| Domain | Evidence-based finding | Suggested ontology annotations | Best source/date |
|---|---|---|---|
| Identity / identifier | **Immunodeficiency 131** is linked to **IRF4** and represented in Open Targets as **MONDO:0976229**. The best-supported core phenotype for this entry is the 2023 **autosomal dominant combined immunodeficiency caused by recurrent IRF4 p.T95R**, termed **multimorphic IRF4 CID (MICI)**. Distinct **allelic IRF4 disorders** include **F359L dominant primary immunodeficiency/antibody deficiency** and **R98W haploinsufficiency with Whipple disease susceptibility**, which should not be conflated with MICI. (pqac-00000000, pqac-00000007, pqac-00000010) | MONDO:0976229; gene: **IRF4**; suggested disease label: combined immunodeficiency | Open Targets disease-target evidence (accessed via tool context; MONDO association) and Fornes et al., *Sci Immunol*, Jan 2023 (pqac-00000000, pqac-00000007) |
| Causal variant and inheritance | **Core MICI:** recurrent heterozygous **IRF4 c.284C>G (p.T95R)** in the DNA-binding domain; **autosomal dominant**, apparently **fully penetrant** in reported cases; mostly **de novo**, with one mosaic mother reported. Variant absent from control databases in the cited summaries. **Allelic disorders:** **F359L (c.1075T>C)** in the interferon activation domain causes dominant antibody/CID phenotype; **R98W** causes **haploinsufficiency** predisposing to Whipple disease with **incomplete penetrance**. (pqac-00000006, pqac-00000007, pqac-00000002, pqac-00000005) | SO: missense_variant; HP: Autosomal dominant inheritance; gene region suggestion: DNA-binding domain / interferon activation domain | Fornes et al., *Sci Immunol*, Jan 2023; Thouenon et al., *J Exp Med*, Mar 2023; Constantine & Lionakis review, Apr 2020 (pqac-00000006, pqac-00000002, pqac-00000005) |
| Cohort and onset | **Core MICI:** **7 patients from 6 unrelated families**, with **very early onset**, often **<1 year**. One detailed proband presented at **11 months** with respiratory failure/infections. **F359L:** **3 patients across 2 generations**; childhood-onset hypogammaglobulinemia, index case symptomatic by **6 months** and diagnosed by **11 months**. **R98W Whipple susceptibility:** kindred data summarized as **4 Whipple disease patients** among **12 heterozygous carriers**; adult onset around **mean 55–58 years**. (pqac-00000006, pqac-00000009, pqac-00000001, pqac-00000005, pqac-00000014) | HP: Infantile onset; HP: Adult onset; HP: Recurrent infections | Fornes et al., Jan 2023; Thouenon et al., Mar 2023; review summarizing Guérin et al., Apr 2020 (pqac-00000006, pqac-00000001, pqac-00000005) |
| Infections | **Core MICI:** profound susceptibility to **opportunistic infections**, especially **Pneumocystis jirovecii pneumonia**, severe viral infections (**CMV**, **EBV**), weakly pathogenic mycobacteria including **BCG / Mycobacterium bovis**, recurrent sinopulmonary infection, and chronic diarrhea. **F359L:** recurrent ENT and other infections including **meningococcal infection**, **Giardia lamblia**, **CMV**, **disseminated varicella zoster virus**, fungal infections, **Bartonella henselae**, conjunctivitis, molluscum contagiosum, and onychomycosis/cutaneous fungal disease. **R98W:** predisposition is specifically linked to **Tropheryma whipplei / Whipple disease** and chronic carriage. (pqac-00000006, pqac-00000009, pqac-00000003, pqac-00000005) | NCBITaxon: *Pneumocystis jirovecii*, CMV, EBV, *Mycobacterium bovis*, *Giardia lamblia*, *Tropheryma whipplei*; HP: Opportunistic infections; HP: Recurrent respiratory infections | Fornes et al., Jan 2023; Jia thesis summary, Jan 2023; Thouenon et al., Mar 2023; Constantine & Lionakis, Apr 2020 (pqac-00000006, pqac-00000009, pqac-00000003, pqac-00000005) |
| Immune phenotype | **Core MICI:** **agammaglobulinemia** or near-complete antibody deficiency with markedly reduced **IgG/IgA/IgM**, reduced **CD19+ B cells**, increased **naïve B cells**, reduced **class-switched memory B cells**, decreased **plasmablasts/plasma cells**, reduced **T\_H17** and **T\_FH** cells, decreased cytokine production, and in one detailed case undetectable vaccine antibodies to tetanus/diphtheria. **F359L:** panhypogammaglobulinemia, very low plasmablast/plasma cell counts, low naïve **CD4/CD8** T cells and increased terminal effector T cells, plus hair/skin pigmentation abnormalities and premature hair graying. **R98W:** in vitro loss of DNA binding/transcription with impaired helper pathways summarized, but classic broad agammaglobulinemia phenotype not emphasized in the cited review summary. (pqac-00000006, pqac-00000007, pqac-00000009, pqac-00000002, pqac-00000004) | HP: Agammaglobulinemia; HP: Hypogammaglobulinemia; HP: Decreased class-switched memory B cells; HP: Decreased plasmablasts; CL: B cell, plasma cell, CD4-positive T cell, T follicular helper cell, T helper 17 cell | Fornes et al., Jan 2023; Jia thesis summary, Jan 2023; Thouenon et al., Mar 2023 (pqac-00000006, pqac-00000009, pqac-00000002) |
