| domain | established finding | quantitative detail | evidence type/strength |
|---|---|---|---|
| Disease definition | Immunodeficiency 61 corresponds to SH3KBP1/CIN85 deficiency, an X-linked primary antibody deficiency caused by germline loss of CIN85/SH3KBP1 | Human evidence currently centers on 1 family with 2 affected male siblings and an asymptomatic carrier mother (pqac-00000004, pqac-00000005) | Human primary disease report; strong for gene-disease link but very limited case count (pqac-00000004, pqac-00000005) |
| Causal gene/locus | SH3KBP1 (CIN85) deletion on chromosome Xp22.12 abolishes prevalent CIN85 transcript/protein expression | 247.5-kbp deletion, exons 2-6, GRCh37 position 19,667,630-19,886,572; adjacent genes unaffected (pqac-00000005) | Human genomic + protein evidence; strong (pqac-00000005) |
| Inheritance | X-linked transmission | 2 affected hemizygous males; mother hemizygous carrier without clinical symptoms; healthy half-brother negative for deletion (pqac-00000005) | Human pedigree evidence; strong within single family (pqac-00000005) |
| Patient 1 demographics | Surviving index case | Male, age 12 years at report; diagnosed genetically after evaluation of antibody deficiency (pqac-00000000, pqac-00000005) | Human case report; strong (pqac-00000000, pqac-00000005) |
| Patient 2 demographics/outcome | More severe affected brother | Male; died at age 15 years, 3 years before report (pqac-00000005) | Human family history/archived DNA; moderate-strong (pqac-00000005) |
| Immunoglobulins: patient 1 | Selective hypogammaglobulinemia affecting IgM and IgG subclasses with preserved total IgG/IgA | IgM 16 mg/dL (ref 48-228); IgG2 55 mg/dL (110-485); IgG4 <0.8 mg/dL (5.2-196); IgG3 60 mg/dL (24-116); IgG1 595 mg/dL (370-910); IgA 79 mg/dL (40-238); total IgG 918 mg/dL (672-1,536) (pqac-00000006) | Human laboratory evidence; strong (pqac-00000006) |
| Immunoglobulins: patient 2 | More profound pan-hypogammaglobulinemia than patient 1 | Serum IgM and IgG2/4 diminished; total IgG and IgA below detection limits (pqac-00000005) | Human retrospective clinical data; moderate (pqac-00000005) |
| Vaccine response | Defective polysaccharide antibody responses with preserved peptide response | Pneumococcal IgG response insufficient against 8/9 serotypes; serotype-specific IgM reached suggested cutoff for only 8/10 serotypes; anti-tetanus-toxoid response normal (pqac-00000000, pqac-00000005, pqac-00000006) | Human functional clinical immunology; strong (pqac-00000000, pqac-00000005, pqac-00000006) |
| Infections/clinical course: patient 1 | Early-childhood severe bacterial infections, then partial clinical improvement | Severe infections especially in winter months until age 4; no obvious compromised immune reactions thereafter, despite persistent laboratory defect (pqac-00000005) | Human longitudinal case history; moderate-strong (pqac-00000005) |
| Infections/clinical course: patient 2 | Persistent susceptibility to recurrent sinopulmonary infection with fatal outcome | Repetitive sinusitis, otitis media, and pneumonia; died of septic shock and multiorgan failure subsequent to bilateral pneumonia at age 15 (pqac-00000000, pqac-00000005) | Human case history; strong for severe phenotype (pqac-00000000, pqac-00000005) |
| Additional reported features | Possible neurobehavioral/constitutional features, uncertain causality | Both brothers reportedly had moderate ADHD, mildly impaired adaptive skills, and obesity at age 11; causal relation to CIN85 deficiency not established (pqac-00000006) | Human observational note; weak/uncertain disease attribution (pqac-00000006) |
| B-cell numbers/phenotype | Peripheral B-cell development largely preserved despite antibody deficiency | B cells 5.3% and 165/µL (ref 7.8-23.7%, 119-578/µL); transitional B cells 5.9%/10 µL; naive B cells 83.6%/138 µL; IgM/IgD memory 4.6%/8 µL; IgM-only memory 0.1%/1 µL; IgG-switched memory 2.5%/4 µL; IgA-switched memory 1.1%/2 µL; plasmablasts 0.3%; CD21low 1.7%; kappa/lambda 1.2 (pqac-00000006, pqac-00000007) | Human flow-cytometry evidence; strong (pqac-00000006, pqac-00000007) |
| T/NK-cell phenotype | T-cell and NK-cell compartments grossly intact | CD4 40%/1,245 µL; CD8 26.2%/815 µL; NK 8.7%; normal CD4 subpopulations including recent thymic emigrants and Tregs; terminally differentiated CD8 cells slightly reduced at 3.7%/30 µL (ref 9-65%, 35-420/µL) (pqac-00000006, pqac-00000008) | Human flow-cytometry evidence; strong (pqac-00000006, pqac-00000008) |
| BCR proximal signaling | CIN85-negative primary B cells show reduced BCR-driven calcium signaling but preserved ERK and PI3K-S6 signaling | Ca2+ flux consistently moderately reduced; inducible ERK phosphorylation normal; robust S6 phosphorylation preserved (pqac-00000007) | Human ex vivo signaling assays; strong (pqac-00000007) |
| NF-kB signaling in B cells | Key disease mechanism is selective failure to couple BCR signaling to canonical NF-kB activation | Very few patient B cells degraded IκBα after 40 min of BCR ligation vs majority of controls; reduced p65 phosphorylation; prolonged BCR stimulation did not substantially improve IκBα degradation; BclXL induction after BCR stimulation compromised (pqac-00000007) | Human ex vivo mechanistic evidence; strong (pqac-00000007) |
