Inborn Errors of Immunity (IEI)

Where this grouping sits

Nested groupings Immune Dysregulation IEIs (IUIS Table 4) 22 members Combined Immunodeficiencies IEIs (IUIS Table 1) 8 members Combined Immunodeficiency with Syndromic Features IEIs (IUIS Table 2) 29 members Predominantly Antibody Deficiencies IEIs (IUIS Table 3) 9 members Congenital Phagocyte Defect IEIs (IUIS Table 5) 14 members Intrinsic and Innate Immunity Defect IEIs (IUIS Table 6) 8 members Autoinflammatory Disorder IEIs (IUIS Table 7) 18 members Complement Deficiency IEIs (IUIS Table 8) 6 members Bone Marrow Failure IEIs (IUIS Table 9) 7 members

121 disease entries belong to this grouping through nested groupings. They appear in the coverage table below as nested members, are evaluated against the membership criteria like direct members, and count toward coverage.

Why this grouping

Grouped on the defining monogenic-immunity mechanism: every member is a germline inborn error disrupting the immune system, as recognized by the International Union of Immunological Societies (IUIS) phenotypic classification. Members are kept as separate Disease entries (and further organized into IUIS-table sub-groupings) because causal gene, inheritance, dominant clinical phenotype (infection vs dysregulation vs autoinflammation), and organ involvement differ. This grouping points down to nested IUIS-table groupings rather than listing all 500-plus entities flatly. The sub-groupings follow the IUIS table structure one-to-one, so an entity's table assignment — recorded per entry as `classifications.iuis_category` — determines exactly one sub-grouping, and the sub-groupings partition the members rather than overlapping. Note this holds for disease entities, not for genes: IUIS explicitly enters one gene in two tables when different variant classes give different phenotypes (RELA, OTULIN, NLRP1, ZAP70, IRAK4, IL6ST, STAT5B, FOXN1), so a gene-keyed query across this tree can legitimately return two sub-groupings. Somatic IEI phenocopies (IUIS Table 10), secondary immunodeficiencies (e.g., HIV/AIDS), and incidental immunodeficiency features in non-IEI syndromes are out of scope.

MONDO alignment & provenance

skos:exactMatch MONDO:0003778 · inborn error of immunity

The grouping concept is the MONDO inborn error of immunity class (MONDO:0003778). Nested IUIS-table sub-groupings are clinical unions below this umbrella; several lack a valid MONDO grouping term (see research/grouping_mondo_gaps.md and sub-grouping notes).

MONDO consistency: consistent Umbrella maps exactly to MONDO:0003778. IUIS sub-table groupings are dismech-curated unions and are not required to is-a-subsume under this term in MONDO.

Membership criteria

NECESSARY (member ⇒ criteria)

A disorder is an inborn error of immunity if it is a Mendelian germline disorder with a causal variant in a gene required for immune development, regulation, or effector function, as assigned to an IUIS IEI phenotypic table. Excludes acquired immunodeficiency and somatic IEI phenocopies.

AND
- OTHER
  Germline monogenic etiology disrupting immune development, regulation, or effector function, recognized by IUIS as an inborn error of immunity.
- NOT OTHER
  Not an acquired or secondary immunodeficiency (e.g., HIV/AIDS) and not a somatic IEI phenocopy (IUIS Table 10).

Coverage and gaps

234 rows 121 via nested groupings DisMech coverage of exact MONDO scope: 38/142 (26.8%) 53 DisMech IDs in scope 38 listed in scope 89 MONDO gaps 15 DisMech not listed 92 DisMech outside/no MONDO

Exact MONDO scope: MONDO:0003778 · inborn error of immunity Completeness is counted over rows inside this exact MONDO scope that are listed in this grouping. Finer MONDO descendants under already-covered DisMech concepts are suppressed (93).

