Selective IgA deficiency (SIgAD) is defined as a serum IgA below 7 mg/dL (0.07 g/L) with normal serum IgG and IgM in an individual older than four years, other causes of hypogammaglobulinemia having been excluded. The four-year threshold avoids diagnosing the physiological delay in IgA ontogeny seen in younger children. SIgAD is the most common primary antibody deficiency, with a prevalence of roughly 1:600 in populations of European ancestry; the frequency is strongly ancestry-dependent and is one to two orders of magnitude lower in East Asian populations. The great majority of affected individuals — on the order of 85-90% — are asymptomatic and are identified incidentally, for example during blood donation or celiac serology. Symptomatic patients present with recurrent sinopulmonary and gastrointestinal infections, and the diagnosis carries strong associations with celiac disease, other autoimmune conditions, atopy, and — in the subset who develop anti-IgA antibodies — anaphylactic reactions to IgA-containing blood products. A minority of patients, particularly those with concomitant IgG subclass deficiency or autoimmunity, progress to common variable immunodeficiency, and SIgAD and CVID are widely regarded as lying on a single disease spectrum. SCOPE: there is no single causal gene. SIgAD is a genetically complex, usually sporadic condition whose largest genetic risk factor is the HLA region, with additional common non-HLA risk alleles and heterozygous TNFRSF13B (TACI) variants that act as disease-modifying rather than disease-causing.
Ask a research question about Selective IgA Deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
Conditions with similar clinical presentations that must be differentiated from Selective IgA Deficiency:
name: Selective IgA Deficiency
creation_date: "2026-08-29T00:00:00Z"
category: Complex
synonyms:
- SIgAD
- IgAD
- selective IgA immunodeficiency
- immunoglobulin A deficiency
disease_term:
preferred_term: Selective IgA Deficiency
term:
id: MONDO:0001341
label: selective IgA deficiency disease
parents:
- Primary Immunodeficiency
- Antibody Deficiency Disorder
description: >-
Selective IgA deficiency (SIgAD) is defined as a serum IgA below 7 mg/dL
(0.07 g/L) with normal serum IgG and IgM in an individual older than four
years, other causes of hypogammaglobulinemia having been excluded. The
four-year threshold avoids diagnosing the physiological delay in IgA ontogeny
seen in younger children. SIgAD is the most common primary antibody
deficiency, with a prevalence of roughly 1:600 in populations of European
ancestry; the frequency is strongly ancestry-dependent and is one to two
orders of magnitude lower in East Asian populations. The great majority of
affected individuals — on the order of 85-90% — are asymptomatic and are
identified incidentally, for example during blood donation or celiac
serology. Symptomatic patients present with recurrent sinopulmonary and
gastrointestinal infections, and the diagnosis carries strong associations
with celiac disease, other autoimmune conditions, atopy, and — in the subset
who develop anti-IgA antibodies — anaphylactic reactions to IgA-containing
blood products. A minority of patients, particularly those with concomitant
IgG subclass deficiency or autoimmunity, progress to common variable
immunodeficiency, and SIgAD and CVID are widely regarded as lying on a single
disease spectrum. SCOPE: there is no single causal gene. SIgAD is a
genetically complex, usually sporadic condition whose largest genetic risk
factor is the HLA region, with additional common non-HLA risk alleles and
heterozygous TNFRSF13B (TACI) variants that act as disease-modifying rather
than disease-causing.
classifications:
harrisons_chapter:
- classification_value: IMMUNE_RHEUMATOLOGIC
notes: >-
SIgAD is a primary antibody deficiency managed by clinical immunology,
and its principal non-infectious burden is autoimmune and allergic.
evidence:
- reference: PMID:27763681
reference_title: "Selective IgA Deficiency: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Selective immunoglobulin A deficiency (SIgAD) is the most common primary
antibody deficiency.
explanation: >-
Characterises SIgAD as a primary antibody deficiency, the immunologic
disease family covered by Harrison's immune/rheumatologic Part.
iuis_category:
classification_value: predominantly antibody deficiency
notes: >-
IUIS 2022 phenotypic classification Table 3 (predominantly antibody
deficiencies), section 4 "Isotype, light chain, or functional deficiencies
with generally normal numbers of B cells". The row lists no genetic defect
and no inheritance pattern.
evidence:
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Selective IgA deficiency Unknown ? Absent IgA with other isotypes
normal, normal subclasses and specific antibodies
explanation: >-
The IUIS 2022 Table 3 row for selective IgA deficiency, in the isotype
deficiency section, with the genetic defect given as Unknown.
inheritance:
- name: Polygenic inheritance
description: >-
SIgAD does not follow a Mendelian pattern. Familial clustering occurs, but
inheritance is complex: the dominant genetic risk factor is the HLA region
(principally the HLA-B*0801-DRB1*0301-DQB1*02 8.1 haplotype and the
DRB1*0701-DQB1*02 haplotype), with additional common non-HLA risk alleles
at IFIH1, PVT1, ATG13-AMBRA1, AHI1 and CLEC16A, and heterozygous
TNFRSF13B variants acting as modifiers.
inheritance_term:
preferred_term: Polygenic inheritance
term:
id: HP:0010982
label: Polygenic inheritance
evidence:
- reference: PMID:22291608
reference_title: "High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The polygenic nature of IgAD is underscored by the recent identification
of several new risk genes in a genome-wide association study.
explanation: >-
States directly that IgAD is polygenic rather than Mendelian.
- reference: PMID:27723758
reference_title: "Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These data suggest that a complex network of genetic effects, including
genes known to influence the biology of IgA production, contributes to
IgAD.
explanation: >-
The GWAS meta-analysis concludes that a complex, multi-locus genetic
architecture underlies IgAD.
prevalence:
- population: European-ancestry populations
measure_type: POINT_PREVALENCE
prevalence_class: ABOVE_1_IN_1000
rate_per_100000: 166.7
notes: >-
Approximately 1:600 in populations of Northern European ancestry, i.e.
about 167 per 100,000. This is a screening-based (serum IgA) estimate and
therefore counts the large asymptomatic majority.
evidence:
- reference: PMID:27723758
reference_title: "Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
IgAD is the most common primary immunodeficiency and is defined by serum
IgA level <0.07 g/L.
explanation: >-
Establishes both the biochemical case definition and the framing of IgAD
as the most common primary immunodeficiency in the European populations
studied.
- reference: PMID:22291608
reference_title: "High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
affecting approximately 1:600 individuals in populations of Northern
European ancestry.
explanation: >-
States the 1:600 Northern-European prevalence directly; the cached full
text carries the ratio in plain characters.