| Stimulus specificity | Defect is selective for BCR pathway rather than global B-cell activation failure | NF-kB activation after TLR9 ligation, CD40 stimulation, or PMA treatment was intact; TLR9/CD40 also preserved for plasmablast differentiation, class switching, and proliferation in vitro (pqac-00000007, pqac-00000008) | Human ex vivo functional evidence; strong (pqac-00000007, pqac-00000008) |
| B-cell activation markers | Surface activation responses downstream of BCR are selectively impaired | BCR-induced CD86 and ICAM-1 up-regulation diminished; CD69 and CD25 only moderately affected; TLR9/CD40 responses similar to controls (pqac-00000007) | Human ex vivo functional evidence; strong (pqac-00000007) |
| T-cell function | No obvious intrinsic T-cell activation defect demonstrated | Naive and memory CD4 T cells showed normal Ca2+ flux and NF-kB activation after TCR/CD28 stimulation; CD69, CD25, ICOS up-regulation normal; IL-4, IFN-γ, IL-17 production and CD4/CD8 proliferation preserved (pqac-00000008) | Human ex vivo functional evidence; strong (pqac-00000008) |
| Mechanistic interpretation | Humoral deficiency is attributed mainly to B-cell intrinsic signaling defects rather than defective T-cell help | Authors conclude poor antigen reactivity of B cells underlies antibody deficiency; hypogammaglobulinemia unlikely due to insufficient T-cell help (pqac-00000008) | Human mechanistic synthesis; moderate-strong (pqac-00000008) |
| Supporting pre-disease mechanistic study | Independent human B-cell work established CIN85 as regulator of Cbl-mediated BCR signaling | CIN85 overexpression inhibited BCR-induced calcium flux and phosphorylation of Syk/PLCγ2; CIN85 knockdown enhanced BCR-induced survival/growth and affected differentiation-associated molecules in human B cells (pqac-00000001, pqac-00000002, pqac-00000003) | Human cell-line and primary-cell mechanistic evidence; supportive but not disease-specific (pqac-00000001, pqac-00000002, pqac-00000003) |
| Mouse B-cell model | Conditional murine B-cell loss of CIN85 recapitulates selective humoral defects | IgM and IgG3 responses to Ficoll-coupled hapten almost blunted; peritoneal B1-cell subset reduced ~7.5-fold; splenic B2 development grossly normal; T-dependent responses had little impact (pqac-00000005, pqac-00000006, pqac-00000010) | In vivo model evidence; strong supportive translational evidence (pqac-00000005, pqac-00000006, pqac-00000010) |
| Human engineered cell model | Gene editing confirms nonredundant role of CIN85 in human BCR signaling | CRISPR/Cas9 CIN85 knockout DG75 cells showed strongly compromised BCR-induced Ca2+ mobilization; signaling-incompetent C-terminal deletion mutant failed to rescue; similar result also seen with independent TALEN approach (pqac-00000007, pqac-00000009) | Human cell model; strong mechanistic validation (pqac-00000007, pqac-00000009) |
| Brain model/comparative biology | Nonimmune CIN85 functions are supported by mouse brain isoform data | Brain-specific CIN85 loss impaired dopamine receptor endocytosis and caused hyperactive behavior in mice, relevant only as indirect support for possible ADHD-like observations (pqac-00000005, pqac-00000010) | Mouse model; indirect/weak for human disease phenotype (pqac-00000005, pqac-00000010) |
| Diagnosis | Diagnosis in reported family required genomic copy-number testing plus immunologic workup | aCGH identified deletion; qPCR verification used; whole-exome sequencing excluded phenotypically relevant variants in 395 primary immunodeficiency genes; immunoblot confirmed loss of CIN85 with normal CD2AP (pqac-00000005, pqac-00000009) | Human diagnostic evidence; strong for this family (pqac-00000005, pqac-00000009) |
| Current clinical implementation | Disease has entered at least some specialized immunology workflows | CIN85 marker reportedly incorporated into routine immune diagnostics in Freiburg and Hannover after publication (pqac-00000004) | Institutional implementation statement; moderate (pqac-00000004) |
| Treatment evidence | No disease-specific treatment study was identified in the retrieved evidence | No disease-specific interventional trial or gene-targeted therapy identified; artifact intentionally avoids extrapolating unproven treatment recommendations (pqac-00000011) | Evidence gap; strong as negative finding within retrieved sources (pqac-00000011) |
| Epidemiology | Extremely rare; prevalence/incidence cannot be estimated | Only 1 reported family and 2 affected males in retrieved primary literature (pqac-00000005) | Evidence gap with minimal published denominator (pqac-00000005) |
| Major evidence gaps | Natural history, penetrance, female-carrier phenotype, full variant spectrum, long-term complications, and optimal management remain undefined | No additional well-characterized families, no disease-specific cohort statistics, no formal genotype-phenotype series, no dedicated trials, and no robust evidence on malignancy/autoimmunity risk specific to SH3KBP1 deficiency (pqac-00000005, pqac-00000011) | Overall literature limitation; strong caution warranted (pqac-00000005, pqac-00000011) |


*Table: This table compiles the core disease-specific evidence for Immunodeficiency 61 / SH3KBP1 (CIN85) deficiency, emphasizing the two reported brothers, their deletion, phenotype, immune findings, mechanism, and supporting models. It is designed to give a concise view of what is established versus what remains unknown.*