1. Disease Information

Overview. Immunodeficiency 102 (IMD102) is an X-linked recessive combined immunodeficiency with immune dysregulation caused by hemizygous loss-of-function variants in SASH3 (SAM and SH3 domain containing 3, also called SLY1, "SH3 protein expressed in lymphocytes 1"), a lymphocyte-restricted signalling adaptor. Affected males present in early childhood with recurrent sinopulmonary, cutaneous and mucosal infections, and most develop refractory autoimmune cytopenias (autoimmune hemolytic anemia, immune thrombocytopenia). The defining laboratory picture is CD4+ T-cell lymphopenia with impaired T-cell proliferation, B- and NK-cell lymphopenia, loss of class-switched memory B cells, low IgM, and — unexpectedly for a lymphocyte-restricted gene — neutropenia.

The index description is Delmonte et al., Blood 2021 (PMID:33876203): "Here, we identified 3 novel SASH3 deleterious variants in 4 unrelated male patients with a history of combined immunodeficiency and immune dysregulation that manifested as recurrent sinopulmonary, cutaneous, and mucosal infections and refractory autoimmune cytopenias." The authors concluded: "These findings define a new type of X-linked combined immunodeficiency in humans that recapitulates many of the abnormalities reported in mice with Sly1−/− and Sly1Δ/Δ mutations."

Identifiers.

Synonyms: IMD102; SASH3 deficiency; SLY1 deficiency; X-linked combined immunodeficiency due to SASH3 deficiency; X-linked CID due to SASH3 deficiency.

Data provenance: all human information is aggregated from published individual patients (index cohort of 4, plus single case reports) — there is no registry, EHR cohort, or natural-history study.

2. Etiology

Causal factor (single, genetic): hemizygous germline loss-of-function variants in SASH3 on Xq26.1. Four variant types reported worldwide as of 2025 (tabulated in PMID:40947476): three nonsense — c.505C>T p.(Gln169*), c.733C>T p.(Arg245*), c.862C>T p.(Arg288*) — and one missense, c.1039C>T p.(Arg347Cys). Arg347 is conserved from Xenopus to human and sits in a putative protein-kinase-A-binding motif adjacent to the Ser349 phosphorylation site, which is the proposed reason a single missense substitution behaves like a null (structural modelling; COMPUTATIONAL evidence).

Risk factors: male sex (all reported patients are hemizygous males); maternal carrier status — "This pathogenic variant was inherited from the mother, who carries the same variant in the heterozygous state" (PMID:40947476). No environmental risk, protective factors, or gene–environment interactions are documented; the disease is fully Mendelian. Penetrance is incomplete or expressivity highly variable: one hemizygous brother carrying p.Arg288* "shares immunophenotypic features but is currently clinical asymptomatic, indicating heterogeneity of SASH3 deficiency" (PMID:37646304).

3. Phenotypes

All frequencies are qualitative — the denominator is ~12 reported patients. Onset of infections is early childhood; the oldest reported patient reached age 56 (index cohort ages 19–56, PMID:33876203).

Research Report: Immunodeficiency 102 (IMD102; SASH3 Deficiency)

MONDO:0024781 · OMIM #301082 · ORPHA:653751 · Gene: SASH3 (Xq26.1) Report date: 2026-09-19. Note on the evidence base: this disease was first described in 2021 and the entire published human literature comprises roughly a dozen patients across one four-patient index cohort and a handful of single case reports. Nearly every claim below therefore rests on small-n human data or on the Sly1-deficient mouse, and the report flags which is which throughout.

1. Disease Information

Overview. Immunodeficiency 102 (IMD102) is an X-linked recessive combined immunodeficiency with immune dysregulation caused by hemizygous loss-of-function variants in SASH3 (SAM and SH3 domain containing 3, also called SLY1, "SH3 protein expressed in lymphocytes 1"), a lymphocyte-restricted signalling adaptor. Affected males present in early childhood with recurrent sinopulmonary, cutaneous and mucosal infections, and most develop refractory autoimmune cytopenias (autoimmune hemolytic anemia, immune thrombocytopenia). The defining laboratory picture is CD4+ T-cell lymphopenia with impaired T-cell proliferation, B- and NK-cell lymphopenia, loss of class-switched memory B cells, low IgM, and — unexpectedly for a lymphocyte-restricted gene — neutropenia.

