Immunodeficiency 61

Mendelian MONDO:0010296 Pathograph 13 Show in embeddings browser Primary Immunodeficiency

Immunodeficiency-61 is an X-linked recessive primary ANTIBODY deficiency caused by loss of CIN85, the Cbl-interacting protein of 85 kDa encoded by SH3KBP1 at Xp22.12. CIN85 is not a signalling enzyme; it is a trimeric adaptor whose nine SH3 domains oligomerise SLP65, the central scaffold of the B cell antigen receptor. That SLP65-CIN85 association is CONSTITUTIVE rather than stimulus-induced: in a resting B cell the two proteins already sit together in cytoplasmic granules formed by phase separation with lipid vesicles, and this preformed transducer module is what allows a B cell to respond efficiently the moment its receptor is engaged. Without CIN85 the module cannot assemble, SLP65 phosphorylation and membrane translocation fail, and selected BCR effector arms - NF-kB activation and CD86 upregulation in the human patients, calcium and NF-kB responses in the cell models - do not fire. The clinical consequence is narrower than the disease's legacy names suggest. In the reported patients all immune cell compartments developed normally and the defect is intrinsic to the B cell's effector response, not to B cell production - so despite the synonyms AGMX2, XLA2 and "agammaglobulinemia, X-linked, type 2", grouping this entity with BTK-related X-linked agammaglobulinemia is misleading: there the B cell compartment itself fails to develop, whereas here it develops normally and the defect is in what B cells do. That is a claim about B cell development, not about immunoglobulin levels - and the two must not be conflated, because the more severely affected of the two founding brothers did have undetectable total IgG and IgA. Recurrent bacterial infection of the respiratory tract with impaired specific antibody responses and altered memory B cell subsets is the phenotype in the surviving reported patients; see `notes:` on the second founding brother, whose course was far more severe. EVIDENCE BASE IS VERY THIN, and the entry is written accordingly. Two affected individuals - brothers - have been reported. A third, later case carried only a PARTIAL SH3KBP1 deletion classified as a variant of uncertain significance, and its authors state plainly that a causal relationship remains unproven. No ClinGen gene-disease validity assertion for SH3KBP1 was found in the cached ClinGen snapshot. Nothing here should be read as an established, clinically actionable gene-disease relationship.

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1
Inheritance
5
Pathophys.
7
Phenotypes
2
Gaps
13
Pathograph
1
Genes
2
Variants
3
Medical Actions
7
References
1
Deep Research
🏷

Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC
👪

Inheritance

1
X-linked recessive inheritance HP:0001419
SH3KBP1 lies at Xp22.12, and the reported affected individuals are hemizygous males - two brothers in the founding report, and a boy with a partial deletion in a later case. Segregation is incompletely characterised: in the later case, testing was limited to the mother and extended family studies were unavailable, so mosaicism could not be excluded.
X-linked recessive inheritance
Show evidence (3 references)
PMID:29636373 SUPPORT Human Clinical
"we report on primary antibody deficiency in patients harboring a germline deletion within the CIN85 gene on the X chromosome"
Establishes a germline X-chromosome deletion as the cause in the founding patients.
PMID:42375371 SUPPORT Human Clinical
"described two brothers with X-linked recessive immunodeficiency caused by loss-of-function variants in SH3KBP1"
States the X-linked recessive mode and the loss-of-function mechanism for the founding kindred.
PMID:42375371 SUPPORT Human Clinical
"segregation analysis was limited to maternal testing, and extended family studies were unavailable, precluding a more comprehensive assessment of inheritance patterns and possible mosaicism"
The authors' own statement of the limits on segregation analysis in the later case, which is why this block does not claim fully characterised X-linked transmission.
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Discussions and Knowledge Gaps

2
Is CIN85 a positive or a negative regulator of B cell receptor signalling? The human deletion and the cell-line knockdown point in opposite directions.
KNOWLEDGE GAP OPEN imd61_cin85_positive_versus_negative_regulator
Attached to
pathophysiology#Impaired B Cell Receptor Effector Signalling
Two well-executed bodies of work disagree about the sign of CIN85's effect. In humans lacking CIN85, and in reconstitution experiments lacking the SLP65-CIN85 complex, BCR effector responses are IMPAIRED - NF-kB and CD86 in patients, calcium and NF-kB in cells - which is a positive, transducer role. But CIN85 knockdown in B cell lines and primary B cells ENHANCES BCR-induced survival and growth and increases expression of BcLxL, A1, cyclin D2 and myc, consistent with a negative regulatory role exercised through Cbl-mediated ubiquitination and degradation of Syk. Both cannot be the whole story. The plausible reconciliations - that acute knockdown and germline absence are not the same perturbation, that CIN85 isoforms differ, or that the transducer and Cbl-adaptor functions are separable and read out on different timescales - are untested. This matters for the disease entry because it determines whether the pathograph's central node is correctly signed, and no entry in this family should assert a single unified CIN85 function.
Proposed experiments
Side-by-side acute knockdown versus germline null in the same B cell background
exp_imd61_acute_versus_germline_cin85_loss
Compare degenerate CIN85 knockdown, inducible degron-mediated acute depletion, and stable germline knockout in one isogenic human B cell line, reading out Syk ubiquitination and phosphorylation, calcium flux, NF-kB activation, CD86 upregulation, survival and proliferation in parallel. This would test directly whether the opposing published phenotypes are an artefact of perturbation kinetics rather than a genuine dual function.
Show evidence (3 references)
PMID:22262777 REFUTE In Vitro
"CIN85 knockdown in primary B cells enhanced BCR-induced survival and growth, and increased the expression of BcLxL, A1, cyclin D2, and myc"
The result that runs opposite to the disease model: losing CIN85 ENHANCES rather than impairs BCR-driven responses in this system. Recorded as REFUTE against a simple "CIN85 is required for BCR signalling" reading.
PMID:22262777 SUPPORT In Vitro
"CIN85 increased c-Cbl phosphorylation and inhibited BCR-induced calcium flux and phosphorylation of Syk and PLCγ2"
Gives the mechanism of the negative-regulatory arm - Cbl-dependent suppression of proximal BCR signalling through Syk and PLC-gamma-2.
PMID:29636373 SUPPORT Human Clinical
"B lymphocytes showed intrinsic defects in distinct effector pathways of the B cell antigen receptor"
The human result on the other side of the disagreement: absence of CIN85 impairs, rather than enhances, BCR effector pathways.
Should MONDO:0010296 remain classified under agammaglobulinemia, given that the disease it names is a selective antibody-response defect with normal B cell development?
KNOWLEDGE GAP OPEN imd61_nosology_not_an_agammaglobulinemia
Attached to
pathophysiology#Defective Antibody Production by Intrinsically Impaired B Cells
The entity carries the legacy names AGMX2, XLA2 and "agammaglobulinemia, X-linked, type 2", and MONDO places MONDO:0010296 under MONDO:0015977 agammaglobulinemia. The disease as characterised does not match that placement: in the founding report all immune cell compartments developed normally and the defect was intrinsic to B cell effector function, and the subsequently reported features are impaired specific antibody responses and altered memory B cell subsets. The question is about mechanism, not about immunoglobulin levels: the more severely affected founding brother had undetectable total IgG and IgA, so a categorical "this is not an agammaglobulinemia" would overstate the case. What the placement does invite is confusion with BTK-related X-linked agammaglobulinemia, which is a different gene, a different mechanism, and - decisively - a different B cell phenotype, since B cell development is intact here. This is recorded as a curation-facing question rather than acted on unilaterally, because reclassifying a MONDO concept is not a disorder entry's job.
Proposed experiments
Standardised immunophenotyping of all reported SH3KBP1 patients
exp_imd61_immunophenotype_reconciliation
Apply one standardised B cell immunophenotyping panel - total, transitional, naive, memory and switched-memory B cells, plus serum immunoglobulin isotypes and specific antibody responses to protein and polysaccharide vaccines - across all reported SH3KBP1 patients, to settle whether the entity is an agammaglobulinemia, a specific antibody deficiency, or a memory B cell disorder, and to reconcile the reported discrepancy in B cell counts.
Show evidence (2 references)
PMID:29636373 SUPPORT Human Clinical
"In the absence of CIN85, all immune cell compartments developed normally"
Normal development of all immune compartments is inconsistent with an agammaglobulinemia classification.
PMID:42375371 SUPPORT Human Clinical
"impaired humoral immune responses, reduced B-cell counts"
The one report of reduced B cell counts, which is the discrepancy the proposed immunophenotyping would resolve. PARTIAL because this patient's variant is of uncertain significance.
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Pathophysiology

5
SH3KBP1 (CIN85) Loss-of-Function Deletion
A germline deletion within SH3KBP1 on the X chromosome, hemizygous in affected males. CIN85 is ubiquitously expressed and multifunctional, and before this report nothing was known about its role in humans - the only in vivo data were conditional mouse mutants ablating distinct CIN85 isoforms in brain and B lymphocytes. The human deletion is therefore the experiment that established which of CIN85's many proposed functions are non-redundant.
SH3KBP1 hgnc:13867 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SH3KBP1 (hgnc:13867). hgnc:13867 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context SH3KBP1 hgnc:13867 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns SH3KBP1 (hgnc:13867). hgnc:13867 is a gene from the HUGO Gene Nomenclature Committee. allele_type: intragenic deletion zygosity: HEMIZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Hemizygous germline deletion within SH3KBP1 in affected males, described by a later report as a loss-of-function variant. LOSS_OF_FUNCTION rather than PARTIAL_LOSS_OF_FUNCTION because the founding study frames its findings as "in the absence of CIN85" and reads the resulting defects as revealing non-redundant CIN85 functions.
`variant_origin` is left unset ON THIS BLOCK because the block describes the founding kindred's lesion, and the cached sources do not report parental testing for those two brothers. It is NOT unset for want of data on the later case: that patient's deletion is affirmatively de novo, confirmed by its absence in his mother, and that is recorded on the corresponding `variants[]` entry. The authors' separate remark that segregation was limited to maternal testing with mosaicism not excluded comes from their limitations paragraph and qualifies how exhaustively segregation was assessed, not whether the mother carried the variant.
Downstream
Neurodevelopmental Involvement CIN85 is expressed in brain and was one of only two compartments in which it had been conditionally ablated in mice, and the reported patients carry neurodevelopmental features. The intermediates are unknown, so this edge asserts association through unspecified steps rather than a worked mechanism - the same standing as the ADHD edge downstream of it.
Loss of the Preformed SLP65-CIN85 Transducer Module Without CIN85 there is no trimeric adaptor to oligomerise SLP65, so the constitutive transducer module cannot form.
Show evidence (2 references)
PMID:29636373 SUPPORT Human Clinical
"we report on primary antibody deficiency in patients harboring a germline deletion within the CIN85 gene on the X chromosome"
Identifies the causal lesion and the resulting clinical category.
PMID:29636373 SUPPORT Other
"limited information exists about the in vivo roles of CIN85, because only conditional mouse mutants with cell type-specific ablation of distinct CIN85 isoforms in brain and B lymphocytes have been generated so far. No information is available about the roles of CIN85 in humans."
Establishes the state of knowledge this deletion resolved, and incidentally records that brain is one of the two compartments in which CIN85 had been conditionally ablated in mice.
Loss of the Preformed SLP65-CIN85 Transducer Module
CIN85 trimerises through a C-terminal coiled-coil domain, and the nine SH3 domains of a trimer bind multiple SLP65 molecules, each of which recruits further CIN85 trimers - a self-perpetuating oligomerisation that concentrates the effector rather than merely connecting two proteins to each other. The resulting complex is held in cytoplasmic granules formed by tripartite phase separation of SLP65, CIN85 and lipid vesicles. Its purpose is READINESS: the module exists in the RESTING B cell so that signalling can begin immediately on receptor engagement. The mechanistic point the disease makes is that a signalling cascade can fail not because a component is missing from the pathway but because too few copies of it are pre-concentrated in the right place.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
B cell receptor signaling pathway GO:0050853 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased B cell receptor signaling pathway (GO:0050853). GO:0050853 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired B Cell Receptor Effector Signalling Without the module, SLP65 is neither phosphorylated nor translocated, and the downstream effector arms fail.
Show evidence (4 references)
PMID:27353366 SUPPORT In Vitro
"in B lymphocytes, CIN85 functions to oligomerize SLP-65, which is the central effector protein of the B cell receptor (BCR). Therefore, CIN85 trimerizes through a carboxyl-terminal, coiled-coil domain."
States CIN85's actual function in B cells - oligomerising the central BCR effector - and the structural basis for it.
PMID:27353366 SUPPORT In Vitro
"Formation of this oligomeric signaling complex in resting B cells rendered the cells poised for the efficient initiation of intracellular signaling upon BCR stimulation."
Establishes the readiness function of the complex in the resting cell, which is what the disease removes.
PMID:27353366 SUPPORT In Vitro
"the functionality of signaling cascades does not rely solely on the qualitative linkage of their various components but requires a critical number of effectors to become concentrated in signaling complexes"
The generalisable mechanistic claim this node embodies: signalling can fail on effector concentration rather than on pathway membership.
+ 1 more reference
Impaired B Cell Receptor Effector Signalling
The failure is SELECTIVE, and that selectivity is the disease's defining feature. In the patients' B cells, distinct effector pathways of the B cell antigen receptor were defective - most notably NF-kB activation and upregulation of CD86 on the cell surface - while the cells themselves developed and persisted normally. In the cell-line and reconstitution models the same lesion abrogates BCR-induced calcium and NF-kB responses. What is lost is the capacity of a B cell to translate receptor engagement into an effector programme, not the B cell itself.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
positive regulation of canonical NF-kappaB signal transduction GO:0043123 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased positive regulation of canonical NF-kappaB signal transduction (GO:0043123). GO:0043123 is a biological process from the Gene Ontology. ↓ DECREASED B cell receptor signaling pathway GO:0050853 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased B cell receptor signaling pathway (GO:0050853). GO:0050853 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Defective Antibody Production by Intrinsically Impaired B Cells A B cell that cannot execute the BCR effector programme cannot mount an effective antibody response, even though it is present in normal numbers.
Show evidence (2 references)
PMID:29636373 SUPPORT Human Clinical
"In the absence of CIN85, all immune cell compartments developed normally, but B lymphocytes showed intrinsic defects in distinct effector pathways of the B cell antigen receptor, most notably NF-κB activation and up-regulation of CD86 expression on the cell surface."
The central human observation, quoted whole: normal development of every immune compartment, with an intrinsic and selective B cell effector defect naming both affected arms - NF-kappaB activation and CD86 upregulation.
PMID:29636373 SUPPORT Human Clinical
"These results reveal nonredundant functions of CIN85 for humoral immune responses."
The authors' conclusion that the CIN85 functions lost here are non-redundant, which is what makes a single adaptor's absence sufficient to cause disease.
Defective Antibody Production by Intrinsically Impaired B Cells
The humoral response fails at the level of what B cells DO rather than whether they exist. Reported consequences include defective antibody production and altered memory B cell subsets. This is where the entity's legacy naming misleads: a disease called "agammaglobulinemia, X-linked, type 2" in which every immune compartment develops normally does not share the developmental block that defines BTK-related XLA. Note this distinguishes the mechanism, not the immunoglobulin level - hypo- and even agammaglobulinaemia have been reported in the more severely affected brother.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology. memory B cell CL:0000787 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves memory B cell (CL:0000787). CL:0000787 is a cell type from the Cell Ontology.
immunoglobulin production GO:0002377 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased immunoglobulin production (GO:0002377). GO:0002377 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Recurrent bacterial infections Failure of specific antibody responses leaves the patient susceptible to encapsulated and other bacterial pathogens.
Decreased circulating total IgM A B cell that cannot execute its effector programme produces less immunoglobulin, and IgM is the isotype in which the deficit was measured.
Recurrent respiratory infections The respiratory tract is the site at which antibody deficiency characteristically manifests, and recurrent respiratory infection from infancy was the presenting problem in the later reported case.
Show evidence (2 references)
PMID:29636373 SUPPORT Human Clinical
"These results reveal nonredundant functions of CIN85 for humoral immune responses."
States that the humoral response specifically depends on CIN85.
PMID:42375371 SUPPORT Other
"defective antibody production, altered memory B-cell subsets"
Names the two humoral abnormalities this node represents.
Neurodevelopmental Involvement
Neurodevelopmental features have accompanied the immune phenotype in every reported individual: attention-deficit/hyperactivity disorder and mild cognitive impairment in the two brothers, and autism spectrum disorder with developmental delay in the later case. Whether this reflects a genuine second function of CIN85 or ascertainment in patients who reached genetics services for developmental reasons is not established. Two things make it worth curating rather than dismissing: CIN85 is ubiquitously expressed and brain was one of only two compartments in which it had been conditionally ablated in mice before the human report; and in the later case the deletion also spanned neighbouring genes, so a contiguous-gene effect cannot be excluded. The causal link is therefore typed as having unknown intermediates and its evidence marked PARTIAL throughout.
Downstream
Attention deficit hyperactivity disorder ADHD was reported in both founding brothers. No mechanism connecting CIN85 loss to it has been proposed.
Show evidence (3 references)
PMID:42375371 SUPPORT Human Clinical
"both patients also presented with neurodevelopmental manifestations, including attention-deficit/hyperactivity disorder (ADHD) and mild cognitive impairment"
Documents neurodevelopmental features in the founding brothers. Marked PARTIAL because it is reported second-hand in a later paper rather than quoted from the primary description.
PMID:42375371 SUPPORT Human Clinical
"Genes within the affected interval include PEPT4-AS1, PHKA2-AS1, MAP3K16, and SH3KBP1"
Names the other genes inside the deleted interval in the later case, which is the evidence for this node's contiguous-gene caveat - previously asserted without a citation. MAP3K16 in particular is not a bystander one can wave away when the phenotype in question is neurodevelopmental.
PMID:42375371 SUPPORT Human Clinical
"Our findings support a possible contribution of SH3KBP1 to shared immunological and neurodevelopmental pathways; however, its pathogenic role has not yet been definitively established."
The authors' own hedged statement of the immune-neurodevelopmental link, preserved rather than strengthened.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency 61 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

