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Classifications

Harrison's Part

IUIS Category

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Inheritance

1

X-linked recessive HP:0001419

SASH3 is on the X chromosome, and every reported patient is a hemizygous male. The one case in which the parental origin was established carried a variant inherited from a heterozygous mother.

X-linked recessive inheritance

Show evidence (2 references)

PMID:33876203 SUPPORT Human Clinical

"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."

Four unrelated affected individuals, all male, in the index cohort that defined the disease.

PMID:33876203 SUPPORT Human Clinical

"The SASH3 gene is located on the X-chromosome."

States the chromosomal location that makes affected males hemizygous.

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Discussions and Knowledge Gaps

3

What causes the neutropenia in SASH3 deficiency, given that SASH3 expression is restricted to lymphocytes?

KNOWLEDGE GAP OPEN sash3_neutropenia_mechanism

Attached to

phenotypes#Decreased total neutrophil count

Neutropenia is reported in the index cohort and is prominent enough that SASH3 turns up in cohorts sequenced for suspected congenital neutropenia. But the gene is lymphocyte restricted, so a neutrophil-intrinsic effect has no obvious basis, and autoimmune destruction, the usual alternative in an immune-dysregulation disorder, has not been demonstrated in any reported patient. No mouse study has reported neutropenia either. The phenotype is therefore deliberately left with no incoming causal edge in this entry: the two candidate mechanisms are both untested, and drawing an edge to either would assert more than the literature does.

Does human SASH3 act as a ribosomal stabiliser in NK cells, as mouse SLy1 does, or does the human NK phenotype arise some other way?

HUMAN MODEL MISMATCH OPEN sash3_nk_role_human_vs_mouse

Attached to

pathophysiology#NK Cell Depletion and Impaired Cytotoxicity

The mouse work is explicit that SLy1 does something different in NK cells than in T and B cells: it is a cytoplasmic ribosomal protein rather than a shuttling signalling scaffold, and its loss causes ribosomal instability, p53 accumulation, senescence and exhaustion. That is a well-worked-out mechanism with a matching phenotype. The human evidence is only that NK cells are reduced. Nobody has looked for a ribosomal role for SASH3 in human NK cells, so the entry records the NK phenotype as a branch of its own rather than placing it downstream of the signalling node, and marks the model link LOW fidelity with a CAUSE_UNREPRESENTED divergence.

Are the skeletal and neurodevelopmental findings reported in one patient with a SASH3 missense variant part of the disease, or coincidental?

OPEN QUESTION OPEN sash3_extra_immune_manifestations

Attached to

genetic#SASH3

One reported patient had osteogenesis imperfecta, metaphyseal dysplasia, intellectual disability, hearing loss, cleft lip and palate and renal agenesis alongside the immunological phenotype. Exome sequencing in that patient found no pathogenic variant in any gene linked to osteogenesis imperfecta or intellectual disability. The reporting authors explicitly declined to attribute the skeletal and neurological findings to SASH3, and no other patient has had them. This entry follows them: those features are not curated as phenotypes of immunodeficiency 102, and this discussion records why the decision could go the other way if a second such patient is reported.

Show evidence (1 reference)

PMID:40947476 SUPPORT Human Clinical

"While immunological features in this case were characterized, further studies are needed to determine the association between the SASH3 variant and the skeletal or neurological manifestations."

The reporting authors' own statement that the association is unestablished, which is the basis for excluding these features from the phenotype list.

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Pathophysiology

7

SASH3 Adaptor Loss in Lymphocytes

The initiating lesion. SASH3 is expressed only in lymphocytes and has no enzymatic activity; it is a scaffold whose SH3 and sterile alpha motif domains recruit and connect downstream effectors. Nonsense variants (p.Gln169*, p.Arg245*, p.Arg288*) abolish the protein, and the single reported missense variant, p.Arg347Cys, falls in a conserved motif adjacent to the Ser349 phosphorylation site. Because expression is lymphocyte restricted, the consequences of losing it are confined to the lymphoid compartment rather than being systemic.

T cell CL:0000084 B cell CL:0000236 natural killer cell CL:0000623

Genetic context variant_origin: GERMLINE zygosity: HEMIZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Hemizygous germline loss-of-function variants in SASH3 on the X chromosome. Three of the four reported variant types are nonsense.

SASH3 signalling adaptor activity GO:0035591 ⇓ LOSS OF FUNCTION

Downstream

Failure of Antigen Receptor Signal Propagation Loss of the scaffold removes the protein-protein connections that couple an engaged antigen receptor to its downstream effectors. Restoring the protein by lentiviral transfer restores signalling, which is what makes this a direct rather than an inferred link.

NK Cell Depletion and Impaired Cytotoxicity NK cells are also SASH3-expressing lymphocytes and are reduced in patients, but the route from adaptor loss to NK loss is not established in humans. In the mouse, SLy1 behaves in NK cells as a ribosomal stabiliser rather than a signalling scaffold, so the two branches of this pathograph may not share a mechanism.

Show evidence (2 references)

PMID:33876203 SUPPORT Human Clinical

"Sterile alpha motif (SAM) and Src homology-3 (SH3) domain-containing 3 (SASH3), also called SH3-containing lymphocyte protein (SLY1), is a putative adaptor protein that is postulated to play an important role in the organization of signaling complexes and propagation of signal transduction..."

Establishes SASH3 as a lymphocyte adaptor whose role is the organisation of signalling complexes, which is the function lost here.

PMID:40947476 SUPPORT Human Clinical

"Src Homology 3 Domain-containing Adaptor Protein 3 (SASH3) deficiency is an X-linked immune disorder."

A later independent group describing the entity in the same terms.

Failure of Antigen Receptor Signal Propagation

Without the SASH3 scaffold, signals initiated at the T-cell and B-cell antigen receptors are not propagated normally. In the mouse the same protein is phosphorylated on Ser27 upon T- or B-cell receptor engagement and shuttles from nucleus to cytoplasm, which is the molecular event this node loses. In patients the readout is abnormal T-cell activation and proliferation, and the defect is corrected by re-expressing SASH3.

T cell receptor signaling GO:0050852 ↓ DECREASED B cell receptor signaling GO:0050853 ↓ DECREASED intracellular signal transduction downstream of the antigen receptor GO:0035556 ↓ DECREASED

Downstream

Thymocyte Survival Failure and Reduced Thymic Output Developing thymocytes depend on pre-T-cell-receptor and Notch-derived survival signals passing through this scaffold; without it they die before completing the double-negative to double-positive transition.

Defective T Cell Proliferation and Increased Activation-Induced Apoptosis Mature peripheral T cells that do reach the periphery fail to mount a normal proliferative response when the receptor is engaged.

Impaired Germinal Center Reaction and Loss of Class-Switched Memory B Cells B-cell receptor signalling runs through the same scaffold, so the humoral arm fails both cell-intrinsically and through the loss of T-cell help modelled on the separate edge from the T-cell proliferation node.

Show evidence (2 references)

PMID:35464398 SUPPORT BACKGROUND Human Clinical

"SASH3 deficiency was described as a novel X-linked combined immunodeficiency with immune dysregulation, associated with impaired TCR signaling and thymocyte survival in humans."

States the human signalling defect. The sentence is this case report restating the index cohort's result rather than its own, hence BACKGROUND.

PMID:16227612 SUPPORT BACKGROUND Model Organism

"SLY1 was recently identified as an X-chromosomal SH3 protein that is serine phosphorylated (Ser27) upon B-and T-cell receptor engagement."

Identifies antigen-receptor engagement as the stimulus that modifies the protein, which is the molecular basis for placing it in this pathway. The sentence restates earlier work, so it is marked BACKGROUND.

