiratory infections, abscesses
C1 inhibitor deficiency	SERPING1	AD	606860	Spontaneous activation of the complement pathway with consumption of C4/C2, spontaneous activation of the contact system with generation of bradykinin from high molecular weight kininogen	Hereditary angioedema
Factor B GOF	CFB	AD GOF	612924	Gain-of-function mutation with increased spontaneous AH50	Atypical hemolytic-uremic syndrome
Factor B deficiency	CFB	AR	615561	Deficient activation of the alternative pathway	Infections with encapsulated organisms
Factor D deficiency	CFD	AR	134350	Absent AH50 hemolytic activity	Neisserial infections
Properdin deficiency	CFP	XL	300383	Absent AH50 hemolytic activity	Neisserial infections
Factor I deficiency	CFI	AR	217030	Spontaneous activation of the alternative complement pathway with consumption of C3	Infections, disseminated neisserial infections, atypical Hemolytic-uremic syndrome, preeclampsia
Factor H deficiency	CFH	AR or AD	134370	Spontaneous activation of the alternative complement pathway with consumption of C3
Factor H-related protein deficiencies	CFHR1	AR or AD	134371,	Normal CH50, AH50, autoantibodies to Factor H., linked deletions of one or more CFHR genes leads to susceptibility autoantibody-mediated aHUS	Older onset atypical hemolytic-uremic syndrome, disseminated neisserial infections
	CFHR2		600889,
	CFHR3		605336,
	CFHR4		605337,
	CFHR5		608593
Thrombomodulin deficiency	THBD	AD	188040	Normal CH50, AH50	Atypical hemolytic-uremic syndrome
Membrane Cofactor Protein (CD46) deficiency	CD46	AD	120920	Inhibitor of complement alternate pathway, decreased C3b binding	Atypical hemolytic-uremic syndrome, infections, preeclampsia
Membrane Attack Complex Inhibitor (CD59) deficiency	CD59	AR	107271	Erythrocytes highly susceptible to complement-mediated lysis	Hemolytic anemia, polyneuropathy
CD55 deficiency (CHAPEL disease)	CD55	AR	125240	Hyperactivation of complement on endothelium	Protein losing enteropathy, thrombosis

Total number of disorders in Table 8: 30

Total number of mutant genes in Table 8: 36

New disorders: 2; C1S AD GOF [95], C1R AD GOF [95]

MAC membrane attack complex, SLE systemic lupus erythematosus

Table 10.

Phenocopies of inborn errors of immunity

Disease	Genetic defect/presumed pathogenesis	Circulating T cells	Circulating B cells	Serum Ig	Associated features/similar PID
1. Phenocopies of inborn errors of immunity
Associated with somatic mutations
Autoimmune lymphoproliferative syndrome (ALPS–SFAS)	Somatic mutation in TNFRSF6	Increased CD4−CD8−double negative (DN) αβ T cells	Normal, but increased number of CD5+ B cells	Normal or increased	Splenomegaly, lymphadenopathy, autoimmune cytopenias, Defective lymphocyte apoptosis/ALPS–FAS (=ALPS type Im)
RAS-associated autoimmune leukoproliferative disease (RALD)	Somatic mutation in KRAS (GOF)	Normal	B cell lymphocytosis	Normal or increased	Splenomegaly, lymphadenopathy, autoimmune cytopenias, granulocytosis, monocytosis/ALPS-like
RAS-associated autoimmune leukoproliferative disease (RALD)	Somatic mutation in NRAS (GOF)	Increased CD4−CD8− double negative (DN) T alpha/beta cells	Lymphocytosis	Normal or increased	Splenomegaly, lymphadenopathy, autoantibodies/ALPS-like
Cryopyrinopathy, (Muckle-Wells/CINCA/NOMID-like syndrome)	Somatic mutation in NLRP3	Normal	Normal	Normal	Urticaria-like rash, arthropathy, neurological signs
Hypereosinophilic syndrome due to somatic mutations in STAT5b	Somatic mutation in STAT5B (GOF)	Normal	Normal	Normal	Eosinophilia, atopic dermatitis, urticarial rash, diarrhea
Associated with autoantibodies
Chronic mucocutaneous candidiasis	AutoAb to IL-17 and/or IL-22	Normal	Normal	Normal	Endocrinopathy, chronic mucocutaneous candidiasis/CMC
Adult-onset immunodeficiency with susceptibility to mycobacteria	AutoAb to IFNγ	Decreased naive T cells	Normal	Normal	Mycobacterial, fungal, Salmonella VZV infections/MSMD, or CID
Recurrent skin infection	AutoAb to IL-6	Normal	Normal	Normal	Staphylococcal infections/STAT3 deficiency
Pulmonary alveolar proteinosis	AutoAb to GM-CSF	Normal	Normal	Normal	Pulmonary alveolar proteinosis, cryptococcal meningitis, disseminated nocardiosis/CSF2RA deficiency
Acquired angioedema	AutoAb to CI inhibitor	Normal	Normal	Normal	Angioedema/C1 INH deficiency (hereditary angioedema)
Atypical hemolytic uremic syndrome	AutoAb to Complement Factor H	Normal	Normal	Normal	aHUS = Spontaneous activation of the alternative complement pathway
Thymoma with hypogammaglobulinemia (Good syndrome)	AutoAb to various cytokines	Increased CD8+ T cells	No B cells	Decreased	Invasive bacterial, viral or opportunistic infections, autoimmunity, PRCA, lichen planus, cytopenia, colitis, chronic diarrhea