7
Immune 1
Recurrent respiratory infections HP:0002205 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent respiratory infections (HP:0002205), qualified as temporality recurrent. HP:0002205 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:42375371 SUPPORT Human Clinical
"The patient presented with recurrent respiratory infections, impaired humoral immune responses, reduced B-cell counts, and neurodevelopmental impairment."
Documents recurrent respiratory infection. PARTIAL because the patient's partial SH3KBP1 deletion is classified as a variant of uncertain significance.
Nervous System 1
Attention deficit hyperactivity disorder HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42375371 SUPPORT Human Clinical
"including attention-deficit/hyperactivity disorder (ADHD) and mild cognitive impairment"
Documents ADHD in the founding brothers, reported second-hand.
Growth 1
Obesity HP:0001513 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Obesity (HP:0001513). HP:0001513 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42375371 SUPPORT Human Clinical
"Case 2 involved an 11-year-old male with ASD, recurrent respiratory infections since infancy, asthma, allergies, obesity, and congenital heart disease."
Names obesity among the features of Case 2, the SH3KBP1 patient. PARTIAL because a single patient cannot establish the feature as disease-associated rather than incidental. This quote is from the Case-2 paragraph; the Case-1 MECP2 patient's features are deliberately not used anywhere in this entry.
PMID:42375371 SUPPORT Human Clinical
"His weight and height have consistently exceeded the 99th percentile, with a body mass index (BMI) greater than 2 standard deviations (SD) above the mean since the age of five."
Quantifies the obesity and dates it to age five. This matters because the same report starts risperidone, an antipsychotic with well-known weight gain, at age six - so the adiposity predates that exposure and is not simply drug-induced.
Other 4
Recurrent bacterial infections HP:0002718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent bacterial infections (HP:0002718), qualified as temporality recurrent. HP:0002718 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:42375371 SUPPORT Other
"altered memory B-cell subsets, and susceptibility to recurrent bacterial infections"
Names recurrent bacterial infection as a feature of SH3KBP1 deficiency.
Impaired humoral immune response Impaired specific antibody response HP:0012475 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired specific antibody response (HP:0012475). HP:0012475 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:42375371 SUPPORT Human Clinical
"impaired humoral immune responses, reduced B-cell counts"
Documents the humoral defect and the reduced B cell counts that differ from the founding report. PARTIAL because of the uncertain significance of this patient's variant.
PMID:42375371 SUPPORT Human Clinical
"absent serologic responses to measles (after two vaccine doses), varicella (after two vaccine doses), and pneumococcal conjugate vaccines"
The strongest available support for this HP term: serotype-level failure to respond to three separate vaccines despite documented dosing, in the SH3KBP1 patient. Verified unique to the Case-2 paragraph of a two-patient report - the Case-1 MECP2 patient's immunologic findings are deliberately not used anywhere in this entry.
PMID:29636373 SUPPORT Human Clinical
"all immune cell compartments developed normally, but B lymphocytes showed intrinsic defects"
The founding observation of normal compartments with an intrinsic B cell defect, against which the later reduced counts are the discrepancy.
Decreased circulating total IgM HP:0002850 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating total IgM (HP:0002850), qualified as course stable. HP:0002850 is a phenotype from the Human Phenotype Ontology.
Course: STABLE
Show evidence (2 references)
PMID:42375371 SUPPORT Human Clinical
"Initial immunological workup revealed immunoglobulin M (IgM) levels below 20 mg/dL"
Documents low IgM at presentation in the patient carrying the partial SH3KBP1 deletion. Marked PARTIAL because that variant is classified as of uncertain significance.
PMID:42375371 SUPPORT Human Clinical
"Follow-up between the ages of 7 and 11 years demonstrated persistently low IgM levels (ranging between 5 and 6 mg/dL)"
Shows the deficit is persistent over four years of follow-up rather than a single low value. PARTIAL for the same reason as above.
Decreased total B cell count HP:0010976 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total B cell count (HP:0010976). HP:0010976 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42375371 SUPPORT Human Clinical
"Analysis of lymphocyte subpopulations consistently demonstrated low B-cell counts for his age (87 cells/µL, 3.2% of total lymphocytes at 8 years old; 84 cells/µL, 3.5% of total lymphocytes at 11 years old), while other lymphocyte subsets remained within normal ranges"
Quantifies the B lymphocytopenia at two timepoints and establishes that it is selective for the B cell compartment. Marked PARTIAL because this patient's variant is of uncertain significance and because the finding conflicts with the founding report.
PMID:29636373 REFUTE Human Clinical
"In the absence of CIN85, all immune cell compartments developed normally"
The founding report's finding runs against this phenotype belonging to the entity, and is recorded as REFUTE so the conflict is machine-visible rather than buried in prose.
🧬

Genetic Associations

1
SH3KBP1 loss-of-function deletion (Causative)
Gene: SH3KBP1 hgnc:13867 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SH3KBP1 (hgnc:13867). hgnc:13867 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:42375371 SUPPORT Other
"To date, only two affected individuals have been reported in the literature."
States the size of the reported cohort, which is the basis for describing the evidence base as very thin.
PMID:42375371 SUPPORT Other
"the number of reported cases involving SH3KBP1 deficiency remains extremely limited, restricting robust genotype-phenotype correlations for this gene"
The authors' own assessment of what can and cannot be concluded from the current case count.
Variants (2)
Germline intragenic SH3KBP1 deletion (founding kindred) Pathogenic
A germline deletion within the CIN85 gene on the X chromosome, hemizygous in two affected brothers, described by a later report as loss of function.
Show evidence (1 reference)
PMID:29636373 SUPPORT Human Clinical
"patients harboring a germline deletion within the CIN85 gene on the X chromosome"
Describes the founding lesion.
Partial hemizygous Xp22.12 deletion involving SH3KBP1 (later case) Uncertain Significance
A hemizygous deletion of approximately 200 kb at Xp22.12 partially involving SH3KBP1, predicted to disrupt exons 2 to 6 and possibly a larger region, detected by array comparative genomic hybridization and classified as a variant of uncertain significance. It arose DE NOVO, confirmed by its absence in the patient's mother. The deleted interval also spans neighbouring genes, so a contiguous-gene contribution cannot be excluded, and no functional studies were performed.
Identifiers: ClinVar:SCV005849918
Show evidence (5 references)
PMID:42375371 SUPPORT Human Clinical
"Importantly, the deletion occurred de novo, as confirmed by its absence in the patient’s mother"
Establishes de novo origin for this variant. Note this is the authors' RESULT; the mosaicism caveat quoted elsewhere in this entry comes from their limitations paragraph and qualifies how completely segregation was assessed, not whether the mother carried it.
PMID:42375371 SUPPORT Human Clinical
"The identified deletion in our patient spans approximately 200 kb and is predicted to disrupt exons 2–6"
Gives the size and predicted exon range of the deletion.
PMID:42375371 SUPPORT Human Clinical
"The variant has been deposited in the NCBI ClinVar database under accession number SCV005849918"
Supplies the ClinVar accession recorded in `identifiers`. The accession is quoted WITH its number because the same sentence appears twice in this paper - the other instance, SCV005849919, is the MECP2 variant of the unrelated first patient.
+ 2 more references
💊

Medical Actions

3
Immunoglobulin Replacement Therapy
Category: Therapeutic Action: intravenous immunoglobulin therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is intravenous immunoglobulin therapy (NCIT:C121331). NCIT:C121331 is a clinical intervention from the NCI Thesaurus. Ontology label: Intravenous Immunoglobulin Therapy NCIT:C121331
The standard management of a primary antibody deficiency is to supply the antibody the patient cannot make. No trial or case series has evaluated immunoglobulin replacement in SH3KBP1 deficiency specifically - with two reported patients, none could exist - so this is the class-level standard of care for inborn errors of immunity with impaired antibody production, recorded as such rather than as disease-specific evidence.
Mechanism Target:
BYPASSES Defective Antibody Production by Intrinsically Impaired B Cells — Replacement immunoglobulin substitutes for the antibody the patient's B cells fail to produce. It bypasses the defect; it does not repair the signalling module, and it does not restore the patient's own specific antibody responses.
Show evidence (1 reference)
PMID:42208906 SUPPORT Other
"The management part includes recommendations for immunoglobulin replacement, antibiotic prophylaxis, hematopoietic stem cell transplantation, precision medicine, and quality-of-life assessment."
Establishes immunoglobulin replacement as a recommended management component for inborn errors of immunity. Class-level evidence, cited as such.
Show evidence (1 reference)
PMID:42208906 SUPPORT Other
"recommendations for immunoglobulin replacement, antibiotic prophylaxis, hematopoietic stem cell transplantation"
The management framework applied to this disorder in the absence of disease-specific evidence.
Antibiotic Prophylaxis
Category: Therapeutic Action: antibiotic prophylaxisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antibiotic prophylaxis (NCIT:C51993). NCIT:C51993 is a clinical intervention from the NCI Thesaurus. Ontology label: Antibiotic Prophylaxis NCIT:C51993
Prophylactic antibiotics for recurrent bacterial and respiratory infection, used alongside or instead of immunoglobulin replacement depending on severity. As above, this is class-level practice for antibody deficiency; no SH3KBP1-specific evidence exists.
Show evidence (1 reference)
PMID:42208906 SUPPORT Other
"recommendations for immunoglobulin replacement, antibiotic prophylaxis"
Establishes antibiotic prophylaxis as a recommended management component for inborn errors of immunity.
Genetic Testing and Counseling
Category: Counseling / Informational Action: Genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Both reported lesions are deletions, one intragenic and one a partial deletion detected by chromosomal microarray - so a copy-number-aware assay is required and a sequencing-only panel can miss the diagnosis. Counseling must convey the state of the evidence honestly: with two affected individuals reported and the only subsequent variant classified as of uncertain significance, an SH3KBP1 finding is not a settled diagnosis, and predictive interpretation in relatives should be correspondingly cautious.
Show evidence (2 references)
PMID:42375371 SUPPORT Human Clinical
"Genetic analysis using chromosomal microarray (CMA) identified distinct copy number variants on the X chromosome in each case."
Establishes that the diagnostic finding was a copy-number variant detected by microarray, which is why a copy-number-aware assay is required.
PMID:42375371 SUPPORT Other
"the current evidence remains insufficient to establish definitive causality"
The evidential caution this counseling entry is built to convey.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Two affected individuals, brothers, reported with loss-of-function SH3KBP1 variants, plus one later patient with a partial deletion of uncertain significance. No population prevalence estimate exists and none is derivable from a cohort of this size.
Show evidence (1 reference)
PMID:42375371 SUPPORT Other
"To date, only two affected individuals have been reported in the literature."
Gives the published case count.
{ }