The index description is Delmonte et al., Blood 2021 (PMID:33876203): "Here, we identified 3 novel SASH3 deleterious variants in 4 unrelated male patients with a history of combined immunodeficiency and immune dysregulation that manifested as recurrent sinopulmonary, cutaneous, and mucosal infections and refractory autoimmune cytopenias." The authors concluded: "These findings define a new type of X-linked combined immunodeficiency in humans that recapitulates many of the abnormalities reported in mice with Sly1−/− and Sly1Δ/Δ mutations."

Identifiers.

Synonyms: IMD102; SASH3 deficiency; SLY1 deficiency; X-linked combined immunodeficiency due to SASH3 deficiency; X-linked CID due to SASH3 deficiency.

Data provenance: all human information is aggregated from published individual patients (index cohort of 4, plus single case reports) — there is no registry, EHR cohort, or natural-history study.

2. Etiology

Causal factor (single, genetic): hemizygous germline loss-of-function variants in SASH3 on Xq26.1. Four variant types reported worldwide as of 2025 (tabulated in PMID:40947476): three nonsense — c.505C>T p.(Gln169*), c.733C>T p.(Arg245*), c.862C>T p.(Arg288*) — and one missense, c.1039C>T p.(Arg347Cys). Arg347 is conserved from Xenopus to human and sits in a putative protein-kinase-A-binding motif adjacent to the Ser349 phosphorylation site, which is the proposed reason a single missense substitution behaves like a null (structural modelling; COMPUTATIONAL evidence).

Risk factors: male sex (all reported patients are hemizygous males); maternal carrier status — "This pathogenic variant was inherited from the mother, who carries the same variant in the heterozygous state" (PMID:40947476). No environmental risk, protective factors, or gene–environment interactions are documented; the disease is fully Mendelian. Penetrance is incomplete or expressivity highly variable: one hemizygous brother carrying p.Arg288* "shares immunophenotypic features but is currently clinical asymptomatic, indicating heterogeneity of SASH3 deficiency" (PMID:37646304).

3. Phenotypes

All frequencies are qualitative — the denominator is ~12 reported patients. Onset of infections is early childhood; the oldest reported patient reached age 56 (index cohort ages 19–56, PMID:33876203).

Supporting quotes: "Patients exhibited CD4+ T-cell lymphopenia, decreased T-cell proliferation, cell cycle progression, and increased T-cell apoptosis in response to mitogens" and "These patients also manifested neutropenia and B-cell and natural killer (NK)-cell lymphopenia" (PMID:33876203). A 2025 case quantified the memory defect precisely: "a considerable reduction in IgM memory B cells (CD19+CD27+IgD+) at 1.6% and switched memory B cells (CD19+CD27+IgD−) at 2.4%" despite normal total B cells and IgG (PMID:40947476).

Severity and course: variable and unpredictable from genotype. The spectrum runs from asymptomatic hemizygous carrier → adult misdiagnosed as CVID for decades ("Our patient displays a milder phenotype than has been reported previously… thus expanding the clinical spectrum", PMID:35464398) → refractory Evans syndrome requiring splenectomy (PMID:37646304). Infections are recurrent/episodic; the autoimmune component is chronic and refractory. Quality-of-life data do not exist for this disease — no EQ-5D, SF-36, or PROMIS study has been published.

Explicitly not curated as phenotypes: one patient had osteogenesis imperfecta, metaphyseal dysplasia, intellectual disability, hearing loss, cleft lip/palate and renal agenesis alongside the immune findings, with no pathogenic variant found in any OI or ID gene — but the reporting authors declined to attribute these to SASH3: "further studies are needed to determine the association between the SASH3 variant and the skeletal or neurological manifestations" (PMID:40947476). No other patient has had them.