aHUS atypical hemolytic uremic syndrome, XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, LOF loss-of-function, GOF gain-of-function, PRCA pure red cell aplasia

Total number of conditions for Table 10: 12

Table 9.

Bone marrow failure

Disease	Genetic defect	Inheritance	Gene OMIM	T cells	B cells	Other affected cells	Associated features	Major Category	Subcategory
Bone marrow failure
Fanconi anemia type A	FANCA	AR	227650	Normal to low	Normal to low	HSC	Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage	Bone marrow failure with immune deficiency	Fanconi Anemia
Fanconi anemia type B	FANCB	XLR	300514
Fanconi anemia type C	FANCC	AR	227645
Fanconi anemia type D1	BRCA2	AR	605724
Fanconi anemia type D2	FANCD2	AR	227646
Fanconi anemia type E	FANCE	AR	600901
Fanconi anemia type F	FANCF	AR	603467
Fanconi anemia type G	XRCC9	AR	614082
Fanconi anemia type I	FANCI	AR	609053
Fanconi anemia type J	BRIP1	AR	609054
Fanconi anemia type L	FANCL	AR	614083
Fanconi anemia type M	FANCM	AR	618096
Fanconi anemia type N	PALB2	AR	610832
Fanconi anemia type O	RAD51C	AR	613390
Fanconi anemia type P	SLX4	AR	613951
Fanconi anemia type Q	ERCC4	AR	615272
Fanconi anemia type R	RAD51	AR	617244
Fanconi anemia type S	BRCA1	AR	617883
Fanconi anemia type T	UBE2T	AR	616435
Fanconi anemia type U	XRCC2	AR	617247
Fanconi anemia type V	MAD2L2	AR	617243
Fanconi anemia type W	RFWD3	AR	617784
MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, enteropathy)	SAMD9	AD GOF	617053	Not reported	Not reported	HSC, myeloid cells	Intrauterine growth retardation, gonadal abnormalities, adrenal failure, MDS with chromosome 7 aberrations, predisposition to infections, enteropathy, absent spleen
Ataxia pancytopenia syndrome	SAMD9L	AD GOF	611170	Normal	Low	HSC, myeloid cells	MDS, neurological features
DKCX1	DKC1	XL	305000	Normal to low	Normal to low	HSC	Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay		Dyskeratosis Congenita
DKCA1	TERC	AD	127550
DKCA2	TERT	AD	187270
DKCA3	TINF2	AD	604319
DKCA4	RTEL1	AD	616373
DKCA5	TINF2	AD	268130
DKCA6	ACD	AD	616553
DKCB1	NOLA3	AR	224230
DKCB2	NOLA2	AR	613987
DKCB3	WRAP53	AR	613988
DKCB4	TERT	AR	613989
DKCB5	RTEL1	AR	615190		Low		Nail dystrophy, leukoplakia, bone marrow failure, severe B cell immunodeficiency, intrauterine growth retardation, growth retardation, microcephaly, cerebellar hypoplasia, and esophageal dysfunction
DKCB6	PARN	AR	616353		Normal to low		Developmental delay, microcephaly, and cerebellar hypoplasia
DKCB7	ACD	AR	616553		Normal to low		Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay
BMFS1 (SRP72-deficiency)	SRP72	AD	602122	NA	NA		Bone marrow failure and congenital nerve deafness
BMFS2	ERCC6L2	AR	615667	NA	NA		Bone marrow failure, learning difficulties, microcephaly
BMFS5	TP53	AD	618165	NA	Low B		Erythroid hypoplasia, B cell deficiency
Coats plus syndrome	STN1	AR	613129	Normal	Normal		Intrauterine growth retardation, premature aging, pancytopenia, hypocellular bone marrow, gastrointestinal hemorrhage due to vascular ectasia, intracranial calcification, abnormal telomeres
	CTC1	AR	617053	Not reported	Not reported