- population: Japanese volunteer blood donors
measure_type: POINT_PREVALENCE
prevalence_class: BAND_1_9_PER_100000
rate_per_100000: 5.4
rate_low: 5.4
rate_high: 6.7
notes: >-
1:18,500 at a serum IgA threshold of <5 mg/dL (5.4 per 100,000) and
1:14,840 at <10 mg/dL (6.7 per 100,000) among 222,597 Japanese blood
donors — one to two orders of magnitude below European-ancestry estimates,
which is the clearest single demonstration that SIgAD frequency is
ancestry-dependent.
evidence:
- reference: PMID:3485858
reference_title: "Selective IgA deficiency in Japanese blood donors: frequency and statistical analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Of the blood donors screened, only 0.007% (1:14,840) were found to be
IgA-deficient (less than 10 mg/dl) by means of the double diffusion
method, while 0.005% (1:18,500) were less than 5 mg/dl
explanation: >-
Provides the Japanese blood-donor frequencies at both IgA thresholds.
- reference: PMID:3485858
reference_title: "Selective IgA deficiency in Japanese blood donors: frequency and statistical analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Statistical analysis of the results clearly showed that the incidence of
SIgAD in Japanese blood donors is very much lower than that in blood
donors of European ancestry.
explanation: >-
Establishes the ancestry dependence of SIgAD frequency directly, by
comparison within one study design.
- population: Ireland (UKPID/ESID registry-ascertained cases, 2020)
measure_type: POINT_PREVALENCE
prevalence_class: BAND_1_9_PER_1000000
rate_per_100000: 0.75
notes: >-
Registry-ascertained minimum prevalence of diagnosed SIgAD, more than two
orders of magnitude below the screening-based European estimate above. The
gap is the expected consequence of the asymptomatic majority never reaching
an immunology service, not a contradiction between the two figures; SIgAD
was nonetheless the fourth most frequent inborn error of immunity in this
registry.
evidence:
- reference: PMID:35604475
reference_title: "Inborn Errors of Immunity on the Island of Ireland - a Cross-Jurisdictional UKPID/ESID Registry Report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the minimum combined prevalence of CVID was 2.93/100,000, HAE
1.04/100,000, unclassified antibody deficiency 0.80/100,000, selective
IgA deficiency 0.75/100,000
explanation: >-
Gives the registry-based minimum prevalence of diagnosed SIgAD for the
combined Irish catchment populations.
progression:
- phase: Progression to common variable immunodeficiency
notes: >-
A minority of patients with SIgAD later lose IgG as well and are
reclassified as CVID. Risk is concentrated in symptomatic patients,
particularly those with an associated IgG subclass deficiency or autoimmune
features, which is the basis for recommending long-term immunological
follow-up rather than one-off diagnosis. The shared familial occurrence and
the shared B-cell defect are the usual arguments for treating SIgAD and
CVID as points on one spectrum.
evidence:
- reference: PMID:18520152
reference_title: "Progression of selective IgA deficiency to common variable immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we present 4 patients with IgAD and autoimmune features who
subsequently developed CVID.
explanation: >-
Documents observed conversion from IgAD to CVID in patients with
autoimmune features.
- reference: PMID:18520152
reference_title: "Progression of selective IgA deficiency to common variable immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All symptomatic IgAD patients, especially those with associated IgG
subclass deficiency or autoimmune features, should be monitored for
evolution to CVID.
explanation: >-
Identifies the subgroup at risk of progression and supports the
surveillance recommendation captured in the notes.
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, it is also known that IgA deficiency may progress into CVID,
which has a less favorable outcome.
explanation: >-
Review confirms progression to CVID as a recognised, prognostically
adverse outcome.
pathophysiology:
- name: Failure of Terminal B Cell Differentiation to IgA-Secreting Plasma Cells
biological_scale: CELLULAR
description: >-
The core defect in SIgAD is a maturation arrest at the last step of the IgA
lineage. B cell numbers are normal and IgA-committed B cells are present and
surface-IgA positive, but they retain an immature phenotype co-expressing
IgM and IgD and do not complete terminal differentiation into IgA-secreting
plasma cells. The block is intrinsic enough to be transferred with
hematopoietic stem cells. Whether it reflects a B-cell-intrinsic defect, a
T-helper or cytokine-environment defect, or several of these in different
patients, is unresolved; IL-21 can restore IgA production from these B cells
ex vivo, which places the block downstream of an inducible signal rather
than at an irreversible lesion.
cell_types:
- preferred_term: IgA-committed B cell
term:
id: CL:0000236
label: B cell
- preferred_term: IgA plasma cell
term:
id: CL:0000987
label: IgA plasma cell
biological_processes:
- preferred_term: plasma cell differentiation
term:
id: GO:0002317
label: plasma cell differentiation
modifier: DECREASED
- preferred_term: isotype switching to IgA isotypes
term:
id: GO:0048290
label: isotype switching to IgA isotypes
modifier: DECREASED
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In IgA deficiency, B cells express IgA; however, they are of immature
phenotype with the coexpression of IgM and IgD, and they cannot fully
develop into IgA-secreting plasma cells
explanation: >-
States the maturation-arrest mechanism precisely: IgA-expressing B cells
are present but cannot complete differentiation into plasma cells.
- reference: PMID:27723758
reference_title: "Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In IgAD, B cells fail to terminally differentiate into IgA+ plasma cells
explanation: >-
Independent statement of the same terminal-differentiation block.
- reference: PMID:27763681
reference_title: "Selective IgA Deficiency: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Pathogenesis of SIgAD is still unknown; however, a defective terminal
differentiation of B cells and defect in switching to IgA-producing plasma
cells are presumed to be responsible.
explanation: >-
Review supports the differentiation/class-switch block while making clear
that the upstream cause remains unknown.
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The defect appears to involve the stem cells since IgA deficiency can be
transferred by bone marrow transplantation
explanation: >-
Transferability with hematopoietic stem cells supports a hematopoietic,
B-lineage-intrinsic rather than a stromal or systemic cause.
notes: >-
Considered as a conformer to germinal_center_reaction#Affinity-Matured
Class-Switched B Cell Output (dismech issue #11897) and not declared. Every
declared conformer of that module substitutes a single lesion that blocks
the reaction broadly; here the defect is isotype-restricted rather than a
failure of the reaction as such — IgG and IgM are normal by the disease's
own case definition, whereas the module's output node covers plasma-cell
and memory-B-cell output in general. The immunoglobulin heavy-chain alpha
loci are structurally intact (see Intact Immunoglobulin Heavy Chain Alpha
Loci below), so there is no lesion in the chain the module models, only a
downstream isotype-specific block whose upstream driver is unresolved (see
the HLA-to-differentiation-block knowledge gap below). Revisit if a
mechanism connecting an upstream lesion to this isotype-specific block is
established.
downstream:
- target: Absent Serum and Secretory IgA
causal_link_type: DIRECT
description: >-
Failure to generate IgA-secreting plasma cells removes the source of both
circulating monomeric IgA and locally produced dimeric secretory IgA.
evidence:
- reference: PMID:27723758
reference_title: "Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
IgAD is the most common primary immunodeficiency and is defined by serum
IgA level <0.07 g/L.
explanation: >-
Ties the plasma-cell differentiation block described in this node to the
defining biochemical outcome, an essentially absent serum IgA.