4. Genetic / Molecular Information

Gene. SASH3 / SLY1, HGNC:15975, Xq26.1, OMIM *300441. Encodes a 380-aa adaptor with a bipartite nuclear localisation signal, an SH3 domain and a sterile alpha motif (SAM), and no catalytic activity. Expression is lymphocyte-restricted. Delmonte et al.: "SASH3… is a putative adaptor protein that is postulated to play an important role in the organization of signaling complexes and propagation of signal transduction cascades in lymphocytes" (PMID:33876203).

Gene family caution. SASH3 is one of three SLy/SASH family members: "The initial characterization of the first member SLy1/SASH3… in 2001 was rapidly followed by identification of SLy2/HACS1… and SASH1/SLy3" (PMID:33710696). SASH1 is ubiquitously expressed and curated as a tumour suppressor — do not conflate.

Variants. All germline, hemizygous, loss-of-function. Three nonsense + one missense (above). ACMG classification: pathogenic/likely pathogenic in ClinVar for the reported nonsense alleles. Population frequency: absent or vanishingly rare in gnomAD for the reported alleles (consistent with an ultra-rare X-linked disorder); no founder allele has been described and all four reported variants arose in unrelated families.

Functional consequence. Loss of function, confirmed by rescue: "Lentivirus-mediated transfer of the SASH3 complementary DNA-corrected protein expression, in vitro proliferation, and signaling in SASH3-deficient Jurkat and patient-derived T cells" (PMID:33876203) — this rescue experiment is what makes the gene–phenotype link causal rather than correlative.

Modifier genes, epigenetics, chromosomal abnormalities: none reported. No methylation, chromatin, or structural-variant data exist for this disease.

5. Environmental Information

Not applicable as a cause. No environmental, lifestyle, occupational, or toxic contributor is described. Infectious agents are consequences, not causes: bacterial sinopulmonary pathogens, cutaneous bacteria (cellulitis), rotavirus gastroenteritis, influenza A, and varicella zoster virus (VZV, NCBITaxon:10335) have all been reported as complications. The VZV episode is mechanistically informative: "Two separate, severe viral infections drew our attention and pointed to an underlying T cell defect: severe varicella zoster virus (VZV) infection at the age of 4 years and bilateral pneumonia due type A influenza infection at the age of 38" (PMID:35464398).

6. Mechanism / Pathophysiology

Ordered causal chain

1. Hemizygous loss-of-function variant in SASH3 (nonsense, or the Arg347Cys missense in a conserved PKA-binding motif) → absence or non-function of the SASH3 adaptor protein in lymphocytes. Because expression is lymphocyte-restricted, consequences are confined to the lymphoid compartment.
2. Loss of the scaffold → failure of antigen-receptor signal propagation. The adaptor's SH3 and SAM domains normally nucleate signalling complexes downstream of the TCR and BCR; without them, engaged receptors do not couple to their effectors. Demonstrated, not inferred: lentiviral SASH3 restoration rescues signalling in both Jurkat cells and patient T cells (PMID:33876203). In mouse, the molecular event lost is Ser27 phosphorylation and nucleus→cytoplasm shuttling on receptor engagement (PMID:16227612); the human protein has not been localised this way.
3. The chain then branches into four arms:

3a. Thymic arm — signalling failure → thymocyte survival failure at the CD4−CD8− double-negative → CD4+CD8+ double-positive transition → reduced thymic output → CD4+ and total T-cell lymphopenia → severe viral infection (VZV) and the cellular half of the combined defect. Human basis is indirect: "In vitro T-cell differentiation of CD34+ cells and molecular signatures of rearrangements at the T-cell receptor α (TRA) locus were indicative of impaired thymocyte survival" (PMID:33876203) — an in vitro differentiation assay plus a rearrangement signature, not thymic tissue. The staging comes from mouse: "SLY1 was identified as a novel anti-apoptotic protein required for developmental progression of T cell precursors to the CD4+CD8+ double-positive stage by protecting from premature programmed cell death initiation in developing CD4−CD8− double-negative thymocytes" (PMID:19604361), with the proximate cause being failed mTOR activation — "SLY1-deficient thymocytes were compromised in inducing nutrient receptor expression and ribosomal protein S6 phosphorylation, indicating a defect in mTOR complex activation." A later knockout study added reduced DN3 proliferation as a second contributor (PMID:36401605).