Status	DisMech entry	MONDO concept	In DisMech	Has MONDO ID	In grouping MONDO	Member state	Conditions satisfied	C1.1 Germline monogenic etiology disrupting immune development, regulation, or effector function, recognized by IUIS as an inborn error of immunity.	C1.2 Not an acquired or secondary immunodeficiency (e.g., HIV/AIDS) and not a somatic IEI phenocopy (IUIS Table 10).
nested in scope	A20 Haploinsufficiency DISEASE Differentiating mechanism A20 is the ubiquitin-editing enzyme that switches NF-kappaB off downstream of TNF, IL-1 and Toll-like receptors, so haploinsufficiency leaves the brake only half applied and NF-kappaB output chronically raised. This is the NF-kappaB arm of Table 7 in its purest form, with no inflammasome sensor and no interferon signature to explain the phenotype. Clinically it presents as early-onset orogenital ulceration, uveitis and arthralgia, and it was first described as a dominantly inherited form of Behcet disease before being recognised as an inborn error of immunity.	A20 haploinsufficiency MONDO:0100222	yes	yes	yes	nested via Autoinflammatory Disorder IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Activated PI3K-delta syndrome DISEASE Differentiating mechanism The only member here driven by pathway hyperactivation rather than a loss: heterozygous gain-of-function PIK3CD (APDS1) or loss-of-function PIK3R1 (APDS2) variants both hyperactivate PI3K-delta-AKT-mTOR signaling, skewing B cells toward transitional forms with reduced switched memory B cells and a hyper-IgM pattern, alongside lymphoproliferation and herpesvirus susceptibility. IUIS 2022 places both forms in Table 3 section 2 (CVID phenotype); the T-cell senescence in the same patients is why older sources read APDS as a combined immunodeficiency.	Activated PI3K-delta syndrome MONDO:0018338	yes	yes	yes	nested via Predominantly Antibody Deficiencies IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Aicardi-Goutieres Syndrome DISEASE Differentiating mechanism The prototype of the type I interferonopathy arm, and the member where the lesion is in nucleic-acid housekeeping rather than in a receptor: defective clearance or mis-sensing of cytosolic DNA and RNA species leaves an endogenous ligand permanently available to the interferon-inducing sensors. That single mechanism is reached through nine different genes, which is why this entry is a lumped series rather than a single genotype. What distinguishes it clinically from every other Table 7 member is the target organ: intracranial calcification, leukodystrophy and chronic CSF lymphocytosis that mimic congenital infection, rather than fever and serositis.	Aicardi-Goutieres syndrome MONDO:0018866	yes	yes	yes	nested via Autoinflammatory Disorder IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Autosomal Dominant Hyper-IgE Syndrome DISEASE Differentiating mechanism Heterozygous dominant-negative STAT3 poisons the obligate STAT3 dimer, collapsing transcriptional output across the IL-6/IL-11/IL-21/IL-23 network. The immune arm (Th17 failure, cold staphylococcal abscesses, pneumatoceles, extreme IgE) is inseparable from a non-immune connective-tissue, skeletal, dental and vascular syndrome — the defining Table 2 pattern, and the anchor of the hyper-IgE subtable.	Autosomal Dominant Hyper-IgE Syndrome MONDO:0007818	yes	yes	yes	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	CD16 Deficiency DISEASE Differentiating mechanism Reported as a homozygous FCGR3A L66H substitution producing a dissociated NK cell functional defect: spontaneous (antibody-independent) cytotoxicity fails while antibody-dependent cellular cytotoxicity is retained, with severe herpesvirus (VZV, EBV) and papillomavirus disease. Unlike the ISGF3 members it breaks an innate effector cell's killing program, not an interferon signalling circuit - IUIS Table 6 section 3. The member entry records the gene-disease relationship as DISPUTED and L66H as of uncertain significance, because the allele sits at roughly 5% frequency with about a hundred homozygotes in gnomAD; listing the entry records the nosology's assignment, not a resolution of that question.	CD16 deficiency MONDO:0014313	yes	yes	yes	nested via Intrinsic and Innate Immunity Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	CD27-related lymphoproliferative and immune disorder DISEASE Differentiating mechanism Biallelic CD27 or CD70 defects impair germinal-center B-cell homeostasis and EBV control, causing lymphoproliferation and Hodgkin-like lymphoma susceptibility.	CD27-related lymphoproliferative and immune disorder MONDO:0014054	yes	yes	yes	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	CTLA4 Haploinsufficiency DISEASE Differentiating mechanism Heterozygous CTLA4 loss reduces inhibitory checkpoint signaling, causing lymphoproliferation, hypogammaglobulinemia, and multi-organ autoimmunity (CHAI disease).	CTLA4 haploinsufficiency MONDO:0014493	yes	yes	yes	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Chediak-Higashi Syndrome DISEASE Differentiating mechanism Biallelic LYST loss disrupts the biogenesis and fusion of lysosomes and lysosome-related organelles, giving pathognomonic giant leukocyte granules. It reaches the HLH phenotype shared with the familial hemophagocytic members by a different route — organelle biogenesis rather than granule exocytosis — and pays for it outside the immune system too, with partial oculocutaneous albinism from the same LRO defect in melanocytes.	Chediak-Higashi syndrome MONDO:0008963	yes	yes	yes	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Chronic Granulomatous Disease DISEASE Differentiating mechanism Defects in the phagocyte NADPH oxidase (NOX2) complex abolish the respiratory burst, so phagocytes are present in normal numbers but cannot kill ingested catalase-positive bacteria and fungi. The functional axis of Table 5, and the member whose second phenotype — sterile granuloma and inflammatory bowel disease — comes from failed resolution of inflammation rather than from infection.	Chronic Granulomatous Disease MONDO:0018305	yes	yes	yes	nested via Congenital Phagocyte Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Common Variable Immunodeficiency DISEASE Differentiating mechanism Heterogeneous defects in B-cell differentiation and class-switch recombination produce hypogammaglobulinemia with recurrent bacterial infections, autoimmunity, and lymphoproliferation; the most common symptomatic primary antibody deficiency.	Common Variable Immunodeficiency MONDO:0015517	yes	yes	yes	nested via Predominantly Antibody Deficiencies IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	FAS-related Autoimmune Lymphoproliferative Syndrome DISEASE Differentiating mechanism FAS (TNFRSF6) pathway defects impair activation-induced lymphocyte apoptosis, causing chronic lymphoproliferation, autoimmunity, and increased lymphoma risk (canonical ALPS).	FAS-related autoimmune lymphoproliferative immune disorder MONDO:1060194	yes	yes	yes	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Griscelli Syndrome Type 2 DISEASE Differentiating mechanism Biallelic RAB27A loss removes the small GTPase that docks cytotoxic granules for regulated exocytosis in CTL and NK cells, so lymphocyte killing fails and patients present with hemophagocytic lymphohistiocytosis. The same RAB27A loss untethers melanosomes in melanocytes, giving the silvery-grey hair and partial albinism that distinguish GS2 from the non-pigmentary FHL members. Unlike Chediak-Higashi, organelle biogenesis is intact — only the transport step is lost.	Griscelli syndrome type 2 MONDO:0011872	yes	yes	yes	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Hyper-IgM Syndrome Type 2 DISEASE Differentiating mechanism Biallelic AICDA loss abolishes class-switch recombination and somatic hypermutation B-cell-intrinsically: an IgM-only repertoire with massive germinal-center hyperplasia. Unlike the CD40LG/CD40 hyper-IgM defects that IUIS places in Table 1, T-cell licensing of macrophages is intact, so there is no opportunistic-infection susceptibility — the contrast that keeps this entity among the antibody deficiencies.	Hyper-IgM Syndrome Type 2 MONDO:0011528	yes	yes	yes	nested via Predominantly Antibody Deficiencies IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	LRBA Deficiency DISEASE Differentiating mechanism Biallelic LRBA loss destabilizes intracellular CTLA-4 recycling, combining hypogammaglobulinemia with lymphoproliferation, enteropathy, and autoimmunity.	LRBA deficiency MONDO:0013863	yes	yes	yes	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Netherton syndrome DISEASE Differentiating mechanism SPINK5 loss-of-function abolishes the serine-protease inhibitor LEKTI, unleashing kallikrein activity in the epidermis: congenital ichthyosis with bamboo-shaft hair, a defective skin barrier and prominent atopy. The grouping's skin-barrier member, where the syndromic surface disease rather than lymphocyte development carries the phenotype.	Netherton syndrome MONDO:0009735	yes	yes	yes	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	STAT2 Deficiency DISEASE Differentiating mechanism Biallelic loss of STAT2, a required subunit of the ISGF3 transcription factor (STAT1-STAT2-IRF9) downstream of the type I (and type III) interferon receptors. ISGF3-dependent induction of antiviral interferon-stimulated genes collapses, producing severe viral illness including disseminated disease after live attenuated viral vaccines (vaccine-strain measles) - IUIS Table 6 section 3 (predisposition to severe viral infection).	STAT2 deficiency MONDO:0014715	yes	yes	yes	nested via Intrinsic and Innate Immunity Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	STAT6 Gain-of-Function Disease DISEASE Differentiating mechanism Heterozygous gain-of-function STAT6 amplifies IL-4/IL-13 type-2 signaling, producing early-onset severe allergic dysregulation with extreme IgE — a hyper-IgE-like syndromic presentation that IUIS groups with dominant-negative STAT3 rather than with the Table 4 dysregulation disorders. The only member here whose defining lesion is excess rather than loss of cytokine signal transduction, and one of the ten Table 2 entities newly recognized in the IUIS 2024 update.	STAT6 gain-of-function disease MONDO:0957807	yes	yes	yes	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Schimke immuno-osseous dysplasia DISEASE Differentiating mechanism Biallelic SMARCAL1 loss removes the annealing helicase that restarts stalled replication forks; the resulting replication stress injures proliferative compartments selectively — growth-plate chondrocytes (spondyloepiphyseal dysplasia with short-trunk short stature), podocytes (steroid-resistant nephrotic syndrome) and lymphocytes (T-cell immunodeficiency). The grouping's immuno-osseous member alongside cartilage-hair hypoplasia, reached through genome maintenance rather than ribonucleoprotein biology.	Schimke immuno-osseous dysplasia MONDO:0009458	yes	yes	yes	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Selective IgA Deficiency DISEASE Differentiating mechanism The most common primary antibody deficiency and the only member with no monogenic cause: a polygenic, HLA-associated failure of terminal IgA plasma-cell differentiation with normal IgG and IgM and normal B-cell counts. The majority of affected individuals are asymptomatic — the opposite pole of Table 3 from the agammaglobulinemias — with mucosal-infection, celiac, autoimmune, and anti-IgA transfusion-reaction risks in the symptomatic minority.	Selective IgA Deficiency MONDO:0001341	yes	yes	yes	nested via Predominantly Antibody Deficiencies IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	X-linked Agammaglobulinemia DISEASE Differentiating mechanism Loss of BTK, the Tec-family kinase transducing pre-BCR and BCR signals, arrests B-lineage maturation at the pre-B stage in marrow. The prototypical Table 3 entity and the only X-linked member here: affected males have a near-absence of circulating B cells and plasma cells with panhypogammaglobulinemia, against largely intact T-cell immunity.	X-linked Agammaglobulinemia MONDO:0010421	yes	yes	yes	nested via Predominantly Antibody Deficiencies IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Hyper-IgM Syndrome Type 1 DISEASE Differentiating mechanism X-linked CD40LG loss disables CD40 engagement on B cells and myeloid cells: immunoglobulin class switching fails (normal-to-high IgM, absent IgG/IgA/IgE) and T-cell licensing of macrophages is lost, giving opportunistic infections (Pneumocystis, Cryptosporidium) despite normal lymphocyte counts — the myeloid-licensing arm is why IUIS places it in Table 1 rather than among antibody deficiencies.	X-linked hyper-IgM syndrome (CD40 ligand deficiency) MONDO:0010626	yes	yes	yes	nested via Combined Immunodeficiencies IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	X-linked Lymphoproliferative Disease Due To SH2D1A Deficiency DISEASE Differentiating mechanism Loss of the SAP adaptor switches SLAM-family receptors from activating to inhibitory signalling, so 2B4 on NK cells and EBV-specific CD8 cytotoxicity both fail and iNKT cells never develop. The EBV-susceptibility arm of the table in its purest form: the trigger is a specific pathogen rather than a constitutive lesion, and the consequences — fulminant infectious mononucleosis with HLH, dysgammaglobulinemia, and B-cell lymphoma — follow from the inability to control it. Distinguished from its XIAP sibling by the lymphoma risk.	X-linked lymphoproliferative disease type 1 (SAP deficiency) MONDO:0024551	yes	yes	yes	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	X-linked Lymphoproliferative Disease Due To XIAP Deficiency DISEASE Differentiating mechanism XIAP loss removes both a caspase brake and the ubiquitin scaffold NOD2 signalling depends on, so lymphocytes die on activation while NOD2 responses in gut epithelium and monocytes fail. The result is HLH that does not require EBV, refractory Crohn-like colitis, and inflammasome dysregulation with elevated IL-18. The key negative separates it from the SAP sibling sharing its clinical name: lymphoma is not part of this disease.	XIAP deficiency (XLP2) MONDO:0010385	yes	yes	yes	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Autoimmune Lymphoproliferative Syndrome DISEASE Differentiating mechanism The ALPS concept itself, curated as a thin root over the Fas-pathway subtypes (ALPS-FAS, ALPS-sFAS, ALPS-FASLG, ALPS-CASP10, ALPS-U) that the 2009 NIH revision retained. It is listed alongside, not instead of, the gene-specific `FAS-related Autoimmune Lymphoproliferative Syndrome` entry: this entry carries the genotype classification axis and the shared apoptosis-defect chain, that one carries the FAS-specific pathophysiology, diagnostics and management. IUIS likewise enumerates FAS, FASLG and CASP10 as separate Table 4 gene entries under one clinical syndrome.	autoimmune lymphoproliferative syndrome MONDO:0017979	yes	yes	yes	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Autosomal Agammaglobulinemia DISEASE Differentiating mechanism The autosomal 10-15% of congenital agammaglobulinemia — the same pre-B developmental block as XLA reached without touching BTK, by biallelic loss of pre-BCR structural components (IGHM, IGLL1) or of its proximal signalling module (CD79A, CD79B, BLNK). Mechanistically it is the demonstration that the Table 3 phenotype tracks pre-BCR assembly and signalling rather than any one gene.	autosomal agammaglobulinemia MONDO:0011096	yes	yes	yes	nested via Predominantly Antibody Deficiencies IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Cartilage-hair hypoplasia DISEASE Differentiating mechanism Biallelic variants in RMRP, a non-coding RNA rather than a protein, disable the RNase MRP endoribonuclease. One RNA-folding lesion reaches four organ systems at once (pre-rRNA processing, cyclin B2 mRNA cleavage, TERT partnering, small-RNA silencing), giving the immuno-osseous Table 2 pattern: metaphyseal chondrodysplasia and hypoplastic hair alongside combined immunodeficiency, anemia and a marked lymphoma excess.	cartilage-hair hypoplasia MONDO:0009595	yes	yes	yes	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Chronic Mucocutaneous Candidiasis DISEASE Differentiating mechanism Not one gene's disease but a convergent phenotype: every established etiology lies somewhere on the IL-17 circuit — the cytokine (IL17F), its receptor chains (IL17RA, IL17RC), the receptor-proximal adaptor (ACT1/TRAF3IP2), the Th17 master transcription factor (RORC), or STAT1 gain of function repressing Th17 development. The clearest demonstration of the Table 6 logic that one circuit guards one pathogen class, here Candida at skin and mucosa.	chronic mucocutaneous candidiasis MONDO:0015279	yes	yes	yes	nested via Intrinsic and Innate Immunity Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Complement Component 2 Deficiency DISEASE Differentiating mechanism Biallelic loss of C2, most often the 28-bp exon 6 splice-boundary deletion, leaves C4b with no partner and so prevents assembly of the classical-pathway C3 convertase C4b2a. The lectin pathway converges on that same convertase, so it fails too; only the alternative pathway is intact, and the lesion is not one of lytic failure but of impaired opsonisation and of poor clearance of immune complexes and apoptotic debris. That gives the early-classical arm its characteristic pairing, absent in the terminal arm: pyogenic infection with encapsulated organisms, Streptococcus pneumoniae rather than Neisseria, alongside lupus-like autoimmunity in roughly a quarter of homozygotes.	complement component 2 deficiency MONDO:0009006	yes	yes	yes	nested via Complement Deficiency IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Complement Component 3 Deficiency DISEASE Differentiating mechanism The convergence point of the cascade, and the only member whose lesion disables all three activation pathways at once. Biallelic C3 loss leaves no C3b to opsonise, no alternative-pathway amplification loop, and no C3b-containing C5 convertase. It therefore combines the phenotypes of the arms on either side: severe pyogenic infection with pneumococci, Haemophilus and meningococci, as in the early classical arm but without an intact alternative pathway to compensate, together with immune-complex membranoproliferative glomerulonephritis and SLE-like disease, each reported in roughly a quarter of patients.	complement component 3 deficiency MONDO:0013417	yes	yes	yes	nested via Complement Deficiency IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Ectodermal Dysplasia and Immunodeficiency 2 DISEASE Differentiating mechanism Autosomal recessive IKBA (NFKBIA) loss impairs NF-kappaB inhibitor function, causing ectodermal dysplasia with combined immunodeficiency (EDA-ID2) overlapping NEMO disease.	ectodermal dysplasia and immunodeficiency 2 MONDO:0012806	yes	yes	yes	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Hepatic veno-occlusive disease-immunodeficiency syndrome DISEASE Differentiating mechanism Biallelic SP110 loss causes hepatic veno-occlusive disease with combined immunodeficiency and failure to control intracellular pathogens (VODI syndrome).	