| Mechanism | **Core MICI p.T95R:** a **multimorphic** mechanism combining **hypermorph** (higher DNA-binding affinity), **hypomorph** (reduced transcription on canonical IRF4 targets), and **neomorph** (binding to noncanonical DNA sites and altered gene-expression programs). Patient/experimental systems showed altered B-cell maturation, plasma-cell differentiation failure, and reduced T-cell effector programs. **F359L:** **neomorphic / dominant-negative** behavior centered on the interferon activation domain, with selective failure of **ISRE** promoter activation but retained **EICE/AICE** activity; impaired **BLIMP1/XBP1** induction and plasma-cell differentiation. **R98W:** **loss-of-function haploinsufficiency** with defective DNA binding/transcription and incomplete penetrance for Whipple disease. (pqac-00000008, pqac-00000011, pqac-00000002, pqac-00000004, pqac-00000005) | GO: DNA-binding transcription factor activity; GO: plasma cell differentiation; GO: immunoglobulin production; GO: T-helper 17 cell differentiation; GO: germinal center formation | Fornes et al., Jan 2023; Thouenon et al., Mar 2023; review summary, Apr 2020 (pqac-00000008, pqac-00000011, pqac-00000002, pqac-00000005) |
| Diagnosis | Evidence supports diagnosis by **genetic testing** identifying heterozygous **IRF4** variants in affected patients, alongside immunophenotyping showing antibody deficiency and B/T-cell abnormalities. In MICI, the paper used extensive **flow cytometry/CyTOF**, **scRNA-seq**, functional lymphocyte assays, and mechanistic assays including **EMSA, HT-SELEX, luciferase, ChIP-seq, surface plasmon resonance**, and single-molecule imaging. In a detailed p.T95R case, immunoglobulins were undetectable (**IgG <0.3 g/L, IgA <0.04 g/L, IgM <0.03 g/L**) with absent tetanus/diphtheria antibodies and 95.2% naïve CD19+ B cells. Standardized disease-specific clinical criteria were **not reported** in the cited evidence. (pqac-00000011, pqac-00000014) | MAXO suggestion: genetic testing; HP: Abnormality of humoral immunity; LOINC-style concepts: serum immunoglobulin measurement | Fornes et al., Jan 2023; Jia thesis summary, Jan 2023 (pqac-00000011, pqac-00000014) |
| Treatment | **No disease-specific targeted therapy or interventional trial was identified.** Reported real-world care is supportive and anti-infective. **Core MICI:** detailed p.T95R proband received **IVIG** and **trimethoprim/sulfamethoxazole prophylaxis**; CMV was treated with **ganciclovir**, then **foscarnet** after antiviral resistance (**UL54 L545S, UL97 M460I**) as bridge to **HSCT**. Outcome after HSCT for this proband was not stated in the extracted evidence. **F359L:** patients required **immunoglobulin replacement therapy**. A previously reported separate homozygous IRF4 splice case (not MICI 131 core) died **2 days post-HSCT** at age 2. (pqac-00000014, pqac-00000001, pqac-00000003) | MAXO: immunoglobulin replacement therapy; antimicrobial prophylaxis; antiviral therapy; hematopoietic stem cell transplantation | Jia thesis summary, Jan 2023; Thouenon et al., Mar 2023 (pqac-00000014, pqac-00000001, pqac-00000003) |
| Model organism | **Core MICI** has direct model support: a **heterozygous Irf4 T95R knock-in mouse** recapitulated key human features, especially **severe defects in antibody production** at baseline and after immunization and reduced antigen-specific germinal-center responses. No disease-specific natural veterinary condition was identified in the searched evidence. (pqac-00000008, pqac-00000011) | NCBITaxon: 10090; CL: germinal center B cell, plasma cell; GO: antibody production | Fornes et al., *Sci Immunol*, Jan 2023 (pqac-00000008, pqac-00000011) |
| Evidence gaps | Missing or not clearly reported in the extracted evidence: OMIM number for “Immunodeficiency 131,” prevalence/incidence, sex ratio, long-term survival, formal quality-of-life data, penetrance estimates for **F359L**, variant-specific carrier frequency, established screening guidelines, prenatal/preimplantation counseling studies, environmental/lifestyle risk modifiers beyond pathogen exposure, protective factors, epigenetic biomarkers, and disease-specific clinical trials. Whipple observational studies exist but are **not** genotype-specific therapeutic trials. (pqac-00000014, pqac-00000000) | Suggested annotation: evidence gap / not reported | Evidence synthesis across extracted sources and trial search contexts (pqac-00000014, pqac-00000000) |


*Table: This table summarizes the best-supported evidence for Immunodeficiency 131 as an IRF4-associated disorder, centering on p.T95R multimorphic IRF4 CID while distinguishing the allelic F359L and R98W phenotypes. It also flags where the literature remains sparse or non-specific.*