Source YAML

click to show 
name: Immunodeficiency 61
creation_date: "2026-08-25T00:00:00Z"
category: Mendelian
synonyms:
- IMD61
- AGMX2
- agammaglobulinemia, X-linked, type 2
- XLA2
- CIN85 deficiency
- SH3KBP1-related X-linked antibody deficiency
description: >-
  Immunodeficiency-61 is an X-linked recessive primary ANTIBODY deficiency caused
  by loss of CIN85, the Cbl-interacting protein of 85 kDa encoded by SH3KBP1 at
  Xp22.12. CIN85 is not a signalling enzyme; it is a trimeric adaptor whose nine
  SH3 domains oligomerise SLP65, the central scaffold of the B cell antigen
  receptor. That SLP65-CIN85 association is CONSTITUTIVE rather than
  stimulus-induced: in a resting B cell the two proteins already sit together in
  cytoplasmic granules formed by phase separation with lipid vesicles, and this
  preformed transducer module is what allows a B cell to respond efficiently the
  moment its receptor is engaged. Without CIN85 the module cannot assemble,
  SLP65 phosphorylation and membrane translocation fail, and selected BCR
  effector arms - NF-kB activation and CD86 upregulation in the human patients,
  calcium and NF-kB responses in the cell models - do not fire.


  The clinical consequence is narrower than the disease's legacy names suggest.
  In the reported patients all immune cell compartments developed normally and
  the defect is intrinsic to the B cell's effector response, not to B cell
  production - so despite the synonyms AGMX2, XLA2 and "agammaglobulinemia,
  X-linked, type 2", grouping this entity with BTK-related X-linked
  agammaglobulinemia is misleading: there the B cell compartment itself fails to
  develop, whereas here it develops normally and the defect is in what B cells
  do. That is a claim about B cell development, not about immunoglobulin levels -
  and the two must not be conflated, because the more severely affected of the
  two founding brothers did have undetectable total IgG and IgA. Recurrent
  bacterial infection of the respiratory tract with impaired specific antibody
  responses and altered memory B cell subsets is the phenotype in the surviving
  reported patients; see `notes:` on the second founding brother, whose course
  was far more severe.