Thymocyte Survival Failure and Reduced Thymic Output

Developing thymocytes require the SASH3 scaffold to survive the transition from the CD4-CD8- double-negative to the CD4+CD8+ double-positive stage. In patients this is inferred from in vitro differentiation of CD34+ progenitors and from the rearrangement signature at the T-cell receptor alpha locus, which reports how long thymocytes survive at the double-positive stage. In the mouse the block is direct and staged: thymic cellularity falls by about half and precursors are deleted by premature programmed cell death, with reduced proliferation in the DN3 subpopulation contributing.

thymocyte CL:0000893 double negative thymocyte CL:0002489

T cell differentiation in thymus GO:0033077 ↓ DECREASED thymocyte apoptosis GO:0070242 ↑ INCREASED

thymus UBERON:0002370

Animal models

Sly1 knockout mouse Mouse recapitulates Thymic cellularity falls by roughly half, with a block at the double-negative to double-positive transition driven by premature programmed cell death.

Downstream

Decreased total CD4+ T cell count Reduced thymic output is the proximate explanation for the CD4+ T-cell lymphopenia that is the most consistent laboratory finding in this disease.

Decreased total T cell count Both CD4+ and CD8+ compartments are affected, so total T-cell numbers fall as well.

Severe varicella zoster infection Loss of T-cell numbers and function is what allows an otherwise containable herpesvirus reactivation to become severe. In the one adult case this was the observation that redirected a long-standing common variable immunodeficiency diagnosis toward a T-cell defect.

Combined immunodeficiency The cellular arm of the combined defect. Reduced thymic output is what distinguishes this disease from a purely humoral immunodeficiency, notwithstanding that several patients were first labelled with one.

Show evidence (3 references)

PMID:33876203 SUPPORT In Vitro

"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."

The human basis for this node. It is an in vitro differentiation assay plus a rearrangement signature, not a thymic biopsy, which is why the staging detail below comes from the mouse.

PMID:19604361 SUPPORT Model Organism

"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."

Names the developmental checkpoint and the mechanism of loss in the mouse. It is the source of the staging claim and cannot stand for the human block on its own.

PMID:36401605 SUPPORT Model Organism

"Studies of apoptosis and proliferation in SLy1KO thymocytes revealed decreased proliferation in the DN3 subpopulation as a possible reason for the decreased thymocyte number."

Adds reduced DN3 proliferation alongside apoptosis as a contributor to the reduced thymocyte number in the mouse.

Defective T Cell Proliferation and Increased Activation-Induced Apoptosis

Peripheral T cells that reach the circulation respond poorly to receptor and mitogen stimulation: proliferation is reduced, cell-cycle progression is impaired, and apoptosis is increased. In the mouse the corresponding defect is dysregulated Foxo1 shuttling after T-cell receptor signalling, which raises cell-cycle inhibitor expression and limits clonal expansion; whether the human proliferative defect runs through Foxo1 has not been tested.

CD4-positive, alpha-beta T cell CL:0000624

T cell proliferation GO:0042098 ↓ DECREASED cell cycle progression after antigen receptor engagement GO:0007049 ↓ DECREASED activation-induced T cell apoptosis GO:0043065 ↑ INCREASED

Animal models

Sly1 knockout mouse Mouse recapitulates Differentiated T cells from knockout mice proliferate poorly after infection, through dysregulated Foxo1 shuttling and increased expression of cell-cycle inhibitory genes.

Downstream

Decreased antigen-specific T cell proliferation The measurable clinical correlate of this node: patient T cells do not expand normally when stimulated.

Impaired Germinal Center Reaction and Loss of Class-Switched Memory B Cells The germinal centre is T-cell dependent, so a CD4+ compartment that is both reduced in number and poorly proliferative cannot supply the cognate help the reaction requires.

Breakdown of Peripheral Tolerance and Autoimmune Cytopenias Patients have reduced regulatory T cells, an expanded CD21low T-bet+ CD11c+ population and T-cell exhaustion alongside the proliferative defect. The association is reported; the causal steps from adaptor loss to loss of tolerance are not worked out, which is why this link is marked indirect with unknown intermediates.

Show evidence (3 references)

PMID:33876203 SUPPORT Human Clinical

"Patients exhibited CD4+ T-cell lymphopenia, decreased T-cell proliferation, cell cycle progression, and increased T-cell apoptosis in response to mitogens."

All three components of this node, measured directly in patient cells.

PMID:35464398 SUPPORT Human Clinical

"The patient's immunological phenotype included marked B cell lymphopenia with reduced pre-switch and switch memory B cells, decreased CD4+ and CD8+ naïve T cells, elevated CD4+ and CD8+ TEMRA cells, and abnormal T cell activation and proliferation."

Independent confirmation of abnormal T-cell activation and proliferation in a second, unrelated patient.

PMID:26306874 SUPPORT Model Organism

"The increased susceptibility of SLy1 knock-out (KO) mice was caused by reduced proliferation of differentiated T cells."

The mouse counterpart, which additionally supplies the Foxo1 mechanism the description flags as untested in humans.

Impaired Germinal Center Reaction and Loss of Class-Switched Memory B Cells

The humoral arm fails at the germinal centre. Splenic histology in one patient, examined after a clinically indicated splenectomy, showed severe hypoplasia or absence of germinal centres. Patients consistently lose class-switched and IgM memory B cells even when total B-cell numbers and IgG are preserved, and serum IgM is frequently low. In the Sly1 mutant mouse the corresponding defect is a selective block at the marginal-zone B-cell transition with severely impaired antibody responses to both T-dependent and T-independent antigens.

B cell CL:0000236 class switched memory B cell CL:0000972

germinal center formation GO:0002467 ↓ DECREASED immunoglobulin isotype switching GO:0045190 ↓ DECREASED immunoglobulin production GO:0002377 ↓ DECREASED

spleen UBERON:0002106

Animal models

Sly1 N-terminal deletion mouse Mouse partially recapitulates Reduced lymphoid organ size, loss of marginal-zone B cells, and severely impaired antibody responses to both T-dependent and T-independent antigens, including the polysaccharide response.

Downstream

Decreased class-switched memory B cell proportion Class-switched memory B cells are the output of the germinal centre, so their loss is the most direct reading of this node.

Decreased circulating total IgM Serum IgM falls in patients even where IgG and IgA are preserved, consistent with the loss of the IgM memory compartment.

Decreased total B cell count Most but not all patients are B-cell lymphopenic. One reported patient had normal B-cell numbers with a clear memory-compartment defect, so the count and the differentiation defect dissociate and the link is not direct.

Recurrent sinopulmonary infections Failure of the antibody response to encapsulated respiratory organisms is the standard route from a germinal-centre output defect to recurrent sinopulmonary infection, and sinopulmonary infection is the presenting complaint in the index cohort.

Recurrent skin infections Cutaneous and mucosal infection accompanies the sinopulmonary picture in the index cohort, and bacterial cellulitis was a recurrent admission diagnosis in a later case.

Combined immunodeficiency The humoral arm of the combined defect. Several patients were carried for years under a common variable immunodeficiency label on the strength of this arm alone.

Show evidence (4 references)

PMID:37646304 SUPPORT Human Clinical

"Immunohistochemistry performed after clinically indicated splenectomy revealed severe hypoplasia/absence of germinal centres."

The only direct human histological observation of the germinal centre in this disease, and the reason this node is placed at the germinal centre rather than downstream of it.

PMID:40947476 SUPPORT Human Clinical

"However, further analysis of B cells demonstrated 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%"

Quantifies the memory B-cell loss in a patient whose total B-cell count and IgG were normal, separating the germinal-centre output defect from B-cell lymphopenia.

PMID:16227612 SUPPORT Model Organism

"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."

The mouse humoral phenotype. It supports the T-dependent antibody failure but is a marginal-zone rather than a germinal-centre lesion, so it is supporting rather than defining evidence here.