3b. Peripheral T-cell arm — signalling failure → defective proliferation, impaired cell-cycle progression and increased activation-induced apoptosis in mature peripheral T cells (measured directly in patient cells, PMID:33876203; independently confirmed in PMID:35464398 and PMID:37646304). Mouse-only mechanism: dysregulated Foxo1 shuttling after TCR signalling raises cell-cycle inhibitor expression — "The increased susceptibility of SLy1 knock-out (KO) mice was caused by reduced proliferation of differentiated T cells" (PMID:26306874). Whether the human proliferative defect runs through Foxo1 is untested.

3c. Humoral arm — BCR signalling failure (cell-intrinsic) plus loss of cognate T-cell help from arm 3b → impaired germinal centre reaction → loss of class-switched and IgM memory B cells, low IgM, poor polysaccharide vaccine responses → recurrent sinopulmonary and cutaneous infection. The only direct human histology: "Immunohistochemistry performed after clinically indicated splenectomy revealed severe hypoplasia/absence of germinal centres" (PMID:37646304). Mouse counterpart is adjacent but not identical — a marginal-zone rather than germinal-centre lesion: "Sly1(d/d) mice exhibit reduced lymphoid organ sizes, diminished marginal zone B-cell numbers, and severely impaired antibody responses against T-dependent and -independent antigens" (PMID:16227612), driven by reduced Notch activity, with "the production of antigen-specific IgM antibodies following immunization with pneumococcal polysaccharides was severely impaired" (PMID:18950867).

3d. NK arm — a mechanistically separate branch. NK cells are reduced in most patients, but the route is not established in humans and may not share a mechanism with arms 3a–3c. In mouse, SLy1 in NK cells is not a signalling scaffold at all: "Unlike the case for T or B lymphocytes, where SLy1 shuttles between the cytoplasm and nucleus to facilitate signal transduction, in NK cells SLy1 functions as a ribosomal protein and is located solely in the cytoplasm" (PMID:28123874), and "In its absence, ribosomal instability results in p53-mediated NK cell senescence and decreased clearance of malignancies." A 2026 follow-up confirms the functional consequence: "SLy1 is indispensable for adequate numbers of viable, activatable NK cells with an intact cytolytic capacity, and that those phenotypic alterations are p53-mediated" (PMID:42327758).

1. Convergent branch: breakdown of peripheral tolerance → refractory autoimmune hemolytic anemia and immune thrombocytopenia (Evans syndrome). Association reported, causal steps unknown: "The autoimmune phenotype was associated with an increased CD21low T-bet+ CD11c+ subset along with decreased regulatory T cells, impaired T-cell proliferation and T-cell exhaustion" (PMID:37646304). Both a thymic selection defect and the Treg deficit are plausible routes; neither has been tested against the other in patients.

2. Unexplained: neutropenia. This does not follow from the chain above and should not be forced into it. SASH3 expression is lymphocyte-restricted, so a neutrophil-intrinsic effect has no obvious basis; autoimmune destruction — the usual alternative in an immune-dysregulation disorder — has not been demonstrated in any reported patient; and no Sly1 mouse study reports neutropenia. Yet the phenotype is prominent enough that SASH3 surfaces in congenital-neutropenia sequencing cohorts: "Half of these cases involved genes traditionally associated with hereditary immunodeficiencies (GINS4, CARD11, ADA2, GINS1, LCP1, SASH3, and WAS)" (PMID:40510848). This is an open knowledge gap, and the honest position is that the mechanism is unknown.

Ontology annotations for the mechanism

Cell types: T cell CL:0000084; CD4-positive αβ T cell CL:0000624; B cell CL:0000236; class-switched memory B cell CL:0000972; NK cell CL:0000623; thymocyte CL:0000893; double-negative thymocyte CL:0002489; regulatory T cell CL:0000815.