hepatic veno-occlusive disease-immunodeficiency syndrome MONDO:0009338	yes	yes	yes	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Hemophagocytic Lymphohistiocytosis DISEASE Differentiating mechanism Biallelic or X-linked defects in the cytotoxic granule exocytosis pathway (PRF1, UNC13D, STX11, STXBP2, RAB27A, LYST, SH2D1A, XIAP) impair CTL/NK killing, causing IFN-gamma-driven cytokine storm and hemophagocytosis.	hereditary hemophagocytic lymphohistiocytosis MONDO:0015541	yes	yes	yes	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Immunodeficiency 61 DISEASE Differentiating mechanism X-linked SH3KBP1 (CIN85) deficiency impairs B-cell receptor signal amplification, with reduced antibody responses despite preserved B-cell development. IUIS 2022 places it in Table 3 section 2 (CVID phenotype) despite the entry's agammaglobulinemia-flavored synonyms.	immunodeficiency 61 MONDO:0010296	yes	yes	yes	nested via Predominantly Antibody Deficiencies IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Immunodeficiency Due To MASP-2 Deficiency DISEASE Differentiating mechanism The second lectin-pathway member, and the one whose lesion is in the enzyme rather than in a recognition molecule. MASP-2 is the only protease that cleaves C4, so homozygosity for MASP2 p.D120G - which abolishes binding to mannose-binding lectin - removes lectin-pathway activity by every route, where ficolin-3 deficiency removes one of several routes into it. That makes this member the sharper test of the grouping's organising claim, and it fails it in the same direction. A complete, non-redundant block of the arm produces no consistent phenotype: the published homozygotes split roughly evenly into affected individuals with no shared presentation and healthy controls, and a targeted study found none among 1495 adults with community-acquired pneumonia or 186 patients with lupus. So the lectin arm's position in the cascade predicts no phenotype even when the block is total, which is a stronger form of the qualification recorded in the `complement_table8_lectin_arm_qualifies_the_claim` discussion than ficolin-3 deficiency alone supplies.	immunodeficiency due to MASP-2 deficiency MONDO:0013423	yes	yes	yes	nested via Complement Deficiency IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Late Complement Component Deficiency DISEASE Differentiating mechanism Biallelic loss of any terminal component (C5, C6, C7, C8, C9) prevents assembly of the membrane attack complex C5b-9 and so abolishes direct serum bactericidal activity. Because Neisseria are killed principally by MAC lysis rather than by opsonophagocytosis, the deficiency produces an almost pathognomonic susceptibility to recurrent invasive meningococcal and disseminated gonococcal disease with otherwise unremarkable immunity — the terminal-pathway arm of Table 8.	immunodeficiency due to a late component of complement deficiency MONDO:0015700	yes	yes	yes	nested via Complement Deficiency IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Ficolin 3 Deficiency DISEASE Differentiating mechanism The lectin-pathway arm, and the only member whose lesion is in a recognition molecule rather than in the cascade it triggers. Homozygosity for the FCN3 +1637delC frameshift leaves no detectable serum ficolin-3 and no ficolin-3-dependent complement activation. Because mannose-binding lectin and the ficolin-2 arm still initiate the same pathway, the block is partial in a way the other members' are not: C2 deficiency removes a convertase subunit that both the classical and lectin pathways converge on, and terminal deficiency removes the lytic machinery outright, whereas losing one of several redundant recognition molecules leaves the pathway reachable by other routes. That redundancy is why this member's phenotype is contested rather than characteristic, and so why it bounds this grouping's organising claim instead of illustrating it. The argument is recorded in the `complement_table8_lectin_arm_qualifies_the_claim` discussion rather than duplicated here.	immunodeficiency due to ficolin3 deficiency MONDO:0013467	yes	yes	yes	nested via Complement Deficiency IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Interleukin-10 Receptor Deficiency DISEASE Differentiating mechanism Biallelic loss of either IL-10 receptor chain (IL10RA or IL10RB) abolishes the IL-10 anti-inflammatory brake on myeloid cells, producing severe infantile-onset enterocolitis with perianal fistulas that is refractory to conventional immunosuppression. It anchors the "immune dysregulation with colitis" arm of Table 4: the lesion is loss of a restraining cytokine circuit in the gut rather than lymphoproliferation or a cytotoxicity defect, and it is curable by allogeneic HSCT.	interleukin-10 receptor deficiency MONDO:0013153	yes	yes	yes	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested in scope	Trichohepatoenteric Syndrome DISEASE Differentiating mechanism Biallelic TTC37 (or SKIV2L) variants disable the SKI complex, a cytoplasmic RNA-exosome cofactor for mRNA surveillance — a housekeeping lesion rather than intestine-specific machinery. Intractable congenital diarrhea, woolly hair, facial dysmorphism and liver disease combine with antibody deficiency in the defining trichohepatoenteric triad.	trichohepatoenteric syndrome MONDO:0009105	yes	yes	yes	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
DisMech not listed	Good Syndrome DISEASE	Good syndrome MONDO:0015696	yes	yes	yes	not listed	not evaluated	not evaluated	not evaluated
DisMech not listed	Atypical Hemolytic Uremic Syndrome DISEASE	atypical hemolytic-uremic syndrome MONDO:0016244	yes	yes	yes	not listed	not evaluated	not evaluated	not evaluated
DisMech not listed	Combined Immunodeficiency Due To DOCK8 Deficiency DISEASE	combined immunodeficiency due to DOCK8 deficiency MONDO:0009478	yes	yes	yes	not listed	not evaluated	not evaluated	not evaluated
DisMech not listed	Combined Immunodeficiency Due To Moesin Deficiency DISEASE	combined immunodeficiency due to moesin deficiency MONDO:0010514	yes	yes	yes	not listed	not evaluated	not evaluated	not evaluated
DisMech not listed	Complement Component 4A Deficiency DISEASE	complement component 4a deficiency MONDO:0013721	yes	yes	yes	not listed	not evaluated	not evaluated	not evaluated
DisMech not listed	ZNF341 Deficiency DISEASE	hyper-IgE recurrent infection syndrome 3, autosomal recessive MONDO:0032654	yes	yes	yes	not listed	not evaluated	not evaluated	not evaluated
DisMech not listed	Idiopathic Multicentric Castleman Disease DISEASE	idiopathic multicentric Castleman disease MONDO:0035838	yes	yes	yes	not listed	not evaluated	not evaluated	not evaluated
DisMech not listed	Immunodeficiency 28 DISEASE	immunodeficiency 28 MONDO:0013953	yes	yes	yes	not listed	not evaluated	not evaluated	not evaluated
DisMech not listed	Immunodeficiency 37 DISEASE	immunodeficiency 37 MONDO:0014491	yes	yes	yes	not listed	not evaluated	not evaluated	not evaluated
DisMech not listed	Immunodeficiency 49 DISEASE	immunodeficiency 49 MONDO:0014981	yes	yes	yes	not listed	not evaluated	not evaluated	not evaluated
DisMech not listed	Immunodeficiency Common Variable 4 DISEASE	immunodeficiency, common variable, 4 MONDO:0013284	yes	yes	yes	not listed	not evaluated	not evaluated	not evaluated
DisMech not listed	Unicentric Castleman Disease DISEASE	localized Castleman disease MONDO:0019753	yes	yes	yes	not listed	not evaluated	not evaluated	not evaluated
DisMech not listed	Lymphoproliferative Syndrome 1 DISEASE	lymphoproliferative syndrome 1 MONDO:0013081	yes	yes	yes	not listed	not evaluated	not evaluated	not evaluated
DisMech not listed	HHV-8-Associated Multicentric Castleman Disease DISEASE	multicentric Castleman disease MONDO:0019754	yes	yes	yes	not listed	not evaluated	not evaluated	not evaluated
DisMech not listed	Selective IgM Deficiency DISEASE	selective IgM deficiency MONDO:0018039	yes	yes	yes	not listed	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	B cell deficiency MONDO:0002211	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	BENTA disease MONDO:0014645	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	C1 inhibitor deficiency MONDO:0007361	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	C1Q deficiency MONDO:0013343	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	C1Q deficiency 1 MONDO:0958182	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	C1Q deficiency 2 MONDO:0958187	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	C1Q deficiency 3 MONDO:0958188	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	Castleman disease MONDO:0015564	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	Dianzani autoimmune lymphoproliferative disease MONDO:0011524	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	IL10-related early-onset inflammatory bowel disease MONDO:0016542	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	NK cell deficiency MONDO:0850199	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	PAX5-related B lymphopenia and autism spectrum disorder MONDO:0100299	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	STAT5 haploinsufficiency MONDO:1060224	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	Say-Barber-Miller syndrome MONDO:0009620	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	T cell and NK cell immunodeficiency MONDO:0850200	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	T-cell immunodeficiency with epidermodysplasia verruciformis MONDO:0017925	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	X-linked immunoneurologic disorder MONDO:0010243	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	X-linked lymphoproliferative syndrome MONDO:0010627	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	agammaglobulinemia MONDO:0015977	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	agammaglobulinemia 10, autosomal dominant MONDO:0030529	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	agammaglobulinemia 8b, autosomal recessive MONDO:0859234	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	agammaglobulinemia 9, autosomal recessive MONDO:0030519	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	agammaglobulinemia, autosomal recessive, due to BOB1 deficiency MONDO:0800146	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	agammaglobulinemia-microcephaly-craniosynostosis-severe dermatitis syndrome MONDO:0012508	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	atypical lymphoproliferative disorder MONDO:0044921	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	autosomal dominant combined immunodeficiency due to ERBIN deficiency MONDO:0958120	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	autosomal dominant combined immunodeficiency due to partial IL6ST deficiency MONDO:0958117	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	autosomal recessive combined immunodeficiency due to IL6R deficiency MONDO:0958118	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	autosomal recessive combined immunodeficiency due to complete IL6ST deficiency MONDO:0958115	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	autosomal recessive combined immunodeficiency due to partial IL6ST deficiency MONDO:0958116	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	classic complement early component deficiency MONDO:0000015	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	combined immunodeficiency with faciooculoskeletal anomalies MONDO:0013226	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	complement component 4b deficiency MONDO:0013720	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	complement component C1r/C1s deficiency MONDO:0009005	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	complement component C1s deficiency MONDO:0013419	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	complement deficiency MONDO:0003832	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	complement factor I deficiency MONDO:0012594	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	complement receptor deficiency MONDO:0022812	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	congenital agammaglobulinemia MONDO:0001902	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome MONDO:0033683	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	dendritic cell deficiency MONDO:0850812	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	disorder of lectin complement activation pathway MONDO:0044209	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	dysgammaglobulinemia MONDO:0001342	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	ectodermal dysplasia and immune deficiency MONDO:0010293	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	ectodermal dysplasia and immunodeficiency 1 MONDO:0020740	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	familial isolated congenital asplenia MONDO:0010066	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	hyper-IgE recurrent infection syndrome 4, autosomal recessive MONDO:0032796	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	hyper-IgE recurrent infection syndrome 4A, autosomal dominant MONDO:0800131	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	hyper-IgE recurrent infection syndrome 5, autosomal recessive MONDO:0030069	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	hyper-IgE syndrome MONDO:0018037	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	hyper-IgM syndrome MONDO:0003947	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	hyper-IgM syndrome type 3 MONDO:0011735	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	hyper-IgM syndrome type 4 MONDO:0011985	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	hyper-IgM syndrome type 5 MONDO:0011971	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	hyperimmunoglobulin syndrome MONDO:0002468	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	immune dysregulation with immunodeficiency due to AIOLOS haploinsufficiency MONDO:0979328	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome MONDO:0033968	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	immuno-osseous dysplasia MONDO:0015708	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	immunodeficiency 33 MONDO:0010386	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	immunodeficiency 39 MONDO:0014597	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	immunodeficiency 47 MONDO:0010504	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	immunodeficiency 94 with autoinflammation and dysmorphic facies MONDO:0030681	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	immunodeficiency due to a classical component pathway complement deficiency MONDO:0015699	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	immunodeficiency with defective T-cell response to interleukin 1 MONDO:0009464	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	immunodeficiency, X-linked, with deficiency of 115,000 Dalton surface glycoprotein MONDO:0010625	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	immunodysregulation with variable immunodeficiency and autoimmunity MONDO:0979233	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	immunoglobulin beta deficiency MONDO:0000583	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	immunoglobulin heavy chain deficiency MONDO:0015697	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	inflammatory bowel disease 25 MONDO:0012941	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	inflammatory bowel disease-recurrent sinopulmonary infections syndrome MONDO:0033969	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	isolated agammaglobulinemia MONDO:0016462	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	lymphoproliferative syndrome MONDO:0016537	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	mannose-binding lectin deficiency MONDO:0013714	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	pediatric Castleman disease MONDO:0019752	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	phagocyte bactericidal dysfunction MONDO:0005910	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	properdin deficiency, X-linked MONDO:0010713	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	recurrent Neisseria infections due to factor D deficiency MONDO:0013487	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	recurrent infections associated with rare immunoglobulin isotypes deficiency MONDO:0013576	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	selective IgD deficiency disease MONDO:0004165	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	selective IgE deficiency disease MONDO:0003738	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	selective IgG immunodeficiency MONDO:0045045	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	selective IgG subclass deficiency MONDO:0001901	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	selective immunoglobulin deficiency disease MONDO:0003739	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	severe combined immunodeficiency due to CD70 deficiency MONDO:0034054	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia MONDO:0018967	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	skeletal dysplasia-T-cell immunodeficiency-developmental delay syndrome MONDO:0033682	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	syndromic agammaglobulinemia MONDO:0016463	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	transient hypogammaglobulinemia MONDO:0003827	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
MONDO gap	No DisMech entry	transient hypogammaglobulinemia of infancy MONDO:0015698	no	yes	yes	not curated	not evaluated	not evaluated	not evaluated