- name: Intact Immunoglobulin Heavy Chain Alpha Loci
biological_scale: MOLECULAR
description: >-
The constant-region alpha-1 and alpha-2 heavy chain genes on chromosome 14
are structurally normal in the great majority of patients. Deletions of the
heavy chain constant-region cluster do exist but are rare and are a
separate IUIS entity; where they occur, the associated deficiencies extend
beyond IgA to IgG2, IgG4 and IgE. This node exists to record a negative
that constrains the mechanism: SIgAD is a regulatory/differentiation
failure, not a structural loss of the genes encoding IgA, which is why no
single causal gene is curated for this disease.
molecular_functions:
- preferred_term: immunoglobulin receptor binding
term:
id: GO:0034987
label: immunoglobulin receptor binding
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The constant α1 and α2 genes are generally normal except for rarely
described cases of heavy chain gene deletions involving various segments
on chromosome 14
explanation: >-
Establishes that the IgA heavy-chain constant-region loci are intact in
typical SIgAD, excluding a structural gene defect as the general
mechanism.
downstream:
- target: Failure of Terminal B Cell Differentiation to IgA-Secreting Plasma Cells
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
With the alpha constant-region genes intact, the deficiency must arise at
the level of IgA-lineage differentiation and class-switch regulation
rather than from absence of the structural genes.
evidence:
- reference: PMID:27763681
reference_title: "Selective IgA Deficiency: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Pathogenesis of SIgAD is still unknown; however, a defective terminal
differentiation of B cells and defect in switching to IgA-producing
plasma cells are presumed to be responsible.
explanation: >-
Locates the presumed defect at differentiation and switching, consistent
with structurally normal IgA loci.
- name: Absent Serum and Secretory IgA
biological_scale: ORGANISM
description: >-
Serum IgA falls below 7 mg/dL (0.07 g/L) with normal IgG and IgM, and the
dimeric secretory IgA normally transported across mucosal epithelium by the
polymeric immunoglobulin receptor is correspondingly reduced. Serum IgA is
what is measured clinically; secretory IgA is not, and residual mucosal IgA
in some patients is one of the proposed explanations for the asymptomatic
majority. A compensatory increase in secretory IgM is seen in most, but not
all, IgA-deficient individuals.
biological_processes:
- preferred_term: immunoglobulin production in mucosal tissue
term:
id: GO:0002426
label: immunoglobulin production in mucosal tissue
modifier: DECREASED
- preferred_term: polymeric immunoglobulin receptor-mediated transcytosis of secretory IgA
term:
id: GO:0002415
label: immunoglobulin transcytosis in epithelial cells mediated by polymeric immunoglobulin receptor
modifier: DECREASED
cell_types:
- preferred_term: mucosal epithelial cell
term:
id: CL:0002563
label: intestinal epithelial cell
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In general, serum IgA level of less than 7 mg/dL (0.07 g/L) is considered
as selective IgA deficiency since this concentration is the lowest
detectable limit established by most of the laboratories.
explanation: >-
Gives the biochemical threshold that defines this node.
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
in most IgA-deficient patients, seemingly as a compensatory mechanism,
production of secretory IgM is increased
explanation: >-
Documents the compensatory secretory-IgM response that partly offsets the
loss of secretory IgA.
downstream:
- target: Impaired Mucosal Immune Exclusion
causal_link_type: DIRECT
description: >-
Secretory IgA is the effector that coats commensal and pathogenic bacteria
at mucosal surfaces; without it, immune exclusion is degraded.
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Bacteria endogenous to the intestinal tract, oral cavity, and
respiratory and genital tracts are coated with secretory IgA. As a
result, the epithelial adherence and penetration of bacteria are
limited, and the bacteria are confined to the mucosal surfaces
explanation: >-
Describes the immune-exclusion function that is lost when secretory IgA
is absent.
- target: Anti-IgA Alloimmunization
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Because IgA is effectively absent, exogenous IgA in transfused blood
products is seen as a foreign antigen and can elicit anti-IgA antibodies.
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
IgA-deficient patients may develop anti-IgA antibodies which have a
potential to cause anaphylactic reactions upon transfusion of any blood
product, such as red blood cells or platelets, which contains trace
amounts of IgA
explanation: >-
Directly links the absence of IgA to anti-IgA antibody formation and
transfusion reactions.
- name: Impaired Mucosal Immune Exclusion
biological_scale: TISSUE
description: >-
Loss of secretory IgA at respiratory and gastrointestinal surfaces permits
increased epithelial adherence and penetration by bacteria and protozoa, and
increased translocation of intact macromolecules across the mucosal barrier.
Both consequences matter: the first drives the infectious phenotype, the
second is a plausible route by which food and microbial antigens reach the
submucosal immune system in quantity.
biological_processes:
- preferred_term: mucosal immune response
term:
id: GO:0002385
label: mucosal immune response
modifier: DECREASED
- preferred_term: defense response to bacterium
term:
id: GO:0042742
label: defense response to bacterium
modifier: DECREASED
cell_types:
- preferred_term: intestinal epithelial cell
term:
id: CL:0002563
label: intestinal epithelial cell
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Since the protective barrier of the gastrointestinal system is impaired in
IgA deficiency, protozoa such as Giardia lamblia can adhere to the
epithelium, proliferate, and cause infection
explanation: >-
Concrete instance of failed mucosal exclusion in the gut.
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Even in the absence of infection, some molecules may enter the
subepidermal and submucosal tissue because of the impaired mucosal
clearance of macromolecules and proteins.
explanation: >-
Supports the second, non-infectious consequence of failed exclusion:
increased antigen translocation across the mucosa.
downstream:
- target: Recurrent Sinopulmonary Infections
causal_link_type: DIRECT
description: >-
Reduced mucosal antibody at the respiratory epithelium underlies the
recurrent bacterial sinopulmonary infections seen in symptomatic patients.
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Infections of the respiratory system are the most common findings in
individuals with IgA deficiency
explanation: >-
Identifies respiratory infection as the dominant infectious consequence.
- target: Immune Dysregulation and Autoimmunity
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Increased translocation of dietary and microbial antigens across a poorly
excluded mucosa is a proposed route from the IgA defect to the celiac and
autoimmune associations; the link is mechanistically plausible rather than
established, since HLA risk is shared between SIgAD and these conditions
and could explain the association without any causal step.