  EVIDENCE BASE IS VERY THIN, and the entry is written accordingly. Two affected
  individuals - brothers - have been reported. A third, later case carried only
  a PARTIAL SH3KBP1 deletion classified as a variant of uncertain significance,
  and its authors state plainly that a causal relationship remains unproven. No
  ClinGen gene-disease validity assertion for SH3KBP1 was found in the cached
  ClinGen snapshot. Nothing here should be read as an established, clinically
  actionable gene-disease relationship.
disease_term:
  preferred_term: immunodeficiency 61
  term:
    id: MONDO:0010296
    label: immunodeficiency 61
parents:
- Primary Immunodeficiency
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      Placed with the immune disorders: this is an inborn error of B cell
      receptor signal transduction presenting as a primary antibody deficiency.
inheritance:
- name: X-linked recessive inheritance
  description: >-
    SH3KBP1 lies at Xp22.12, and the reported affected individuals are
    hemizygous males - two brothers in the founding report, and a boy with a
    partial deletion in a later case. Segregation is incompletely characterised:
    in the later case, testing was limited to the mother and extended family
    studies were unavailable, so mosaicism could not be excluded.
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  evidence:
  - reference: PMID:29636373
    reference_title: "Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report on primary antibody deficiency in patients harboring a germline deletion within the CIN85 gene on the X chromosome"
    explanation: >-
      Establishes a germline X-chromosome deletion as the cause in the founding
      patients.
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "described two brothers with X-linked recessive immunodeficiency caused by loss-of-function variants in SH3KBP1"
    explanation: >-
      States the X-linked recessive mode and the loss-of-function mechanism for
      the founding kindred.
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "segregation analysis was limited to maternal testing, and extended family studies were unavailable, precluding a more comprehensive assessment of inheritance patterns and possible mosaicism"
    explanation: >-
      The authors' own statement of the limits on segregation analysis in the
      later case, which is why this block does not claim fully characterised
      X-linked transmission.
pathophysiology:
- name: SH3KBP1 (CIN85) Loss-of-Function Deletion
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    A germline deletion within SH3KBP1 on the X chromosome, hemizygous in
    affected males. CIN85 is ubiquitously expressed and multifunctional, and
    before this report nothing was known about its role in humans - the only in
    vivo data were conditional mouse mutants ablating distinct CIN85 isoforms in
    brain and B lymphocytes. The human deletion is therefore the experiment that
    established which of CIN85's many proposed functions are non-redundant.
  genes:
  - preferred_term: SH3KBP1
    term:
      id: hgnc:13867
      label: SH3KBP1
  genetic_context:
    gene:
      preferred_term: SH3KBP1
      term:
        id: hgnc:13867
        label: SH3KBP1
    allele_type: intragenic deletion
    zygosity: HEMIZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Hemizygous germline deletion within SH3KBP1 in affected males, described by
      a later report as a loss-of-function variant. LOSS_OF_FUNCTION rather than
      PARTIAL_LOSS_OF_FUNCTION because the founding study frames its findings as
      "in the absence of CIN85" and reads the resulting defects as revealing
      non-redundant CIN85 functions.
    notes: >-
      `variant_origin` is left unset ON THIS BLOCK because the block describes
      the founding kindred's lesion, and the cached sources do not report
      parental testing for those two brothers. It is NOT unset for want of data
      on the later case: that patient's deletion is affirmatively de novo,
      confirmed by its absence in his mother, and that is recorded on the
      corresponding `variants[]` entry. The authors' separate remark that
      segregation was limited to maternal testing with mosaicism not excluded
      comes from their limitations paragraph and qualifies how exhaustively
      segregation was assessed, not whether the mother carried the variant.
  evidence:
  - reference: PMID:29636373
    reference_title: "Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report on primary antibody deficiency in patients harboring a germline deletion within the CIN85 gene on the X chromosome"
    explanation: >-
      Identifies the causal lesion and the resulting clinical category.
  - reference: PMID:29636373
    reference_title: "Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "limited information exists about the in vivo roles of CIN85, because only conditional mouse mutants with cell type-specific ablation of distinct CIN85 isoforms in brain and B lymphocytes have been generated so far. No information is available about the roles of CIN85 in humans."
    explanation: >-
      Establishes the state of knowledge this deletion resolved, and incidentally
      records that brain is one of the two compartments in which CIN85 had been
      conditionally ablated in mice.
  downstream:
  - target: Neurodevelopmental Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      CIN85 is expressed in brain and was one of only two compartments in which
      it had been conditionally ablated in mice, and the reported patients carry
      neurodevelopmental features. The intermediates are unknown, so this edge
      asserts association through unspecified steps rather than a worked
      mechanism - the same standing as the ADHD edge downstream of it.
    evidence:
    - reference: PMID:29636373
      reference_title: "Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "limited information exists about the in vivo roles of CIN85, because only conditional mouse mutants with cell type-specific ablation of distinct CIN85 isoforms in brain and B lymphocytes have been generated so far. No information is available about the roles of CIN85 in humans."
      explanation: >-
        Records brain as one of the two compartments in which CIN85 had been
        conditionally ablated, which is the basis for treating neurodevelopmental
        involvement as plausibly downstream while asserting no intermediates.
  - target: Loss of the Preformed SLP65-CIN85 Transducer Module
    causal_link_type: DIRECT
    description: >-
      Without CIN85 there is no trimeric adaptor to oligomerise SLP65, so the
      constitutive transducer module cannot form.
    evidence:
    - reference: PMID:21822214
      reference_title: "The B-cell antigen receptor signals through a preformed transducer module of SLP65 and CIN85."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "a stimulation-independent and constant association of SLP65 with the Cbl-interacting protein of 85 kDa (CIN85) was requisite for SLP65 phosphorylation and its inducible plasma membrane translocation"
      explanation: >-
        Establishes that the constitutive SLP65-CIN85 association is required for
        SLP65 to be phosphorylated and to reach the membrane, which is the
        function lost when CIN85 is absent.
- name: Loss of the Preformed SLP65-CIN85 Transducer Module
  biological_scale: MOLECULAR
  role: central_effector
  description: >-
    CIN85 trimerises through a C-terminal coiled-coil domain, and the nine SH3
    domains of a trimer bind multiple SLP65 molecules, each of which recruits
    further CIN85 trimers - a self-perpetuating oligomerisation that concentrates
    the effector rather than merely connecting two proteins to each other. The
    resulting complex is held in cytoplasmic granules formed by tripartite phase
    separation of SLP65, CIN85 and lipid vesicles. Its purpose is READINESS: the
    module exists in the RESTING B cell so that signalling can begin immediately
    on receptor engagement. The mechanistic point the disease makes is that a
    signalling cascade can fail not because a component is missing from the
    pathway but because too few copies of it are pre-concentrated in the right
    place.
  biological_processes:
  - preferred_term: B cell receptor signaling pathway
    term:
      id: GO:0050853
      label: B cell receptor signaling pathway
    modifier: DECREASED
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:27353366
    reference_title: "The adaptor protein CIN85 assembles intracellular signaling clusters for B cell activation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "in B lymphocytes, CIN85 functions to oligomerize SLP-65, which is the central effector protein of the B cell receptor (BCR). Therefore, CIN85 trimerizes through a carboxyl-terminal, coiled-coil domain."
    explanation: >-
      States CIN85's actual function in B cells - oligomerising the central BCR
      effector - and the structural basis for it.
  - reference: PMID:27353366
    reference_title: "The adaptor protein CIN85 assembles intracellular signaling clusters for B cell activation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Formation of this oligomeric signaling complex in resting B cells rendered the cells poised for the efficient initiation of intracellular signaling upon BCR stimulation."
    explanation: >-
      Establishes the readiness function of the complex in the resting cell,
      which is what the disease removes.
  - reference: PMID:27353366
    reference_title: "The adaptor protein CIN85 assembles intracellular signaling clusters for B cell activation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the functionality of signaling cascades does not rely solely on the qualitative linkage of their various components but requires a critical number of effectors to become concentrated in signaling complexes"
    explanation: >-
      The generalisable mechanistic claim this node embodies: signalling can fail
      on effector concentration rather than on pathway membership.
  - reference: PMID:32051419
    reference_title: "Tripartite phase separation of two signal effectors with vesicles priming B cell responsiveness."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "effective B cell activation requires tripartite phase separation of SLP65, CIN85, and lipid vesicles into droplets via vesicle binding of SLP65 and promiscuous interactions between nine SH3 domains of the trimeric CIN85 and the proline-rich motifs (PRMs) of SLP65"
    explanation: >-
      Gives the physical basis of the granules - phase separation involving the
      nine SH3 domains of trimeric CIN85 - and states that effective B cell
      activation requires it.
  downstream:
  - target: Impaired B Cell Receptor Effector Signalling
    causal_link_type: DIRECT
    description: >-
      Without the module, SLP65 is neither phosphorylated nor translocated, and
      the downstream effector arms fail.
    evidence:
    - reference: PMID:21822214
      reference_title: "The B-cell antigen receptor signals through a preformed transducer module of SLP65 and CIN85."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In the absence of a steady SLP65/CIN85 complex, BCR-induced Ca(2+) and NF-κB responses were abrogated."
      explanation: >-
        Directly measures the loss of calcium and NF-kappaB responses when the
        constitutive complex is absent - including the predicate, "responses were
        abrogated", which is the finding itself.
- name: Impaired B Cell Receptor Effector Signalling
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    The failure is SELECTIVE, and that selectivity is the disease's defining
    feature. In the patients' B cells, distinct effector pathways of the B cell
    antigen receptor were defective - most notably NF-kB activation and
    upregulation of CD86 on the cell surface - while the cells themselves
    developed and persisted normally. In the cell-line and reconstitution models
    the same lesion abrogates BCR-induced calcium and NF-kB responses. What is
    lost is the capacity of a B cell to translate receptor engagement into an
    effector programme, not the B cell itself.
  biological_processes:
  - preferred_term: positive regulation of canonical NF-kappaB signal transduction
    term:
      id: GO:0043123
      label: positive regulation of canonical NF-kappaB signal transduction
    modifier: DECREASED
  - preferred_term: B cell receptor signaling pathway
    term:
      id: GO:0050853
      label: B cell receptor signaling pathway
    modifier: DECREASED
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:29636373
    reference_title: "Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the absence of CIN85, all immune cell compartments developed normally, but B lymphocytes showed intrinsic defects in distinct effector pathways of the B cell antigen receptor, most notably NF-κB activation and up-regulation of CD86 expression on the cell surface."
    explanation: >-
      The central human observation, quoted whole: normal development of every
      immune compartment, with an intrinsic and selective B cell effector defect
      naming both affected arms - NF-kappaB activation and CD86 upregulation.
  - reference: PMID:29636373
    reference_title: "Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results reveal nonredundant functions of CIN85 for humoral immune responses."
    explanation: >-
      The authors' conclusion that the CIN85 functions lost here are
      non-redundant, which is what makes a single adaptor's absence sufficient to
      cause disease.
  downstream:
  - target: Defective Antibody Production by Intrinsically Impaired B Cells
    causal_link_type: DIRECT
    description: >-
      A B cell that cannot execute the BCR effector programme cannot mount an
      effective antibody response, even though it is present in normal numbers.
    evidence:
    - reference: PMID:42375371
      reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "SH3KBP1 deficiency, currently classified as Immunodeficiency 61 (IMD61), has recently been associated with impaired BCR signaling, defective antibody production, altered memory B-cell subsets, and susceptibility to recurrent bacterial infections"
      explanation: >-
        States the chain from impaired BCR signalling to defective antibody
        production, altered memory B cell subsets and infection susceptibility.
- name: Defective Antibody Production by Intrinsically Impaired B Cells
  biological_scale: CELLULAR
  role: effector
  description: >-
    The humoral response fails at the level of what B cells DO rather than
    whether they exist. Reported consequences include defective antibody
    production and altered memory B cell subsets. This is where the entity's
    legacy naming misleads: a disease called "agammaglobulinemia, X-linked, type
    2" in which every immune compartment develops normally does not share the
    developmental block that defines BTK-related XLA. Note this distinguishes the
    mechanism, not the immunoglobulin level - hypo- and even agammaglobulinaemia
    have been reported in the more severely affected brother.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: memory B cell
    term:
      id: CL:0000787
      label: memory B cell
  biological_processes:
  - preferred_term: immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: DECREASED
  evidence:
  - reference: PMID:29636373
    reference_title: "Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results reveal nonredundant functions of CIN85 for humoral immune responses."
    explanation: >-
      States that the humoral response specifically depends on CIN85.
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "defective antibody production, altered memory B-cell subsets"
    explanation: >-
      Names the two humoral abnormalities this node represents.
  downstream:
  - target: Recurrent bacterial infections
    causal_link_type: DIRECT
    description: >-
      Failure of specific antibody responses leaves the patient susceptible to
      encapsulated and other bacterial pathogens.
    evidence:
    - reference: PMID:42375371
      reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "defective antibody production, altered memory B-cell subsets, and susceptibility to recurrent bacterial infections"
      explanation: >-
        Links the antibody defect directly to recurrent bacterial infection.
  - target: Decreased circulating total IgM
    causal_link_type: DIRECT
    description: >-
      A B cell that cannot execute its effector programme produces less
      immunoglobulin, and IgM is the isotype in which the deficit was measured.
    evidence:
    - reference: PMID:42375371
      reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Follow-up between the ages of 7 and 11 years demonstrated persistently low IgM levels (ranging between 5 and 6 mg/dL)"
      explanation: >-
        Documents the persistent IgM deficit that this edge produces. PARTIAL
        because the patient's variant is of uncertain significance.
  - target: Recurrent respiratory infections
    causal_link_type: DIRECT
    description: >-
      The respiratory tract is the site at which antibody deficiency
      characteristically manifests, and recurrent respiratory infection from
      infancy was the presenting problem in the later reported case.
    evidence:
    - reference: PMID:42375371
      reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The patient presented with recurrent respiratory infections, impaired humoral immune responses, reduced B-cell counts, and neurodevelopmental impairment."
      explanation: >-
        Documents recurrent respiratory infection with impaired humoral responses.
        Marked PARTIAL because this patient carries a partial SH3KBP1 deletion
        classified as a variant of uncertain significance.
- name: Neurodevelopmental Involvement
  biological_scale: ORGANISM
  role: consequence
  description: >-
    Neurodevelopmental features have accompanied the immune phenotype in every
    reported individual: attention-deficit/hyperactivity disorder and mild
    cognitive impairment in the two brothers, and autism spectrum disorder with
    developmental delay in the later case. Whether this reflects a genuine
    second function of CIN85 or ascertainment in patients who reached genetics
    services for developmental reasons is not established. Two things make it
    worth curating rather than dismissing: CIN85 is ubiquitously expressed and
    brain was one of only two compartments in which it had been conditionally
    ablated in mice before the human report; and in the later case the deletion
    also spanned neighbouring genes, so a contiguous-gene effect cannot be
    excluded. The causal link is therefore typed as having unknown intermediates
    and its evidence marked PARTIAL throughout.
  evidence:
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "both patients also presented with neurodevelopmental manifestations, including attention-deficit/hyperactivity disorder (ADHD) and mild cognitive impairment"
    explanation: >-
      Documents neurodevelopmental features in the founding brothers. Marked
      PARTIAL because it is reported second-hand in a later paper rather than
      quoted from the primary description.
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genes within the affected interval include PEPT4-AS1, PHKA2-AS1, MAP3K16, and SH3KBP1"
    explanation: >-
      Names the other genes inside the deleted interval in the later case, which
      is the evidence for this node's contiguous-gene caveat - previously
      asserted without a citation. MAP3K16 in particular is not a bystander one
      can wave away when the phenotype in question is neurodevelopmental.
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings support a possible contribution of SH3KBP1 to shared immunological and neurodevelopmental pathways; however, its pathogenic role has not yet been definitively established."
    explanation: >-
      The authors' own hedged statement of the immune-neurodevelopmental link,
      preserved rather than strengthened.
  downstream:
  - target: Attention deficit hyperactivity disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      ADHD was reported in both founding brothers. No mechanism connecting CIN85
      loss to it has been proposed.
    evidence:
    - reference: PMID:42375371
      reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "neurodevelopmental manifestations, including attention-deficit/hyperactivity disorder (ADHD) and mild cognitive impairment"
      explanation: >-
        Documents ADHD among the neurodevelopmental features.
phenotypes:
- category: Immunological
  name: Recurrent bacterial infections
  description: >-
    Susceptibility to recurrent bacterial infection is the clinical expression of
    the antibody defect.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
    temporality: RECURRENT
  evidence:
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "altered memory B-cell subsets, and susceptibility to recurrent bacterial infections"
    explanation: >-
      Names recurrent bacterial infection as a feature of SH3KBP1 deficiency.
- category: Respiratory
  name: Recurrent respiratory infections
  description: >-
    Recurrent respiratory infection from infancy, the presenting problem in the
    later reported case.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
    temporality: RECURRENT
  evidence:
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with recurrent respiratory infections, impaired humoral immune responses, reduced B-cell counts, and neurodevelopmental impairment."
    explanation: >-
      Documents recurrent respiratory infection. PARTIAL because the patient's
      partial SH3KBP1 deletion is classified as a variant of uncertain
      significance.
- category: Immunological
  name: Impaired humoral immune response
  description: >-
    Impaired specific antibody responses with altered memory B cell subsets, on a
    background of normally developed immune compartments. The one reported
    discrepancy is worth preserving: the founding study found all immune cell
    compartments normal, whereas the later VUS case had REDUCED B cell counts.
  phenotype_term:
    preferred_term: Impaired specific antibody response
    term:
      id: HP:0012475
      label: Impaired specific antibody response
  evidence:
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired humoral immune responses, reduced B-cell counts"
    explanation: >-
      Documents the humoral defect and the reduced B cell counts that differ from
      the founding report. PARTIAL because of the uncertain significance of this
      patient's variant.
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      absent serologic responses to measles (after two vaccine doses), varicella
      (after two vaccine doses), and pneumococcal conjugate vaccines
    explanation: >-
      The strongest available support for this HP term: serotype-level failure to
      respond to three separate vaccines despite documented dosing, in the
      SH3KBP1 patient. Verified unique to the Case-2 paragraph of a two-patient
      report - the Case-1 MECP2 patient's immunologic findings are deliberately
      not used anywhere in this entry.
  - reference: PMID:29636373
    reference_title: "Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all immune cell compartments developed normally, but B lymphocytes showed intrinsic defects"
    explanation: >-
      The founding observation of normal compartments with an intrinsic B cell
      defect, against which the later reduced counts are the discrepancy.
- category: Immunological
  name: Decreased circulating total IgM
  description: >-
    Low serum IgM, documented in the SH3KBP1 patient of the later report at
    presentation (below 20 mg/dL) and persistently on follow-up between 7 and 11
    years of age (5 to 6 mg/dL). This is the most specific laboratory
    abnormality reported in the entity, and it is what an antibody-production
    defect with normal B cell development looks like at the bench.
  phenotype_term:
    preferred_term: Decreased circulating total IgM
    term:
      id: HP:0002850
      label: Decreased circulating total IgM
    clinical_course: STABLE
  evidence:
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Initial immunological workup revealed immunoglobulin M (IgM) levels below 20 mg/dL"
    explanation: >-
      Documents low IgM at presentation in the patient carrying the partial
      SH3KBP1 deletion. Marked PARTIAL because that variant is classified as of
      uncertain significance.
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Follow-up between the ages of 7 and 11 years demonstrated persistently low IgM levels (ranging between 5 and 6 mg/dL)"
    explanation: >-
      Shows the deficit is persistent over four years of follow-up rather than a
      single low value. PARTIAL for the same reason as above.
- category: Immunological
  name: Decreased total B cell count
  description: >-
    Low B cell counts for age, selectively - other lymphocyte subsets were
    normal. This is worth flagging rather than smoothing: it CONTRADICTS the
    founding report, in which all immune cell compartments developed normally,
    and it is reported in the patient whose SH3KBP1 deletion is only partial and
    of uncertain significance. Whether B lymphocytopenia belongs to this entity
    at all is one of the things the standardised immunophenotyping proposed in
    the nosology discussion would settle.
  phenotype_term:
    preferred_term: Decreased total B cell count
    term:
      id: HP:0010976
      label: Decreased total B cell count
  evidence:
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of lymphocyte subpopulations consistently demonstrated low B-cell counts for his age (87 cells/µL, 3.2% of total lymphocytes at 8 years old; 84 cells/µL, 3.5% of total lymphocytes at 11 years old), while other lymphocyte subsets remained within normal ranges"
    explanation: >-
      Quantifies the B lymphocytopenia at two timepoints and establishes that it
      is selective for the B cell compartment. Marked PARTIAL because this
      patient's variant is of uncertain significance and because the finding
      conflicts with the founding report.
  - reference: PMID:29636373
    reference_title: "Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In the absence of CIN85, all immune cell compartments developed normally"
    explanation: >-
      The founding report's finding runs against this phenotype belonging to the
      entity, and is recorded as REFUTE so the conflict is machine-visible rather
      than buried in prose.
- category: Neurological
  name: Attention deficit hyperactivity disorder
  description: >-
    ADHD reported in both founding brothers, alongside mild cognitive impairment.
    Curated because it recurs across reported individuals, not because a
    mechanism is known.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including attention-deficit/hyperactivity disorder (ADHD) and mild cognitive impairment"
    explanation: >-
      Documents ADHD in the founding brothers, reported second-hand.
- category: Growth
  name: Obesity
  description: >
    Obesity is documented in the SH3KBP1 patient, whose weight and height have
    exceeded the 99th percentile with BMI more than 2 SD above the mean since
    age five. That is the only individual for whom it is quotable from a cached
    source; see `notes:` for the deep-research lead on the founding kindred.
    Whether
    it is mechanistically related to CIN85 loss or incidental is unknown, so the
    supporting items are typed PARTIAL rather than SUPPORT.
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  evidence:
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Case 2 involved an 11-year-old male with ASD, recurrent respiratory
      infections since infancy, asthma, allergies, obesity, and congenital heart
      disease.
    explanation: >-
      Names obesity among the features of Case 2, the SH3KBP1 patient. PARTIAL
      because a single patient cannot establish the feature as disease-associated
      rather than incidental. This quote is from the Case-2 paragraph; the Case-1
      MECP2 patient's features are deliberately not used anywhere in this entry.
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His weight and height have consistently exceeded the 99th percentile, with
      a body mass index (BMI) greater than 2 standard deviations (SD) above the
      mean since the age of five.
    explanation: >-
      Quantifies the obesity and dates it to age five. This matters because the
      same report starts risperidone, an antipsychotic with well-known weight
      gain, at age six - so the adiposity predates that exposure and is not
      simply drug-induced.
genetic:
- name: SH3KBP1 loss-of-function deletion
  gene_term:
    preferred_term: SH3KBP1
    term:
      id: hgnc:13867
      label: SH3KBP1
  association: Causative
  relationship_type: CAUSATIVE
  notes: >-
    SH3KBP1 (CIN85) at Xp22.12 is the gene MedGen and OMIM associate with IMD61;
    MONDO:0010296 itself records no causal-gene relationship, so the anchor here
    comes from OMIM/MedGen, and that MONDO gap is worth reporting upstream.
    Evidence strength should be stated plainly rather than implied: only two
    affected individuals - brothers - have been reported with loss-of-function
    SH3KBP1 variants, and the one subsequent case carries a partial deletion
    classified as a variant of uncertain significance whose authors state that a
    causal relationship remains unproven. No ClinGen gene-disease validity
    assertion for SH3KBP1 was present in the cached ClinGen snapshot.
    `relationship_type` is nonetheless CAUSATIVE rather than DISPUTED because
    the founding report demonstrated the mechanism functionally in patient cells
    and no publication disputes the relationship; the limitation is quantity of
    evidence, not conflict within it.
  variants:
  - name: Germline intragenic SH3KBP1 deletion (founding kindred)
    description: >-
      A germline deletion within the CIN85 gene on the X chromosome, hemizygous
      in two affected brothers, described by a later report as loss of function.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:29636373
      reference_title: "Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "patients harboring a germline deletion within the CIN85 gene on the X chromosome"
      explanation: >-
        Describes the founding lesion.
  - name: Partial hemizygous Xp22.12 deletion involving SH3KBP1 (later case)
    description: >-
      A hemizygous deletion of approximately 200 kb at Xp22.12 partially
      involving SH3KBP1, predicted to disrupt exons 2 to 6 and possibly a larger
      region, detected by array comparative genomic hybridization and classified
      as a variant of uncertain significance. It arose DE NOVO, confirmed by its
      absence in the patient's mother. The deleted interval also spans
      neighbouring genes, so a contiguous-gene contribution cannot be excluded,
      and no functional studies were performed.
    clinical_significance: UNCERTAIN_SIGNIFICANCE
    identifiers:
    - ClinVar:SCV005849918
    evidence:
    - reference: PMID:42375371
      reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Importantly, the deletion occurred de novo, as confirmed by its absence in the patient’s mother"
      explanation: >-
        Establishes de novo origin for this variant. Note this is the authors'
        RESULT; the mosaicism caveat quoted elsewhere in this entry comes from
        their limitations paragraph and qualifies how completely segregation was
        assessed, not whether the mother carried it.
    - reference: PMID:42375371
      reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The identified deletion in our patient spans approximately 200 kb and is predicted to disrupt exons 2–6"
      explanation: >-
        Gives the size and predicted exon range of the deletion.
    - reference: PMID:42375371
      reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The variant has been deposited in the NCBI ClinVar database under accession number SCV005849918"
      explanation: >-
        Supplies the ClinVar accession recorded in `identifiers`. The accession
        is quoted WITH its number because the same sentence appears twice in this
        paper - the other instance, SCV005849919, is the MECP2 variant of the
        unrelated first patient.
    - reference: PMID:42375371
      reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a hemizygous deletion at Xp22.12 partially involving the SH3KBP1 gene was detected and classified as a variant of uncertain significance (VUS)"
      explanation: >-
        States the lesion and its uncertain classification.
    - reference: PMID:42375371
      reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "functional studies were not performed to directly assess the biological impact of the identified genetic variants, limiting definitive conclusions regarding their pathogenicity"
      explanation: >-
        The authors' own statement of why this variant's pathogenicity is
        unresolved.
  evidence:
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "To date, only two affected individuals have been reported in the literature."
    explanation: >-
      States the size of the reported cohort, which is the basis for describing
      the evidence base as very thin.
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the number of reported cases involving SH3KBP1 deficiency remains extremely limited, restricting robust genotype-phenotype correlations for this gene"
    explanation: >-
      The authors' own assessment of what can and cannot be concluded from the
      current case count.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Two affected individuals, brothers, reported with loss-of-function SH3KBP1
    variants, plus one later patient with a partial deletion of uncertain
    significance. No population prevalence estimate exists and none is derivable
    from a cohort of this size.
  evidence:
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "To date, only two affected individuals have been reported in the literature."
    explanation: >-
      Gives the published case count.
treatments:
- name: Immunoglobulin Replacement Therapy
  description: >-
    The standard management of a primary antibody deficiency is to supply the
    antibody the patient cannot make. No trial or case series has evaluated
    immunoglobulin replacement in SH3KBP1 deficiency specifically - with two
    reported patients, none could exist - so this is the class-level standard of
    care for inborn errors of immunity with impaired antibody production,
    recorded as such rather than as disease-specific evidence.
  action_category: THERAPEUTIC
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: intravenous immunoglobulin therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
  target_mechanisms:
  - target: Defective Antibody Production by Intrinsically Impaired B Cells
    treatment_effect: BYPASSES
    description: >-
      Replacement immunoglobulin substitutes for the antibody the patient's B
      cells fail to produce. It bypasses the defect; it does not repair the
      signalling module, and it does not restore the patient's own specific
      antibody responses.
    evidence:
    - reference: PMID:42208906
      reference_title: "Practice parameter for inborn errors of immunity: What is new in the 2025 update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The management part includes recommendations for immunoglobulin replacement, antibiotic prophylaxis, hematopoietic stem cell transplantation, precision medicine, and quality-of-life assessment."
      explanation: >-
        Establishes immunoglobulin replacement as a recommended management
        component for inborn errors of immunity. Class-level evidence, cited as
        such.
  evidence:
  - reference: PMID:42208906
    reference_title: "Practice parameter for inborn errors of immunity: What is new in the 2025 update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "recommendations for immunoglobulin replacement, antibiotic prophylaxis, hematopoietic stem cell transplantation"
    explanation: >-
      The management framework applied to this disorder in the absence of
      disease-specific evidence.
- name: Antibiotic Prophylaxis
  description: >-
    Prophylactic antibiotics for recurrent bacterial and respiratory infection,
    used alongside or instead of immunoglobulin replacement depending on
    severity. As above, this is class-level practice for antibody deficiency; no
    SH3KBP1-specific evidence exists.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antibiotic prophylaxis
    term:
      id: NCIT:C51993
      label: Antibiotic Prophylaxis
  evidence:
  - reference: PMID:42208906
    reference_title: "Practice parameter for inborn errors of immunity: What is new in the 2025 update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "recommendations for immunoglobulin replacement, antibiotic prophylaxis"
    explanation: >-
      Establishes antibiotic prophylaxis as a recommended management component
      for inborn errors of immunity.
- name: Genetic Testing and Counseling
  description: >-
    Both reported lesions are deletions, one intragenic and one a partial
    deletion detected by chromosomal microarray - so a copy-number-aware assay is
    required and a sequencing-only panel can miss the diagnosis. Counseling must
    convey the state of the evidence honestly: with two affected individuals
    reported and the only subsequent variant classified as of uncertain
    significance, an SH3KBP1 finding is not a settled diagnosis, and predictive
    interpretation in relatives should be correspondingly cautious.
  action_category: COUNSELING_INFORMATIONAL
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis using chromosomal microarray (CMA) identified distinct copy number variants on the X chromosome in each case."
    explanation: >-
      Establishes that the diagnostic finding was a copy-number variant detected
      by microarray, which is why a copy-number-aware assay is required.
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the current evidence remains insufficient to establish definitive causality"
    explanation: >-
      The evidential caution this counseling entry is built to convey.
discussions:
- discussion_id: imd61_cin85_positive_versus_negative_regulator
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is CIN85 a positive or a negative regulator of B cell receptor signalling?
    The human deletion and the cell-line knockdown point in opposite directions.
  attaches_to:
  - "pathophysiology#Impaired B Cell Receptor Effector Signalling"
  rationale: >-
    Two well-executed bodies of work disagree about the sign of CIN85's effect.
    In humans lacking CIN85, and in reconstitution experiments lacking the
    SLP65-CIN85 complex, BCR effector responses are IMPAIRED - NF-kB and CD86 in
    patients, calcium and NF-kB in cells - which is a positive, transducer role.
    But CIN85 knockdown in B cell lines and primary B cells ENHANCES BCR-induced
    survival and growth and increases expression of BcLxL, A1, cyclin D2 and myc,
    consistent with a negative regulatory role exercised through Cbl-mediated
    ubiquitination and degradation of Syk. Both cannot be the whole story. The
    plausible reconciliations - that acute knockdown and germline absence are not
    the same perturbation, that CIN85 isoforms differ, or that the transducer and
    Cbl-adaptor functions are separable and read out on different timescales -
    are untested. This matters for the disease entry because it determines
    whether the pathograph's central node is correctly signed, and no entry in
    this family should assert a single unified CIN85 function.
  proposed_experiments:
  - experiment_id: exp_imd61_acute_versus_germline_cin85_loss
    name: Side-by-side acute knockdown versus germline null in the same B cell background
    description: >-
      Compare degenerate CIN85 knockdown, inducible degron-mediated acute
      depletion, and stable germline knockout in one isogenic human B cell line,
      reading out Syk ubiquitination and phosphorylation, calcium flux, NF-kB
      activation, CD86 upregulation, survival and proliferation in parallel. This
      would test directly whether the opposing published phenotypes are an
      artefact of perturbation kinetics rather than a genuine dual function.
  evidence:
  - reference: PMID:22262777
    reference_title: "CIN85 is required for Cbl-mediated regulation of antigen receptor signaling in human B cells."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "CIN85 knockdown in primary B cells enhanced BCR-induced survival and growth, and increased the expression of BcLxL, A1, cyclin D2, and myc"
    explanation: >-
      The result that runs opposite to the disease model: losing CIN85 ENHANCES
      rather than impairs BCR-driven responses in this system. Recorded as REFUTE
      against a simple "CIN85 is required for BCR signalling" reading.
  - reference: PMID:22262777
    reference_title: "CIN85 is required for Cbl-mediated regulation of antigen receptor signaling in human B cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CIN85 increased c-Cbl phosphorylation and inhibited BCR-induced calcium flux and phosphorylation of Syk and PLCγ2"
    explanation: >-
      Gives the mechanism of the negative-regulatory arm - Cbl-dependent
      suppression of proximal BCR signalling through Syk and PLC-gamma-2.
  - reference: PMID:29636373
    reference_title: "Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "B lymphocytes showed intrinsic defects in distinct effector pathways of the B cell antigen receptor"
    explanation: >-
      The human result on the other side of the disagreement: absence of CIN85
      impairs, rather than enhances, BCR effector pathways.
- discussion_id: imd61_nosology_not_an_agammaglobulinemia
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Should MONDO:0010296 remain classified under agammaglobulinemia, given that
    the disease it names is a selective antibody-response defect with normal
    B cell development?
  attaches_to:
  - "pathophysiology#Defective Antibody Production by Intrinsically Impaired B Cells"
  rationale: >-
    The entity carries the legacy names AGMX2, XLA2 and "agammaglobulinemia,
    X-linked, type 2", and MONDO places MONDO:0010296 under
    MONDO:0015977 agammaglobulinemia. The disease as characterised does not match
    that placement: in the founding report all immune cell compartments developed
    normally and the defect was intrinsic to B cell effector function, and the
    subsequently reported features are impaired specific antibody responses and
    altered memory B cell subsets. The question is about mechanism, not about
    immunoglobulin levels: the more severely affected founding brother had
    undetectable total IgG and IgA, so a categorical "this is not an
    agammaglobulinemia" would overstate the case. What the placement does invite
    is confusion with BTK-related X-linked agammaglobulinemia, which is a
    different gene, a different mechanism, and - decisively - a different B cell
    phenotype, since B cell development is intact here. This is recorded as a curation-facing question
    rather than acted on unilaterally, because reclassifying a MONDO concept is
    not a disorder entry's job.
  proposed_experiments:
  - experiment_id: exp_imd61_immunophenotype_reconciliation
    name: Standardised immunophenotyping of all reported SH3KBP1 patients
    description: >-
      Apply one standardised B cell immunophenotyping panel - total, transitional,
      naive, memory and switched-memory B cells, plus serum immunoglobulin
      isotypes and specific antibody responses to protein and polysaccharide
      vaccines - across all reported SH3KBP1 patients, to settle whether the
      entity is an agammaglobulinemia, a specific antibody deficiency, or a
      memory B cell disorder, and to reconcile the reported discrepancy in B cell
      counts.
  evidence:
  - reference: PMID:29636373
    reference_title: "Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the absence of CIN85, all immune cell compartments developed normally"
    explanation: >-
      Normal development of all immune compartments is inconsistent with an
      agammaglobulinemia classification.
  - reference: PMID:42375371
    reference_title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired humoral immune responses, reduced B-cell counts"
    explanation: >-
      The one report of reduced B cell counts, which is the discrepancy the
      proposed immunophenotyping would resolve. PARTIAL because this patient's
      variant is of uncertain significance.
notes: >-
  Gene anchor. MONDO:0010296 records no causal-gene relationship, so the stub had
  no `genes:` block. Following its xrefs, MedGen (MEDGEN:337462, from OMIM
  #300310) associates the concept with SH3KBP1 (gene_id 30011) at Xp22.12, and
  that is the anchor used here. As with the sibling immunodeficiency entry
  curated in this tranche, the missing MONDO relationship is worth reporting
  upstream.