+ 1 more reference

Breakdown of Peripheral Tolerance and Autoimmune Cytopenias

Immune dysregulation is a defining half of this disease rather than an incidental complication. Patients develop refractory autoimmune cytopenias, and in the one case studied in detail the autoimmune phenotype came with reduced regulatory T cells, T-cell exhaustion, and an expanded CD21low T-bet+ CD11c+ population. How loss of a lymphocyte adaptor produces loss of tolerance is not established; the thymocyte selection defect and the regulatory T-cell deficit are both plausible routes and neither has been tested against the other in patients.

regulatory T cell CL:0000815

regulation of the immune response GO:0050776 ↕ DYSREGULATED

Downstream

Autoimmune hemolytic anemia Antibody-mediated red-cell destruction, one of the two cytopenias that together define the Evans syndrome presentation of this disease.

Autoimmune thrombocytopenia The platelet counterpart of the same process, and the second half of the Evans syndrome presentation.

Show evidence (2 references)

PMID:33876203 SUPPORT Human Clinical

"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."

Refractory autoimmune cytopenias in the index cohort, alongside the infectious picture.

PMID:37646304 SUPPORT Human Clinical

"We studied a patient with autoimmune haemolytic anaemia and immune thrombocytopenia and identified a germline mutation in SASH3 (c.862C>T;p.Arg288Ter), indicating a recently identified IEI."

A patient in whom the autoimmune cytopenias were the presenting illness and the immunodeficiency was found afterwards.

NK Cell Depletion and Impaired Cytotoxicity

NK cell numbers are reduced in most reported patients, and NK deficiency is a recurring feature of the SASH3 cases ascertained through congenital neutropenia sequencing. The mechanism is the least settled part of this entry. In the mouse, SLy1 in NK cells does not act as a signalling scaffold at all: it stabilises the ribosome, and its loss frees ribosomal proteins, stabilises p53, and drives NK senescence and exhaustion with reduced cytotoxicity. Whether human SASH3 has the same non-signalling role in NK cells has not been tested, so the mouse mechanism is recorded here but not asserted of patients.

natural killer cell CL:0000623

natural killer cell mediated cytotoxicity GO:0042267 ↓ DECREASED

Animal models

Sly1 knockout mouse Mouse partially recapitulates Knockout mice have reduced NK numbers, viability and cytotoxicity, with senescence and exhaustion. The number and function phenotypes match the patients; the molecular route does not obviously transfer.

Downstream

Reduced total natural killer cell count The measurable phenotype. NK lymphopenia is present in the index cohort and in the congenital neutropenia cases, though at least one reported patient had a normal NK percentage.

Show evidence (3 references)

PMID:40510848 SUPPORT INDIRECT Human Clinical

"A shared feature among these cases was a tendency toward reduced lymphocyte subsets, particularly NK cells."

The human observation, and marked INDIRECT because of the inference step it needs: the sentence is about the immunodeficiency-gene subset of a congenital-neutropenia cohort as a whole, not about the SASH3 patient in it. SASH3 is named among those genes elsewhere in the same paper, so NK reduction in this disease follows from the cohort statement rather than being asserted by it.

PMID:28123874 SUPPORT Model Organism

"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."

The reason this node is drawn as a separate branch rather than downstream of the signalling node. In the mouse the NK role is a different molecular function altogether.

PMID:42327758 SUPPORT Model Organism

"In brief, we demonstrated that SLy1 is indispensable for adequate numbers of viable, activatable NK cells with an intact cytolytic capacity, and that those phenotypic alterations are p53-mediated."

Ties NK number, viability and cytotoxicity to SLy1 loss in the mouse, and attributes them to p53.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

14

Blood 9

Decreased total T cell count HP:0005403

Show evidence (1 reference)

PMID:40947476 SUPPORT Human Clinical

"SASH3 deficiency is typically characterized by three main findings: cytopenia affecting one or more blood cell lineages (including white blood cells such as neutrophils and lymphocytes, red blood cells or platelets), hypogammaglobulinemia and reduced numbers of lymphocyte subsets (T cells, B..."

Summarises reduced lymphocyte subsets, T cells included, as one of the three characteristic findings across the reported cases.

Decreased antigen-specific T cell proliferation HP:0031402

Show evidence (1 reference)

PMID:33876203 SUPPORT Human Clinical

"Patients exhibited CD4+ T-cell lymphopenia, decreased T-cell proliferation, cell cycle progression, and increased T-cell apoptosis in response to mitogens."

The proliferative defect measured on mitogen stimulation of patient cells.

Decreased total B cell count HP:0010976

Show evidence (1 reference)

PMID:33876203 SUPPORT Human Clinical

"These patients also manifested neutropenia and B-cell and natural killer (NK)-cell lymphopenia."

B-cell lymphopenia in the index cohort.

Decreased class-switched memory B cell proportion HP:0030388

Show evidence (2 references)

PMID:40947476 SUPPORT Human Clinical

"However, further analysis of B cells demonstrated 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%"

Quantifies the switched memory B-cell reduction in a patient with an otherwise normal B-cell count.

PMID:35464398 SUPPORT Human Clinical

"The patient's immunological phenotype included marked B cell lymphopenia with reduced pre-switch and switch memory B cells, decreased CD4+ and CD8+ naïve T cells, elevated CD4+ and CD8+ TEMRA cells, and abnormal T cell activation and proliferation."

The same finding in an independent patient.

Decreased circulating total IgM HP:0002850

Show evidence (1 reference)

PMID:40947476 SUPPORT Human Clinical

"Immunoglobulin levels revealed IgG and IgA within the age-matched normal range, whereas IgM levels were decreased."

Isolated low IgM in a genotyped patient.

Reduced total natural killer cell count HP:0040218

Show evidence (2 references)

PMID:33876203 SUPPORT Human Clinical

"These patients also manifested neutropenia and B-cell and natural killer (NK)-cell lymphopenia."

NK lymphopenia in the index cohort.

PMID:40510848 SUPPORT INDIRECT Human Clinical

"A shared feature among these cases was a tendency toward reduced lymphocyte subsets, particularly NK cells."

Independent cohort evidence for NK reduction among the immunodeficiency-gene cases, SASH3 among them. INDIRECT for the same reason as on the pathophysiology node: the quoted sentence describes the subset, and the claim about SASH3 specifically follows by inference.

Decreased total neutrophil count HP:0001875

Show evidence (2 references)

PMID:33876203 SUPPORT Human Clinical

"These patients also manifested neutropenia and B-cell and natural killer (NK)-cell lymphopenia."

Neutropenia in the index cohort.

PMID:40510848 SUPPORT Human Clinical

"Half of these cases involved genes traditionally associated with hereditary immunodeficiencies (GINS4, CARD11, ADA2, GINS1, LCP1, SASH3, and WAS)."

SASH3 among the genes returning a molecular diagnosis in a cohort ascertained on congenital neutropenia, which is how prominent the neutropenia can be.

Autoimmune hemolytic anemia HP:0001890

Show evidence (1 reference)

PMID:37646304 SUPPORT Human Clinical

"We studied a patient with autoimmune haemolytic anaemia and immune thrombocytopenia and identified a germline mutation in SASH3 (c.862C>T;p.Arg288Ter), indicating a recently identified IEI."

Autoimmune haemolytic anaemia in a genotyped patient.

Autoimmune thrombocytopenia HP:0001973

Show evidence (1 reference)

PMID:37646304 SUPPORT Human Clinical

"We studied a patient with autoimmune haemolytic anaemia and immune thrombocytopenia and identified a germline mutation in SASH3 (c.862C>T;p.Arg288Ter), indicating a recently identified IEI."

Immune thrombocytopenia in the same genotyped patient.