nested outside grouping MONDO	22q11.2 Deletion Syndrome DISEASE Differentiating mechanism Hemizygous 22q11.2 deletion (TBX1 haploinsufficiency and contiguous genes) causes DiGeorge spectrum disease with thymic hypoplasia, T-cell deficiency, conotruncal heart defects, and hypocalcemia.	22q11.2 deletion syndrome MONDO:0018923	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	ARPC1B Deficiency DISEASE Differentiating mechanism Biallelic ARPC1B loss removes the hematopoietically expressed isoform of the ARPC1 subunit of the Arp2/3 actin-branching complex, a lesion isoform redundancy cannot cover in blood cells. Thrombocytopenia with bleeding, eczema, recurrent infection, cutaneous vasculitis and raised IgA/IgE give a Wiskott-Aldrich-like actin defect reached one complex downstream of WASp.	ARPC1B deficiency MONDO:0060583	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Ataxia-telangiectasia DISEASE Differentiating mechanism Biallelic ATM loss cripples the kinase that orchestrates the DNA double-strand-break response, yielding progressive cerebellar neurodegeneration, oculocutaneous telangiectasia, cellular radiosensitivity and high malignancy risk alongside a variable combined immunodeficiency. The prototype of the Table 2 DNA-repair-defect subtable, spanning a continuum from classic childhood-onset disease to later-onset variant A-T with residual kinase activity.	Ataxia-telangiectasia MONDO:0008840	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Autoinflammation, immune dysregulation, and eosinophilia DISEASE Differentiating mechanism Heterozygous germline JAK1 gain-of-function variants (the row IUIS names "JAK1 GOF") drive hyperactive baseline and cytokine-induced STAT phosphorylation, producing severe early-onset atopy, eosinophilia, eosinophilic enteritis and autoimmunity. It is the constitutively active kinase counterpart of SOCS1 haploinsufficiency's lost brake on the same pathway, and it is directly treatable with JAK inhibitors.	Autoinflammation, immune dysregulation, and eosinophilia MONDO:0033558	yes	yes	no	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Barth syndrome DISEASE Differentiating mechanism Defective tafazzin-mediated cardiolipin remodeling destabilizes the mitochondrial inner membrane, and the neutrophil is one of the tissues that fails. The member that reaches Table 5 through bioenergetics: the IUIS affected-function cell reads "mitochondrial function", not a phagocyte-specific process. Scope note — neutropenia is one feature of a cardiomyopathy-led mitochondrial disorder, and the entry binds the current HGNC symbol TAFAZZIN where the source prints the legacy TAZ.	Barth syndrome MONDO:0010543	yes	yes	no	nested via Congenital Phagocyte Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Blau Syndrome DISEASE Differentiating mechanism Gain-of-function variants in the NOD2 nucleotide-binding domain drive constitutive NF-kappaB signalling from a cytosolic NOD-like receptor that, unlike NLRP3 and NLRP1, does not nucleate an inflammasome. The output is organised granuloma rather than an IL-1beta fever: the triad is granulomatous dermatitis, boggy synovitis with camptodactyly, and uveitis. This is also the member that has to be held apart from a common polygenic disease, since the NOD2 variants that raise Crohn disease risk are loss-of-function and sit in a different part of the protein.	Blau syndrome MONDO:0008523	yes	yes	no	nested via Autoinflammatory Disorder IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Bloom syndrome DISEASE Differentiating mechanism Biallelic BLM loss removes the RecQ helicase that dissolves homologous-recombination intermediates without crossover, causing hyper-recombination with markedly increased sister-chromatid exchange as the diagnostic cellular readout. Severe pre- and postnatal growth deficiency, photosensitive facial rash and striking early multi-cancer predisposition dominate a phenotype in which the immunodeficiency is comparatively mild.	Bloom syndrome MONDO:0008876	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	CHARGE syndrome DISEASE Differentiating mechanism Heterozygous loss of the CHD7 chromatin remodeler perturbs neural crest-driven organogenesis — coloboma, heart defects, choanal atresia, semicircular canal hypoplasia, ear anomalies — and can include thymic hypoplasia with a DiGeorge-like T-cell deficiency, placing this multiple-anomaly disorder beside 22q11.2 deletion in the thymic-defect arm of Table 2.	CHARGE syndrome MONDO:0008965	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	CINCA Syndrome DISEASE Differentiating mechanism Gain-of-function NLRP3 drives constitutive inflammasome assembly and excessive IL-1beta release — the inflammasome arm of Table 7, and its severe end: CINCA/NOMID is the most severe cryopyrin-associated periodic syndrome phenotype, with neonatal urticarial rash, chronic aseptic meningitis, sensorineural hearing loss and epiphyseal overgrowth.	CINCA syndrome MONDO:0011776	yes	yes	no	nested via Autoinflammatory Disorder IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	COPA Syndrome DISEASE Differentiating mechanism Heterozygous COPA variants impair COPI-mediated retrograde Golgi-to-ER trafficking, so the SURF4 adapter fails to retrieve STING; STING accumulates and signals ligand-independently. The type I interferonopathy arm of Table 7, and the member that reaches autoinflammation through a housekeeping vesicular-transport defect rather than an immune sensor, presenting as interstitial lung disease with arthritis and autoantibodies.	COPA syndrome MONDO:0014629	yes	yes	no	nested via Autoinflammatory Disorder IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Cernunnos-XLF deficiency DISEASE Differentiating mechanism Biallelic NHEJ1 (Cernunnos/XLF) deficiency impairs nonhomologous end-joining, causing microcephaly, growth retardation, and combined T-/B-cell immunodeficiency with radiosensitivity.	Cernunnos-XLF deficiency MONDO:0012650	yes	yes	no	nested via Combined Immunodeficiencies IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Cohen Syndrome DISEASE Differentiating mechanism Loss of the VPS13B bulk lipid-transport protein impairs Golgi membrane expansion and Golgi-dependent glycosylation and secretion, and a mild-to-moderate neutropenia is present in almost all affected individuals. The member with the weakest mechanistic link between the causal lesion and the phagocyte phenotype — the route from VPS13B loss to the neutropenia is not established — held here on the strength of the IUIS row (affected function: myeloid differentiation) rather than on a curated mechanism. Scope note — otherwise curated as an intellectual-disability syndrome.	Cohen syndrome MONDO:0008999	yes	yes	no	nested via Congenital Phagocyte Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	DEF6 Deficiency DISEASE Differentiating mechanism The third route to CTLA-4 insufficiency in this grouping, and the one furthest from the receptor itself. Biallelic loss of the guanine nucleotide exchange factor DEF6 leaves RAB11-dependent vesicular delivery of CTLA-4 to the T-cell surface unable to proceed, so regulatory T cells hold a normal CTLA-4 protein pool they cannot mobilise. Where CTLA4 haploinsufficiency removes half the protein and LRBA deficiency fails to recycle it away from lysosomal degradation, this lesion blocks the outbound trafficking step. All three converge on too little surface CTLA-4 and all three respond to abatacept, which is why the trafficking machinery and the receptor sit in one grouping.	DEF6 deficiency MONDO:0030457	yes	yes	no	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Deficiency of Adenosine Deaminase 2 DISEASE Differentiating mechanism The only member whose defective product is a secreted enzyme rather than an intracellular sensor, adaptor or signalling node. Loss of extracellular adenosine deaminase activity, and of the growth-factor function of the same protein, skews monocytes toward a proinflammatory phenotype and destabilises endothelium, so the disease presents as medium-vessel vasculitis: livedo racemosa, early-onset lacunar and haemorrhagic stroke, and a polyarteritis-nodosa-like picture. It is also the Table 7 member most clearly separated by treatment, answering to TNF blockade rather than IL-1 blockade, and it can add hypogammaglobulinaemia and marrow failure that overlap the antibody-deficiency and bone-marrow-failure tables.	Deficiency of adenosine deaminase 2 MONDO:0014306	yes	yes	no	nested via Autoinflammatory Disorder IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Dyskeratosis Congenita DISEASE Differentiating mechanism Impaired telomere maintenance, so telomeres shorten below the length that sustains self-renewal and the stem and progenitor compartment exhausts. IUIS Table 9 enters the disease as fourteen gene rows sharing one subcategory cell, DKCX1 through DKCB7, spanning the telomerase RNP (DKC1, TERC, TERT, NOP10, NHP2, WRAP53), the shelterin complex (TINF2, ACD), the helicase RTEL1 and the deadenylase PARN. DKC1 is bound here as the X-linked founding locus. The separator from Fanconi anemia is that nothing is wrong with the repair of a lesion; the defect is in the maintenance of a structure, which is why the phenotype is a replicative-exhaustion one and includes pulmonary and hepatic fibrosis rather than chromosomal breakage.	Dyskeratosis Congenita MONDO:0015780	yes	yes	no	nested via Bone Marrow Failure IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	EFL1-related Shwachman-Diamond syndrome DISEASE Differentiating mechanism The EFL1-defined molecular subtype of Shwachman-Diamond syndrome, curated separately because the lesion is in the GTPase partner rather than in SBDS itself: biallelic EFL1 variants impair EIF6 eviction during late 60S maturation directly, reaching the same node from the other side of the same complex. Scope note — this member and the Shwachman-Diamond syndrome member deliberately split the four Table 5 rows printed under the Shwachman-Diamond label; this entry claims the EFL1 row only.	EFL1-related Shwachman-Diamond syndrome MONDO:0044205	yes	yes	no	nested via Congenital Phagocyte Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	FADD-Related Immunodeficiency DISEASE Differentiating mechanism Biallelic FADD loss disables the adaptor that nucleates the FAS death-inducing signalling complex, so patients carry the ALPS biomarker profile (impaired Fas-dependent apoptosis, expanded double-negative T cells) and IUIS files it in the ALPS section. It differs from the other ALPS members in its Fas-independent features — recurrent febrile encephalopathic crises, hepatopathy, cardiac malformations and functional hyposplenism with invasive bacterial infection — without the florid lymphoproliferation of ALPS-FAS.	FADD-related immunodeficiency MONDO:0013408	yes	yes	no	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	T-cell Immunodeficiency, Congenital Alopecia, and Nail Dystrophy DISEASE Differentiating mechanism Human nude SCID: biallelic FOXN1 loss prevents thymic epithelial cell differentiation, so no functional thymic microenvironment forms and athymia abolishes thymopoiesis. The same transcription factor acts in terminally differentiating skin epithelium, adding congenital alopecia and nail dystrophy — a two-organ lesion from one epithelial transcription factor, with the profoundest T-cell deficit in the grouping.	FOXN1 deficiency (nude SCID) MONDO:0011132	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Fanconi_Anemia DISEASE Differentiating mechanism Biallelic defects in the FA/BRCA interstrand-crosslink repair pathway, so the replication fork cannot resolve a crosslink and the cell accumulates chromosomal breaks and radial figures. Fanconi anemia is the largest single block in IUIS Table 9: twenty-two rows, one per complementation group, Types A through W, each with its own gene and OMIM number. FANCA is bound here as the commonest of those loci, not as the disease's only gene. What separates it from the other members of this grouping is that the initiating lesion is crosslink repair rather than telomere maintenance, transcription-coupled repair or a haematopoietic transcription factor, and that the marrow failure arrives packaged with the congenital anomaly pattern the table's associated-features cell lists.	Fanconi anemia MONDO:0019391	yes	yes	no	nested via Bone Marrow Failure IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	G6PC3 Deficiency DISEASE Differentiating mechanism Biallelic G6PC3 loss is a metabolite-repair failure: unhydrolyzed 1,5-anhydroglucitol-6-phosphate accumulates in granulocytes, inhibits hexokinase and stalls early glycolysis, causing neutrophil dysfunction and neutropenia. The quantitative axis of Table 5, and the member that shows a housekeeping enzymopathy reaching the immune system through a cell-type-specific metabolic vulnerability.	G6PC3 deficiency (severe congenital neutropenia type 4) MONDO:0012930	yes	yes	no	nested via Congenital Phagocyte Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	H Syndrome DISEASE Differentiating mechanism Loss of the equilibrative nucleoside transporter hENT3 disables nucleoside efflux from lysosomes and mitochondria in myeloid cells, and the resulting inflammation arrives as tissue histiocytic infiltration rather than as a circulating cytokine fever. That makes it the Table 7 member whose lesion is a transporter and whose read-out is a histiocytosis, with cutaneous hyperpigmentation, hypertrichosis and induration as the defining signs. SLC29A3 is allelic across a spectrum that also includes pigmented hypertrichotic dermatosis with insulin-dependent diabetes and Faisalabad histiocytosis, which IUIS records in the same row.	H syndrome MONDO:0011273	yes	yes	no	nested via Autoinflammatory Disorder IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Heme Oxygenase 1 Deficiency DISEASE Differentiating mechanism Biallelic loss of heme oxygenase 1 disables the macrophage-intrinsic heme catabolism and iron recycling program, so heme-dependent damage drives haemolysis, nephritis and systemic inflammation. The grouping's exemplar of IUIS Table 6 section 8 (other inborn errors of immunity related to non-hematopoietic tissues): an innate housekeeping lesion presenting as inflammation rather than as narrow infection susceptibility.	Heme oxygenase 1 deficiency MONDO:0013536	yes	yes	no	nested via Intrinsic and Innate Immunity Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Hennekam lymphangiectasia-lymphedema syndrome 1 DISEASE Differentiating mechanism Biallelic CCBE1 loss impairs VEGF-C-dependent lymphangiogenesis, producing generalized lymphatic dysplasia: intestinal lymphangiectasia with protein-losing enteropathy, peripheral and facial lymphedema, and intellectual disability. The immunodeficiency is attritional — hypogammaglobulinemia and lymphopenia from enteric loss of protein and lymphocytes rather than a lymphocyte-intrinsic defect.	Hennekam lymphangiectasia-lymphedema syndrome 1 MONDO:0009337	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Hennekam lymphangiectasia-lymphedema syndrome 2 DISEASE Differentiating mechanism Biallelic FAT4 mutations in the giant atypical cadherin reproduce the Hennekam lymphangiectasia-lymphedema triad in CCBE1-mutation-negative families, reaching the same generalized lymphatic dysplasia through planar-cell-polarity signaling rather than the VEGF-C maturation axis of the CCBE1 form.	Hennekam lymphangiectasia-lymphedema syndrome 2 MONDO:0014454	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Hermansky-Pudlak Syndrome DISEASE Differentiating mechanism Only the AP-3 subtypes — HPS-2 (AP3B1) and HPS-10 (AP3D1) — are IUIS Table 4 members: the AP-3 adaptor complex sorts cargo into lysosome-related organelles including cytotoxic granules, so its loss adds neutropenia and impaired CTL/NK cytotoxicity with HLH risk to the oculocutaneous albinism and bleeding diathesis shared by all HPS subtypes. The BLOC-complex subtypes (HPS-1/3/4/5/6/7/8/9/11) share the pigmentary and platelet phenotype but are not inborn errors of immunity.	Hermansky-Pudlak syndrome MONDO:0019312	yes	yes	no	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	IKBKG ectodermal dysplasia with immunodeficiency DISEASE Differentiating mechanism X-linked NEMO (IKBKG) hypomorphic variants impair NF-kappaB signaling, causing ectodermal dysplasia with combined immunodeficiency and susceptibility to mycobacterial and pyogenic infections.	IKBKG-related immunodeficiency with or without ectodermal dysplasia MONDO:0100162	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	IPEX Syndrome DISEASE Differentiating mechanism Loss-of-function FOXP3 variants abolish the master transcription factor of CD4+CD25+ regulatory T cells, so dominant peripheral tolerance fails outright. Where the checkpoint members (CTLA4, LRBA) attenuate Treg function, IPEX removes the Treg compartment itself — the X-linked prototype of monogenic autoimmunity, presenting in infant boys with autoimmune enteropathy, endocrinopathy and dermatitis.	IPEX syndrome MONDO:0010580	yes	yes	no	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Jacobsen Syndrome DISEASE Differentiating mechanism A contiguous-gene deletion of distal 11q (breakpoint at or telomeric to 11q23.3), not a single-gene lesion: haploinsufficiency across the deleted segment produces growth retardation, psychomotor delay, characteristic facies and Paris-Trousseau thrombocytopenia attributed to FLI1 haploinsufficiency, with variable antibody deficiency. With 22q11.2 deletion, one of the grouping's two chromosomal-deletion members carrying no single causal gene binding.	Jacobsen syndrome MONDO:0007838	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Kabuki Syndrome DISEASE Differentiating mechanism Heterozygous KMT2D (less commonly KDM6A) variants impair epigenetic control of developmental gene expression, combining the characteristic facial gestalt, infantile hypotonia, intellectual disability and congenital heart disease with frequent humoral immune dysfunction and hypogammaglobulinemia — a chromatin-machinery member whose immune arm is B-cell rather than T-cell weighted.	Kabuki syndrome MONDO:0016512	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Kindler Epidermolysis Bullosa DISEASE Differentiating mechanism Biallelic FERMT1 loss removes kindlin-1 from focal adhesions of basal keratinocytes, causing a mechanobullous dermatosis with congenital blistering, photosensitivity and progressive poikiloderma. It is the outlier of the Treg-defect section: IUIS records intracellular accumulation of IgG, IgM, IgA and C3 in colloid bodies beneath the basement membrane as the functional defect, and the entry's Table 4 membership follows the committee's placement rather than a strong immunological phenotype.	Kindler syndrome MONDO:0008260	yes	yes	no	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Loeys-Dietz Syndrome DISEASE Differentiating mechanism Heterozygous mutations in TGF-beta signaling components (most commonly TGFBR1/TGFBR2) cause the connective-tissue triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Its immune arm is allergic dysregulation — food allergy and eosinophilic gastrointestinal disease — making it the vasculopathy-dominant member whose Table 2 listing rests on TGF-beta-driven immune skewing rather than lymphopenia.	Loeys-Dietz syndrome MONDO:0018954	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	MHC class II deficiency DISEASE Differentiating mechanism Biallelic loss of any of four MHC-II transactivation factors (CIITA, RFXANK, RFX5, RFXAP — complementation groups A-D) abolishes HLA class II expression on antigen-presenting cells, collapsing CD4+ T-cell selection and help; combined cellular and humoral deficiency with normal lymphocyte counts, distinguishing it from the cytopenic Table 1 members.	MHC class II deficiency MONDO:0008855	yes	yes	no	nested via Combined Immunodeficiencies IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Muckle-Wells Syndrome DISEASE Differentiating mechanism The intermediate rung of the NLRP3 spectrum, sharing its gain-of-function inflammasome mechanism with familial cold autoinflammatory syndrome and CINCA. It is distinguished from the former by attacks that are not cold-triggered and from the latter by the absence of neonatal central nervous system and epiphyseal disease. Its own defining late complications are progressive sensorineural hearing loss and AA amyloidosis, which is what makes early IL-1 blockade a disease-modifying rather than purely symptomatic treatment here.	