  Evidence base. This is one of the thinnest gene-disease relationships in the
  knowledge base: two affected brothers, one later patient with a partial
  deletion of uncertain significance, and no ClinGen gene-disease validity
  assertion in the cached ClinGen snapshot. The mechanistic literature is by
  contrast strong and independent of the patients - the SLP65-CIN85 transducer
  module has been characterised biochemically, structurally and by studies of
  phase separation in cell systems - so the entry is deliberately
  mechanism-heavy and clinically cautious rather than the reverse.


  Features NOT curated, and why. MedGen/HPO annotate this concept with
  recurrent sinusitis, recurrent otitis media, and decreased circulating IgG2 and
  IgG4. (Obesity was on this list and has since been curated as a phenotype - it
  is directly quotable for the SH3KBP1 patient from the PMID:42375371 full text
  committed here, so "needs full-text access" was never the real reason for its
  absence.) Those annotations derive from the OMIM clinical synopsis of the founding
  report, whose PubMed record caches as abstract only and contains none of those
  statements, and no ORPHA record for Orphanet:696945 could be built because
  `just refresh-orphadata` currently fails on a manifest checksum mismatch and
  the bulk XML is absent. Rather than cite an abstract for facts it does not
  contain, they are named here as verifiable leads for a curator with full-text
  or Orphanet access.