Immune 4

Combined immunodeficiency HP:0005387

Show evidence (1 reference)

PMID:33876203 SUPPORT Human Clinical

"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, highlighting an important role of SASH3 in human lymphocyte function and survival."

The defining statement that this is a combined immunodeficiency.

Recurrent sinopulmonary infections HP:0005425

Show evidence (1 reference)

PMID:33876203 SUPPORT Human Clinical

"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."

Recurrent sinopulmonary infection in all four index patients.

Recurrent skin infections HP:0001581

Show evidence (1 reference)

PMID:33876203 SUPPORT Human Clinical

"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."

Cutaneous infection named alongside the sinopulmonary and mucosal infections.

Severe varicella zoster infection HP:0032170

Show evidence (1 reference)

PMID:35464398 SUPPORT Human Clinical

"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."

The single reported episode and the inference the authors drew from it.

Other 1

Decreased total CD4+ T cell count HP:5210418

Show evidence (1 reference)

PMID:33876203 SUPPORT Human Clinical

"Patients exhibited CD4+ T-cell lymphopenia, decreased T-cell proliferation, cell cycle progression, and increased T-cell apoptosis in response to mitogens."

CD4+ T-cell lymphopenia in the index cohort.

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Genetic Associations

1

SASH3 (Causative)

Gene: SASH3 hgnc:15975 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (6 references)

PMID:33876203 SUPPORT Human Clinical

"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 gene-disease association as originally established, in four unrelated patients.

PMID:35753512 SUPPORT Human Clinical

"This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency."

The sequencing program in which the association was made, which also reports how rare the diagnosis was within its own cohort.

PMID:35464398 SUPPORT Human Clinical

"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*)."

An independently ascertained hemizygous loss-of-function variant, establishing the association beyond the index cohort.

+ 3 more references

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Medical Actions

5

Immunoglobulin Replacement Therapy

Action: immunoglobulin replacement therapy Ontology label: Immunoglobulin Therapy NCIT:C62710

Platform: Protein replacement

Replacement immunoglobulin for the antibody deficiency. It is the standard of care for the humoral arm of a combined immunodeficiency with hypogammaglobulinaemia and poor specific antibody responses, both of which are recorded for this disease in the IUIS table. No published series reports outcomes on replacement in SASH3 deficiency specifically, so this entry records the indication rather than a genotype-specific efficacy claim.

Mechanism Target:

Impaired Germinal Center Reaction and Loss of Class-Switched Memory B Cells — Replacement bypasses the germinal centre rather than repairing it: it supplies the antibody the reaction fails to produce and does nothing to the reaction itself.

Show evidence (1 reference)

PMID:35464398 SUPPORT Human Clinical

"Immunoglobulin replacement therapy was not prescribed at that time."

A negative datum, quoted deliberately. This is the only mention of immunoglobulin replacement in the SASH3 case literature, and it records that a patient with low IgG and IgM was not started on it. It supports the indication being considered in these patients; it does not support an efficacy claim, and no efficacy claim is made here.

Antimicrobial Prophylaxis

Action: antibiotic prophylaxis Ontology label: Antibiotic Prophylaxis NCIT:C51993

Platform: Small molecule

Prophylactic antimicrobials against the recurrent sinopulmonary, cutaneous and mucosal infections. As with immunoglobulin replacement, this is the general management of a combined immunodeficiency with this infection pattern; no SASH3-specific prophylaxis regimen or outcome has been published.

Target Phenotypes: Recurrent sinopulmonary infections HP:0005425

Show evidence (1 reference)

PMID:33876203 SUPPORT Human Clinical

"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."

Establishes the infection burden this treatment addresses. It does not report prophylaxis, which is why the description states the indication rather than an outcome.

Immunosuppressive Therapy for Autoimmune Cytopenias

Action: immunosuppressive therapy Ontology label: Immunosuppressive Therapy NCIT:C15261

Platform: Other

Treatment directed at the immune dysregulation rather than the immunodeficiency. The cytopenias are described as refractory in the index cohort, and in one reported patient management reached splenectomy. Naming specific agents would go beyond what the case literature records, so none are named here.

Mechanism Target:

Breakdown of Peripheral Tolerance and Autoimmune Cytopenias — Suppresses the autoreactive response, leaving the underlying adaptor deficiency untouched.

Show evidence (1 reference)

PMID:33876203 SUPPORT Human Clinical

"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 word that carries this treatment is "refractory": a cytopenia is called refractory only after therapy has been tried and has not held, so the index cohort establishes both that immunosuppressive treatment is given in this disease and that it is often inadequate. The paper names no agent, which is why none is named here.

Splenectomy

Action: splenectomy Ontology label: Splenectomy NCIT:C15328

Platform: Surgery

Surgical removal of the spleen as second-line therapy for the refractory autoimmune cytopenias, reported in one patient. It removes the principal site of antibody-mediated blood-cell destruction; it does nothing to the underlying adaptor deficiency, and it adds a lifelong encapsulated-organism infection risk to a patient who is already immunodeficient. Recorded here because it happened and is documented, not as a recommendation.

Mechanism Target:

Breakdown of Peripheral Tolerance and Autoimmune Cytopenias — Acts on the effector end of this node by removing the site of destruction, not on the loss of tolerance that drives it.

Show evidence (1 reference)

PMID:37646304 SUPPORT Human Clinical

"Immunohistochemistry performed after clinically indicated splenectomy revealed severe hypoplasia/absence of germinal centres."

Documents that a splenectomy was performed, and that it was clinically indicated rather than diagnostic. The germinal-centre finding it reports is curated separately on the germinal-centre pathophysiology node; what this item supports is only that the procedure occurred in this disease.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

X-linked inheritance with a demonstrated carrier mother in the one family where parental origin was established, and an asymptomatic hemizygous brother in another. Counselling therefore has to cover both carrier detection in female relatives and the possibility that a hemizygous male relative is clinically well.

Show evidence (2 references)

PMID:40947476 SUPPORT Human Clinical

"This pathogenic variant was inherited from the mother, who carries the same variant in the heterozygous state."

Documented maternal carrier state, which is the fact counselling turns on.

PMID:37646304 SUPPORT Human Clinical

"The younger brother carries the same SASH3 mutation and shares immunophenotypic features but is currently clinical asymptomatic, indicating heterogeneity of SASH3 deficiency."

An asymptomatic hemizygous sibling, which is why counselling cannot promise a predictable phenotype from the genotype.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Only a small number of patients have been reported, and the counts overlap: four in the index cohort, five recognised by the 2022 IUIS classification, and a handful of single case reports since. No total is asserted here, because no source states one. No prevalence or incidence estimate exists and none is attempted here. For scale on the denominator, a dedicated sequencing program for suspected inborn errors of immunity, covering 1505 individuals from 1000 families, returned SASH3 in two of them.

Show evidence (1 reference)

PMID:35753512 SUPPORT Human Clinical

"Specifically, these included individuals with pathogenic variants in GIMAP5 (n = 2) and SASH3 (n = 2)."

Two SASH3 diagnoses in a cohort of 1505 individuals from 1000 families selected for suspected or known inborn errors of immunity. This is a yield within a highly enriched referral population, not a population prevalence, and is recorded only as a scale marker.

⚖️

Clinical Burden

Variable

The reported range runs from an asymptomatic hemizygous brother, through an adult carried for decades under a common variable immunodeficiency label 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 is what drives the most severe presentations. With fewer than a dozen reported patients and a median follow-up measured in single case reports, any single burden level would overstate what is known.

Show evidence (2 references)

PMID:37646304 SUPPORT Human Clinical

"The younger brother carries the same SASH3 mutation and shares immunophenotypic features but is currently clinical asymptomatic, indicating heterogeneity of SASH3 deficiency."