Total number of disorders in Table 9: 43

Total number of mutant genes in Table 9: 43

HSC hematopoietic stem cell, NK natural killer, CNS central nervous system, GI gastrointestinal, MDS myelodysplastic syndrome, DKCX X-inked dyskeratosis congenital, DKCA autosomal dominant dyskeratosis congenita, DKCB autosomal recessive dyskeratosis congenita, BMFS bone marrow failure syndrome

The advances in our understanding of clinical immunology continue to expand at a vast and remarkable rate, with the addition in this update of many—64, distributed across all tables (Fig. 1b)—novel genetic defects underlying inborn errors of immunity. Perhaps not surprisingly, most if not all of these new variants were identified by NGS, thus highlighting that whole exome/whole genome sequencing has become the gold standard for identifying novel pathogenic gene variants [6–8]. Indeed, since the first application of NGS to identify novel inborn errors of immunity was published in 2010 [18], ~ 45% of all currently known disease-causing variants have been discovered by whole exome/genome sequencing. Thus, a typical approach to identifying a pathogenic variant in a new patient might now consist of first sequencing a phenotype-driven panel of genes and advancing to whole exome/genome sequencing if the cause of disease remains elusive.

In this update, we increase the list of immunological diseases to 404, with 430 known genetic defects identified as causing these conditions. The unbiased application of NGS to the discovery and characterization of novel inborn errors of immunity continues to inform clinical and basic immunology. Thus, additional phenotypes have been identified for conditions resulting from variants in known and novel genes; the penetrance of genetic variants on clinical phenotypes has been shown to be highly variable; and clinical entities sharing common phenotypes have been discovered. For example, this update includes the findings that bi-allelic mutations in ZNF341 [19, 20], IL6ST (encoding gp130, a common component of the receptors for IL-6, IL-11, IL-27, LIF, OSM, CNTF) [21, 22], or IL6R [23, 24] all cause conditions that resemble autosomal dominant hyper-IgE syndrome due to dominant negative mutations in STAT3 [15]. Detailed analyses of these patients revealed a novel mechanism of regulating STAT3 signaling (via the transcription factor ZNF341) and defined the exact consequences of impaired IL-6/IL-6R/gp130 and putatively IL-11/IL-11R/gp130 signaling to the phenotype of AD-HIES.

Furthermore, key findings over the past 2 years continue to reveal that distinct mechanisms of disease (GOF, LOF, dominant negative, haploinsufficient), as well as different modes of inheritance (autosomal recessive, autosomal dominant) of variants in the same gene can cause disparate clinical conditions. This is a fascinating aspect of the genetics of human disease, and a salient reminder to be cognizant of the nature of the genetic variants identified from NGS. It is these genes that have several entries in this update. A few recent examples include:

1. Heterozygous variants in CARD11 [25, 26] or STAT5B [27] can be pathogenic due to negative dominance. This was potentially unexpected because autosomal recessive LOF variants in both of these genes were previously reported to cause combined immunodeficiency and severe immune dysregulation, respectively, yet heterozygous relatives of these affected individuals were healthy [28, 29].

2. While heterozygous dominant negative mutations in TCF3, encoding the transcription factor E47, cause B cell deficiency and agammaglobulinemia [30], nonsense mutations in TCF3 have now been identified that are pathogenic only in an autosomal recessive state, as heterozygous carriers of these particular allelic variants remained healthy [31, 32].

3. A heterozygous hypermorphic variant in IKBKB was found to cause a combined immunodeficiency [33] not too dissimilar to the original description of bi-allelic, recessive variants in IKBKB [34]. Similarly, bi-allelic LOF mutations in PIK3CD are now known to cause B cell deficiency and agammaglobulinemia [35–37], which is quite distinct from the immune dysregulated state of individuals with monoallelic activating PIK3CD mutations [1, 37]. This observation nicely parallels the earlier findings of either homozygous or heterozygous mutations in PIK3R1 that clinically phenocopy recessive or activating mutations in PIK3CD respectively [1, 37].

4. Distinct diseases can result from heterozygous mutations in IKZF1 (Ikaros): combined immunodeficiency due to dominant negative alleles [38] or CVID due to haploinsufficiency [39].