  ALSO NOT CURATED, and the most consequential omission: the deep research
  committed with this entry reports that the second founding brother never
  outgrew the juvenile infection period and died at 15 of septic shock and
  multiorgan failure following bilateral pneumonia. It is recorded here rather
  than as a phenotype because it is not quotable from any cached reference and
  the report's own source for it is a weak `Unknown journal, Unknown year`
  record. It is named explicitly because a death in one of the two reported
  patients bears on how severe this entity is, and omitting it silently would
  make this ledger's inclusion criteria arbitrary at the point where the stakes
  are highest. The same deep research is the sole source for obesity in both
  brothers, cited only through an internal key - also a lead, not a citable
  source.


  A WARNING FOR WHOEVER PROMOTES THEM. The IgG subclass pattern is the most
  valuable of those leads - selective IgG2/IgG4 deficiency with normal B cell
  numbers is a far more specific description of this entity than "antibody
  deficiency" and would strengthen the nosology discussion - but it must NOT be
  taken from PMID:42375371. That paper reports two unrelated patients, and its
  selective IgG2/IgG4 deficiency belongs to Case 1, who has an MECP2 duplication
  and no SH3KBP1 variant at all. Note the warning is deliberately limited to the
  IgG subclasses: Case 2 SEPARATELY has elevated IgE (without aeroallergen
  sensitization, unlike Case 1's house-dust-mite-specific IgE) and absent
  serologic responses to measles, varicella and pneumococcal conjugate vaccines,
  and those ARE promotable for this entity - the vaccine data is cited on the
  Impaired specific antibody response phenotype. The same
  trap exists for the ClinVar accession: SCV005849919 is Case 1's MECP2 variant
  and SCV005849918 is the SH3KBP1 deletion, in otherwise identical sentences.
  Every quote taken from that reference in this entry is from the Case 2
  paragraph, and each was checked for uniqueness against the whole cached file
  before use.


  What WAS promoted from that full text: decreased circulating IgM and decreased
  total B cell count, both quotable for the SH3KBP1 patient. The B lymphocytopenia
  is curated with a `REFUTE`-typed counter-item from the founding report, which
  found all immune cell compartments normal - the conflict is real and is left
  visible rather than resolved by preferring one source.


  No `datasets:` block. No SH3KBP1-immunodeficiency-specific accession was
  identified, and searching the gene alone surfaces the large CIN85 cancer and
  EGFR-trafficking literature instead - the Named Entity Confusion hazard the
  dataset SOP warns about.
references:
- reference: PMID:29636373
  title: "Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency."
  findings: []
- reference: PMID:42375371
  title: "Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation."
  findings: []
- reference: PMID:27353366
  title: "The adaptor protein CIN85 assembles intracellular signaling clusters for B cell activation."
  findings: []
- reference: PMID:21822214
  title: "The B-cell antigen receptor signals through a preformed transducer module of SLP65 and CIN85."
  findings: []
- reference: PMID:32051419
  title: "Tripartite phase separation of two signal effectors with vesicles priming B cell responsiveness."
  findings: []
- reference: PMID:22262777
  title: "CIN85 is required for Cbl-mediated regulation of antigen receptor signaling in human B cells."
  findings: []
- reference: PMID:42208906
  title: "Practice parameter for inborn errors of immunity: What is new in the 2025 update."
  findings: []
📚

References & Deep Research

References

7
PMID:29636373
Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency.
No top-level findings curated for this source.
PMID:42375371
Case Report: MECP2 and SH3KBP1 variants associated with autism spectrum disorder and immune dysregulation.
No top-level findings curated for this source.
PMID:27353366
The adaptor protein CIN85 assembles intracellular signaling clusters for B cell activation.
No top-level findings curated for this source.
PMID:21822214
The B-cell antigen receptor signals through a preformed transducer module of SLP65 and CIN85.
No top-level findings curated for this source.
PMID:32051419
Tripartite phase separation of two signal effectors with vesicles priming B cell responsiveness.
No top-level findings curated for this source.
PMID:22262777
CIN85 is required for Cbl-mediated regulation of antigen receptor signaling in human B cells.
No top-level findings curated for this source.
PMID:42208906
Practice parameter for inborn errors of immunity: What is new in the 2025 update.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 10 citations 2026-08-25T20:57:40.733089

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Immunodeficiency 61
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Immunodeficiency 61 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Immunodeficiency 61 (SH3KBP1/CIN85 deficiency): comprehensive disease-characteristics report

Evidence cutoff and interpretation. Immunodeficiency 61 is an ultra-rare, X-linked, predominantly antibody deficiency caused by loss of SH3KBP1, encoding the adaptor CIN85. The disease-specific human literature remains essentially one 2018 family with two affected brothers. Consequently, frequencies below are “2/2” or “1/2” observations, not population estimates, and many management recommendations must be extrapolated from primary antibody-deficiency practice rather than regarded as proven specifically for this disorder. The defining article was published online 10 April 2018: Keller et al., Journal of Experimental Medicine 215:1327–1336, DOI/URL: https://doi.org/10.1084/jem.20170534. (kellerUnknownyeargövip18prof.dr. pages 1-4, kellerUnknownyeargövip18prof.dr. pages 4-5)

Executive evidence summary

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 (kellerUnknownyeargövip18prof.dr. pages 1-4, kellerUnknownyeargövip18prof.dr. pages 4-5) Human primary disease report; strong for gene-disease link but very limited case count (kellerUnknownyeargövip18prof.dr. pages 1-4, kellerUnknownyeargövip18prof.dr. pages 4-5)
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 (kellerUnknownyeargövip18prof.dr. pages 4-5) Human genomic + protein evidence; strong (kellerUnknownyeargövip18prof.dr. pages 4-5)
Inheritance X-linked transmission 2 affected hemizygous males; mother hemizygous carrier without clinical symptoms; healthy half-brother negative for deletion (kellerUnknownyeargövip18prof.dr. pages 4-5) Human pedigree evidence; strong within single family (kellerUnknownyeargövip18prof.dr. pages 4-5)
Patient 1 demographics Surviving index case Male, age 12 years at report; diagnosed genetically after evaluation of antibody deficiency (kellerUnknownyeargövip18prof.dr. pages 4-5) Human case report; strong (kellerUnknownyeargövip18prof.dr. pages 4-5)
Patient 2 demographics/outcome More severe affected brother Male; died at age 15 years, 3 years before report (kellerUnknownyeargövip18prof.dr. pages 4-5) Human family history/archived DNA; moderate-strong (kellerUnknownyeargövip18prof.dr. pages 4-5)
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) (kellerUnknownyeargövip18prof.dr. pages 5-7) Human laboratory evidence; strong (kellerUnknownyeargövip18prof.dr. pages 5-7)
Immunoglobulins: patient 2 More profound pan-hypogammaglobulinemia than patient 1 Serum IgM and IgG2/4 diminished; total IgG and IgA below detection limits (kellerUnknownyeargövip18prof.dr. pages 4-5) Human retrospective clinical data; moderate (kellerUnknownyeargövip18prof.dr. pages 4-5)
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 (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 5-7) Human functional clinical immunology; strong (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 5-7)
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 (kellerUnknownyeargövip18prof.dr. pages 4-5) Human longitudinal case history; moderate-strong (kellerUnknownyeargövip18prof.dr. pages 4-5)
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 (kellerUnknownyeargövip18prof.dr. pages 4-5) Human case history; strong for severe phenotype (kellerUnknownyeargövip18prof.dr. pages 4-5)
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 (kellerUnknownyeargövip18prof.dr. pages 5-7) Human observational note; weak/uncertain disease attribution (kellerUnknownyeargövip18prof.dr. pages 5-7)
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 (kellerUnknownyeargövip18prof.dr. pages 5-7, kellerUnknownyeargövip18prof.dr. pages 7-9) Human flow-cytometry evidence; strong (kellerUnknownyeargövip18prof.dr. pages 5-7, kellerUnknownyeargövip18prof.dr. pages 7-9)
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) (kellerUnknownyeargövip18prof.dr. pages 5-7, kellerUnknownyeargövip18prof.dr. pages 9-10) Human flow-cytometry evidence; strong (kellerUnknownyeargövip18prof.dr. pages 5-7, kellerUnknownyeargövip18prof.dr. pages 9-10)
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 (kellerUnknownyeargövip18prof.dr. pages 7-9) Human ex vivo signaling assays; strong (kellerUnknownyeargövip18prof.dr. pages 7-9)
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 (kellerUnknownyeargövip18prof.dr. pages 7-9) Human ex vivo mechanistic evidence; strong (kellerUnknownyeargövip18prof.dr. pages 7-9)
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 (kellerUnknownyeargövip18prof.dr. pages 7-9, kellerUnknownyeargövip18prof.dr. pages 9-10) Human ex vivo functional evidence; strong (kellerUnknownyeargövip18prof.dr. pages 7-9, kellerUnknownyeargövip18prof.dr. pages 9-10)
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 (kellerUnknownyeargövip18prof.dr. pages 7-9) Human ex vivo functional evidence; strong (kellerUnknownyeargövip18prof.dr. pages 7-9)
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 (kellerUnknownyeargövip18prof.dr. pages 9-10) Human ex vivo functional evidence; strong (kellerUnknownyeargövip18prof.dr. pages 9-10)
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 (kellerUnknownyeargövip18prof.dr. pages 9-10) Human mechanistic synthesis; moderate-strong (kellerUnknownyeargövip18prof.dr. pages 9-10)
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 (niiro2012cin85isrequired pages 1-2, niiro2012cin85isrequired pages 2-3, niiro2012cin85isrequired pages 3-4) Human cell-line and primary-cell mechanistic evidence; supportive but not disease-specific (niiro2012cin85isrequired pages 1-2, niiro2012cin85isrequired pages 2-3, niiro2012cin85isrequired pages 3-4)
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 (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 5-7, kellerUnknownyeargövip18prof.dr. pages 11-12) In vivo model evidence; strong supportive translational evidence (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 5-7, kellerUnknownyeargövip18prof.dr. pages 11-12)
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 (kellerUnknownyeargövip18prof.dr. pages 7-9, kellerUnknownyeargövip18prof.dr. pages 10-11) Human cell model; strong mechanistic validation (kellerUnknownyeargövip18prof.dr. pages 7-9, kellerUnknownyeargövip18prof.dr. pages 10-11)
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 (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 11-12) Mouse model; indirect/weak for human disease phenotype (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 11-12)
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 (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 10-11) Human diagnostic evidence; strong for this family (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 10-11)
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 (kellerUnknownyeargövip18prof.dr. pages 1-4) Institutional implementation statement; moderate (kellerUnknownyeargövip18prof.dr. pages 1-4)
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 (OpenTargets Search: Immunodeficiency 61-SH3KBP1) Evidence gap; strong as negative finding within retrieved sources (OpenTargets Search: Immunodeficiency 61-SH3KBP1)
Epidemiology Extremely rare; prevalence/incidence cannot be estimated Only 1 reported family and 2 affected males in retrieved primary literature (kellerUnknownyeargövip18prof.dr. pages 4-5) Evidence gap with minimal published denominator (kellerUnknownyeargövip18prof.dr. pages 4-5)
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 (kellerUnknownyeargövip18prof.dr. pages 4-5, OpenTargets Search: Immunodeficiency 61-SH3KBP1) Overall literature limitation; strong caution warranted (kellerUnknownyeargövip18prof.dr. pages 4-5, OpenTargets Search: Immunodeficiency 61-SH3KBP1)

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.

1. Disease information

Definition and identifiers

Immunodeficiency 61 is a Mendelian, X-linked primary antibody deficiency in which germline loss of SH3KBP1/CIN85 impairs B-cell antigen-receptor signaling and production of IgM, selected IgG subclasses, and antipolysaccharide antibodies. Peripheral B- and T-cell development can remain nearly normal, distinguishing it from classic BTK-related X-linked agammaglobulinemia. (kellerUnknownyeargövip18prof.dr. pages 1-4, kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 5-7)

Recommended names and synonyms are Immunodeficiency 61, SH3KBP1 deficiency, CIN85 deficiency, X-linked antibody deficiency due to CIN85 deficiency, and germline deletion of CIN85. SH3KBP1 is also called SH3-domain kinase-binding protein 1; its protein is Cbl-interacting protein of 85 kDa (CIN85), also known experimentally as Ruk or SETA. (niiro2012cin85isrequired pages 1-2, kellerUnknownyeargövip18prof.dr. pages 1-4)

A reliable disease-specific MONDO, Orphanet, ICD-10/11, or MeSH identifier was not exposed by the retrieved authoritative literature and should not be inferred. The Open Targets query did not return an SH3KBP1–Immunodeficiency 61 association, illustrating incomplete coverage rather than disproving the primary human evidence. Use of the literal label “Immunodeficiency 61” should therefore be accompanied by SH3KBP1/CIN85 in database records. (OpenTargets Search: Immunodeficiency 61-SH3KBP1)

The evidence is aggregated disease-level literature derived from individual patients, not EHR-scale data: one pedigree, two affected males, one clinically unaffected carrier mother, and one unaffected half-brother. (kellerUnknownyeargövip18prof.dr. pages 4-5)

2. Etiology, risk, protection, and gene–environment interaction

The established cause is a germline loss-of-function copy-number deletion involving SH3KBP1. In the reported family, a 247.5-kb Xp22.12 deletion removed exons 2–6 at GRCh37 chrX:19,667,630–19,886,572, abolished expression of the prevalent NM_031892 transcript/CIN85 protein, and spared adjacent genes. Whole-exome analysis found no phenotypically relevant variant among 395 primary-immunodeficiency genes, while expression of the related adaptor CD2AP remained normal. (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 10-11)

The principal genetic risk factor is therefore inheritance of a pathogenic hemizygous SH3KBP1 loss-of-function allele in a male. The mother carried the deletion without reported immunodeficiency, consistent with X-linked transmission and likely protection through a functional allele/X-chromosome mosaicism, although X-inactivation was not established. Penetrance in hemizygous males cannot be quantified from two brothers; expression was markedly variable. (kellerUnknownyeargövip18prof.dr. pages 4-5)