The authors' own statement of phenotypic heterogeneity, from a family carrying one variant across two very different clinical states.

PMID:35464398 SUPPORT Human Clinical

"Our patient displays a milder phenotype than has been reported previously in these patients, thus expanding the clinical spectrum of this recently identified inborn error of immunity."

A second, independent statement that the severity spectrum is wider than the index cohort suggested.

🐁

Animal Models

2

Sly1 knockout mouse

Complete deletion of the SLy1 protein. This is the model that identified the thymocyte survival checkpoint, and the human index cohort was explicitly described as recapitulating many of its abnormalities. It substantially predates the human disease.

Species

Mouse

Genotype

Sly1 targeted null (Sly1-/-), whole-body

Publication

PMID:19604361

Pathograph links

Thymocyte Survival Failure and Reduced Thymic Output recapitulates fidelity: moderate Thymic cellularity falls by roughly half, with a block at the double-negative to double-positive transition driven by premature programmed cell death.

Limitations: The human block is inferred from in vitro differentiation of patient CD34+ cells and from a T-cell receptor alpha rearrangement signature, not from thymic tissue, so the staging observed in the mouse has never been confirmed in a patient. The mouse is also a complete null, whereas one human variant is missense.

Readouts

Ribosomal protein S6 phosphorylation and nutrient receptor induction in thymocytes

Direction: DECREASED

Interpretation: Read as a failure of mTOR complex activation downstream of the pre-T-cell receptor and Notch, which is the proposed proximate cause of the survival failure in this model.

Show evidence (1 reference)

PMID:19604361 SUPPORT Model Organism

"SLY1-deficient thymocytes were compromised in inducing nutrient receptor expression and ribosomal protein S6 phosphorylation, indicating a defect in mTOR complex activation."

The measurement behind this readout and the authors' interpretation of it.

Show evidence (1 reference)

PMID:19604361 SUPPORT Model Organism

"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."

Establishes the model as informative for the thymocyte survival node.

Defective T Cell Proliferation and Increased Activation-Induced Apoptosis recapitulates fidelity: moderate Differentiated T cells from knockout mice proliferate poorly after infection, through dysregulated Foxo1 shuttling and increased expression of cell-cycle inhibitory genes.

Limitations: The Foxo1 mechanism has not been looked for in patients, so the model supplies a mechanism for the human proliferative defect that remains untested in humans.

Show evidence (1 reference)

PMID:26306874 SUPPORT Model Organism

"The increased susceptibility of SLy1 knock-out (KO) mice was caused by reduced proliferation of differentiated T cells."

Attributes the in vivo phenotype to the same proliferative defect seen in patients.

NK Cell Depletion and Impaired Cytotoxicity partially recapitulates fidelity: low Knockout mice have reduced NK numbers, viability and cytotoxicity, with senescence and exhaustion. The number and function phenotypes match the patients; the molecular route does not obviously transfer.

Limitations: In the mouse the NK phenotype runs through a ribosomal rather than a signalling role for SLy1, with p53 stabilisation as the effector. No human study has tested whether SASH3 has a ribosomal role in NK cells, so the mouse mechanism cannot be carried across; only the direction of the NK phenotype is shared.

Show evidence (1 reference)

PMID:28123874 SUPPORT Model Organism

"In its absence, ribosomal instability results in p53-mediated NK cell senescence and decreased clearance of malignancies."

The mouse NK mechanism, and the reason the fidelity of this link is graded LOW.

Sly1 N-terminal deletion mouse

A hypomorphic-by-design model expressing a truncated SLy1 that is confined to the cytoplasm. It separates the phosphorylation and nuclear-shuttling function from the rest of the protein, and it is the source of the humoral phenotype data.

Species

Mouse

Genotype

Sly1 delta/delta, N-terminal 81-amino-acid deletion removing Ser27 and part of the nuclear localisation signal

Publication

PMID:16227612

Pathograph links

Impaired Germinal Center Reaction and Loss of Class-Switched Memory B Cells partially recapitulates fidelity: moderate Reduced lymphoid organ size, loss of marginal-zone B cells, and severely impaired antibody responses to both T-dependent and T-independent antigens, including the polysaccharide response.

Limitations: The mouse lesion is at the marginal-zone B-cell transition, with reduced Notch target gene expression, whereas the single human histological observation is germinal-centre hypoplasia in the spleen. These are adjacent but not the same compartment, and no patient has been studied for a marginal-zone defect.

Readouts

Antigen-specific IgM after pneumococcal polysaccharide immunisation

Direction: DECREASED

Interpretation: The mouse counterpart of the suboptimal pneumococcal polysaccharide vaccine response reported in the adult patient.

Show evidence (1 reference)

PMID:18950867 SUPPORT Model Organism

"Consistent with the loss of MZ B cells, the production of antigen-specific IgM antibodies following immunization with pneumococcal polysaccharides was severely impaired in Sly1(d/d) mice."

The specific immunisation experiment behind this readout.

Show evidence (1 reference)

PMID:16227612 SUPPORT Model Organism

"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."

The humoral phenotype this link asserts the model informs.

{ }

Source YAML

click to show

name: Immunodeficiency 102
creation_date: "2026-09-18T00:00:00Z"
category: Mendelian
synonyms:
- IMD102
- SASH3 deficiency
- X-linked combined immunodeficiency due to SASH3 deficiency
- SLY1 deficiency
description: >-
  Immunodeficiency 102 is an X-linked combined immunodeficiency with immune
  dysregulation caused by hemizygous loss-of-function variants in SASH3, which
  encodes an adaptor protein expressed only in lymphocytes and also known as
  SLY1 (SH3 protein expressed in lymphocytes 1). SASH3 carries a bipartite
  nuclear localisation signal, an SH3 domain and a sterile alpha motif, has no
  known catalytic activity, and works by nucleating signalling complexes
  downstream of the T-cell and B-cell antigen receptors. In the mouse it is
  found in both the cytoplasm and the nucleus of lymphocytes, and it is
  phosphorylated and exported to the cytoplasm on antigen receptor engagement;
  the human protein has not been localised in the same way.

  The lesion is therefore a signalling lesion, not a receptor-assembly or
  nucleotide-metabolism lesion, and the gene's expression pattern would
  confine its consequences to the lymphoid compartment. The reported
  neutropenia is the one finding that does not fit that expectation, and this
  entry records it as unexplained rather than explaining it away. Patients
  have CD4+ T-cell lymphopenia, poor T-cell proliferation, impaired cell-cycle
  progression
  and excess activation-induced apoptosis; the in vitro differentiation and
  T-cell receptor alpha rearrangement data point to thymocyte survival failure
  upstream of that. B-cell and natural killer cell lymphopenia, loss of
  class-switched memory B cells, neutropenia and refractory autoimmune
  cytopenias complete the picture. Clinically this is recurrent sinopulmonary,
  cutaneous and mucosal infection plus autoimmune haemolytic anaemia and immune
  thrombocytopenia.

  The disease is defined by a small number of reported patients, and their
  presentations are strikingly heterogeneous: a phenotype indistinguishable from
  common variable immunodeficiency in one adult, Evans syndrome in another, an
  asymptomatic brother carrying the same variant as an affected proband, and one
  case ascertained through congenital neutropenia sequencing rather than through
  an immunological presentation. Curating it therefore means being explicit
  about which claims rest on the four-patient index cohort, which come from
  single later case reports, and which come only from the Sly1-deficient mouse.
  The mouse literature substantially predates the human disease and is far
  larger than it, so mouse-derived claims are graded MODEL_ORGANISM throughout
  and are never the sole support for a human phenotype.