Muckle-Wells syndrome MONDO:0008633	yes	yes	no	nested via Autoinflammatory Disorder IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Neutrophil Immunodeficiency Syndrome DISEASE Differentiating mechanism The dominant-negative RAC2 p.Asp57Asn allele disables a single haematopoietic Rho-GTPase branch point that controls two effector arms at once — NOX2 assembly and chemoattractant-driven actin polymerization — so one allele breaks both killing and getting there. The member that sits on both axes of the table simultaneously, and the one where the IUIS classification itself splits on OMIM number rather than disease name: this is the AD LOF arm (MIM 608203, Table 5), not the AD GOF arm (Table 1) or the AR arm (Table 3), which share MIM 602049.	Neutrophil Immunodeficiency Syndrome MONDO:0011988	yes	yes	no	nested via Congenital Phagocyte Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Nijmegen breakage syndrome DISEASE Differentiating mechanism NBN (nibrin) defects disable the MRN double-strand-break sensor, producing chromosomal instability with delayed p53-mediated damage response and abnormal neurogenesis. Distinguished from its DNA-repair sibling ataxia-telangiectasia by progressive microcephaly and growth retardation rather than ataxia and telangiectasia, with immunodeficiency and marked lymphoma susceptibility.	Nijmegen breakage syndrome MONDO:0009623	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Nijmegen Breakage Syndrome-like Disorder DISEASE Differentiating mechanism Biallelic hypomorphic RAD50 variants destabilise the MRE11-RAD50-NBN double-strand-break sensor, abolishing damage-induced MRN focus formation and impairing ATM activation. The result is checkpoint failure, radioresistant DNA synthesis and chromosomal instability, clinically phenocopying Nijmegen breakage syndrome. RAD50 is one of the three entities newly added to Table 9 in the IUIS 2024 update, and its placement there rather than in the syndromic combined-immunodeficiency table (where NBS itself sits) is the distinction this grouping turns on.	Nijmegen breakage syndrome-like disorder MONDO:0013118	yes	yes	no	nested via Bone Marrow Failure IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Papillon-Lefevre Disease DISEASE Differentiating mechanism Biallelic cathepsin C loss leaves the three neutrophil serine proteases never activated and, in mature neutrophils, absent altogether. The member that bounds what a Table 5 assignment claims: patients are not broadly immunocompromised, their neutrophils kill bacteria in vitro about as well as controls, and the IUIS affected-function cell is narrow (chemotaxis only). The disease is a tissue-selective failure of oxygen-independent defence in the anaerobic periodontal pocket rather than a systemic phagocyte failure.	Papillon-Lefevre syndrome MONDO:0009490	yes	yes	no	nested via Congenital Phagocyte Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Revesz Syndrome DISEASE Differentiating mechanism Heterozygous TINF2 variants in a nine-residue window of exon 6 produce the severe infantile end of the telomere biology spectrum. It is listed in IUIS Table 9 as the DKCA5 row within the dyskeratosis congenita block, identified by OMIM 268130. It is kept as a separate member rather than folded into Dyskeratosis Congenita because the tissues that fail differ: bilateral exudative retinopathy and intracranial calcification with cerebellar hypoplasia sit alongside the marrow failure, and neither limb exists in the Dyskeratosis Congenita pathograph. Upstream the mechanism is the same shelterin lesion, so this member and Dyskeratosis Congenita are a severity and tissue-distribution split, not a mechanistic one.	Revesz syndrome MONDO:0009990	yes	yes	no	nested via Bone Marrow Failure IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Roifman-syndrome DISEASE Differentiating mechanism Biallelic RNU4ATAC mutations disable the U4atac snRNA of the minor (U12-dependent) spliceosome, impairing splicing of a subset of essential genes. Antibody deficiency with recurrent infections combines with spondyloepiphyseal dysplasia, growth retardation and intellectual disability — with cartilage-hair hypoplasia, one of the grouping's non-coding-RNA lesions.	Roifman syndrome MONDO:0014722	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	STING-Associated Vasculopathy with Onset in Infancy DISEASE Differentiating mechanism The gain of function is in the sensing adaptor itself: mutant STING adopts an active conformation and signals without ligand, so interferon induction no longer requires any accumulated nucleic acid. That makes SAVI the direct counterpart of COPA syndrome, which reaches the same STING node from the opposite direction by failing to retrieve it from the Golgi. What distinguishes SAVI clinically is the acral small-vessel vasculopathy, which can progress to ulceration and tissue loss, combined with early-onset interstitial lung disease.	STING-associated vasculopathy with onset in infancy MONDO:0014405	yes	yes	no	nested via Autoinflammatory Disorder IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	STK4 Deficiency DISEASE Differentiating mechanism Biallelic STK4 (MST1) loss impairs naive T-cell survival via FOXO1 and IL-7R/BCL2, with defective lymphocyte adhesion and chemotaxis; combined T- and B-cell lymphopenia with autoimmunity and EBV-driven lymphoproliferation.	STK4 deficiency MONDO:0013934	yes	yes	no	nested via Combined Immunodeficiencies IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Shwachman-Diamond syndrome DISEASE Differentiating mechanism A ribosomopathy reaching the phagocyte compartment through translation rather than through any immune-specific pathway: loss of SBDS uncouples EFL1 GTP hydrolysis from eIF6 release, blocking 80S assembly, and the granulopoietic compartment is one of the three tissues that tolerates the resulting global translation deficit least well. The member that shows Table 5 admitting a bone-marrow-failure syndrome on the strength of its neutropenia, and the only member covering several Table 5 rows at once (SBDS, DNAJC21 and SRP54; the EFL1 row is carried by the sibling entry below).	Shwachman-Diamond syndrome MONDO:0009833	yes	yes	no	nested via Congenital Phagocyte Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	TNF Receptor-Associated Periodic Syndrome DISEASE Differentiating mechanism Cysteine-disrupting TNFRSF1A variants cause the 55-kD TNF receptor to misfold and be retained in the endoplasmic reticulum instead of reaching the surface and being shed, so the primary lesion is protein folding and trafficking rather than inflammasome or interferon signalling. IUIS places it accordingly in the non-inflammasome section, even though the resulting phenotype is a periodic fever indistinguishable at first glance from the inflammasome members. Attack duration is the most useful bedside discriminator: episodes typically run one to three weeks rather than days, with migratory myalgia under an overlying rash and periorbital oedema.	TNF receptor 1-associated periodic fever syndrome MONDO:0007727	yes	yes	no	nested via Autoinflammatory Disorder IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Vici Syndrome DISEASE Differentiating mechanism Loss of EPG5 blocks the late autophagosome-lysosome fusion step of macroautophagy. The immunodeficiency is one arm of a cardinal pentad (callosal agenesis, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, combined immunodeficiency) — the only Table 2 member here whose syndromic breadth follows from a defect in a general catabolic pathway rather than a lymphocyte- or skeleton-specific one.	Vici syndrome MONDO:0009452	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Wiedemann-Steiner Syndrome DISEASE Differentiating mechanism Heterozygous KMT2A variants — usually de novo — disrupt the H3K4 methyltransferase of the epigenetic machinery, giving developmental delay, hypertrichosis cubiti, growth restriction and characteristic facies with variably present immune findings. The sibling chromatin-disorder to Kabuki syndrome, distinguished by its hypertrichosis and milder, more variable immunodeficiency.	Wiedemann-Steiner syndrome MONDO:0011518	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Wiskott-Aldrich syndrome DISEASE Differentiating mechanism X-linked loss or dysfunction of WASp, the hematopoietic actin regulator, disrupts cytoskeletal remodeling in leukocytes and platelets at once. The result pairs combined immunodeficiency and immune dysregulation with microthrombocytopenia, bleeding and eczema — the anchor of the Table 2 congenital-thrombocytopenia subtable — plus a marked lymphoid-malignancy excess.	Wiskott-Aldrich syndrome MONDO:0010518	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	ZAP70 Deficiency DISEASE Differentiating mechanism Biallelic ZAP70 loss removes the kinase that transduces TCR engagement: CD8+ T cells fail positive selection and are absent, while CD4+ T cells reach normal numbers but cannot signal through the TCR — a selective CD8 lymphopenia with nonfunctional CD4 cells unique in Table 1.	ZAP70 deficiency MONDO:0010023	yes	yes	no	nested via Combined Immunodeficiencies IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Autoimmune Polyendocrine Syndrome Type 1 DISEASE Differentiating mechanism Biallelic AIRE loss impairs thymic negative selection, causing multi-organ autoimmunity with chronic mucocutaneous candidiasis and endocrine failure (APECED/IPEX-like regulatory failure).	autoimmune polyendocrine syndrome type 1 MONDO:0009411	yes	yes	no	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	SOCS1 Haploinsufficiency DISEASE Differentiating mechanism Heterozygous SOCS1 loss removes half the dose of the negative-feedback brake on JAK-STAT signalling, so lymphocytes over-respond to ordinary cytokine levels (increased STAT activation to IFN-gamma, IL-2 and IL-4). The result is early-onset multisystemic autoimmunity with cytopenias and incomplete penetrance — a dosage-sensitive restraint defect rather than a receptor or cytotoxicity lesion, and one of the seven new Table 4 genes in the 2022 update.	autoinflammatory syndrome with immunodeficiency MONDO:0800130	yes	yes	no	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	DNASE2 Deficiency DISEASE Differentiating mechanism The type I interferonopathy arm reached through a lysosomal nuclease rather than a cytosolic one: DNase II cannot digest the DNA of engulfed apoptotic cells and expelled erythroblast nuclei, so undegraded self DNA engages cGAS-STING. It is distinguished among the interferonopathy members by its neonatal haematologic onset, severe transfusion-dependent anemia, thrombocytopenia and hepatosplenomegaly from birth, which reflect DNase II's non-redundant role in definitive erythropoiesis, before the later membranoproliferative glomerulonephritis, liver fibrosis and deforming arthropathy. JAK inhibition is the mechanism-directed therapy.	autoinflammatory-pancytopenia syndrome due to DNASE2 deficiency MONDO:0800132	yes	yes	no	nested via Autoinflammatory Disorder IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Autosomal Dominant Aplasia and Myelodysplasia DISEASE Differentiating mechanism Heterozygous germline SRP72 variants, entered in IUIS Table 9 as BMFS1. The lesion is in the signal recognition particle, so the failing process is co-translational targeting of nascent secretory and membrane proteins rather than any form of genome maintenance. That makes it the mechanistic outlier among this grouping's members, and the table's associated-features cell carries the matching clinical oddity, congenital nerve deafness beside the marrow failure. The lymphocyte columns are recorded as NA, so the IEI status rests on stem and progenitor failure alone.	autosomal dominant aplasia and myelodysplasia MONDO:0013851	yes	yes	no	nested via Bone Marrow Failure IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Autosomal Recessive Osteopetrosis 1 DISEASE Differentiating mechanism Biallelic loss of function of TCIRG1, encoding the osteoclast-specific a3 subunit of the vacuolar H+-ATPase, leaves osteoclasts unable to acidify the resorption lacuna. Where the other members lose a cytokine circuit or a lymphocyte lineage, this one loses an osteoclast-intrinsic effector function with no lymphocyte or cytokine-signalling defect at all — the narrowest possible reading of "intrinsic" in this table's name, restricted to a single non-hematopoietic tissue (bone) rather than a pathogen class.	autosomal recessive osteopetrosis 1 MONDO:0009815	yes	yes	no	nested via Intrinsic and Innate Immunity Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Cherubism DISEASE Differentiating mechanism Stabilising SH3BP2 variants leave the adaptor resistant to degradation, so macrophage and osteoclast NF-kappaB and TNF signalling run hot. Cherubism is the one Table 7 member whose inflammation is anatomically confined: symmetric osteolytic giant-cell lesions of the mandible and maxilla, with no fever, no serositis and no systemic acute-phase response. It is also the only one that characteristically regresses after puberty, so the natural history rather than the cytokine profile is what sets it apart from its siblings.	cherubism MONDO:0007315	yes	yes	no	nested via Autoinflammatory Disorder IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Congenital Disorder of Glycosylation, Type ICC DISEASE Differentiating mechanism X-linked MAGT1 loss (XMEN disease) impairs magnesium transport and N-linked glycosylation, decreasing NKG2D expression on NK and CD8+ T cells and crippling their control of Epstein-Barr virus. It sits in the EBV-susceptibility arm of Table 4: chronic EBV viremia with EBV-driven lymphoma risk rather than autoimmunity or lymphoproliferation from an apoptosis defect.	congenital disorder of glycosylation, type ICC MONDO:0026729	yes	yes	no	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	deafness-lymphedema-leukemia syndrome DISEASE Differentiating mechanism GATA2 haploinsufficiency depletes the monocyte and dendritic-cell compartments from the stem-cell end rather than disabling a mature phagocyte, giving multilineage cytopenias with mycobacterial, HPV and fungal susceptibility on a background of MDS/AML predisposition. The member whose phagocyte defect is a transcription-factor dosage problem, and the one where the phagocyte lesion is inseparable from a malignancy risk. Scope note — IUIS names this row generically as "GATA2 deficiency"; this entry is the Emberger presentation (lymphedema is named in the row's own associated-features cell), and MonoMAC/DCML deficiency (MONDO:0013607) will share the same row when curated.	deafness-lymphedema-leukemia syndrome MONDO:0013540	yes	yes	no	nested via Congenital Phagocyte Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Familial Mediterranean Fever DISEASE Differentiating mechanism The archetypal inflammasome member, but built on pyrin rather than NLRP3: recessive loss-of-function MEFV variants remove the autoinhibition that normally keeps the pyrin inflammasome silent. Because pyrin is regulated through RhoA and the microtubule cytoskeleton, this is the member defined by colchicine responsiveness, which no other Table 7 disorder shares. Attacks are short, typically one to three days of fever with serositis, and the untreated long-term risk that distinguishes it is AA amyloidosis.	familial Mediterranean fever MONDO:0018088	yes	yes	no	nested via Autoinflammatory Disorder IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Familial Cold Autoinflammatory Syndrome DISEASE Differentiating mechanism The mildest end of the NLRP3 cryopyrin-associated periodic syndrome spectrum, and the only member with an external physical trigger: attacks follow generalised cold exposure within about two hours, rather than arising unprovoked. Its mechanism is shared with Muckle-Wells syndrome and CINCA, so what separates the three is threshold and target tissue rather than pathway. The entry also carries the genetically distinct cold-urticarial and inflammasome-adjacent disorders caused by NLRP12, PLCG2 and NLRP1, which reach a similar phenotype through separate circuits.	familial cold autoinflammatory syndrome MONDO:0018768	yes	yes	no	nested via Autoinflammatory Disorder IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Glycogen Storage Disease Type I DISEASE Differentiating mechanism Loss of the SLC37A4 glucose-6-phosphate transporter leaves neutrophils unable to maintain energy homeostasis, and accumulating 1,5-anhydroglucitol-6-phosphate drives ER stress and apoptosis — the same metabolite-repair logic as the G6PC3 member, reached through the transporter rather than the catalytic subunit, which makes the two the clearest mechanistic pair in the grouping. Scope note — only the GSD Ib subtype is the IUIS Table 5 row; this is a combined Ia+Ib entry and the Ia subtype explicitly has no neutropenia. iuis_category is single-valued and cannot be scoped to a subtype, so the restriction lives in that entry's notes.	glycogen storage disease type I MONDO:0002413	yes	yes	no	nested via Congenital Phagocyte Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Hereditary Angioedema DISEASE Differentiating mechanism The regulatory arm, and the one member whose lesion is disinhibition rather than deficiency of effector function. Heterozygous SERPING1 variants reduce functional C1 inhibitor well below the 50% haploinsufficiency predicts — increased catabolism, and trans-inhibition of the wild-type allele by some mutants, typically leave 5-30% of normal activity, which is why a heterozygous serpin defect causes disease at all. C1 inhibitor is the serpin that restrains C1r/C1s and MASP1/MASP2 in the complement cascade and factor XIIa and plasma kallikrein in the contact system. Complement consumption shows up as the low C4 used diagnostically, but the attacks themselves are bradykinin-driven, so the phenotype is recurrent non-urticarial subcutaneous, abdominal and laryngeal edema rather than infection or autoimmunity. Note the scope caveat recorded on that entry's `iuis_category`: only its SERPING1 subtypes are IUIS Table 8 disease, not its normal-C1-INH arm.	hereditary angioedema MONDO:0019623	yes	yes	no	nested via Complement Deficiency IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Hereditary Pulmonary Alveolar Proteinosis DISEASE Differentiating mechanism Biallelic loss of a GM-CSF receptor subunit prevents alveolar macrophage maturation, so surfactant and cholesterol are never cleared and proteinaceous material fills the alveoli. The member that makes the point that "phagocyte" in this table is a compartment and not a cell type: the failing phagocyte is the tissue macrophage, the lesion is in a cytokine receptor rather than in a killing or motility machine, and the clinical presentation is respiratory rather than infectious. Covers both Table 5 rows of the pulmonary alveolar proteinosis pair, CSF2RA and CSF2RB. The autosomal recessive CSF2RB arm of the same receptor lesion, printed in the source table with the transposed gene symbol "CSFR2B".	