Molecular profiling. No disease-specific transcriptomic, proteomic, metabolomic, lipidomic, single-cell, or spatial dataset has been published for IMD102 patients. The available functional-genomics analogue is the Sly1 mouse ribosome work (PMID:28123874). This is a genuine gap, not an omission from this report.

7. Anatomical Structures Affected

• Primary organs/systems: immune system; thymus (UBERON:0002370) — site of the developmental block; spleen (UBERON:0002106) — germinal centre hypoplasia documented histologically; bone marrow (UBERON:0002371) — neutropenia, mechanism unknown; peripheral blood/lymphoid tissue generally.
• Secondary involvement: respiratory tract (recurrent sinopulmonary infection — lung UBERON:0002048, nasal/paranasal sinuses UBERON:0001825), skin (UBERON:0002097), mucosae, and hematologic system (immune-mediated destruction of erythrocytes and platelets).
• Cell populations: as listed in §6. Note the dissociation — the target is a cell lineage set, not an anatomical site; damage to spleen and thymus is developmental/architectural rather than destructive.
• Subcellular: cytoplasm (GO:0005737) and nucleus (GO:0005634) — the mouse protein shuttles between them on receptor engagement; in NK cells (mouse) it is cytoplasmic and ribosome-associated (GO:0022626, cytosolic ribosome).
• Lateralization: not applicable (systemic).

8. Temporal Development

Onset: early childhood for infections in most patients (OMIM describes onset of recurrent infections in early childhood). One case was ascertained in adulthood after decades under a CVID label; one hemizygous carrier remains asymptomatic into adulthood. Onset pattern is insidious and recurrent rather than acute.

Course: chronic and lifelong. Infections are episodic; autoimmune cytopenias are chronic and refractory — the index cohort's use of that word is itself informative, since a cytopenia is called refractory only after therapy has failed to hold. No staging system exists. Progression rate is not characterized: there is no natural-history study, no longitudinal cohort, and no registry. The oldest reported patient was 56 years old at description (PMID:33876203), so survival into the sixth decade is documented.

Critical periods / remission: no data. Spontaneous remission has not been reported; treatment-induced remission of cytopenias is inconsistent (hence "refractory"), and one patient required splenectomy.

9. Inheritance and Population

Inheritance: X-linked recessive (HP:0001419). "The SASH3 gene is located on the X-chromosome" (PMID:33876203); all reported patients are hemizygous males. The one family in which parental origin was established showed maternal heterozygous carriage (PMID:40947476). Heterozygous female carriers have not been reported as affected, though the number of carriers examined is very small and skewed X-inactivation has not been studied.

Penetrance / expressivity: incomplete penetrance or extremely variable expressivity is documented — the asymptomatic hemizygous brother sharing p.Arg288* with an Evans-syndrome proband (PMID:37646304) is the key observation. No genetic anticipation (not a repeat disorder); no germline mosaicism reported; no founder effect; no consanguinity role (X-linked); no carrier-frequency estimate exists.

Epidemiology: Orphanet classifies prevalence as <1 / 1,000,000 (ultra-rare). No incidence figure exists and none should be asserted. For scale on the denominator, a dedicated sequencing program for suspected inborn errors of immunity covering 1,505 individuals from 1,000 families returned SASH3 in two: "Specifically, these included individuals with pathogenic variants in GIMAP5 (n = 2) and SASH3 (n = 2)" (PMID:35753512) — a yield within a heavily enriched referral population, not a population prevalence. The 2022 IUIS classification recognised five reported patients (PMID:35748970); counts in the literature overlap and no authoritative worldwide total has been published.

Demographics: sex ratio effectively 100% male among affected individuals (X-linked recessive). No ethnic or geographic clustering has been reported; the four index patients were unrelated and no variant is population-specific.