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
This process may facilitate antibody production against certain antigens
and intolerance to certain foods
explanation: >-
Supports the proposed antigen-translocation route to food intolerance;
the source itself frames this as a mechanism that "may" operate, so the
quote bears on the claim indirectly.
- name: Immune Dysregulation and Autoimmunity
biological_scale: ORGANISM
description: >-
SIgAD carries a markedly increased burden of autoimmune disease, most
strikingly celiac disease (about 35-fold) and type 1 diabetes (about
10-fold), and also juvenile idiopathic arthritis, SLE, inflammatory bowel
disease, thyroid disease and rheumatoid arthritis. The GWAS evidence points
at a shared genetic basis rather than a purely downstream consequence: IgAD
risk loci are significantly enriched for established autoimmunity loci, and
the dominant HLA haplotype is the same 8.1 haplotype that confers risk for
several of these conditions. Autoantibodies are detectable in IgA-deficient
individuals without overt clinical autoimmune disease.
cell_types:
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
biological_processes:
- preferred_term: adaptive immune response
term:
id: GO:0002250
label: adaptive immune response
modifier: ABNORMAL
evidence:
- reference: PMID:24584841
reference_title: "Association between IgA deficiency & other autoimmune conditions: a population-based matched cohort study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Individuals with IgA deficiency more often had celiac disease (6.7 % vs.
0.19 % in controls) and type 1 diabetes (5.9 % vs. 0.57 %) corresponding
to a 35-fold higher PR for celiac disease and 10-fold higher for type 1
diabetes.
explanation: >-
Quantifies the two strongest autoimmune associations in a nationwide
matched cohort of 2100 IgA-deficient individuals.
- reference: PMID:20694011
reference_title: "Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These findings support the hypothesis that autoimmune mechanisms may
contribute to the pathogenesis of IgAD.
explanation: >-
GWAS enrichment of autoimmunity loci in IgAD supports a shared
immune-dysregulation basis rather than a purely secondary association.
downstream:
- target: Celiac Disease
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Celiac disease is the single strongest disease association with SIgAD and
is the reason IgA-based celiac serology is unreliable in these patients.
evidence:
- reference: PMID:27723758
reference_title: "Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The prevalence of Celiac disease is 35 times higher in IgAD patients
whereas the prevalence of systemic lupus erythematosus (SLE) and type 1
diabetes (T1D) is 10 times higher.
explanation: >-
Quantifies the celiac association independently of the Swedish cohort
study.
- name: HLA Class II Haplotype Susceptibility
biological_scale: MOLECULAR
description: >-
The HLA region is the largest genetic risk factor for SIgAD. High-density
SNP mapping and HLA imputation across three European populations place the
primary signal at HLA-DQB1*02, arising from the independent effects of the
HLA-B*0801-DRB1*0301-DQB1*02 and DRB1*0701-DQB1*02 haplotypes, with a
secondary risk signal at DRB1*0102 and a strongly protective effect of
DRB1*1501. Risk is conferred by the common extended 8.1 haplotype acting
multiplicatively rather than by a single distinct SIgAD haplotype. Because
the same haplotype confers risk for celiac disease and type 1 diabetes,
this node is also the most economical explanation available for part of the
autoimmune association.
evidence:
- reference: PMID:22291608
reference_title: "High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Among the characterized susceptibility loci, the association with specific
HLA haplotypes represents the major genetic risk factor for IgAD.
explanation: >-
States that HLA is the dominant genetic risk factor for IgAD.
- reference: PMID:22291608
reference_title: "High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
resulting from the combined independent effects of the
HLA-B*0801-DRB1*0301-DQB1*02 and -DRB1*0701-DQB1*02 haplotypes
explanation: >-
Identifies the two specific risk haplotypes underlying the primary
HLA-DQB1*02 signal.
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
IgA deficiency is not associated with a distinct haplotype; rather, the
risk is conferred by the common extended MHC haplotype HLA A1, B8, DR3,
and DQ2 (the 8.1 haplotype) acting in a multiplicative manner
explanation: >-
Supports the specific claim that risk comes from the common 8.1 haplotype
rather than a SIgAD-specific one.
downstream:
- target: Failure of Terminal B Cell Differentiation to IgA-Secreting Plasma Cells
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
HLA class II haplotype is the largest measured contributor to SIgAD risk
and therefore sits upstream of the B-cell differentiation block, though
no mechanism connecting the haplotype to the maturation arrest has been
established.
evidence:
- reference: PMID:22291608
reference_title: "High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Among the characterized susceptibility loci, the association with
specific HLA haplotypes represents the major genetic risk factor for
IgAD.
explanation: >-
Supports HLA as the dominant upstream risk factor; the intervening
mechanism is not established by this or any cited source, so the quote
bears on the edge indirectly.
- name: Anti-IgA Alloimmunization
biological_scale: ORGANISM
description: >-
A subset of IgA-deficient individuals develop antibodies against IgA. On
exposure to IgA-containing blood products these can precipitate an
anaphylactic transfusion reaction; the antibody capable of a type I
hypersensitivity reaction is of IgE isotype, although IgG anti-IgA is what
is routinely measured. Roughly one third of severely IgA-deficient
individuals carry detectable anti-IgA, and a comparable proportion was found
among Japanese as among European-ancestry IgA-deficient donors. The
predictive value of a positive test in someone who has never reacted is
low, so the finding drives product selection rather than a diagnosis.
biological_processes:
- preferred_term: immunoglobulin production
term:
id: GO:0002377
label: immunoglobulin production
evidence:
- reference: PMID:15679454
reference_title: "Review: IgA anaphylactic transfusion reactions. Part I. Laboratory diagnosis, incidence, and supply of IgA-deficient products."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The test methods used to establish the diagnosis of IgA deficiency and
identify the approximately one third of these individuals with anti-IgA
are discussed
explanation: >-
Quantifies the proportion of IgA-deficient individuals carrying anti-IgA
antibodies.
- reference: PMID:3485858
reference_title: "Selective IgA deficiency in Japanese blood donors: frequency and statistical analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Anti-IgA antibodies were found in 3 (25.0%) of 12 IgA-deficient blood
donors whose IgA levels were less than 5 mg/dl, a prevalence rate
comparable to that in donors of European ancestry.
explanation: >-
Shows anti-IgA alloimmunization occurs at a similar rate across
ancestries even though SIgAD frequency itself differs sharply.