hereditary pulmonary alveolar proteinosis MONDO:0012580	yes	yes	no	nested via Congenital Phagocyte Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Hypercatabolic Hypoproteinemia DISEASE Differentiating mechanism Biallelic B2M loss destroys the FcRn salvage receptor along with MHC class I: IgG and albumin are catabolized instead of recycled, producing hypogammaglobulinemia by accelerated loss rather than failed synthesis — the only Table 1 mechanism acting on antibody half-life instead of lymphocyte development or signaling.	hypercatabolic hypoproteinemia MONDO:0009434	yes	yes	no	nested via Combined Immunodeficiencies IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Immunodeficiency 101 (Varicella Zoster Virus-Specific) DISEASE Differentiating mechanism Heterozygous partial-loss-of-function POLR3F missense variants impair RNA polymerase III sensing of AT-rich viral DNA, and because the VZV genome is distinctively AT-rich the susceptibility is restricted to a single virus - the narrowest pathogen restriction in the grouping, and the POLR3F arm of the IUIS three-gene RNA polymerase III deficiency row (Table 6 section 3).	immunodeficiency 101 (varicella zoster virus-specific) MONDO:0030813	yes	yes	no	nested via Intrinsic and Innate Immunity Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Immunodeficiency 131 DISEASE Differentiating mechanism A recurrent heterozygous IRF4 p.Thr95Arg substitution in the DNA-binding domain acts simultaneously as hypomorph, hypermorph and neomorph (multimorphic), altering IRF4's DNA-binding specificity rather than merely reducing its output. The result is agammaglobulinemia with impaired B-cell maturation and class switching plus reduced TH17/TFH populations, and susceptibility to Pneumocystis jirovecii pneumonia — an autosomal dominant combined immunodeficiency, and one of the seven Table 1 entities newly recognized in the IUIS 2024 update.	immunodeficiency 131 MONDO:0976229	yes	yes	no	nested via Combined Immunodeficiencies IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Immunodeficiency 14B, Autosomal Recessive DISEASE Differentiating mechanism Biallelic PIK3CD loss-of-function — the recessive mirror image of APDS1 on the same gene: absent p110-delta catalytic activity impairs B-cell antibody responses, producing severe bacterial infections with autoimmune complications. IUIS 2022 lists it in Table 3 section 1 alongside the agammaglobulinemias.	immunodeficiency 14b, autosomal recessive MONDO:0023655	yes	yes	no	nested via Predominantly Antibody Deficiencies IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Immunodeficiency 60 DISEASE Differentiating mechanism Autosomal dominant haploinsufficiency for the transcriptional repressor BACH2 impairs regulatory T-cell differentiation, placing it with the Tregopathy members rather than the cytotoxic-granule or apoptosis members. What distinguishes it inside that subcategory is that the same lesion also hits the B-cell arm: BACH2 is a lineage specification factor for both compartments, so a single dosage defect yields lymphocytic colitis and progressive T-cell lymphopenia alongside impaired memory B-cell development and sinopulmonary infection. IUIS places it in Table 4 on that basis, although ClinGen curated the gene through its Antibody Deficiencies expert panel and rates the relationship Moderate.	immunodeficiency 60 MONDO:0032723	yes	yes	no	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Immunodeficiency 65 (IRF9 Deficiency) DISEASE Differentiating mechanism Biallelic loss of IRF9, the DNA-binding subunit of the same ISGF3 complex. The sibling lesion to STAT2 deficiency, distinguished by its subunit and its founding phenotype (life-threatening influenza A pneumonitis), with a hyperinflammatory second arm from prolonged, USP18-unrestrained signalling through the type I interferon receptor - IUIS Table 6 section 3.	immunodeficiency 65, susceptibility to viral infections MONDO:0032848	yes	yes	no	nested via Intrinsic and Innate Immunity Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Immunodeficiency 80 with or without Congenital Cardiomyopathy DISEASE Differentiating mechanism Biallelic hypomorphic MCM10 variants impair the essential activator of the CMG replicative helicase; replication stress falls on the NK compartment (absent terminally mature NK cells with CMV susceptibility) or the fetal heart (congenital restrictive cardiomyopathy). Listed by IUIS in the Table 2 DNA-repair subsection beside GINS1 deficiency, which it phenocopies — reclassified here from the former innate-immunity-defect reading on 2026-08-26.	immunodeficiency 80 with or without congenital cardiomyopathy MONDO:0030266	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Immunodeficiency 88 DISEASE Differentiating mechanism Biallelic loss of function of TBX21 removes T-bet, the transcription factor that specifies type 1 immunity. Where the other members lose a cytokine circuit or an effector lineage through a general cellular defect, this one loses the transcriptional instruction that builds the IFN-gamma-producing compartment: NK, iNKT, MAIT and Vdelta2+ gamma-delta T lymphocytes fail to develop. The purely adaptive CD8+ and CD4+ TH1-star cells that remain make IFN-gamma normally and do not compensate, which is the entry's demonstration that these innate and innate-like compartments are non-redundant for anti-mycobacterial immunity in humans.	immunodeficiency 88 MONDO:0030483	yes	yes	no	nested via Intrinsic and Innate Immunity Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Immunodeficiency 93 and Hypertrophic Cardiomyopathy DISEASE Differentiating mechanism Biallelic loss of FNIP1, the folliculin-interacting protein, gives profoundly decreased or absent circulating B cells with hypogammaglobulinemia — Table 3 by its humoral phenotype — but uniquely among the members here couples it to hypertrophic cardiomyopathy, a non-immune manifestation of the same metabolic-regulator defect.	immunodeficiency 93 and hypertrophic cardiomyopathy MONDO:0030528	yes	yes	no	nested via Predominantly Antibody Deficiencies IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome DISEASE Differentiating mechanism DNMT3B, ZBTB24, or CDCA7 defects cause DNA hypomethylation with centromeric instability, facial dysmorphism, and progressive combined immunodeficiency (ICF syndrome).	immunodeficiency-centromeric instability-facial anomalies syndrome MONDO:0000133	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Immunoskeletal Dysplasia with Neurodevelopmental Abnormalities DISEASE Differentiating mechanism Hypomorphic biallelic EXTL3 alleles yield structurally aberrant heparan sulfate — longer chains, abnormal sulfation — rather than its absence. Because HS proteoglycans tune morphogen and cytokine signaling as co-receptors, one glycosyltransferase lesion is transduced in opposite directions by tissue, coupling spondyloepimetaphyseal dysplasia and neurodevelopmental disease to a T-cell-deficient combined immunodeficiency.	immunoskeletal dysplasia with neurodevelopmental abnormalities MONDO:0044312	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Leukocyte Adhesion Deficiency 1 DISEASE Differentiating mechanism Biallelic ITGB2 loss prevents assembly of the beta-2 integrin heterodimers (LFA-1, Mac-1, p150,95), so neutrophils cannot convert rolling into firm adhesion and never transmigrate. The adhesion arm of the table, and the sibling of LAD2's trafficking lesion: both produce tissue neutropenia alongside blood neutrophilia, but here the receptor itself is absent rather than its ligand unfucosylated. Severity tracks residual CD18 expression, and the periodontal disease is driven by a dysregulated IL-23/IL-17 axis rather than by unpoliced infection.	leukocyte adhesion deficiency 1 MONDO:0007293	yes	yes	no	nested via Congenital Phagocyte Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Leukocyte Adhesion Deficiency Type II DISEASE Differentiating mechanism A Golgi GDP-fucose transporter failure starves the fucosyltransferases of their donor substrate, so neutrophils lose sialyl-Lewis X and cannot roll along activated endothelium. The trafficking arm of the table: neutrophils are made in normal or excess numbers and never reach tissue, which is why the blood count is high while the infection risk is that of a phagocyte deficiency. Distinct from every other member in that its causal lesion is a general glycosylation defect whose other branches (Bombay blood phenotype, growth failure) are immunologically inert.	leukocyte adhesion deficiency type II MONDO:0009953	yes	yes	no	nested via Congenital Phagocyte Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Lysinuric protein intolerance DISEASE Differentiating mechanism Biallelic SLC7A7 loss disables the y+LAT1 cationic amino acid transporter, and IUIS places the disease in the FHL section for its macrophage phenotype: a hyper-inflammatory response of macrophages with normal NK cell function, plus pulmonary alveolar proteinosis and bleeding tendency. It reaches immune dysregulation through a metabolic transport lesion rather than a cytotoxicity, checkpoint or apoptosis defect, which distinguishes it from every other FHL-section member.	lysinuric protein intolerance MONDO:0009109	yes	yes	no	nested via Immune Dysregulation IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Mevalonate Kinase Deficiency DISEASE Differentiating mechanism The only member that is simultaneously an inborn error of metabolism: biallelic MVK loss of function blocks the isoprenoid branch immediately downstream of mevalonate, and the resulting shortage of geranylgeranyl pyrophosphate leaves RhoA unprenylated, which releases pyrin. It therefore converges on the same pyrin inflammasome as familial Mediterranean fever while starting from a metabolic rather than an immune lesion, and IUIS itself records the link from the block to the inflammation as not fully resolved. Residual enzyme activity sets the phenotype on a continuous scale from hyper-IgD syndrome to mevalonic aciduria with neurological involvement, which none of the other members show.	mevalonate kinase deficiency MONDO:0017708	yes	yes	no	nested via Autoinflammatory Disorder IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Pancytopenia-Developmental Delay Syndrome DISEASE Differentiating mechanism Biallelic ERCC6L2 variants, entered in IUIS Table 9 as BMFS2. ERCC6L2 works with DNA-PK to keep RNA polymerase II transcription from colliding with damage, so the defect is transcription-coupled repair rather than the interstrand-crosslink repair of Fanconi anemia or the telomere maintenance of the dyskeratosis congenita members. The table's associated-features cell pairs the marrow failure with learning difficulties and microcephaly, and as with BMFS1 the lymphocyte columns are NA.	pancytopenia-developmental delay syndrome MONDO:0014317	yes	yes	no	nested via Bone Marrow Failure IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Proteasome-Associated Autoinflammatory Syndrome DISEASE Differentiating mechanism Reaches the type I interferon arm through proteostasis failure rather than nucleic-acid sensing: loss-of-function defects in immunoproteasome subunits and proteasome assembly factors let ubiquitinated substrates accumulate, and the ensuing cell-intrinsic stress response drives chronic interferon signalling. That distinguishes it from Aicardi-Goutieres syndrome and SAVI, which start from a nucleic-acid ligand and a sensor respectively. The clinical signature is equally distinctive: annular violaceous plaques evolving to progressive lipodystrophy with joint contractures, a combination no other member produces.	proteasome-associated autoinflammatory syndrome MONDO:0009726	yes	yes	no	nested via Autoinflammatory Disorder IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Psoriasis 14, Pustular DISEASE Differentiating mechanism Loss of the interleukin-36 receptor antagonist leaves IL-36 alpha, beta and gamma signalling unopposed on keratinocytes, which drives IL-8 release and massive neutrophil recruitment into the epidermis. The lesion is therefore an absent brake on an IL-1-family cytokine rather than an overactive sensor, the same logic IUIS applies to DIRA in the neighbouring row. What sets it apart from the rest of Table 7 is the compartment: recurrent sterile pustular flares confined largely to skin, rather than fever with serositis or vasculopathy.	psoriasis 14, pustular MONDO:0013626	yes	yes	no	nested via Autoinflammatory Disorder IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Purine nucleoside phosphorylase deficiency DISEASE Differentiating mechanism An inborn error of the purine salvage pathway: without PNP, deoxyguanosine accumulates and is phosphorylated to dGTP, a substrate-toxicity chain that falls preferentially on T cells. The only classical metabolic-enzyme member here, coupling a T-cell-predominant combined immunodeficiency to neurological disease and autoimmunity.	purine nucleoside phosphorylase deficiency MONDO:0013171	yes	yes	no	nested via Combined Immunodeficiency with Syndromic Features IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia DISEASE Differentiating mechanism Heterozygous MECOM variants, entered in IUIS Table 9 as MECOM deficiency and recorded in the table's own footnote as the single new inborn error of immunity added to Table 9 in the 2022 update. MECOM is a haematopoietic transcription factor, so unlike every other member here the lesion is in the transcriptional programme that maintains the stem cell rather than in a genome-maintenance or telomere pathway. It is also the only member whose immune arm is a named B-cell deficiency in the table's own B-cell column, and the only one carrying a skeletal malformation, radioulnar synostosis, that is a fusion rather than a reduction defect.	radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome MONDO:0011555	yes	yes	no	nested via Bone Marrow Failure IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Severe Combined Immunodeficiency DISEASE Differentiating mechanism The severe end of IUIS Table 1: profound failure of T-lymphocyte development that abrogates adaptive immunity from birth, reached by three mechanistically distinct routes — defective common-gamma-chain cytokine receptor signaling (IL2RG, JAK3, IL7R), failed V(D)J recombination or DNA double-strand-break repair (RAG1, RAG2, DCLRE1C/Artemis), and purine-salvage metabolite toxicity (ADA). Unlike the gene-specific Table 1 members alongside it, this entry is curated as the SCID concept itself, with the causal genes carried as subtypes.	severe combined immunodeficiency MONDO:0015974	yes	yes	no	nested via Combined Immunodeficiencies IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Severe Congenital Neutropenia 1, Autosomal Dominant DISEASE Differentiating mechanism Heterozygous ELANE missense variants produce a misfolded neutrophil elastase that triggers the unfolded protein response in granulocytic precursors, killing them at the promyelocyte stage. The defect of phagocyte number rather than function, and the archetype of the table's neutropenia arm: marrow arrest rather than a mature cell that cannot act. Uniquely among the members here it carries a defined leukemic route — somatic CSF3R truncation under long-term G-CSF — and the same gene's other allelic disease, cyclic neutropenia, is merged into this IUIS row.	severe congenital neutropenia 1, autosomal dominant MONDO:0042490	yes	yes	no	nested via Congenital Phagocyte Defect IEIs	unknown	UNKNOWN	UNKNOWN
nested outside grouping MONDO	Spondyloenchondrodysplasia DISEASE Differentiating mechanism The only member that is both an interferonopathy and a skeletal dysplasia, because one enzyme serves both roles. Loss of tartrate-resistant acid phosphatase leaves osteopontin phosphorylated, which drives type I interferon through plasmacytoid dendritic cells, while the same enzyme loss disturbs the vertebral and metaphyseal growth plates and produces platyspondyly with enchondroma-like lesions. Clinically it adds prominent lupus-like autoimmunity and spastic paraparesis, so it sits at the intersection of the interferon arm and the bone nosology rather than cleanly inside either.	spondyloenchondrodysplasia with immune dysregulation MONDO:0011939	yes	yes	no	nested via Autoinflammatory Disorder IEIs	unknown	UNKNOWN	UNKNOWN
DisMech only	Autoinflammatory Disorder IEIs GROUPING Differentiating mechanism IUIS Table 7 — autoinflammatory disorders: sterile, antigen-independent innate inflammation via inflammasome/IL-1, type I interferon, or NF-kappaB dysregulation (CAPS, COPA syndrome, the interferonopathies).	No MONDO identity	yes	no	no MONDO ID	listed	not evaluated	not evaluated	not evaluated
DisMech only	Bone Marrow Failure IEIs GROUPING Differentiating mechanism IUIS Table 9 — bone marrow failure: immunodeficiency arising from failure of the haematopoietic stem and progenitor compartment through genome-maintenance, DNA-replication or telomere-biology lesions.	No MONDO identity	yes	no	no MONDO ID	listed	not evaluated	not evaluated	not evaluated
DisMech only	Combined Immunodeficiencies IEIs GROUPING Differentiating mechanism IUIS Table 1 — combined immunodeficiencies affecting cellular and humoral immunity (SCID, CID, Omenn syndrome).	No MONDO identity	yes	no	no MONDO ID	listed	not evaluated	not evaluated	not evaluated
DisMech only	Combined Immunodeficiency with Syndromic Features IEIs GROUPING Differentiating mechanism IUIS Table 2 — combined immunodeficiencies with associated or syndromic features (DiGeorge, Wiskott-Aldrich, ectodermal dysplasia with immunodeficiency, ICF).	No MONDO identity	yes	no	no MONDO ID	listed	not evaluated	not evaluated	not evaluated
DisMech only	Complement Deficiency IEIs GROUPING Differentiating mechanism IUIS Table 8 — complement deficiencies, where the position of the defect within the cascade predicts the phenotype (terminal-component defects and neisserial infection; early classical-pathway defects and lupus-like immune-complex disease).	No MONDO identity	yes	no	no MONDO ID	listed	not evaluated	not evaluated	not evaluated
DisMech only	Congenital Phagocyte Defect IEIs GROUPING Differentiating mechanism IUIS Table 5 — congenital defects of phagocyte number or function (chronic granulomatous disease, severe congenital neutropenia, leukocyte adhesion deficiency).	No MONDO identity	yes	no	no MONDO ID	listed	not evaluated	not evaluated	not evaluated
DisMech only	Immune Dysregulation IEIs GROUPING Differentiating mechanism IUIS Table 4 — diseases of immune dysregulation (HLH, ALPS, IPEX/APECED, CTLA4/LRBA checkpoint defects, interferonopathies).	No MONDO identity	yes	no	no MONDO ID	listed	not evaluated	not evaluated	not evaluated
DisMech only	Intrinsic and Innate Immunity Defect IEIs GROUPING Differentiating mechanism IUIS Table 6 — defects in intrinsic and innate immunity, producing susceptibility restricted to one pathogen class (Mendelian susceptibility to mycobacterial disease, chronic mucocutaneous candidiasis, herpesvirus and HPV susceptibility).	No MONDO identity	yes	no	no MONDO ID	listed	not evaluated	not evaluated	not evaluated
DisMech only	Predominantly Antibody Deficiencies IEIs GROUPING Differentiating mechanism IUIS Table 3 — predominantly antibody deficiencies (XLA, CVID, selective IgA/IgM deficiency, hyper-IgM syndromes).	No MONDO identity	yes	no	no MONDO ID	listed	not evaluated	not evaluated	not evaluated

