| Domain | Established observation | Evidence type/strength | Knowledge-base annotation |
|---|---|---|---|
| Disease identity | Immunodeficiency 89 and autoimmunity is a Mendelian inborn error of immunity associated with **CARD10**. (pqac-00000000) | Curated disease–gene association; supported by one primary family report | **MONDO:0030484**; disease category: Mendelian immunodeficiency with immune dysregulation |
| Human evidence | Reported in **two affected siblings from one consanguineous family**; no independently replicated kindred was identified. (pqac-00000005, pqac-00000006) | Very limited human evidence; single-family case report | Case count: 2; family count: 1; inheritance proposed as autosomal recessive |
| Causal candidate variant | Both siblings were homozygous for **CARD10 c.1258C>T (p.Arg420Cys; R420C)** in exon 7 and the conserved coiled-coil domain. (pqac-00000005, pqac-00000006) | Segregation plus computational prediction; functional evidence incomplete | Gene: **CARD10**; variant: missense, germline, homozygous; pathogenic mechanism not conclusively classified as loss-of-function, gain-of-function, or hypomorphic |
| Core phenotype | Recurrent infections, asthma with low blood eosinophils, autoimmune anemia, Crohn disease/intestinal inflammation, gastrointestinal discomfort, and seasonal urticaria were reported across the siblings. (pqac-00000005, pqac-00000006) | Direct clinical observation; frequencies cannot be generalized beyond n=2 | Immunodeficiency, autoimmunity, allergy, and gastrointestinal inflammation; variable expressivity |
| Pulmonary disease | At age 42, the more severely affected brother had bronchiectasis with infection, lung abscess, and pulmonary bulla on high-resolution CT. (pqac-00000005, pqac-00000006) | Direct imaging evidence in one patient | Chronic respiratory infection and structural lung damage |
| Gastrointestinal disease | At age 42, the sister’s gastrointestinal biopsy showed local proliferative gastritis and colitis interpreted as early Crohn disease. (pqac-00000005, pqac-00000006) | Direct histopathology in one patient; disease interpretation by authors | Inflammatory bowel involvement; stomach and intestinal mucosa affected |
| Molecular consequence | Patient reconstitution studies showed **decreased CARD10 mRNA and protein expression** with R420C. (pqac-00000005) | Disease-specific functional observation, but assay scope and rescue evidence were limited | Reduced gene-product abundance; precise biochemical mechanism unresolved |
| Cellular and cytokine findings | The more affected sibling had reduced intermediate/nonclassical monocytes and monocyte-derived HLA-DR⁺CD11c⁺CD16⁺ cells; several immune-cell/cytokine measures were decreased, whereas autoantibodies and IL-8, GROα, MCP-1, MIP-1α, and SDF1α were increased. (pqac-00000005, pqac-00000006) | Direct comparative immunophenotyping within the family; no independent cohort | Monocyte/dendritic-cell abnormality, impaired immune output, and concurrent inflammatory/autoimmune signaling |
| Mechanism | CARD10 normally scaffolds the **CARD10–BCL10–MALT1 (CBM)** complex, connecting receptor signals to IKK/NF-κB and JNK/AP-1 signaling; attributing the patients’ phenotype specifically to reduced CBM/NF-κB activity remains **partly inferred**. (pqac-00000003, pqac-00000005, pqac-00000009) | Established pathway biology plus disease-specific expression findings; causal signaling defect not directly demonstrated for R420C | Upstream lesion: CARD10 variant; proposed downstream process: defective CBM signaling and immune/epithelial dysregulation |
| Course and modifiers | Disease was described as slowly progressive over approximately 20–30 years. Earlier, more severe disease in the brother was hypothesized to relate to unhealthy lifestyle and metal-dust exposure, but causality was not established. (pqac-00000006) | Longitudinal clinical description; gene–environment interaction is speculative | Chronic progressive course; variable expressivity; environmental modification unproven |
| Epidemiology and prognosis | No population prevalence, incidence, penetrance estimate, carrier frequency, survival rate, or life-expectancy data are available. (pqac-00000013) | Evidence absent | Ultra-rare designation is reasonable, but no numerical epidemiologic estimate should be assigned |
| Treatment and trials | The defining report supplied no disease-specific treatment outcomes, and no dedicated interventional trial or approved CARD10-targeted therapy was identified. (pqac-00000013) | Evidence absent | Management remains phenotype-directed and extrapolated from general immunodeficiency, infection, asthma, autoimmunity, and inflammatory-bowel-disease practice |


*Table: Compact evidence-grade summary of the genetic, clinical, molecular, and mechanistic findings supporting Immunodeficiency 89 and autoimmunity, with major evidence gaps explicitly identified.*