10. Diagnostics

Laboratory. The diagnostic core is lymphocyte immunophenotyping plus functional testing: - Full blood count with differential — cytopenias across lineages including neutropenia - Lymphocyte subsets by flow cytometry — CD4+ and total T-cell lymphopenia, B-cell lymphopenia, NK lymphopenia, reduced naïve CD4+/CD8+ with elevated TEMRA, reduced pre-switch and switched memory B cells (CD19+CD27+IgD+ and CD19+CD27+IgD−) - Serum immunoglobulins — hypogammaglobulinemia, frequently with disproportionately low IgM - T-cell proliferation assays to mitogens/anti-CD3 — reduced, with impaired cell-cycle progression and increased apoptosis - Specific antibody responses, including pneumococcal polysaccharide — suboptimal - TREC/TRA rearrangement analysis — the TRA rearrangement signature is what reports thymocyte survival (PMID:33876203)

Relevant LOINC-coded measurements: CD4 count, CD19 count, CD56/CD16 NK count, absolute neutrophil count, quantitative IgG/IgA/IgM.

Genetic testing is required for diagnosis; the phenotype is not specific. Reported routes: NGS custom-targeted immunodeficiency gene panel ("Genetic testing using an NGS-based custom-targeted gene panel revealed a novel hemizygous loss-of-function variant in the SASH3 gene (c.505C>T/p.Gln169*)", PMID:35464398), clinical exome sequencing (PMID:35753512), and whole-exome/whole-genome sequencing in congenital-neutropenia workups (PMID:40510848). Practical recommendation: SASH3 should be on any IEI panel used to evaluate combined immunodeficiency, CVID-like presentations, Evans syndrome, or unexplained congenital neutropenia in a male. Karyotype, CMA, FISH, mtDNA and repeat-expansion testing have no role. Functional confirmation by lentiviral rescue of patient T cells exists as a research assay (PMID:33876203) but is not a clinical test.

Histopathology: splenic immunohistochemistry showing germinal centre hypoplasia/absence has been documented once, after clinically indicated splenectomy (PMID:37646304) — informative but not a diagnostic route.

Differential diagnosis. This is the clinically important point: IMD102 is systematically misdiagnosed. The published differentials are (a) common variable immunodeficiency — one patient carried that label for decades until two severe viral infections redirected attention to a T-cell defect (PMID:35464398); (b) Evans syndrome / other IEI with immune dysregulation — "Increasing evidence suggests multilineage cytopenias (also known as Evans syndrome) may be caused by inborn errors of immunity (IEI) with immune dysregulation" (PMID:37646304); (c) severe congenital neutropenia (PMID:40510848); (d) other X-linked CIDs, ALPS, CTLA4/LRBA haploinsufficiency. Distinguishing features favouring SASH3: male sex with X-linked pedigree, the combination of CD4 lymphopenia plus NK lymphopenia plus neutropenia, and refractory autoimmune cytopenias.

Screening: no newborn screening program detects this disease. TREC-based SCID newborn screening has not been reported to identify a SASH3 patient and should not be assumed to — the T-cell defect is partial. Cascade family testing for the familial variant is appropriate once a proband is identified, and should be offered to at-risk male relatives (who may be asymptomatic) and female relatives (carrier status).

11. Outcome / Prognosis

There are no survival, mortality, or quality-of-life data for this disease. No 5- or 10-year survival figure, no life-expectancy estimate, no disease-specific mortality rate has been published. Survival into the sixth decade is documented (index cohort included a 56-year-old).

Burden is best characterized as variable. The reported range runs from an asymptomatic hemizygous brother, through an adult managed for decades as CVID with two severe viral episodes, to refractory autoimmune cytopenias requiring splenectomy. Recurrent sinopulmonary, cutaneous and mucosal infection is the common thread, and the immune dysregulation rather than the infection burden drives the most severe presentations. Two independent author groups state the heterogeneity explicitly (PMID:37646304; PMID:35464398).

Complications: recurrent bacterial and viral infection with hospitalisation; refractory cytopenias; splenectomy and its own lifelong infection risk. A theoretical malignancy concern arises from the mouse NK ribosomopathy work ("decreased clearance of malignancies", PMID:28123874) and from the Sly1 knockout tumour data (PMID:36401605), but no malignancy has been reported in a SASH3-deficient patient and this should not be presented to patients as an established risk.

Prognostic factors and biomarkers: none validated. Genotype does not predict phenotype — the same nonsense allele produced Evans syndrome in one brother and no disease in another.