- reference: PMID:15679454
reference_title: "Review: IgA anaphylactic transfusion reactions. Part I. Laboratory diagnosis, incidence, and supply of IgA-deficient products."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
in populations of IgA-deficient individuals screened for anti-IgA, the
predictive value of the test in the absence of a prior reaction is quite
low
explanation: >-
Supports the caveat that a positive anti-IgA screen does not by itself
predict a reaction.
downstream:
- target: Anaphylactic Transfusion Reaction
causal_link_type: DIRECT
description: >-
Anti-IgA antibodies mediate severe reactions to blood products containing
trace IgA, which is why affected patients require IgA-depleted or
IgA-deficient products.
evidence:
- reference: PMID:15679454
reference_title: "Review: IgA anaphylactic transfusion reactions. Part I. Laboratory diagnosis, incidence, and supply of IgA-deficient products."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Individuals with demonstrated anti-IgA are thereafter committed to
receiving IgA-depleted cellular products or IgA-deficient plasma and
derivatives to prevent recurrent severe reactions.
explanation: >-
Confirms the causal role of anti-IgA in recurrent severe transfusion
reactions and the resulting product restriction.
phenotypes:
- name: Absent or Markedly Reduced Serum IgA
category: Immunologic
frequency: OBLIGATE
description: >-
Serum IgA below 7 mg/dL (0.07 g/L) is the defining laboratory finding and
is present by definition in every case.
phenotype_term:
preferred_term: Decreased circulating IgA concentration
term:
id: HP:0002720
label: Decreased circulating IgA concentration
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Immunoglobulin (Ig) A deficiency (OMIM 137100) is defined as decreased or
absent level of serum IgA in the presence of normal serum levels of IgG
and IgM in a patient older than 4 years of age, in whom other causes of
hypogammaglobulinemia have been excluded
explanation: >-
The diagnostic definition, including the normal IgG/IgM requirement and
the four-year age threshold.
- name: Asymptomatic Presentation
category: Immunologic
frequency: VERY_FREQUENT
description: >-
The majority of individuals meeting the biochemical definition never
develop clinical disease and are found incidentally. This is the single
most important epidemiological fact about SIgAD and the reason
screening-based and registry-based prevalence estimates differ by two
orders of magnitude.
phenotype_term:
preferred_term: asymptomatic IgA deficiency
notes: >-
Deliberately unbound: HPO has no term for an asymptomatic presentation,
and HP:0002720 (Decreased circulating IgA concentration) — the obvious
candidate — already grounds the obligate laboratory phenotype and does
not carry the asymptomatic meaning. A new-term request would be the
correct future binding.
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In fact, 85–90% of IgA-deficient individuals are asymptomatic.
explanation: >-
Quantifies the asymptomatic majority, supporting the VERY_FREQUENT band.
- reference: PMID:27763681
reference_title: "Selective IgA Deficiency: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Although more patients with SIgAD are asymptomatic, selected patients
suffer from different clinical complications such as pulmonary infections,
allergies, autoimmune diseases, gastrointestinal disorders and malignancy.
explanation: >-
Independent review confirms that most patients are asymptomatic and names
the complication spectrum of the symptomatic minority.
- name: Recurrent Sinopulmonary Infections
category: Immunologic
description: >-
Recurrent bacterial infections of the upper and lower respiratory tract,
predominantly Haemophilus influenzae and Streptococcus pneumoniae, are the
most common clinical finding in symptomatic patients.
phenotype_term:
preferred_term: Recurrent sinopulmonary infections
term:
id: HP:0005425
label: Recurrent sinopulmonary infections
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These infections are mostly due to bacteria, e.g., Haemophilus influenzae
and Streptococcus pneumoniae.
explanation: >-
Names the organisms responsible for the characteristic respiratory
infections.
- reference: PMID:26739713
reference_title: "Risk of Infections Among 2100 Individuals with IgA Deficiency: a Nationwide Cohort Study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
respiratory tract infections (17.8 vs. 6.3% in controls; PR = 3.2)
explanation: >-
Quantifies the excess risk of respiratory tract infection requiring
hospital care in a matched nationwide cohort.
- name: Increased Risk of Infection Requiring Hospital Care
category: Immunologic
frequency: FREQUENT
description: >-
Across a nationwide cohort of 2100 IgA-deficient individuals, 36.1% had a
hospital record of any infection compared with 18.8% of matched controls,
with significant excesses for gastrointestinal infection, sepsis,
meningitis, otitis and urinary tract infection as well as respiratory
infection.
phenotype_term:
preferred_term: Recurrent infections
term:
id: HP:0002719
label: Recurrent infections
evidence:
- reference: PMID:26739713
reference_title: "Risk of Infections Among 2100 Individuals with IgA Deficiency: a Nationwide Cohort Study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Individuals with IgA deficiency were more likely to have a record of any
infection (36.1 vs. 18.8% in controls) corresponding to a PR of 2.4 (95%CI
2.2-2.6).
explanation: >-
The 36.1% figure supports the FREQUENT (30-79%) frequency band for
infections severe enough to reach hospital care.
- name: Gastrointestinal Infections
category: Gastrointestinal
description: >-
Impaired mucosal exclusion permits gastrointestinal infection, classically
giardiasis, at about three times the population rate.
phenotype_term:
preferred_term: Frequent Giardia lamblia infestation
term:
id: HP:0005215
label: Frequent Giardia lamblia infestation
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Since the protective barrier of the gastrointestinal system is impaired in
IgA deficiency, protozoa such as Giardia lamblia can adhere to the
epithelium, proliferate, and cause infection
explanation: >-
Identifies Giardia lamblia infection as the characteristic gastrointestinal
infection of SIgAD and gives its mechanism.
- reference: PMID:26739713
reference_title: "Risk of Infections Among 2100 Individuals with IgA Deficiency: a Nationwide Cohort Study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
gastrointestinal infections (6.0 vs. 1.8% in controls; PR = 3.5)
explanation: >-
Quantifies the excess of gastrointestinal infection in the matched
nationwide cohort.
- name: Bronchiectasis
category: Respiratory
description: >-
End-organ airway damage secondary to recurrent or chronic respiratory
infection, seen in a subset of symptomatic patients.
phenotype_term:
preferred_term: Bronchiectasis
term:
id: HP:0002110
label: Bronchiectasis
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Some patients may develop end organ damage such as bronchiectasis
secondary to recurring or chronic infections
explanation: >-
Documents bronchiectasis as a recognised structural complication of the
recurrent infections.
- name: Celiac Disease
category: Gastrointestinal
frequency: OCCASIONAL
description: >-
Celiac disease was present in 6.7% of IgA-deficient individuals versus
0.19% of matched controls, a 35-fold excess. IgA-based celiac serology
(IgA anti-transglutaminase, anti-endomysial) is uninterpretable in these
patients and IgG-isotype assays must be used instead.
phenotype_term:
preferred_term: Celiac disease
term:
id: HP:0002608
label: Celiac disease
evidence:
- reference: PMID:24584841
reference_title: "Association between IgA deficiency & other autoimmune conditions: a population-based matched cohort study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Individuals with IgA deficiency more often had celiac disease (6.7 % vs.