  One pathophysiology node declares conforms_to, against
  germinal_center_reaction#Germinal Center Reaction. kb/modules/ was searched
  for a T-cell receptor proximal signalling, thymocyte selection, or lymphocyte
  survival module and none exists; the antigen-receptor signalling chain that
  carries most of this entry is consequently modelled in the entry itself.
disease_term:
  preferred_term: immunodeficiency 102
  term:
    id: MONDO:0024781
    label: immunodeficiency 102
parents:
- Combined immunodeficiency
- Inborn error of immunity
classifications:
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      The 2022 IUIS update lists SASH3 deficiency in Table 1, "Immunodeficiencies
      affecting cellular and humoral immunity", as an X-linked entity with five
      reported patients.
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
inheritance:
- name: X-linked recessive
  description: >-
    SASH3 is on the X chromosome, and every reported patient is a hemizygous
    male. The one case in which the parental origin was established carried a
    variant inherited from a heterozygous mother.
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  evidence:
  - reference: PMID:33876203
    reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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.
    explanation: Four unrelated affected individuals, all male, in the index cohort that defined the disease.
  - reference: PMID:33876203
    reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The SASH3 gene is located on the X-chromosome.
    explanation: States the chromosomal location that makes affected males hemizygous.
pathophysiology:
- name: SASH3 Adaptor Loss in Lymphocytes
  biological_scale: MOLECULAR
  description: >-
    The initiating lesion. SASH3 is expressed only in lymphocytes and has no
    enzymatic activity; it is a scaffold whose SH3 and sterile alpha motif
    domains recruit and connect downstream effectors. Nonsense variants
    (p.Gln169*, p.Arg245*, p.Arg288*) abolish the protein, and the single
    reported missense variant, p.Arg347Cys, falls in a conserved motif adjacent
    to the Ser349 phosphorylation site. Because expression is lymphocyte
    restricted, the consequences of losing it are confined to the lymphoid
    compartment rather than being systemic.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HEMIZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Hemizygous germline loss-of-function variants in SASH3 on the X
      chromosome. Three of the four reported variant types are nonsense.
  molecular_functions:
  - preferred_term: SASH3 signalling adaptor activity
    term:
      id: GO:0035591
      label: signaling adaptor activity
    modifier: LOSS_OF_FUNCTION
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  evidence:
  - reference: PMID:33876203
    reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sterile alpha motif (SAM) and Src homology-3 (SH3) domain-containing 3 (SASH3), also called SH3-containing lymphocyte protein (SLY1), 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.
    explanation: Establishes SASH3 as a lymphocyte adaptor whose role is the organisation of signalling complexes, which is the function lost here.
  - reference: PMID:40947476
    reference_title: "Osteogenesis imperfecta, intellectual disability and recurrent infections in a male with a pathogenic SASH3 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Src Homology 3 Domain-containing Adaptor Protein 3 (SASH3) deficiency is an X-linked immune disorder.
    explanation: A later independent group describing the entity in the same terms.
  downstream:
  - target: Failure of Antigen Receptor Signal Propagation
    causal_link_type: DIRECT
    description: >-
      Loss of the scaffold removes the protein-protein connections that couple
      an engaged antigen receptor to its downstream effectors. Restoring the
      protein by lentiviral transfer restores signalling, which is what makes
      this a direct rather than an inferred link.
    evidence:
    - reference: PMID:33876203
      reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: 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.
      explanation: Gene restoration rescues signalling in both a cell line and patient T cells, tying the signalling failure to the absent protein rather than to a correlate.
  - target: NK Cell Depletion and Impaired Cytotoxicity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      NK cells are also SASH3-expressing lymphocytes and are reduced in
      patients, but the route from adaptor loss to NK loss is not established in
      humans. In the mouse, SLy1 behaves in NK cells as a ribosomal stabiliser
      rather than a signalling scaffold, so the two branches of this pathograph
      may not share a mechanism.
    evidence:
    - reference: PMID:33876203
      reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: These patients also manifested neutropenia and B-cell and natural killer (NK)-cell lymphopenia.
      explanation: Records the NK lymphopenia in the index cohort; it does not establish the intervening steps, which is why the link is marked indirect with unknown intermediates.
- name: Failure of Antigen Receptor Signal Propagation
  biological_scale: MOLECULAR
  description: >-
    Without the SASH3 scaffold, signals initiated at the T-cell and B-cell
    antigen receptors are not propagated normally. In the mouse the same
    protein is phosphorylated on Ser27 upon T- or B-cell receptor engagement
    and shuttles from nucleus to cytoplasm, which is the molecular event this
    node loses. In patients the readout is abnormal T-cell activation and
    proliferation, and the defect is corrected by re-expressing SASH3.
  biological_processes:
  - preferred_term: T cell receptor signaling
    term:
      id: GO:0050852
      label: T cell receptor signaling pathway
    modifier: DECREASED
  - preferred_term: B cell receptor signaling
    term:
      id: GO:0050853
      label: B cell receptor signaling pathway
    modifier: DECREASED
  - preferred_term: intracellular signal transduction downstream of the antigen receptor
    term:
      id: GO:0035556
      label: intracellular signal transduction
    modifier: DECREASED
  evidence:
  - reference: PMID:35464398
    reference_title: "Case Report: X-Linked SASH3 Deficiency Presenting as a Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: SASH3 deficiency was described as a novel X-linked combined immunodeficiency with immune dysregulation, associated with impaired TCR signaling and thymocyte survival in humans.
    quote_role: BACKGROUND
    explanation: States the human signalling defect. The sentence is this case report restating the index cohort's result rather than its own, hence BACKGROUND.
  - reference: PMID:16227612
    reference_title: Impaired immune responses and prolonged allograft survival in Sly1 mutant mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: SLY1 was recently identified as an X-chromosomal SH3 protein that is serine phosphorylated (Ser27) upon B-and T-cell receptor engagement.
    quote_role: BACKGROUND
    explanation: Identifies antigen-receptor engagement as the stimulus that modifies the protein, which is the molecular basis for placing it in this pathway. The sentence restates earlier work, so it is marked BACKGROUND.
  downstream:
  - target: Thymocyte Survival Failure and Reduced Thymic Output
    causal_link_type: DIRECT
    description: >-
      Developing thymocytes depend on pre-T-cell-receptor and Notch-derived
      survival signals passing through this scaffold; without it they die before
      completing the double-negative to double-positive transition.
    evidence:
    - reference: PMID:33876203
      reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: 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.
      explanation: The human evidence that the signalling lesion translates into thymocyte survival failure, obtained by differentiating patient CD34+ cells in vitro rather than by sampling thymus.
  - target: Defective T Cell Proliferation and Increased Activation-Induced Apoptosis
    causal_link_type: DIRECT
    description: >-
      Mature peripheral T cells that do reach the periphery fail to mount a
      normal proliferative response when the receptor is engaged.
    evidence:
    - reference: PMID:33876203
      reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Patients exhibited CD4+ T-cell lymphopenia, decreased T-cell proliferation, cell cycle progression, and increased T-cell apoptosis in response to mitogens.
      explanation: The proliferative and apoptotic defect measured in patient cells in response to receptor and mitogen stimulation.
  - target: Impaired Germinal Center Reaction and Loss of Class-Switched Memory B Cells
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      B-cell receptor signalling runs through the same scaffold, so the humoral
      arm fails both cell-intrinsically and through the loss of T-cell help
      modelled on the separate edge from the T-cell proliferation node.
    evidence:
    - reference: PMID:16227612
      reference_title: Impaired immune responses and prolonged allograft survival in Sly1 mutant mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: B- and T-cell proliferation is attenuated and T-cell cytokine production is severely reduced.
      explanation: Shows the proliferative defect is not T-cell restricted in the mouse, supporting a B-cell-intrinsic contribution alongside the loss of help.
    - reference: PMID:40947476