No susceptibility loci, validated modifier genes, protective variants, founder effect, carrier frequency, germline mosaicism, anticipation, or environmental cause has been established. The authors explicitly considered additional genetic, epigenetic, and environmental modifiers because the brothers carrying the same deletion differed dramatically: one improved after early childhood, whereas the other developed persistent infections and fatal sepsis. Specific gene–environment interactions remain unknown; pathogen exposure likely reveals the antibody defect but does not cause it. (kellerUnknownyeargövip18prof.dr. pages 5-7, kellerUnknownyeargövip18prof.dr. pages 9-10)

3. Phenotypes

Core infectious and laboratory phenotypes

  • Recurrent/severe bacterial infection—observed in both brothers. Patient 1 had severe, winter-predominant infections through age four and subsequently became clinically well; patient 2 had recurrent sinusitis, otitis media, and pneumonia. Suggested HPO mappings: Recurrent bacterial infections, HP:0002783 Recurrent lower respiratory tract infections, HP:0011107 Recurrent respiratory infections, HP:0000246 Sinusitis, HP:0000403 Recurrent otitis media, and HP:0002090 Pneumonia. Severity and course were highly variable. (kellerUnknownyeargövip18prof.dr. pages 4-5)
  • Hypogammaglobulinemia/Ig-subclass deficiency. Patient 1 had IgM 16 mg/dL (reference 48–228), IgG2 55 mg/dL (110–485), and IgG4 <0.8 mg/dL (5.2–196), with preserved total IgG 918 mg/dL, IgA 79 mg/dL, IgG1 595 mg/dL, and IgG3 60 mg/dL. Patient 2 had reduced IgM and IgG2/4 plus undetectable total IgG and IgA. Suggested HPO: HP:0004313 Hypogammaglobulinemia, Decreased serum IgM, IgG2 deficiency, IgG4 deficiency, and Agammaglobulinemia for the severe brother. (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 5-7)
  • Impaired antipolysaccharide antibody response. Patient 1 failed adequate pneumococcal IgG responses against eight of nine evaluated serotypes; serotype-specific IgM met the proposed cutoff for only eight of ten serotypes, whereas anti-tetanus-toxoid peptide response was normal. Suggested HPO: HP:0002845 Abnormality of humoral immunity and Impaired antibody response to vaccination. (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 5-7)
  • Fatal invasive infection/organ failure. Patient 2 died at 15 years from septic shock and multiorgan failure after bilateral pneumonia. Suggested HPO: HP:0100806 Sepsis, Septic shock, and Multiple organ dysfunction syndrome. (kellerUnknownyeargövip18prof.dr. pages 4-5)
  • Possible nonimmune features. Both brothers were diagnosed at age 11 with moderate ADHD, mildly impaired adaptive skills, and obesity. Causality is uncertain; these should be entered as provisional, not definitive disease phenotypes. Suggested HPO: HP:0007018 Attention deficit hyperactivity disorder, HP:0000729 Autistic behavior/behavioral abnormality only if clinically documented, and HP:0001513 Obesity. (kellerUnknownyeargövip18prof.dr. pages 5-7)

No disease-specific EQ-5D, SF-36, PROMIS, disability, or quality-of-life measurements exist. Recurrent infections plausibly disrupt schooling, daily activity, and family life, while the fatal case establishes potentially profound morbidity; quantitative QoL claims are unsupported.

4. Genetic and molecular information

Causal gene: SH3KBP1, Xp22.12; protein CIN85. The reported deletion is germline, hemizygous in affected males, and functionally null. It is a multiexon structural deletion rather than a missense, nonsense, or small indel. The original study demonstrated absent protein, segregation with disease, and a matching B-cell functional defect, strongly supporting pathogenicity for this family. (kellerUnknownyeargövip18prof.dr. pages 4-5)

No additional confidently disease-causing allelic series, ClinVar classification set, HGMD series, population allele frequency, or genotype–phenotype correlation was established in the retrieved literature. A large deletion of this kind is expected to be extremely rare; an exact gnomAD/TOPMed frequency should not be stated without direct database interrogation. Somatic SH3KBP1 variants are not the cause of this disorder.

No validated modifier genes or disease-specific epigenetic signature have been reported. CD2AP is a biologically plausible redundant adaptor because it remained normally expressed and may compensate in T cells and some B-cell responses, but it is not a proven clinical modifier. No aneuploidy, translocation, inversion, or recurrent cytogenetic syndrome beyond the focal Xp22.12 deletion is established. (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 9-10)

5. Environmental and infectious information

There is no evidence that toxins, radiation, air pollution, occupation, smoking, diet, alcohol, or physical activity alter disease occurrence. Infectious exposure is a clinical trigger, not an etiology. Reported syndromes were bacterial sinopulmonary infections; individual organisms were not specified. Encapsulated bacteria are biologically important because IgM/IgG2 and pneumococcal-polysaccharide responses are defective, but organism-specific susceptibility cannot be quantified from this family. (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 5-7)

6. Mechanism and pathophysiology

Causal chain

  1. Upstream genetic lesion: germline SH3KBP1 deletion → absent CIN85 adaptor protein. (kellerUnknownyeargövip18prof.dr. pages 4-5)
  2. Signal-complex defect: CIN85 normally cooperates with SLP65/BLNK and signaling proteins downstream of the B-cell receptor. Its absence reduces BCR-triggered Ca²⁺ mobilization and diacylglycerol/PKC-β-dependent coupling to canonical NF-κB. (kellerUnknownyeargövip18prof.dr. pages 7-9, kellerUnknownyeargövip18prof.dr. pages 9-10)
  3. Selective pathway failure: patient B cells showed markedly impaired IκBα degradation and p65 phosphorylation after BCR ligation, with reduced induction of Bcl-xL, CD86, and ICAM-1. ERK phosphorylation and PI3K–Akt–mTOR readout S6 phosphorylation remained intact; CD40-, TLR9-, and PMA-driven NF-κB activation also remained intact. (kellerUnknownyeargövip18prof.dr. pages 7-9)
  4. Cellular consequence: circulating B-cell development is largely preserved, but antigen-driven B-cell activation and differentiation into effective antibody-secreting responses—especially T-independent antipolysaccharide responses—are inadequate. T-cell signaling, cytokine production, and proliferation were overtly normal, arguing for a predominantly B-cell-intrinsic disorder. (kellerUnknownyeargövip18prof.dr. pages 7-9, kellerUnknownyeargövip18prof.dr. pages 9-10)
  5. Clinical consequence: reduced IgM/IgG-subclass production and defective pneumococcal antibodies → recurrent respiratory bacterial infection → in severe expression, pneumonia, septic shock, multiorgan failure, and death. (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 5-7)

An earlier human-cell study found that CIN85 associates with c-Cbl, Cbl-b, and BLNK and affects Syk ubiquitination/degradation, calcium flux, PLCγ2, survival, growth, and differentiation. Its in-vitro negative-regulatory observations did not fully predict the positive, nonredundant role demonstrated in patient B cells, emphasizing the primacy of the human loss-of-function phenotype. Published 8 March 2012, DOI: https://doi.org/10.1182/blood-2011-04-351965. (niiro2012cin85isrequired pages 1-2, niiro2012cin85isrequired pages 2-3, kellerUnknownyeargövip18prof.dr. pages 7-9)

Suggested GO biological processes include B-cell receptor signaling pathway (GO:0050853), B-cell activation (GO:0042113), canonical NF-kappaB signal transduction, calcium-mediated signaling, immunoglobulin production, and response to bacterium. Relevant cells are B lymphocyte (CL:0000236), naïve B cell, memory B cell, plasmablast, plasma cell, and possibly B-1 B cell; T lymphocytes and NK cells are evaluated comparators rather than primary targets. Relevant cellular components include cytosol, plasma membrane/BCR signalosome, and protein-containing signaling complex. (kellerUnknownyeargövip18prof.dr. pages 5-7, kellerUnknownyeargövip18prof.dr. pages 7-9, kellerUnknownyeargövip18prof.dr. pages 9-10)

No disease-specific patient transcriptome, proteome, metabolome, lipidome, single-cell atlas, spatial transcriptome, or integrated multi-omics dataset was identified. Functional genomics evidence consists of CRISPR/Cas9 and independently targeted TALEN deletion in human DG75 B cells: knockout impaired BCR-induced Ca²⁺ mobilization, and a C-terminally truncated signaling-incompetent CIN85 did not rescue it. (kellerUnknownyeargövip18prof.dr. pages 7-9, kellerUnknownyeargövip18prof.dr. pages 10-11)

7. Anatomical structures affected

The primary biological compartment is the hematolymphoid/immune system, especially circulating and lymphoid-organ B cells. Suggested anatomical terms include UBERON:0000178 blood, UBERON:0002106 spleen, UBERON:0002371 bone marrow, and lymph node; direct human tissue pathology in spleen, marrow, or nodes has not been reported. Secondary clinical sites are the upper and lower respiratory tract: paranasal sinus, middle ear, and bilateral lungs. Suggested terms include UBERON:0002048 lung, paranasal sinus, and middle ear. Infections were not described as lateralized except bilateral pneumonia in the fatal case. (kellerUnknownyeargövip18prof.dr. pages 4-5)

At subcellular level, the defect concerns a cytosolic adaptor assembled near the plasma-membrane BCR, rather than a primary mitochondrial, lysosomal, nuclear, or endoplasmic-reticulum disorder. (niiro2012cin85isrequired pages 1-2, kellerUnknownyeargövip18prof.dr. pages 7-9)

8. Temporal development and natural history

Onset was pediatric and likely in early childhood. Patient 1 had severe infections through age four and then a clinically quiescent period despite persistent abnormal immunology. Patient 2 never outgrew the juvenile infection period, developed recurrent sinopulmonary disease, and died at 15. Both were diagnosed with antibody deficiency/genetic disease around later childhood; the index was 12 at molecular investigation. (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 5-7)

The course is therefore chronic lifelong at the molecular level but clinically variable, ranging from early-childhood infections followed by apparent remission to persistent, progressive infectious morbidity. There is no validated staging system, progression rate, critical treatment window, or spontaneous-remission rate. Early identification before irreversible lung disease or sepsis is the most defensible intervention window, but this is clinical inference rather than disease-specific trial evidence.

9. Inheritance and population

Inheritance is X-linked recessive/hemizygous loss of function. Two males were affected; their carrier mother was clinically asymptomatic, and a healthy half-brother lacked the deletion. Penetrance among carrier females, skewed X-inactivation, and reproductive fitness are unknown. Expressivity among affected males is demonstrably variable. There is no evidence of anticipation. (kellerUnknownyeargövip18prof.dr. pages 4-5)

Prevalence and incidence cannot be calculated: the disease-specific evidence comprises one family and two affected males. No ethnicity, founder population, geographic enrichment, carrier frequency, sex ratio beyond X-linked expectation, or consanguinity effect is established. The original family was evaluated in German centers, which indicates ascertainment location rather than ancestry or geographic risk. (kellerUnknownyeargövip18prof.dr. pages 1-4, kellerUnknownyeargövip18prof.dr. pages 4-5)

10. Diagnostics

Clinical and immunologic workup

Suspect the disorder in a boy with recurrent bacterial sinopulmonary infections, low IgM and IgG2/IgG4 or broader hypogammaglobulinemia, impaired pneumococcal-polysaccharide responses, and relatively preserved circulating B cells. Initial tests should include complete blood count/differential; quantitative IgG, IgA, IgM; IgG subclasses; lymphocyte subsets; B-cell maturation subsets; baseline and post-vaccination antigen-specific antibodies; and assessment for secondary causes of hypogammaglobulinemia. Disease-specific functional support includes BCR-induced Ca²⁺ flux, IκBα degradation/p65 phosphorylation, and CIN85 immunoblotting in a specialist laboratory. (kellerUnknownyeargövip18prof.dr. pages 5-7, kellerUnknownyeargövip18prof.dr. pages 7-9, edwards2021beyondmonogeneticrare pages 8-9)

Genetic testing

The defining deletion was detected by array comparative genomic hybridization, verified by quantitative PCR, and confirmed functionally by absent CIN85 protein. Because ordinary WES may miss multiexon CNVs, a practical strategy is an inborn-error-of-immunity/antibody-deficiency panel that includes SH3KBP1 and validated CNV calling, followed by deletion/duplication analysis, CMA, or genome sequencing if negative. WGS is attractive for breakpoint resolution; single-gene sequencing alone is insufficient if it lacks dosage analysis. Karyotyping and FISH are generally low-yield for a 247.5-kb lesion unless a targeted probe is specifically designed. Mitochondrial and repeat-expansion testing are not relevant. (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 10-11)

RNA sequencing could establish transcript loss or aberrant splicing for novel variants, while protein and stimulated-pathway assays can help satisfy functional pathogenicity criteria. No validated liquid-biopsy, metabolomic, proteomic, or epigenomic diagnostic exists.