0.19 % in controls) and type 1 diabetes (5.9 % vs. 0.57 %) corresponding
to a 35-fold higher PR for celiac disease and 10-fold higher for type 1
diabetes.
explanation: >-
The 6.7% cohort prevalence supports the OCCASIONAL (5-29%) frequency band.
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with IgA deficiency are not expected to develop IgA isotype
antibodies against gliadin, tissue transglutaminase, or endomysium;
however, they may have IgG isotype antibodies against those antigens.
explanation: >-
Supports the serological caveat: IgA-based celiac testing fails and IgG
isotype assays are required.
- name: Autoimmunity
category: Immunologic
frequency: OCCASIONAL
description: >-
Beyond celiac disease, IgA-deficient individuals carry significantly
elevated prevalences of type 1 diabetes, juvenile idiopathic arthritis,
SLE, inflammatory bowel disease, thyroid disease and rheumatoid arthritis.
Reported overall autoimmunity frequencies in clinical series range from
about 19% to 28% depending on the age of the population studied.
phenotype_term:
preferred_term: Autoimmunity
term:
id: HP:0002960
label: Autoimmunity
evidence:
- reference: PMID:24584841
reference_title: "Association between IgA deficiency & other autoimmune conditions: a population-based matched cohort study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Individuals with IgA deficiency have a higher prevalence of several other
autoimmune disorders.
explanation: >-
Nationwide matched cohort conclusion establishing the autoimmune excess.
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In a 2004 study, the second most common association with IgA deficiency
after recurrent infections was autoimmunity (28%)
explanation: >-
Provides a clinical-series frequency for autoimmunity consistent with the
OCCASIONAL band's upper range.
- name: Atopy and Allergic Disease
category: Immunologic
description: >-
Asthma, atopic dermatitis, allergic rhinoconjunctivitis, urticaria, drug
allergy and food allergy are all over-represented. Reported frequencies
vary very widely with case definition and ascertainment method — from 13%
in one survey to 84% in a series using skin-prick testing — so no single
frequency band is asserted here.
phenotype_term:
preferred_term: Allergy
term:
id: HP:0012393
label: Allergy
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
allergic manifestations including asthma, atopic dermatitis, allergic
rhinitis/conjunctivitis, urticaria, drug allergy, and food allergy were
noted in 84% of patients (age range 4–32 years) with selective IgA
deficiency
explanation: >-
Names the allergic manifestation spectrum; the widely varying reported
frequencies are the reason no frequency band is set on this phenotype.
- name: Anaphylactic Transfusion Reaction
category: Immunologic
description: >-
Patients with anti-IgA antibodies can develop anaphylaxis on exposure to
blood products containing trace IgA. This is rare but is the one
life-threatening complication that can occur in an otherwise entirely
asymptomatic patient, which is why awareness and medical alert
identification are recommended irrespective of symptoms.
phenotype_term:
preferred_term: Anaphylactic shock
term:
id: HP:0100845
label: Anaphylactic shock
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
IgA-deficient patients may develop anti-IgA antibodies which have a
potential to cause anaphylactic reactions upon transfusion of any blood
product, such as red blood cells or platelets, which contains trace
amounts of IgA
explanation: >-
Establishes the anaphylactic transfusion reaction and its anti-IgA
mechanism.
- reference: PMID:15679454
reference_title: "Review: IgA anaphylactic transfusion reactions. Part I. Laboratory diagnosis, incidence, and supply of IgA-deficient products."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Despite yielding a definitive diagnosis in fewer than 20 percent of
anaphylactic transfusion reactions, investigation for IgA deficiency and
the presence of presumably pathogenic IgG anti-IgA is useful in patient
management.
explanation: >-
Places the IgA/anti-IgA mechanism in the context of anaphylactic
transfusion reactions overall, where it explains a minority of cases.
genetic:
- name: HLA Class II Haplotype Association
association: Predisposing
relationship_type: SUSCEPTIBILITY
notes: >-
No gene_term is bound here because the association is to extended MHC
haplotypes rather than to a single gene: the primary signal is HLA-DQB1*02
arising from the HLA-B*0801-DRB1*0301-DQB1*02 and DRB1*0701-DQB1*02
haplotypes, with a secondary signal at DRB1*0102 and a protective effect of
DRB1*1501. Naming one HLA gene would misstate what was measured.
evidence:
- reference: PMID:22291608
reference_title: "High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We confirmed the complex nature of the association with the HLA locus,
which is the result of multiple effects spanning the entire HLA region.
explanation: >-
Supports treating the HLA contribution as a multi-locus haplotype effect
rather than a single-gene association.
- reference: PMID:22291608
reference_title: "High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
while additional secondary signals were associated with the DRB1*0102
(combined P = 5.86×10(-17); OR = 4.28) and the DRB1*1501 (combined P =
2.24×10(-35); OR = 0.13) alleles
explanation: >-
Gives the secondary risk allele and the protective allele with their
effect sizes.
- name: TNFRSF13B (TACI) Variants
association: Disease-modifying
relationship_type: MODIFIER
gene_term:
preferred_term: TNFRSF13B
term:
id: hgnc:18153
label: TNFRSF13B
notes: >-
Heterozygous TNFRSF13B variants are found in a subset of SIgAD patients and
also in CVID patients, sometimes in the same family, but they occur in
healthy individuals too. IUIS states explicitly that such variants are
likely disease-modifying rather than disease-causing, and they are typed
MODIFIER here for that reason — this is not a causal gene for SIgAD.
evidence:
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Heterozygous variants in TNFRSF13B have been detected in healthy
individuals, thus such variants are likely to be disease-modifying rather
explanation: >-
The IUIS 2022 footnote stating that heterozygous TNFRSF13B variants are
disease-modifying rather than disease-causing.
- reference: PMID:16007086
reference_title: "TACI is mutant in common variable immunodeficiency and IgA deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We found that 4 of 19 unrelated individuals with common variable
immunodeficiency (CVID) and 1 of 16 individuals with IgA deficiency
(IgAD) had a missense mutation in one allele of TNFRSF13B (encoding
TACI).
explanation: >-
Original report of heterozygous TACI variants in IgAD as well as CVID,
at a frequency far short of accounting for the disease.
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, it is controversial whether TACI mutations have a cause–effect
relationship with IgA deficiency or CVID
explanation: >-
Review records the unresolved causal status of TACI variants, supporting
the MODIFIER rather than CAUSATIVE typing.