5. Similar to STAT1 [40], variants in RAC2 [41–45] or CARD11 [25, 26, 28] can be pathogenic either as monoallelic GOF or LOF or bi-allelic recessive LOF.

Thus, these findings have revealed the fundamental importance of elucidating the impact of a novel variant on the function of the encoded protein and thus the mechanism of pathogenicity. Furthermore, these new entries are an important reminder not to overlook the potential significance of identifying heterozygous variants in genes previously believed to cause disease only in a biallelic manner or to result in a previously defined specific clinical entity. Indeed, there are now at least 35 genes that have multiple entries in the current update, reflecting the distinct mechanisms by which variants result in or cause disease (e.g., STAT1, STAT3, NLRP1, RAC2, ZAP70, CARD11, IKBKB, WAS, JAK1, IFIH1, C3, C1R, C1S–GOF or LOF; STAT5, STAT1, CARD11, ACD, CFH, CFHR1–5, FOXN1, RAC2, TCF3, AICDA, PIK3R1, IFNGR1, TREX1, TICAM1, IRF8–AD or AR; PIK3CD–AD GOF, AR LOF; IKZF1–AD, or haploinsufficient; NLRP3—distinct disease phenotypes despite all resulting from GOF alleles).

As noted above, genetic, biochemical, and functional analyses of putative novel pathogenic variants need to meet stringent criteria to be considered for inclusion in this update [17]. These criteria can make reporting genetic findings from single cases challenging, as often the best evidence that a novel variant is disease-causing is to identify additional, similarly affected but unrelated individuals with the same variants, or functionally similar variants in the same gene. While this can be challenging, particularly in light of the rarity of individual inborn errors of immunity, robust mechanistic laboratory investigations continue to provide compelling data from single patients, with or without evidence from animal models. Specifically, homozygous LOF mutations in IRF9 [46] and IL18BP [47] were identified and rigorously characterized in single patients and found to be the molecular cause of life-threatening influenza and fulminant viral hepatitis, respectively.

The study and discovery of novel inborn errors of immunity can also enable improved patient management by implementing gene-specific targeted therapies. Thus, JAK inhibitors are being used to treat disorders of immune dysregulation resulting from GOF mutations in JAK1, STAT1 or STAT3 [11], while mTOR inhibitors such as rapamycin or PI3K p110δ-specific inhibitors have been reported for the treatment of individuals with PIK3CD GOF or PIK3R1 LOF mutations [37]. Regarding novel gene defects, immune dysregulation due to DEF6 deficiency was successfully treated with abatacept (CTLA4-Ig) [48]. This correlated with impaired CTLA4 expression and function in DEF6-deficient T cells [48] and parallels the therapeutic use of abatacept and belatacept for LRBA-deficiency and CTLA4 haploinsufficiency, both of which are characterized by reduced CTLA4 expression in affected regulatory T cells [49, 50]. From a theoretical perspective, the finding that MSMD can be caused by mutations in IL12RB2, IL23R or SPPL2A and that these mutations are associated with impaired production of IFNγ—a requisite of anti-mycobacterial immunity—implies that IFNγ administration could be therapeutically beneficial in these clinical settings [51, 52]. Similarly, recombinant IL18BP could potentially ameliorate viral-induced liver toxicity due to IL18BP deficiency [47].

The goals of the IUIS Expert Committee on Inborn Errors of Immunity are to increase awareness, facilitate recognition, promote optimal treatment, and support research in the field of disorders of immunity. Thus, this 2019 Update and the accompanying “Phenotypical IUIS Classification” publications are intended as resources for clinicians and researchers. Importantly, these tables underpin the design of panels used for targeted gene sequencing to facilitate genetic diagnoses or inborn errors. In the past 5 years, the number of gene defects underlying inborn errors of immunity has nearly doubled from ~ 250 to 430 (Fig. 1a). The human genome contains 1800–2000 genes that are known to be involved in immune responses [13]. Thus, the discovery and study of inborn errors of immunity has elegantly illustrated that > 20% of these immune genes play non-redundant roles in host defense and immune regulation. With the improved identification and phenotyping of patients with rare diseases, combined with high throughput genome sequencing, the number of genes fundamentally required for immunity will no doubt continue to increase, further revealing critical and novel roles for specific genes, molecules, pathways and cell types in immune responses, as well as mechanisms of disease pathogenesis and targets for immunotherapies. The field of inborn errors of immunity, and the global clinical and research communities, will therefore continue to provide key insights into basic and clinical immunology.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.