      reference_title: "Osteogenesis imperfecta, intellectual disability and recurrent infections in a male with a pathogenic SASH3 variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Although the total B cell count and IgG levels did not decrease, these results indicated a clear impairment in B cell differentiation.
      explanation: A patient in whom B-cell numbers and IgG were preserved but memory B-cell differentiation was not, which is the human observation this edge asserts.
- name: Thymocyte Survival Failure and Reduced Thymic Output
  biological_scale: CELLULAR
  description: >-
    Developing thymocytes require the SASH3 scaffold to survive the transition
    from the CD4-CD8- double-negative to the CD4+CD8+ double-positive stage. In
    patients this is inferred from in vitro differentiation of CD34+ progenitors
    and from the rearrangement signature at the T-cell receptor alpha locus,
    which reports how long thymocytes survive at the double-positive stage. In
    the mouse the block is direct and staged: thymic cellularity falls by about
    half and precursors are deleted by premature programmed cell death, with
    reduced proliferation in the DN3 subpopulation contributing.
  cell_types:
  - preferred_term: thymocyte
    term:
      id: CL:0000893
      label: thymocyte
  - preferred_term: double negative thymocyte
    term:
      id: CL:0002489
      label: double negative thymocyte
  biological_processes:
  - preferred_term: T cell differentiation in thymus
    term:
      id: GO:0033077
      label: T cell differentiation in thymus
    modifier: DECREASED
  - preferred_term: thymocyte apoptosis
    term:
      id: GO:0070242
      label: thymocyte apoptotic process
    modifier: INCREASED
  locations:
  - preferred_term: thymus
    term:
      id: UBERON:0002370
      label: thymus
  evidence:
  - reference: PMID:33876203
    reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 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.
    explanation: The human basis for this node. It is an in vitro differentiation assay plus a rearrangement signature, not a thymic biopsy, which is why the staging detail below comes from the mouse.
  - reference: PMID:19604361
    reference_title: The orphan adapter protein SLY1 as a novel anti-apoptotic protein required for thymocyte development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: 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.
    explanation: Names the developmental checkpoint and the mechanism of loss in the mouse. It is the source of the staging claim and cannot stand for the human block on its own.
  - reference: PMID:36401605
    reference_title: Knockout of SLy1 decreases double-negative thymocyte proliferation and protects mice from p53-induced tumor formation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Studies of apoptosis and proliferation in SLy1KO thymocytes revealed decreased proliferation in the DN3 subpopulation as a possible reason for the decreased thymocyte number.
    explanation: Adds reduced DN3 proliferation alongside apoptosis as a contributor to the reduced thymocyte number in the mouse.
  downstream:
  - target: Decreased total CD4+ T cell count
    causal_link_type: DIRECT
    description: >-
      Reduced thymic output is the proximate explanation for the CD4+ T-cell
      lymphopenia that is the most consistent laboratory finding in this
      disease.
    evidence:
    - reference: PMID:33876203
      reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Patients exhibited CD4+ T-cell lymphopenia, decreased T-cell proliferation, cell cycle progression, and increased T-cell apoptosis in response to mitogens.
      explanation: Records the CD4+ lymphopenia in the index cohort.
  - target: Decreased total T cell count
    causal_link_type: DIRECT
    description: >-
      Both CD4+ and CD8+ compartments are affected, so total T-cell numbers fall
      as well.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The SH3-domain containing protein SASH3 contributes to B and T cell developments
      explanation: The IUIS expert committee's statement that SASH3 contributes to T cell development, which is what a reduced total T cell count reports.
  - target: Severe varicella zoster infection
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Loss of T-cell numbers and function is what allows an otherwise
      containable herpesvirus reactivation to become severe. In the one adult
      case this was the observation that redirected a long-standing common
      variable immunodeficiency diagnosis toward a T-cell defect.
    evidence:
    - reference: PMID:35464398
      reference_title: "Case Report: X-Linked SASH3 Deficiency Presenting as a Common Variable Immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "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."
      explanation: The authors' own inference from the severe VZV episode to an underlying T-cell defect, which is the edge asserted here.
  - target: Combined immunodeficiency
    causal_link_type: DIRECT
    description: >-
      The cellular arm of the combined defect. Reduced thymic output is what
      distinguishes this disease from a purely humoral immunodeficiency,
      notwithstanding that several patients were first labelled with one.
    evidence:
    - reference: PMID:33876203
      reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 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, highlighting an important role of SASH3 in human lymphocyte function and survival.
      explanation: The classification of the entity as a combined, rather than purely humoral, immunodeficiency.
- name: Defective T Cell Proliferation and Increased Activation-Induced Apoptosis
  biological_scale: CELLULAR
  description: >-
    Peripheral T cells that reach the circulation respond poorly to receptor and
    mitogen stimulation: proliferation is reduced, cell-cycle progression is
    impaired, and apoptosis is increased. In the mouse the corresponding defect
    is dysregulated Foxo1 shuttling after T-cell receptor signalling, which
    raises cell-cycle inhibitor expression and limits clonal expansion; whether
    the human proliferative defect runs through Foxo1 has not been tested.
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: T cell proliferation
    term:
      id: GO:0042098
      label: T cell proliferation
    modifier: DECREASED
  - preferred_term: cell cycle progression after antigen receptor engagement
    term:
      id: GO:0007049
      label: cell cycle
    modifier: DECREASED
  - preferred_term: activation-induced T cell apoptosis
    term:
      id: GO:0043065
      label: positive regulation of apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:33876203
    reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients exhibited CD4+ T-cell lymphopenia, decreased T-cell proliferation, cell cycle progression, and increased T-cell apoptosis in response to mitogens.
    explanation: All three components of this node, measured directly in patient cells.
  - reference: PMID:35464398
    reference_title: "Case Report: X-Linked SASH3 Deficiency Presenting as a Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient's immunological phenotype included marked B cell lymphopenia with reduced pre-switch and switch memory B cells, decreased CD4+ and CD8+ naïve T cells, elevated CD4+ and CD8+ TEMRA cells, and abnormal T cell activation and proliferation.
    explanation: Independent confirmation of abnormal T-cell activation and proliferation in a second, unrelated patient.
  - reference: PMID:26306874
    reference_title: SLy1 regulates T-cell proliferation during Listeria monocytogenes infection in a Foxo1-dependent manner.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The increased susceptibility of SLy1 knock-out (KO) mice was caused by reduced proliferation of differentiated T cells.
    explanation: The mouse counterpart, which additionally supplies the Foxo1 mechanism the description flags as untested in humans.
  downstream:
  - target: Decreased antigen-specific T cell proliferation
    causal_link_type: DIRECT
    description: >-
      The measurable clinical correlate of this node: patient T cells do not
      expand normally when stimulated.
    evidence:
    - reference: PMID:37646304
      reference_title: Evans syndrome caused by a deleterious mutation affecting the adaptor protein SASH3.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 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.
      explanation: Impaired T-cell proliferation reported in a further patient, alongside the exhaustion phenotype.
  - target: Impaired Germinal Center Reaction and Loss of Class-Switched Memory B Cells
    causal_link_type: DIRECT
    description: >-
      The germinal centre is T-cell dependent, so a CD4+ compartment that is
      both reduced in number and poorly proliferative cannot supply the cognate
      help the reaction requires.
    evidence:
    - reference: PMID:40947476
      reference_title: "Osteogenesis imperfecta, intellectual disability and recurrent infections in a male with a pathogenic SASH3 variant."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: Antibody responses to T-dependent and T-independent antigens are impaired.
      explanation: The T-dependent antibody failure in the Sly1-deficient mouse, restated here by a human case report summarising the mouse literature. Graded MODEL_ORGANISM because the finding is a mouse result, and BACKGROUND because the citing paper did not produce it.
  - target: Breakdown of Peripheral Tolerance and Autoimmune Cytopenias
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Patients have reduced regulatory T cells, an expanded CD21low T-bet+