- name: IFIH1
association: Predisposing
relationship_type: SUSCEPTIBILITY
gene_term:
preferred_term: IFIH1
term:
id: hgnc:18873
label: IFIH1
notes: >-
The first and, for some years, only non-HLA genome-wide significant IgAD
locus. The common nonsynonymous variant rs1990760 is a shared autoimmunity
allele also associated with type 1 diabetes and SLE; a rare IFIH1 variant
(p.Ile923Val) was subsequently associated in the larger meta-analysis.
evidence:
- reference: PMID:20694011
reference_title: "Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition to the known association of HLA with IgAD, we identified
association with a nonsynonymous variant in IFIH1 (rs1990760G>A, P = 7.3 x
10(-10)) which was previously associated with type 1 diabetes and systemic
lupus erythematosus.
explanation: >-
Original GWAS association of IFIH1 with IgAD, noting the shared
autoimmunity risk allele.
- name: PVT1
association: Predisposing
relationship_type: SUSCEPTIBILITY
gene_term:
preferred_term: PVT1
term:
id: hgnc:9709
label: PVT1
notes: >-
One of four loci reaching genome-wide significance in the 1,635-case IgAD
meta-analysis; a common-variant risk locus of small effect, not a causal
gene.
evidence:
- reference: PMID:27723758
reference_title: "Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Peak new variants (PVT1, P = 4.3 × 10-11; ATG13-AMBRA1, P = 6.7 × 10-10;
AHI1, P = 8.4 × 10-10; CLEC16A, P = 1.4 × 10-9) overlapped with
autoimmune markers (3/4)
explanation: >-
Reports the genome-wide significant association of PVT1 and the three
other new loci with IgAD.
- name: CLEC16A
association: Predisposing
relationship_type: SUSCEPTIBILITY
gene_term:
preferred_term: CLEC16A
term:
id: hgnc:29013
label: CLEC16A
notes: >-
A known general autoimmunity locus that showed suggestive association in
the 2010 GWAS and reached genome-wide significance in the 2016
meta-analysis.
evidence:
- reference: PMID:27723758
reference_title: "Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Peak new variants (PVT1, P = 4.3 × 10-11; ATG13-AMBRA1, P = 6.7 × 10-10;
AHI1, P = 8.4 × 10-10; CLEC16A, P = 1.4 × 10-9) overlapped with
autoimmune markers (3/4)
explanation: >-
Reports the genome-wide significant CLEC16A association in the IgAD
meta-analysis.
- reference: PMID:20694011
reference_title: "Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Variants in CLEC16A, another known autoimmunity locus, showed suggestive
evidence for association (rs6498142C>G, P = 1.8 x 10(-7))
explanation: >-
The earlier, sub-genome-wide signal for CLEC16A that the later
meta-analysis confirmed.
treatments:
- name: Antibiotic Therapy and Prophylaxis
therapeutic_modality: SMALL_MOLECULE
description: >-
Treatment of intercurrent bacterial infections, and — in patients with
recurrent infections — continuous or seasonal prophylactic antibiotics.
This is the mainstay of active management in symptomatic SIgAD; there is no
treatment for the IgA deficiency itself.
treatment_term:
preferred_term: antibiotic therapy
term:
id: NCIT:C15620
label: Antibiotic Therapy
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
If the patient experiences recurrent infections, daily prophylactic
antibiotics on a continuous or seasonal intermittent basis may be
beneficial.
explanation: >-
States the indication and the two dosing patterns for antibiotic
prophylaxis in SIgAD.
- reference: PMID:27763681
reference_title: "Selective IgA Deficiency: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
There is no specific treatment for patients with symptomatic IgA
deficiency, although prophylactic antibiotic therapy along with
circumstantial immunoglobulin replacement with justification and
supportive care (using a product that contains minimal IgA) could be
helpful for patients with a severe phenotype.
explanation: >-
Confirms that management is supportive, with antibiotic prophylaxis first
and immunoglobulin replacement only in justified circumstances.
- name: Observation Without Treatment
therapeutic_modality: OTHER
description: >-
Asymptomatic patients — the large majority — require no treatment. What
they do require is education about the transfusion risk and, in symptomatic
patients or those with IgG subclass deficiency, periodic immunological
review for evolution to CVID.
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
IgA-deficient patients who are diagnosed coincidentally and/or who do not
have any symptoms do not need any treatment.
explanation: >-
States directly that incidentally diagnosed, asymptomatic patients need no
treatment.
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, awareness and education are of prime importance, particularly to
prevent a potential anaphylactic reaction secondary to blood transfusion.
explanation: >-
Supports the education component that accompanies non-treatment.
- name: IgA-Deficient or Washed Blood Products
therapeutic_modality: OTHER
description: >-
Where transfusion is required, the product should come from an IgA-deficient
donor or be saline-washed red cells, and the patient should ideally be
screened for anti-IgA beforehand. Patients with demonstrated anti-IgA are
thereafter restricted to IgA-depleted or IgA-deficient products
indefinitely. Medical alert identification is recommended.
treatment_term:
preferred_term: blood transfusion using IgA-deficient or washed products
term:
id: NCIT:C15192
label: Blood Transfusion
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The blood product should be prepared from an IgA-deficient individual, or
saline-washed red blood cells should be the choice.
explanation: >-
States the two acceptable product options for transfusing an IgA-deficient
patient.
- reference: PMID:15679454
reference_title: "Review: IgA anaphylactic transfusion reactions. Part I. Laboratory diagnosis, incidence, and supply of IgA-deficient products."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Individuals with demonstrated anti-IgA are thereafter committed to
receiving IgA-depleted cellular products or IgA-deficient plasma and
derivatives to prevent recurrent severe reactions.
explanation: >-
Establishes the indefinite product restriction for anti-IgA-positive
patients.
- name: Immunoglobulin Replacement (Restricted Indication)
therapeutic_modality: OTHER
description: >-
Immunoglobulin replacement is NOT routine therapy for SIgAD. It is
considered only where there is a concomitant IgG subclass deficiency or
specific antibody deficiency, and then a product with minimal IgA content
must be used to avoid sensitising or provoking a reaction in a patient with
anti-IgA. Note that immunoglobulin products cannot replace IgA in any case,
since they contain essentially none — the indication is for the associated
IgG defect, not for the IgA deficiency.
treatment_term:
preferred_term: immunoglobulin therapy
term:
id: NCIT:C62710
label: Immunoglobulin Therapy
therapeutic_agent:
- preferred_term: therapeutic immune globulin
term:
id: NCIT:C2701
label: Therapeutic Immune Globulin
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In case of associated IgG subclass deficiency and/or specific antibody
deficiency, immunoglobulin treatment via venous or subcutaneous route with
a product that contains minimal IgA may be given.
explanation: >-
Defines the restricted indication and the minimal-IgA product requirement,
supporting the claim that replacement is not routine in SIgAD.
- reference: PMID:18520152
reference_title: "Progression of selective IgA deficiency to common variable immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Early diagnosis of this conversion and institution of immunoglobulin
therapy is effective in preventing severe bacterial infections and
pulmonary insufficiency.
explanation: >-
Supports immunoglobulin therapy as the treatment once a patient has
converted to CVID, i.e. once the IgG defect is present.