12. Treatment

No published series reports treatment outcomes in SASH3 deficiency. Everything below is standard management of a combined immunodeficiency with this phenotype, with the disease-specific evidence stated honestly.

Hematopoietic stem cell transplantation is the obvious curative candidate for a combined immunodeficiency, and it is conspicuously absent from the literature: no reported SASH3 patient has been described as transplanted. The full texts of the human SASH3 papers were searched for "transplant", "HSCT" and "stem cell" with no hit relevant to these patients. Asserting HSCT as established therapy here would be inventing a treatment record — though it is a reasonable consideration for a severely affected patient in a specialist multidisciplinary setting, and gene therapy is mechanistically plausible given that lentiviral SASH3 transfer rescues patient T cells in vitro (PMID:33876203).

No pharmacogenomic, targeted, RNA-based, or immunotherapy data exist. No clinical trial (ClinicalTrials.gov or ICTRP) is registered for this disease.

13. Prevention

Primary prevention of the genetic lesion is not possible. Preventive management is therefore secondary and tertiary:

• Genetic counseling and cascade testing in affected families — the maternal carrier state is documented and X-linked recurrence risk (50% of sons affected, 50% of daughters carriers) applies. Prenatal diagnosis and preimplantation genetic testing are technically available for a known familial variant; no published case describes their use here.
• Early diagnosis is the single highest-yield intervention, because the disease is systematically mislabelled as CVID, Evans syndrome, or congenital neutropenia. Including SASH3 on IEI panels is the practical measure.
• Infection prophylaxis and immunoglobulin replacement as tertiary prevention (see §12).
• Immunization: routine inactivated vaccines are appropriate; live vaccines require caution in a combined immunodeficiency with documented severe VZV — though no SASH3-specific vaccine guidance has been published, and the general IEI principle is what applies.
• No behavioural, dietary, environmental, or public-health intervention is relevant.

14. Other Species / Natural Disease

No naturally occurring animal disease corresponding to SASH3 deficiency has been described. There is no OMIA entry, no companion-animal or wildlife counterpart, no breed predisposition (no VBO term applies), no zoonotic or cross-species transmission dimension.

Orthologs: mouse Sash3/Sly1 (MGI:1921381, NCBI Gene 74131) — the deduced mouse and human proteins contain 381 and 380 amino acids respectively and share 94% sequence identity, which is the basis for treating the mouse as an informative model. A zebrafish ortholog sash3 exists (ZFIN ZDB-GENE-130411-1) but no disease model has been published in that species. The gene is lymphocyte-restricted across species, and the lymphoid function appears evolutionarily conserved.

15. Model Organisms

Two mouse models carry the entire mechanistic literature. Note the chronology: the Sly1 mouse work begins in 2005, sixteen years before the human disease was described in 2021, and remains the larger literature.

(a) Sly1 knockout mouse (complete null, whole-body) — MGI; principal reference PMID:19604361. - Recapitulates thymocyte survival failure (fidelity MODERATE): thymic cellularity falls by roughly half with a block at the DN→DP transition driven by premature programmed cell death; readout is decreased ribosomal protein S6 phosphorylation and nutrient-receptor induction, read as failed mTOR activation. - Recapitulates the peripheral T-cell proliferative defect (fidelity MODERATE), via Foxo1 (PMID:26306874). - Partially recapitulates the NK phenotype (fidelity LOW): numbers, viability and cytotoxicity match the patients, but the molecular route does not transfer — in mouse the mechanism is ribosomal instability and p53-mediated senescence (PMID:28123874; PMID:42327758), and no human study has tested whether SASH3 has a ribosomal role in human NK cells. - Additional finding: knockout protects mice from p53-induced tumour formation and decreases DN thymocyte proliferation (PMID:36401605).

(b) Sly1Δ/Δ N-terminal deletion mouse (81-aa deletion removing Ser27 and part of the NLS; the truncated protein is confined to the cytoplasm) — PMID:16227612. This is the source of the humoral data: partially recapitulates the germinal-centre/memory-B-cell defect (fidelity MODERATE) with reduced lymphoid organ size, loss of marginal-zone B cells, and severely impaired T-dependent and T-independent antibody responses, including the pneumococcal polysaccharide IgM response (PMID:18950867), mediated by reduced Notch activity. It also showed prolonged allograft survival.