Open questions & knowledge gaps

Curated open questions about this grouping's boundary, coverage, or evidence. These record what is not settled, so they are claims about the curation rather than about the biology unless the rationale says otherwise.

KNOWLEDGE GAP iei_tree_coverage_against_iuis_2024

What fraction of the IUIS catalogue does this tree actually represent, and is the sample it holds representative or biased?

As of 2026-08-20 the tree reaches 36 curated Disease entries against the IUIS 2024 catalogue of 508 genes and 17 phenocopies — roughly 7%. That in itself is expected for a mechanism knowledge base that curates in depth rather than enumerating. What matters for anyone querying the tree is that the coverage is uneven in a way the member counts make visible: Tables 2 and 4 hold ten and nine entries respectively, while Tables 8 and 9 hold one each and Table 10 (phenocopies) is out of scope by design. A query that treats this grouping as a sample of IEI will therefore over-weight syndromic combined immunodeficiency and immune dysregulation and under-weight complement and marrow failure. The gap is curation coverage, not a scientific uncertainty, but it should not be inferred from the tree's structure alone.

Proposed experiments

Census KB IEI coverage against the IUIS 2024 per-table counts — For each of the nine in-scope IUIS tables, compare the count of kb/disorders/ entries carrying the matching `classifications.iuis_category` against the published per-table entity count (Table 1, 73; Table 2, 83; Table 3, 48; Table 4, 72; Table 5, 45; Table 6, 86; Table 7, 69; Table 8, 36; Table 9, 47) and publish the per-table coverage ratio. This turns the sampling bias above into a number a consumer of the grouping can read, and gives curation a table-level priority ordering rather than a flat backlog.

KNOWLEDGE GAP iuis_category_backfill_candidates

Which further kb/disorders/ entries belong in an IUIS table, and what evidence fixes the assignment for a disease that is mechanistically an obvious IEI but whose table placement has never been curated?

Several entries carry an unmistakable IEI phenotype but no `classifications.iuis_category`, so the sub-groupings' NECESSARY criteria cannot be evaluated for them and they cannot be listed without asserting a table placement the entry does not itself record. Identified 2026-08-20: STAT2 Deficiency (a break in type I interferon signal transduction, giving the Table 6 signature of susceptibility restricted to viral disease); Wiskott-Aldrich Syndrome and Ataxia Telangiectasia (Table 2); and Aicardi-Goutieres Syndrome, Familial Cold Autoinflammatory Syndrome and Proteasome-Associated Autoinflammatory Syndrome (Table 7). The general problem is that table assignment is curated per Disease entry while grouping membership is curated on the grouping, so an entry can be mechanistically obvious and still structurally invisible to the audit. The gap is bookkeeping rather than biology, but leaving it implicit is what let five IUIS tables go unrepresented in this tree until 2026-08-20. Hosted on the umbrella rather than on any one sub-grouping because the candidates span Tables 2, 6 and 7. Updated 2026-09-17: Wiskott-Aldrich Syndrome, Ataxia Telangiectasia, Aicardi-Goutieres Syndrome, Familial Cold Autoinflammatory Syndrome and Proteasome-Associated Autoinflammatory Syndrome now all carry `classifications.iuis_category` and are resolved from this list. STAT2 Deficiency remains open — PR #11810 classifies it but has not yet merged to `main`; re-check once it lands. Two further calls, raised by #11879's review of #11810, are recorded here as **non-assignment** decisions rather than open candidates, so the reasoning is not re-derived from scratch: - **Osteopetrosis** (the umbrella entry) is deliberately left unclassified. All seven IUIS Table 6 osteopetrosis rows (CLCN7, SNX10, OSTM1, PLEKHM1, TCIRG1, TNFRSF11A, TNFSF11) are autosomal recessive, but the umbrella entry explicitly lumps autosomal dominant ADO2/Albers-Schönberg, which IUIS does not list. `iuis_category` is single-valued and entry-level, so tagging the umbrella would assert the IUIS placement over forms outside the IUIS entity. The AR-specific `Autosomal Recessive Osteopetrosis 1` entry (TCIRG1, MONDO:0009815) has no such scope mismatch and was classified and added to `Intrinsic_and_Innate_Immunity_Defect_IEIs` instead. - **Hidradenitis Suppurativa** is deliberately left unclassified. The IUIS Table 6 rows (NCSTN, PSEN, PSENEN) are the familial autosomal-dominant gamma-secretase entities; the KB entry is the sporadic-inclusive disease, carrying those genes only as familial-subset susceptibility loci. Tagging the whole entry as an inborn error of immunity would over-claim beyond what the familial subset supports. See also #11877, which independently tracks entries that already carry an `iuis_category` but are absent from their matching sub-grouping's `members:` — a different gap (listing) from the one this discussion tracks (classification).

Proposed experiments

Backfill iuis_category across candidate IEI entries — For each kb/disorders/ entry with an IEI phenotype and no `classifications.iuis_category`, cite the IUIS 2024 classification (PMID:41608114) or a disease-specific source that states the table placement, add the assignment with a verified snippet, then add the entry to the matching sub-grouping. Each needs its own sourced assignment, which is why the backfill was not done as part of the pass that surfaced it. Remaining open candidate as of 2026-09-17: STAT2 Deficiency (pending PR #11810).

KNOWLEDGE GAP iei_phenocopy_scope_boundary

Should IUIS Table 10 phenocopies be modelled somewhere in dismech, given that they are deliberately excluded from this grouping?

This grouping excludes IUIS Table 10 because its members are not germline monogenic disorders and so fail the NECESSARY criteria — 8 of the 17 are caused by somatic mutations and 9 by neutralizing anti-cytokine autoantibodies. The exclusion is correct for this grouping but leaves the concepts homeless: an anti-IFN-gamma autoantibody syndrome is mechanistically an immunodeficiency, is diagnosed and managed in the same clinics, and phenocopies a curated germline entry closely enough that the two are differential diagnoses of each other. Whether dismech should carry them as ordinary Disease entries outside this tree, as a sibling non-IEI grouping, or not at all is an open scope decision, not something the criteria here settle.

Evidence

PMID:41608114 — “Total number of conditions for Table 10: 17 (8 due to somatic mutations; 9 due to autoantibodies).”

