Table 3. Predominantly antibody... | Rockefeller University Press

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	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
E47 transcription factor deficiency	TCF3	AR	619824		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
FNIP1 deficiency (6 patients)	FNIP1	AR	619705		Early-onset recurrent infections, bronchiectasis, fibrosis, interstitial pneumonia; neutropenia (severe or intermittent); Crohn’s disease (one patient); congenital heart defects, muscular hypotonia; developmental delay
PU1 deficiency	SPI1	AD	619707		Sinopulmonary infections with encapsulated bacteria, viral infections
PAX5 deficiency (n = 1)	*PAX5*	AR			Early B-cell developmental block, B cell strongly decreased, transitional and naïve mature B cells expressed lower CD19 and IgD—natural effector and memory B cells, as well as plasmablasts, were absent in the blood of the patient; a-/hypo-gammaglobulinemia, recurrent infections, autism spectrum disorder (ASD), and sensorimotor and cognitive defects
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	NA	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
Activated p110δ syndrome (APDS)	PIK3R1	AD	616005 (APDS2)	Normal/increased IgM, reduced IgG and IgA	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 the expression of CD19, thereby phenocopying CD19 mutations)
CD81 deficiency	CD81	AR	186845	Low IgG, low or normal IgA and IgM
CD20 deficiency	MS4A1(CD20)	AR	112210	Low IgG, normal or elevated IgM and IgA	Recurrent infections
CD21 deficiency	CR2 (CD21)	AR	120650	Low IgG, impaired anti-pneumococcal response	Recurrent infections
TACI deficiency^{^a}	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 IgA, 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, IgA, and IgM; 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 neurological disease; also known as congenital disorder of glycosylation type IIb (CDG-IIb)
PIK3CG deficiency	PIK3CG	AR	619802	Reduced memory B cells, hypogammaglobulinemia	Recurrent infections, cytopenia/lymphopenia, eosinophilia, splenomegaly, lymphadenopathy, HLH-like
BOB1 deficiency	POU2AF1	AR	NA	Reduced memory B cells, agammaglobulinemia	Recurrent respiratory infections, possible chronic viral infection of CNS with progressive tetraparesis
KARS1 deficiency	*KARS1*	AR	619147	Impaired B-cell metabolism (decreased mitochondrial numbers and activity). B-cell lymphopenia, hypogammaglobulinemia, impaired vaccine responses	Severe developmental delay, sensorineural deafness, acute disseminated encephalomyelitis, central and peripheral nervous system impairment, heart and liver disease. Recurrent/severe infections
PI4KA deficiency	*PI4KA*	AR	619708	Reduced total B cells, few memory B cells, hypogammaglobulinemia	Recurrent infections; autoimmune/autoinflammatory, neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus with polymicrogyria, cerebellar hypoplasia, arthrogryposis), and gastrointestinal (inflammatory bowel disease, multiple intestinal atresia) manifestations
3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells, hyper-IgM
AID deficiency	AICDA	AR	605258	IgG and IgA decreased, IgM increased; normal memory B cells but lacking somatic hypermutation	Bacterial infections, enlarged lymph nodes and germinal centers; autoimmunity
AID deficiency	AICDA	AD	NA	IgG absent or decreased, IgA undetected, IgM increased; normal memory B cells with intact somatic hypermutation	Bacterial infections, enlarged lymph nodes and germinal centers. Variants 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
CTNNBL1 deficiency	CTNNBL1	AR	619846	Reduced memory B cells, Ig class switch recombination and somatic hypermutation defects, progressive hypogammaglobulinemia	CVID, autoimmune cytopenias, recurrent infections, hyperplastic germinal centers
APRIL deficiency	TNFSF13	AR	NA	Normal total B-cell counts, reduced memory B cells, hypogammaglobulinemia	CVID, chronic but mild infections, alopecia areata
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	ND		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	ND		Reduced IgA with a decrease in one or more IgG subclass	Recurrent bacterial infections May be asymptomatic
Selective IgA deficiency	Unknown	ND		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	ND		Normal	Reduced ability to produce antibodies to specific antigens
Transient hypogammaglobulinemia of infancy	Unknown	ND		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	ND		Absent serum IgM	Pneumococcal/bacterial