Model limitations — three that matter for interpretation: 1. Thymic staging is unconfirmed in humans. The human block is inferred from in vitro CD34+ differentiation and a TRA rearrangement signature, never from thymic tissue. 2. Compartment mismatch in the humoral arm. The mouse lesion is at the marginal-zone B-cell transition; the single human histological observation is germinal-centre hypoplasia in spleen. Marginal-zone B cells and their Notch dependence are much better defined in mouse than in human, so the lesions are adjacent but not equivalent, and no patient has been studied for a marginal-zone defect. 3. The NK mechanism may not transfer at all (see above) — this is a genuine human/model mismatch, not merely a fidelity caveat. 4. The mouse models are a complete null and a designed hypomorph; one human variant is missense. And no Sly1 mouse reports neutropenia, the one human phenotype that most needs a model.

Other model systems: SASH3-deficient Jurkat T cells and patient-derived primary T cells with lentiviral rescue are the established in vitro system (PMID:33876203); in vitro T-cell differentiation of patient CD34+ progenitors is the human developmental assay. No iPSC, organoid, organ-chip, zebrafish, or Drosophila model has been published. No CRISPR or RNAi screen has targeted this disease.

Evidence Base Summary and Caveats

Three things this report deliberately does not claim. (1) A worldwide patient count — the published counts overlap and no source states a total. (2) A mechanism for the neutropenia — both candidate explanations are untested, and the honest curation is an open knowledge gap rather than an invented causal edge. (3) That the mouse NK ribosomopathy operates in human patients — it is a well-worked-out mouse mechanism with a matching human phenotype and no human mechanistic data, which is a different epistemic state from a validated model.

Sources: - OMIM #301082 — IMMUNODEFICIENCY 102; IMD102 - OMIM *300441 — SAM- AND SH3 DOMAIN-CONTAINING PROTEIN 3; SASH3 - Orphanet: X-linked combined immunodeficiency due to SASH3 deficiency (ORPHA:653751) - UniProt O75995 — SAM and SH3 domain-containing protein 3 - MGI:1921381 — Sash3 (mouse) - Delmonte et al., Blood 2021 (PMID:33876203) - Case Report: X-Linked SASH3 Deficiency Presenting as a Common Variable Immunodeficiency (PMID:35464398) - Osteogenesis imperfecta, intellectual disability and recurrent infections in a male with a pathogenic SASH3 variant (PMID:40947476) - GeneCards: SASH3 - ZFIN: sash3

Reference Validation

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All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• NCIT:C15329 (1 mention) - the report calls it "Splenectomy"; NCIT calls it Surgical Procedure

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• HP:0002850 (1 mention) - the report calls it "Decreased circulating total IgM"; HP calls it Decreased circulating IgM concentration
• GO:0035591 (1 mention) - the report calls it "Signalling adaptor activity (lost)"; GO calls it signaling adaptor activity, and lists "signalling adaptor activity" among its other names
• GO:0042267 (1 mention) - the report calls it "NK cell mediated cytotoxicity (↓)"; GO calls it natural killer cell mediated cytotoxicity, and lists "NK cell mediated cytotoxicity" among its other names
• GO:0050776 (1 mention) - the report calls it "Regulation of immune response (dysregulated)"; GO calls it regulation of immune response
• GO:0005737 (1 mention) - the report calls it "Subcellular: cytoplasm"; GO calls it cytoplasm**
• NCIT:C62710 (1 mention) - the report calls it "Immunoglobulin replacement therapy"; NCIT calls it Immunoglobulin Therapy
• NCIT:C51993 (1 mention) - the report calls it "Antimicrobial prophylaxis"; NCIT calls it Antibiotic Prophylaxis
• NCIT:C15261 (1 mention) - the report calls it "Immunosuppressive therapy for autoimmune cytopenias"; NCIT calls it Immunosuppressive Therapy

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.