- name: Vaccination and Vaccine Response Assessment
therapeutic_modality: VACCINE
description: >-
Routine immunisation is given as normal. Assessment of specific antibody
responses to protein and polysaccharide antigens is part of the diagnostic
workup and identifies the subset with an additional specific antibody
defect, which is the group in whom management diverges.
treatment_term:
preferred_term: vaccination
term:
id: NCIT:C15346
label: Vaccination
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Evaluation of a suspected IgA deficiency would generally include a
complete blood count with differential, quantitative serum immunoglobulin
levels, serum IgG subclasses, specific antibody response to protein and
polysaccharide antigens, and lymphocyte subsets.
explanation: >-
Establishes specific antibody response testing to vaccine-type antigens as
part of the standard SIgAD evaluation.
diagnosis:
- name: Serum Immunoglobulin Quantification
description: >-
Diagnosis rests on quantitative serum immunoglobulins showing IgA below
7 mg/dL with normal IgG and IgM, in a patient over four years of age, after
excluding secondary causes including drugs known to lower serum IgA. The
workup additionally includes IgG subclasses, specific antibody responses and
lymphocyte subsets, plus testing directed at the associated conditions.
Normal IgG and IgM are as much part of the case definition as the low IgA:
they are what separate SIgAD from CVID and from the combined isotype
deficiencies, and loss of IgG during follow-up is the event that
reclassifies a patient as CVID.
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Immunoglobulin (Ig) A deficiency (OMIM 137100) is defined as decreased or
absent level of serum IgA in the presence of normal serum levels of IgG
and IgM in a patient older than 4 years of age, in whom other causes of
hypogammaglobulinemia have been excluded
explanation: >-
The diagnostic definition, requiring normal serum IgG and IgM alongside
the reduced IgA.
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The threshold of 4 years of age is used to avoid premature diagnosis of
IgA deficiency which may be transient in younger children due to delayed
ontogeny of IgA system after birth.
explanation: >-
Explains the age criterion in the diagnostic definition.
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
It would be prudent to take into account the medications that may cause
decreased serum levels of IgA in the patient.
explanation: >-
Supports the requirement to exclude drug-induced secondary IgA reduction
before diagnosing SIgAD.
differential_diagnoses:
- name: Common Variable Immunodeficiency
description: >-
CVID also features low IgA but with low IgG (and often low IgM) and
impaired specific antibody responses. Normal IgG and IgM are what define
SIgAD; a patient who loses IgG on follow-up is reclassified as CVID rather
than as having two diseases.
evidence:
- reference: PMID:18520152
reference_title: "Progression of selective IgA deficiency to common variable immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Common variable immunodeficiency (CVID) is a primary antibody deficiency
disease that shares many clinical features with IgAD.
explanation: >-
Establishes the clinical overlap that makes CVID the principal
differential.
- name: Partial IgA Deficiency
description: >-
Serum IgA above 7 mg/dL but more than two standard deviations below the
age-specific mean is termed partial IgA deficiency and is common; it is not
the same entity and is not covered by this record.
evidence:
- reference: PMID:20101521
reference_title: Selective IgA deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
When serum IgA level is higher than 7 mg/dL but two standard deviations
below normal for age, the condition may be referred to as partial IgA
deficiency, which is quite common.
explanation: >-
Defines partial IgA deficiency and distinguishes it from selective IgA
deficiency.
- name: IgG Subclass Deficiency with IgA Deficiency
description: >-
A separate IUIS Table 3 section 4 entity in which reduced IgA is
accompanied by reduction in one or more IgG subclasses. By definition SIgAD
has normal IgG subclasses; the combined entity carries a higher infection
burden and is the group in whom immunoglobulin replacement is considered.
evidence:
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
IgG subclass deficiency with IgA deficiency Unknown ? Reduced IgA with
decrease in one or more IgG subclass
explanation: >-
The IUIS row for the neighbouring entity, showing the IgG subclass
reduction that distinguishes it from selective IgA deficiency.
discussions:
- discussion_id: sigad_hla_to_differentiation_block
kind: KNOWLEDGE_GAP
attaches_to:
- pathophysiology#Failure of Terminal B Cell Differentiation to IgA-Secreting Plasma Cells
prompt: >-
What converts HLA class II haplotype risk into a block on terminal
differentiation of IgA-committed B cells?
rationale: >-
HLA is the largest measured genetic risk factor for SIgAD and the GWAS loci
are largely shared autoimmunity alleles, but no source connects either to
the observed maturation arrest. The pathophysiology chain in this entry is
therefore intact from the differentiation block onward and open upstream of
it. Two further facts sharpen the gap: IL-21 restores IgA production from
these B cells ex vivo, so the block is not irreversible, and 85-90% of
people meeting the biochemical definition never develop disease, so
whatever the mechanism is, it is not sufficient for clinical illness.
- discussion_id: sigad_asymptomatic_majority
kind: KNOWLEDGE_GAP
attaches_to:
- phenotypes#Asymptomatic Presentation
prompt: >-
Why are the large majority of individuals with absent serum IgA
asymptomatic?
rationale: >-
Two candidate explanations are on record and neither is settled. Serum IgA
is measured and secretory IgA is not, so some individuals classified as
IgA-deficient may retain protective mucosal IgA; and compensatory secretory
IgM is increased in most but not all IgA-deficient patients. Resolving this
would also explain why the same biochemical finding is incidental in a
blood donor and disabling in a patient with bronchiectasis.
references:
- reference: PMID:20101521
title: Selective IgA deficiency.
- reference: PMID:27763681
title: "Selective IgA Deficiency: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and Management."
- reference: PMID:27723758
title: "Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency."
- reference: PMID:22291608
title: "High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency."
- reference: PMID:20694011
title: "Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency."
- reference: PMID:24584841
title: "Association between IgA deficiency & other autoimmune conditions: a population-based matched cohort study."
- reference: PMID:26739713
title: "Risk of Infections Among 2100 Individuals with IgA Deficiency: a Nationwide Cohort Study."
- reference: PMID:18520152
title: "Progression of selective IgA deficiency to common variable immunodeficiency."
- reference: PMID:3485858
title: "Selective IgA deficiency in Japanese blood donors: frequency and statistical analysis."
- reference: PMID:15679454
title: "Review: IgA anaphylactic transfusion reactions. Part I. Laboratory diagnosis, incidence, and supply of IgA-deficient products."
- reference: PMID:35604475
title: "Inborn Errors of Immunity on the Island of Ireland - a Cross-Jurisdictional UKPID/ESID Registry Report."
- reference: PMID:35748970
title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
- reference: PMID:16007086
title: "TACI is mutant in common variable immunodeficiency and IgA deficiency."