Source

View YAML on GitHub

Raw YAML

name: Inborn Errors of Immunity
display_name: Inborn Errors of Immunity (IEI)
creation_date: "2026-06-13T00:00:00Z"
description: >-
  Inborn errors of immunity (IEI) are Mendelian disorders caused by germline
  variants in genes required for immune development, regulation, or effector
  function. The IUIS Expert Committee's 2024 classification — the current
  edition, superseding the 2022 update — describes 559 IEI across 508 genes and
  17 phenocopies, of which 67 monogenic defects and 2 phenocopies are new since
  2022, organized into ten phenotypic tables spanning recurrent infection,
  immune dysregulation, autoinflammation, complement deficiency and bone marrow
  failure. Each condition is individually rare, but together they are not: a
  recent US study put the incidence of IEI at 6 per 10,000 people.
grouping_basis:
- SHARED_MECHANISM
- CLINICAL_CONVENTION
grouping_rationale: >-
  Grouped on the defining monogenic-immunity mechanism: every member is a
  germline inborn error disrupting the immune system, as recognized by the
  International Union of Immunological Societies (IUIS) phenotypic
  classification. Members are kept as separate Disease entries (and further
  organized into IUIS-table sub-groupings) because causal gene, inheritance,
  dominant clinical phenotype (infection vs dysregulation vs autoinflammation),
  and organ involvement differ. This grouping points down to nested IUIS-table
  groupings rather than listing all 500-plus entities flatly. The sub-groupings
  follow the IUIS table structure one-to-one, so an entity's table assignment —
  recorded per entry as `classifications.iuis_category` — determines exactly one
  sub-grouping, and the sub-groupings partition the members rather than
  overlapping. Note this holds for disease entities, not for genes: IUIS
  explicitly enters one gene in two tables when different variant classes give
  different phenotypes (RELA, OTULIN, NLRP1, ZAP70, IRAK4, IL6ST, STAT5B,
  FOXN1), so a gene-keyed query across this tree can legitimately return two
  sub-groupings.
  Somatic IEI phenocopies (IUIS Table 10), secondary immunodeficiencies (e.g.,
  HIV/AIDS), and incidental immunodeficiency features in non-IEI syndromes are
  out of scope.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0003778
      label: inborn error of immunity
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping concept is the MONDO inborn error of immunity class
      (MONDO:0003778). Nested IUIS-table sub-groupings are clinical unions
      below this umbrella; several lack a valid MONDO grouping term (see
      research/grouping_mondo_gaps.md and sub-grouping notes).
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        Umbrella maps exactly to MONDO:0003778. IUIS sub-table groupings
        are dismech-curated unions and are not required to is-a-subsume
        under this term in MONDO.
membership_criteria:
- description: >-
    A disorder is an inborn error of immunity if it is a Mendelian germline
    disorder with a causal variant in a gene required for immune development,
    regulation, or effector function, as assigned to an IUIS IEI phenotypic
    table. Excludes acquired immunodeficiency and somatic IEI phenocopies.
  criteria_semantics: NECESSARY
  logic:
    operator: AND
    operands:
    - criterion_predicate: OTHER
      description: >-
        Germline monogenic etiology disrupting immune development, regulation,
        or effector function, recognized by IUIS as an inborn error of immunity.
    - criterion_predicate: OTHER
      negated: true
      description: >-
        Not an acquired or secondary immunodeficiency (e.g., HIV/AIDS) and not
        a somatic IEI phenocopy (IUIS Table 10).
  evidence:
  - reference: PMID:41608114
    reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Inborn errors of immunity (IEIs) are, by definition, caused by damaging
      germline variants in single genes.
    explanation: >-
      The IUIS Expert Committee's definitional statement, which is the positive
      conjunct of these criteria: germline, monogenic. It is also what excludes
      the acquired and somatic-phenocopy conditions named in the negated
      conjunct.
  - reference: PMID:41608114
    reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      IEIs are currently categorized into 10 tables, with subtables segregating
      groups of disorders into overlapping phenotypes.
    explanation: >-
      Establishes the ten-table structure that the nested sub-groupings mirror
      one-to-one, and therefore that a complete IEI tree needs ten branches
      rather than the four this grouping originally carried.
members:
- member: Immune Dysregulation IEIs
  member_type: GROUPING
  differentiating_mechanisms:
  - description: >-
      IUIS Table 4 — diseases of immune dysregulation (HLH, ALPS, IPEX/APECED,
      CTLA4/LRBA checkpoint defects, interferonopathies).
- member: Combined Immunodeficiencies IEIs
  member_type: GROUPING
  differentiating_mechanisms:
  - description: >-
      IUIS Table 1 — combined immunodeficiencies affecting cellular and humoral
      immunity (SCID, CID, Omenn syndrome).
- member: Combined Immunodeficiency with Syndromic Features IEIs
  member_type: GROUPING
  differentiating_mechanisms:
  - description: >-
      IUIS Table 2 — combined immunodeficiencies with associated or syndromic
      features (DiGeorge, Wiskott-Aldrich, ectodermal dysplasia with
      immunodeficiency, ICF).
- member: Predominantly Antibody Deficiencies IEIs
  member_type: GROUPING
  differentiating_mechanisms:
  - description: >-
      IUIS Table 3 — predominantly antibody deficiencies (XLA, CVID, selective
      IgA/IgM deficiency, hyper-IgM syndromes).
- member: Congenital Phagocyte Defect IEIs
  member_type: GROUPING
  differentiating_mechanisms:
  - description: >-
      IUIS Table 5 — congenital defects of phagocyte number or function
      (chronic granulomatous disease, severe congenital neutropenia,
      leukocyte adhesion deficiency).
- member: Intrinsic and Innate Immunity Defect IEIs
  member_type: GROUPING
  differentiating_mechanisms:
  - description: >-
      IUIS Table 6 — defects in intrinsic and innate immunity, producing
      susceptibility restricted to one pathogen class (Mendelian
      susceptibility to mycobacterial disease, chronic mucocutaneous
      candidiasis, herpesvirus and HPV susceptibility).
- member: Autoinflammatory Disorder IEIs
  member_type: GROUPING
  differentiating_mechanisms:
  - description: >-
      IUIS Table 7 — autoinflammatory disorders: sterile, antigen-independent
      innate inflammation via inflammasome/IL-1, type I interferon, or
      NF-kappaB dysregulation (CAPS, COPA syndrome, the interferonopathies).
- member: Complement Deficiency IEIs
  member_type: GROUPING
  differentiating_mechanisms:
  - description: >-
      IUIS Table 8 — complement deficiencies, where the position of the defect
      within the cascade predicts the phenotype (terminal-component defects and
      neisserial infection; early classical-pathway defects and lupus-like
      immune-complex disease).
- member: Bone Marrow Failure IEIs
  member_type: GROUPING
  differentiating_mechanisms:
  - description: >-
      IUIS Table 9 — bone marrow failure: immunodeficiency arising from failure
      of the haematopoietic stem and progenitor compartment through
      genome-maintenance, DNA-replication or telomere-biology lesions.
references:
- reference: PMID:41608114
  title: >-
    Human inborn errors of immunity: 2024 update on the classification from the
    International Union of Immunological Societies Expert Committee.
  findings:
  - statement: >-
      The current (2024) IUIS classification, superseding the June 2022 update
      this grouping was originally written against. Catalogues 508 genes and 17
      phenocopies across ten phenotypic tables, of which 67 monogenic defects
      and 2 phenocopies are new since 2022.
  - statement: >-
      Gives the per-table entity counts the sub-groupings are measured against:
      Table 1, 73 genes; Table 2, 83; Table 3, 48; Table 4, 72 defects; Table 5,
      45 defects; Table 6, 86; Table 7, 69 disorders; Table 8, 36; Table 9, 47;
      Table 10, 17 phenocopies.
- reference: PMID:41608113
  title: >-
    The 2024 update of IUIS phenotypic classification of human inborn errors of
    immunity.
  findings:
  - statement: >-
      The phenotypic companion to the genotypic classification, and the one this
      tree is structurally closest to: it describes 559 IEI and presents the
      classification as decision trees keyed on clinical and immunological
      phenotype rather than on gene. Relevant because the sub-groupings here
      are phenotype-organized (infection vs dysregulation vs autoinflammation)
      and inherit that framing.
discussions:
- discussion_id: iei_tree_coverage_against_iuis_2024
  kind: KNOWLEDGE_GAP
  prompt: >-
    What fraction of the IUIS catalogue does this tree actually represent, and
    is the sample it holds representative or biased?
  rationale: >-
    As of 2026-08-20 the tree reaches 36 curated Disease entries against the
    IUIS 2024 catalogue of 508 genes and 17 phenocopies — roughly 7%. That in
    itself is expected for a mechanism knowledge base that curates in depth
    rather than enumerating. What matters for anyone querying the tree is that
    the coverage is uneven in a way the member counts make visible: Tables 2 and
    4 hold ten and nine entries respectively, while Tables 8 and 9 hold one each
    and Table 10 (phenocopies) is out of scope by design. A query that treats
    this grouping as a sample of IEI will therefore over-weight syndromic
    combined immunodeficiency and immune dysregulation and under-weight
    complement and marrow failure. The gap is curation coverage, not a
    scientific uncertainty, but it should not be inferred from the tree's
    structure alone.
  proposed_experiments:
  - experiment_id: iei_coverage_census_against_iuis_tables
    name: Census KB IEI coverage against the IUIS 2024 per-table counts
    description: >-
      For each of the nine in-scope IUIS tables, compare the count of
      kb/disorders/ entries carrying the matching
      `classifications.iuis_category` against the published per-table entity
      count (Table 1, 73; Table 2, 83; Table 3, 48; Table 4, 72; Table 5, 45;
      Table 6, 86; Table 7, 69; Table 8, 36; Table 9, 47) and publish the
      per-table coverage ratio. This turns the sampling bias above into a
      number a consumer of the grouping can read, and gives curation a
      table-level priority ordering rather than a flat backlog.
- discussion_id: iuis_category_backfill_candidates
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which further kb/disorders/ entries belong in an IUIS table, and what
    evidence fixes the assignment for a disease that is mechanistically an
    obvious IEI but whose table placement has never been curated?
  rationale: >-
    Several entries carry an unmistakable IEI phenotype but no
    `classifications.iuis_category`, so the sub-groupings' NECESSARY criteria
    cannot be evaluated for them and they cannot be listed without asserting a
    table placement the entry does not itself record. Identified 2026-08-20:
    STAT2 Deficiency (a break in type I interferon signal transduction, giving
    the Table 6 signature of susceptibility restricted to viral disease);
    Wiskott-Aldrich Syndrome and Ataxia Telangiectasia (Table 2); and
    Aicardi-Goutieres Syndrome, Familial Cold Autoinflammatory Syndrome and
    Proteasome-Associated Autoinflammatory Syndrome (Table 7). The general
    problem is that table assignment is curated per Disease entry while grouping
    membership is curated on the grouping, so an entry can be mechanistically
    obvious and still structurally invisible to the audit. The gap is
    bookkeeping rather than biology, but leaving it implicit is what let five
    IUIS tables go unrepresented in this tree until 2026-08-20. Hosted on the
    umbrella rather than on any one sub-grouping because the candidates span
    Tables 2, 6 and 7.

    Updated 2026-09-17: Wiskott-Aldrich Syndrome, Ataxia Telangiectasia,
    Aicardi-Goutieres Syndrome, Familial Cold Autoinflammatory Syndrome and
    Proteasome-Associated Autoinflammatory Syndrome now all carry
    `classifications.iuis_category` and are resolved from this list. STAT2
    Deficiency remains open — PR #11810 classifies it but has not yet merged
    to `main`; re-check once it lands. Two further calls, raised by #11879's
    review of #11810, are recorded here as **non-assignment** decisions rather
    than open candidates, so the reasoning is not re-derived from scratch:

    - **Osteopetrosis** (the umbrella entry) is deliberately left unclassified.
      All seven IUIS Table 6 osteopetrosis rows (CLCN7, SNX10, OSTM1, PLEKHM1,
      TCIRG1, TNFRSF11A, TNFSF11) are autosomal recessive, but the umbrella
      entry explicitly lumps autosomal dominant ADO2/Albers-Schönberg, which
      IUIS does not list. `iuis_category` is single-valued and entry-level, so
      tagging the umbrella would assert the IUIS placement over forms outside
      the IUIS entity. The AR-specific `Autosomal Recessive Osteopetrosis 1`
      entry (TCIRG1, MONDO:0009815) has no such scope mismatch and was
      classified and added to `Intrinsic_and_Innate_Immunity_Defect_IEIs`
      instead.
    - **Hidradenitis Suppurativa** is deliberately left unclassified. The IUIS
      Table 6 rows (NCSTN, PSEN, PSENEN) are the familial autosomal-dominant
      gamma-secretase entities; the KB entry is the sporadic-inclusive disease,
      carrying those genes only as familial-subset susceptibility loci.
      Tagging the whole entry as an inborn error of immunity would over-claim
      beyond what the familial subset supports.

    See also #11877, which independently tracks entries that already carry an
    `iuis_category` but are absent from their matching sub-grouping's
    `members:` — a different gap (listing) from the one this discussion tracks
    (classification).
  proposed_experiments:
  - experiment_id: backfill_iuis_category_across_candidate_entries
    name: Backfill iuis_category across candidate IEI entries
    description: >-
      For each kb/disorders/ entry with an IEI phenotype and no
      `classifications.iuis_category`, cite the IUIS 2024 classification
      (PMID:41608114) or a disease-specific source that states the table
      placement, add the assignment with a verified snippet, then add the entry
      to the matching sub-grouping. Each needs its own sourced assignment, which
      is why the backfill was not done as part of the pass that surfaced it.
      Remaining open candidate as of 2026-09-17: STAT2 Deficiency (pending PR
      #11810).
- discussion_id: iei_phenocopy_scope_boundary
  kind: KNOWLEDGE_GAP
  prompt: >-
    Should IUIS Table 10 phenocopies be modelled somewhere in dismech, given
    that they are deliberately excluded from this grouping?
  rationale: >-
    This grouping excludes IUIS Table 10 because its members are not germline
    monogenic disorders and so fail the NECESSARY criteria — 8 of the 17 are
    caused by somatic mutations and 9 by neutralizing anti-cytokine
    autoantibodies. The exclusion is correct for this grouping but leaves the
    concepts homeless: an anti-IFN-gamma autoantibody syndrome is
    mechanistically an immunodeficiency, is diagnosed and managed in the same
    clinics, and phenocopies a curated germline entry closely enough that the
    two are differential diagnoses of each other. Whether dismech should carry
    them as ordinary Disease entries outside this tree, as a sibling
    non-IEI grouping, or not at all is an open scope decision, not something
    the criteria here settle.
  evidence:
  - reference: PMID:41608114
    reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Total number of conditions for Table 10: 17 (8 due to somatic mutations;
      9 due to autoantibodies).
    explanation: >-
      Quantifies the excluded set and confirms its two non-germline mechanisms,
      which is why Table 10 fails this grouping's NECESSARY criteria rather
      than merely being uncurated.
notes: >-
  Nine IUIS-table sub-groupings, one per in-scope table; Table 10 (phenocopies)
  is excluded by the membership criteria rather than uncurated — see the
  `iei_phenocopy_scope_boundary` discussion. Per-disease IUIS assignment belongs
  in `classifications.iuis_category` on each Disease entry, and each
  sub-grouping's NECESSARY criterion is a `HAS_CLASSIFICATION` leaf reading that
  slot, so membership is machine-auditable via `just check-groupings` rather
  than aspirational.

  Expanded 2026-08-20 from four sub-groupings to nine. Tables 5-9 (phagocyte
  defects, intrinsic and innate immunity, autoinflammatory disorders,
  complement deficiencies, bone marrow failure) already had curated members
  carrying the right `iuis_category` but no sub-grouping to hang from, so eight
  IEI entries were unreachable from this umbrella. Thirteen further entries were
  added to the four existing sub-groupings in the same pass.

  Mechanism modules for IEI pathway families remain a follow-up before
  NECESSARY_AND_SUFFICIENT CONFORMS_TO_MODULE criteria can be used. MONDO
  descendant coverage and mapping consistency:
  `uv run python scripts/grouping_mondo_gaps.py` (see research/grouping_mondo_gaps.md).