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	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
E47 transcription factor deficiency	TCF3	AR	619824		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
FNIP1 deficiency (6 patients)	FNIP1	AR	619705		Early-onset recurrent infections, bronchiectasis, fibrosis, interstitial pneumonia; neutropenia (severe or intermittent); Crohn’s disease (one patient); congenital heart defects, muscular hypotonia; developmental delay
PU1 deficiency	SPI1	AD	619707		Sinopulmonary infections with encapsulated bacteria, viral infections
PAX5 deficiency (n = 1)	*PAX5*	AR			Early B-cell developmental block, B cell strongly decreased, transitional and naïve mature B cells expressed lower CD19 and IgD—natural effector and memory B cells, as well as plasmablasts, were absent in the blood of the patient; a-/hypo-gammaglobulinemia, recurrent infections, autism spectrum disorder (ASD), and sensorimotor and cognitive defects
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	NA	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
Activated p110δ syndrome (APDS)	PIK3R1	AD	616005 (APDS2)	Normal/increased IgM, reduced IgG and IgA	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 the expression of CD19, thereby phenocopying CD19 mutations)
CD81 deficiency	CD81	AR	186845	Low IgG, low or normal IgA and IgM
CD20 deficiency	MS4A1(CD20)	AR	112210	Low IgG, normal or elevated IgM and IgA	Recurrent infections
CD21 deficiency	CR2 (CD21)	AR	120650	Low IgG, impaired anti-pneumococcal response	Recurrent infections
TACI deficiency^{^a}	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 IgA, 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, IgA, and IgM; 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 neurological disease; also known as congenital disorder of glycosylation type IIb (CDG-IIb)
PIK3CG deficiency	PIK3CG	AR	619802	Reduced memory B cells, hypogammaglobulinemia	Recurrent infections, cytopenia/lymphopenia, eosinophilia, splenomegaly, lymphadenopathy, HLH-like
BOB1 deficiency	POU2AF1	AR	NA	Reduced memory B cells, agammaglobulinemia	Recurrent respiratory infections, possible chronic viral infection of CNS with progressive tetraparesis
KARS1 deficiency	*KARS1*	AR	619147	Impaired B-cell metabolism (decreased mitochondrial numbers and activity). B-cell lymphopenia, hypogammaglobulinemia, impaired vaccine responses	Severe developmental delay, sensorineural deafness, acute disseminated encephalomyelitis, central and peripheral nervous system impairment, heart and liver disease. Recurrent/severe infections
PI4KA deficiency	*PI4KA*	AR	619708	Reduced total B cells, few memory B cells, hypogammaglobulinemia	Recurrent infections; autoimmune/autoinflammatory, neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus with polymicrogyria, cerebellar hypoplasia, arthrogryposis), and gastrointestinal (inflammatory bowel disease, multiple intestinal atresia) manifestations
3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells, hyper-IgM
AID deficiency	AICDA	AR	605258	IgG and IgA decreased, IgM increased; normal memory B cells but lacking somatic hypermutation	Bacterial infections, enlarged lymph nodes and germinal centers; autoimmunity
AID deficiency	AICDA	AD	NA	IgG absent or decreased, IgA undetected, IgM increased; normal memory B cells with intact somatic hypermutation	Bacterial infections, enlarged lymph nodes and germinal centers. Variants 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
CTNNBL1 deficiency	CTNNBL1	AR	619846	Reduced memory B cells, Ig class switch recombination and somatic hypermutation defects, progressive hypogammaglobulinemia	CVID, autoimmune cytopenias, recurrent infections, hyperplastic germinal centers
APRIL deficiency	TNFSF13	AR	NA	Normal total B-cell counts, reduced memory B cells, hypogammaglobulinemia	CVID, chronic but mild infections, alopecia areata
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	ND		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	ND		Reduced IgA with a decrease in one or more IgG subclass	Recurrent bacterial infections May be asymptomatic
Selective IgA deficiency	Unknown	ND		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	ND		Normal	Reduced ability to produce antibodies to specific antigens
Transient hypogammaglobulinemia of infancy	Unknown	ND		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	ND		Absent serum IgM	Pneumococcal/bacterial

EBV, Epstein-Barr virus; COPD, chronic obstructive pulmonary disease; ND, not determined; CNS, central nervous system; VODI, hepatic veno-occlusive disease with immunodeficiency; IBD, inflammatory bowel disease; CVID, common variable immunodeficiency; Ab, antibody.

CVID disorders 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 mutant genes in Table 3: 48.

New IEIs: 3, PAX5, KARS1, and PI4K4 (48, 49, 50).

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

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