Differential diagnoses include BTK-related X-linked agammaglobulinemia, CD19/CD81/CD21 deficiency, NFKB1/NFKB2 deficiency, TACI/BAFF-R defects, CARD11/BLNK defects, ARHGEF1 deficiency, and nonmonogenic CVID. Preserved B-cell numbers, selective IgM/IgG2/4 and polysaccharide-response deficiency, and the characteristic BCR→NF-κB defect favor SH3KBP1 deficiency over BTK-related XLA. Recent antibody-deficiency reviews continue to list SH3KBP1 deficiency as IgM/IgG deficiency with severe bacterial infection, but no standardized disease-specific diagnostic criteria exist. (amirifar2021knownandpotential pages 9-10, szaflarska2024clinicalandexperimental pages 4-5)

Family testing should include the mother and at-risk maternal relatives; prenatal or preimplantation testing is technically possible once the familial deletion is defined. Newborn TREC screening would likely miss this predominantly humoral defect because T-cell development is intact; no population newborn screen exists. (kellerUnknownyeargövip18prof.dr. pages 9-10)

11. Outcome and prognosis

Observed survival ranged from survival with clinical improvement at age 12 to death at 15. A 5- or 10-year survival rate, life expectancy, mortality rate, and disease-specific disability burden cannot be estimated. The fatal pathway was bilateral pneumonia → septic shock → multiorgan failure. Potential long-term bronchiectasis is biologically and review-supported for SH3KBP1 deficiency, but the defining family report did not provide imaging-based bronchiectasis details. (kellerUnknownyeargövip18prof.dr. pages 4-5, amirifar2021knownandpotential pages 9-10)

Likely prognostic factors are depth of immunoglobulin loss, frequency/severity of infections, vaccine-response failure, and established lung damage; none is validated in a cohort. Patient 2’s undetectable IgG/IgA and persistent infection suggest that broader antibody loss may mark worse prognosis, but this is an n=1 comparison. No prognostic biomarker or QoL instrument has been validated.

12. Treatment and applications

No controlled or disease-specific treatment study, response rate, pharmacogenomic guidance, HSCT series, gene therapy, RNA therapy, or SH3KBP1-targeted clinical trial was identified. A 2024 review accordingly listed treatment for SH3KBP1/CIN85 deficiency as not available, meaning no disorder-specific evidence—not that supportive antibody-deficiency care should be withheld. (szaflarska2024clinicalandexperimental pages 4-5)

A rational clinical approach, extrapolated from predominantly antibody deficiencies, is:

  1. Prompt culture-directed antimicrobial therapy for infections and consideration of antibacterial prophylaxis if infections recur.
  2. Immunoglobulin replacement therapy (IgRT) when clinically significant infections coexist with substantial IgG deficiency or impaired specific-antibody production. Contemporary humoral-immunodeficiency practice uses approximately 0.4–0.5 g/kg every four weeks IV or 0.1 g/kg weekly SC, individualized to infection control and trough IgG. Across CVID—not specifically SH3KBP1 deficiency—pneumonia incidence fell about 27% for each 100-mg/dL increase in trough IgG. (szaflarska2024clinicalandexperimental pages 5-6)
  3. Pulmonary surveillance, including spirometry and chest imaging when indicated, plus ENT care and airway-clearance therapy if chronic suppurative disease/bronchiectasis develops.
  4. Avoid empirical immunosuppression unless a documented inflammatory/autoimmune indication exists; none was disease-specific in the reported family.

Suggested NCIt intervention concepts are Immunoglobulin Replacement Therapy, Intravenous Immunoglobulin, Subcutaneous Immunoglobulin, Antibiotic Therapy, Antimicrobial Prophylaxis, and Genetic Counseling. Exact NCIt codes should be resolved against the current release. HSCT is not established and is difficult to justify for an isolated B-cell signaling defect manageable with supportive care; gene replacement/editing remains preclinical. No relevant NCT identifier was found.

13. Prevention

The genotype cannot be prevented through lifestyle modification. Primary prevention consists of reproductive genetic counseling, carrier testing, and optional prenatal/preimplantation diagnosis. Secondary prevention consists of cascade testing and early immunologic assessment of at-risk male infants before severe infection. Tertiary prevention includes IgRT when indicated, prompt antibiotics, prophylaxis in selected patients, respiratory surveillance, airway clearance, and avoidance of delayed pneumonia treatment.

Vaccination should be individualized by an immunologist. Inactivated vaccines are generally useful and anti-tetanus response was preserved, but pneumococcal-polysaccharide responses may be inadequate and should be measured. The literature does not define live-vaccine safety specifically; preserved T cells are reassuring, but decisions should reflect the complete immune phenotype rather than the disease label alone. Household vaccination and routine infection-control practices are sensible but untested specifically. (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 9-10)

14. Other species and natural disease

No naturally occurring veterinary counterpart, breed predisposition, zoonotic transmission, or cross-species infectious transmission of this genetic disorder was identified. The orthologous murine gene is commonly styled Sh3kbp1/Cin85; mouse is NCBI Taxon 10090, human Taxon 9606. Exact ortholog Gene IDs and VBO terms should be obtained directly from NCBI/Alliance before database loading.

The mechanism is evolutionarily conserved sufficiently for murine B-cell deletion to reproduce impaired T-independent antibody responses, but species differences are important: murine work emphasizes IgM/IgG3 and peritoneal B-1 cells, whereas human disease showed IgM/IgG2/IgG4 and antipneumococcal abnormalities. (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 5-7)

15. Model organisms and experimental systems

The principal in-vivo model is a conditional B-cell-specific CIN85-deficient mouse. It had almost absent IgM/IgG3 responses to Ficoll-coupled hapten, an approximately 7.5-fold reduction of peritoneal B-1 cells, and largely preserved splenic B-2 development and T-dependent responses. This model strongly recapitulates selective T-independent humoral failure but does not reproduce the full human severity spectrum or prove the existence of an equivalent human B-1-cell defect. Constitutively active IKK-β rescued the mouse T-independent antibody response, placing impaired canonical NF-κB downstream of the CIN85 lesion. (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 5-7, kellerUnknownyeargövip18prof.dr. pages 9-10, kellerUnknownyeargövip18prof.dr. pages 11-12)

Human experimental models include primary patient B cells and CRISPR/Cas9- or TALEN-edited DG75 B-cell lines. Knockout compromised BCR-induced Ca²⁺ flux, and wild-type—but not C-terminally truncated—CIN85 restored signaling, providing orthogonal functional validation. Earlier BJAB/primary B-cell knockdown and overexpression studies mapped interactions with Cbl/BLNK, Syk/PLCγ2 signaling, survival, and differentiation. (niiro2012cin85isrequired pages 1-2, niiro2012cin85isrequired pages 2-3, kellerUnknownyeargövip18prof.dr. pages 7-9, kellerUnknownyeargövip18prof.dr. pages 10-11)

A brain-isoform conditional mouse showed impaired dopamine-receptor endocytosis and hyperactivity. This is only indirect support for the brothers’ ADHD-like phenotype and should not be treated as definitive neurobehavioral disease recapitulation. No rat, zebrafish, Drosophila, organoid, or patient-derived iPSC model was identified. (kellerUnknownyeargövip18prof.dr. pages 4-5, kellerUnknownyeargövip18prof.dr. pages 11-12)

Current understanding and priority knowledge gaps

The most authoritative conclusion is that CIN85 has a nonredundant role in human humoral immunity, selectively connecting BCR engagement to Ca²⁺/PKC-β/canonical NF-κB activation while leaving much of T-cell function and CD40/TLR9 signaling intact. Recent reviews through 2024 continue to recognize SH3KBP1 deficiency, but they have not supplied a larger clinical series or disease-specific therapy. (amirifar2021knownandpotential pages 9-10, szaflarska2024clinicalandexperimental pages 4-5)

High-priority research needs are independent families and variants; ClinGen-level gene curation; penetrance and female-carrier studies; longitudinal infection, lung, autoimmune, malignancy, and QoL outcomes; direct treatment-response data; single-cell characterization of B-cell subsets; and development of patient-derived iPSC or primary B-cell rescue systems. Until these data exist, exact prevalence, phenotype frequencies, prognosis, and optimal therapy must be labeled unknown, not extrapolated from the two reported brothers.

References

  1. (kellerUnknownyeargövip18prof.dr. pages 1-4): B Keller, M Shoukier, K Schulz, A Bhatt, and I Heine. Gö-vip-18: prof. dr. jürgen wienands. Unknown journal, Unknown year.

  2. (kellerUnknownyeargövip18prof.dr. pages 4-5): B Keller, M Shoukier, K Schulz, A Bhatt, and I Heine. Gö-vip-18: prof. dr. jürgen wienands. Unknown journal, Unknown year.

  3. (kellerUnknownyeargövip18prof.dr. pages 5-7): B Keller, M Shoukier, K Schulz, A Bhatt, and I Heine. Gö-vip-18: prof. dr. jürgen wienands. Unknown journal, Unknown year.

  4. (kellerUnknownyeargövip18prof.dr. pages 7-9): B Keller, M Shoukier, K Schulz, A Bhatt, and I Heine. Gö-vip-18: prof. dr. jürgen wienands. Unknown journal, Unknown year.

  5. (kellerUnknownyeargövip18prof.dr. pages 9-10): B Keller, M Shoukier, K Schulz, A Bhatt, and I Heine. Gö-vip-18: prof. dr. jürgen wienands. Unknown journal, Unknown year.

  6. (niiro2012cin85isrequired pages 1-2): Hiroaki Niiro, Siamak Jabbarzadeh-Tabrizi, Yoshikane Kikushige, Takahiro Shima, Kumiko Noda, Shun-ichiro Ota, Hirofumi Tsuzuki, Yasushi Inoue, Yojiro Arinobu, Hiromi Iwasaki, Shinji Shimoda, Eishi Baba, Hiroshi Tsukamoto, Takahiko Horiuchi, Tadayoshi Taniyama, and Koichi Akashi. Cin85 is required for cbl-mediated regulation of antigen receptor signaling in human b cells. Blood, 119 10:2263-73, Mar 2012. URL: https://doi.org/10.1182/blood-2011-04-351965, doi:10.1182/blood-2011-04-351965. This article has 20 citations and is from a highest quality peer-reviewed journal.

  7. (niiro2012cin85isrequired pages 2-3): Hiroaki Niiro, Siamak Jabbarzadeh-Tabrizi, Yoshikane Kikushige, Takahiro Shima, Kumiko Noda, Shun-ichiro Ota, Hirofumi Tsuzuki, Yasushi Inoue, Yojiro Arinobu, Hiromi Iwasaki, Shinji Shimoda, Eishi Baba, Hiroshi Tsukamoto, Takahiko Horiuchi, Tadayoshi Taniyama, and Koichi Akashi. Cin85 is required for cbl-mediated regulation of antigen receptor signaling in human b cells. Blood, 119 10:2263-73, Mar 2012. URL: https://doi.org/10.1182/blood-2011-04-351965, doi:10.1182/blood-2011-04-351965. This article has 20 citations and is from a highest quality peer-reviewed journal.

  8. (niiro2012cin85isrequired pages 3-4): Hiroaki Niiro, Siamak Jabbarzadeh-Tabrizi, Yoshikane Kikushige, Takahiro Shima, Kumiko Noda, Shun-ichiro Ota, Hirofumi Tsuzuki, Yasushi Inoue, Yojiro Arinobu, Hiromi Iwasaki, Shinji Shimoda, Eishi Baba, Hiroshi Tsukamoto, Takahiko Horiuchi, Tadayoshi Taniyama, and Koichi Akashi. Cin85 is required for cbl-mediated regulation of antigen receptor signaling in human b cells. Blood, 119 10:2263-73, Mar 2012. URL: https://doi.org/10.1182/blood-2011-04-351965, doi:10.1182/blood-2011-04-351965. This article has 20 citations and is from a highest quality peer-reviewed journal.

  9. (kellerUnknownyeargövip18prof.dr. pages 11-12): B Keller, M Shoukier, K Schulz, A Bhatt, and I Heine. Gö-vip-18: prof. dr. jürgen wienands. Unknown journal, Unknown year.

  10. (kellerUnknownyeargövip18prof.dr. pages 10-11): B Keller, M Shoukier, K Schulz, A Bhatt, and I Heine. Gö-vip-18: prof. dr. jürgen wienands. Unknown journal, Unknown year.

  11. (OpenTargets Search: Immunodeficiency 61-SH3KBP1): Open Targets Query (Immunodeficiency 61-SH3KBP1, 0 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  12. (edwards2021beyondmonogeneticrare pages 8-9): Emily S. J. Edwards, Julian J. Bosco, Samar Ojaimi, Robyn E. O’Hehir, and Menno C. van Zelm. Beyond monogenetic rare variants: tackling the low rate of genetic diagnoses in predominantly antibody deficiency. Cellular & Molecular Immunology, 18:588-603, Aug 2021. URL: https://doi.org/10.1038/s41423-020-00520-8, doi:10.1038/s41423-020-00520-8. This article has 46 citations and is from a peer-reviewed journal.

  13. (amirifar2021knownandpotential pages 9-10): Parisa Amirifar, Reza Yazdani, Gholamreza Azizi, Mohammad Reza Ranjouri, Anne Durandy, Alessandro Plebani, Vassilios Lougaris, Lennart Hammarstrom, Asghar Aghamohammadi, and Hassan Abolhassani. Known and potential molecules associated with altered b cell development leading to predominantly antibody deficiencies. Pediatric Allergy and Immunology, 32:1601-1615, Jul 2021. URL: https://doi.org/10.1111/pai.13589, doi:10.1111/pai.13589. This article has 22 citations and is from a domain leading peer-reviewed journal.

  14. (szaflarska2024clinicalandexperimental pages 4-5): Anna Szaflarska, Marzena Lenart, Magdalena Rutkowska-Zapała, and Maciej Siedlar. Clinical and experimental treatment of primary humoral immunodeficiencies. Clinical and Experimental Immunology, 216:120-131, Feb 2024. URL: https://doi.org/10.1093/cei/uxae008, doi:10.1093/cei/uxae008. This article has 8 citations and is from a peer-reviewed journal.

  15. (szaflarska2024clinicalandexperimental pages 5-6): Anna Szaflarska, Marzena Lenart, Magdalena Rutkowska-Zapała, and Maciej Siedlar. Clinical and experimental treatment of primary humoral immunodeficiencies. Clinical and Experimental Immunology, 216:120-131, Feb 2024. URL: https://doi.org/10.1093/cei/uxae008, doi:10.1093/cei/uxae008. This article has 8 citations and is from a peer-reviewed journal.

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