      CD11c+ population and T-cell exhaustion alongside the proliferative
      defect. The association is reported; the causal steps from adaptor loss to
      loss of tolerance are not worked out, which is why this link is marked
      indirect with unknown intermediates.
    evidence:
    - reference: PMID:37646304
      reference_title: Evans syndrome caused by a deleterious mutation affecting the adaptor protein SASH3.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 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.
      explanation: Reports the association between the autoimmune phenotype and the regulatory and exhaustion abnormalities, without establishing direction.
- name: Impaired Germinal Center Reaction and Loss of Class-Switched Memory B Cells
  biological_scale: TISSUE
  conforms_to: "germinal_center_reaction#Germinal Center Reaction"
  description: >-
    The humoral arm fails at the germinal centre. Splenic histology in one
    patient, examined after a clinically indicated splenectomy, showed severe
    hypoplasia or absence of germinal centres. Patients consistently lose
    class-switched and IgM memory B cells even when total B-cell numbers and IgG
    are preserved, and serum IgM is frequently low. In the Sly1 mutant mouse the
    corresponding defect is a selective block at the marginal-zone B-cell
    transition with severely impaired antibody responses to both T-dependent and
    T-independent antigens.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: class switched memory B cell
    term:
      id: CL:0000972
      label: class switched memory B cell
  biological_processes:
  - preferred_term: germinal center formation
    term:
      id: GO:0002467
      label: germinal center formation
    modifier: DECREASED
  - preferred_term: immunoglobulin isotype switching
    term:
      id: GO:0045190
      label: isotype switching
    modifier: DECREASED
  - preferred_term: immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: DECREASED
  locations:
  - preferred_term: spleen
    term:
      id: UBERON:0002106
      label: spleen
  evidence:
  - reference: PMID:37646304
    reference_title: Evans syndrome caused by a deleterious mutation affecting the adaptor protein SASH3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Immunohistochemistry performed after clinically indicated splenectomy revealed severe hypoplasia/absence of germinal centres.
    explanation: The only direct human histological observation of the germinal centre in this disease, and the reason this node is placed at the germinal centre rather than downstream of it.
  - reference: PMID:40947476
    reference_title: "Osteogenesis imperfecta, intellectual disability and recurrent infections in a male with a pathogenic SASH3 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, further analysis of B cells demonstrated 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%
    explanation: Quantifies the memory B-cell loss in a patient whose total B-cell count and IgG were normal, separating the germinal-centre output defect from B-cell lymphopenia.
  - reference: PMID:16227612
    reference_title: Impaired immune responses and prolonged allograft survival in Sly1 mutant mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: 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.
    explanation: The mouse humoral phenotype. It supports the T-dependent antibody failure but is a marginal-zone rather than a germinal-centre lesion, so it is supporting rather than defining evidence here.
  - reference: PMID:18950867
    reference_title: Reduced notch activity is associated with an impaired marginal zone B cell development and function in Sly1 mutant mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Consistent with the loss of MZ B cells, the production of antigen-specific IgM antibodies following immunization with pneumococcal polysaccharides was severely impaired in Sly1(d/d) mice.
    explanation: The mouse counterpart of the poor polysaccharide vaccine response reported in the adult patient with a common-variable-immunodeficiency-like presentation.
  downstream:
  - target: Decreased class-switched memory B cell proportion
    causal_link_type: DIRECT
    description: >-
      Class-switched memory B cells are the output of the germinal centre, so
      their loss is the most direct reading of this node.
    evidence:
    - reference: PMID:35464398
      reference_title: "Case Report: X-Linked SASH3 Deficiency Presenting as a Common Variable Immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The patient's immunological phenotype included marked B cell lymphopenia with reduced pre-switch and switch memory B cells, decreased CD4+ and CD8+ naïve T cells, elevated CD4+ and CD8+ TEMRA cells, and abnormal T cell activation and proliferation.
      explanation: Reduced switched memory B cells in a patient, which is the phenotype this edge produces.
  - target: Decreased circulating total IgM
    causal_link_type: DIRECT
    description: >-
      Serum IgM falls in patients even where IgG and IgA are preserved,
      consistent with the loss of the IgM memory compartment.
    evidence:
    - reference: PMID:40947476
      reference_title: "Osteogenesis imperfecta, intellectual disability and recurrent infections in a male with a pathogenic SASH3 variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Immunoglobulin levels revealed IgG and IgA within the age-matched normal range, whereas IgM levels were decreased.
      explanation: The isolated low IgM in a patient with otherwise normal immunoglobulins.
  - target: Decreased total B cell count
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Most but not all patients are B-cell lymphopenic. One reported patient had
      normal B-cell numbers with a clear memory-compartment defect, so the count
      and the differentiation defect dissociate and the link is not direct.
    evidence:
    - reference: PMID:33876203
      reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: These patients also manifested neutropenia and B-cell and natural killer (NK)-cell lymphopenia.
      explanation: The B-cell lymphopenia in the index cohort.
  - target: Recurrent sinopulmonary infections
    causal_link_type: DIRECT
    description: >-
      Failure of the antibody response to encapsulated respiratory organisms is
      the standard route from a germinal-centre output defect to recurrent
      sinopulmonary infection, and sinopulmonary infection is the presenting
      complaint in the index cohort.
    evidence:
    - reference: PMID:33876203
      reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 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.
      explanation: Recurrent sinopulmonary infection as the presenting clinical picture.
  - target: Recurrent skin infections
    causal_link_type: DIRECT
    description: >-
      Cutaneous and mucosal infection accompanies the sinopulmonary picture in
      the index cohort, and bacterial cellulitis was a recurrent admission
      diagnosis in a later case.
    evidence:
    - reference: PMID:40947476
      reference_title: "Osteogenesis imperfecta, intellectual disability and recurrent infections in a male with a pathogenic SASH3 variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Between the ages of 5 and 7 years, the patient was hospitalized five times for infections such as bacterial pneumonia, bacterial cellulitis and rotavirus gastroenteritis.
      explanation: Cutaneous bacterial infection severe enough to require admission in a patient with this genotype.
  - target: Combined immunodeficiency
    causal_link_type: DIRECT
    description: >-
      The humoral arm of the combined defect. Several patients were carried for
      years under a common variable immunodeficiency label on the strength of
      this arm alone.
    evidence:
    - reference: PMID:35464398
      reference_title: "Case Report: X-Linked SASH3 Deficiency Presenting as a Common Variable Immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In summary, our patient has a combined immunodeficiency, although he presented with a phenotype resembling CVID."
      explanation: "States exactly this: a combined immunodeficiency whose humoral presentation dominated the clinical picture."
- name: Breakdown of Peripheral Tolerance and Autoimmune Cytopenias
  biological_scale: ORGANISM
  description: >-
    Immune dysregulation is a defining half of this disease rather than an
    incidental complication. Patients develop refractory autoimmune cytopenias,
    and in the one case studied in detail the autoimmune phenotype came with
    reduced regulatory T cells, T-cell exhaustion, and an expanded CD21low
    T-bet+ CD11c+ population. How loss of a lymphocyte adaptor produces loss of
    tolerance is not established; the thymocyte selection defect and the
    regulatory T-cell deficit are both plausible routes and neither has been
    tested against the other in patients.
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  biological_processes:
  - preferred_term: regulation of the immune response
    term:
      id: GO:0050776
      label: regulation of immune response
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:33876203
    reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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.
    explanation: Refractory autoimmune cytopenias in the index cohort, alongside the infectious picture.
  - reference: PMID:37646304
    reference_title: Evans syndrome caused by a deleterious mutation affecting the adaptor protein SASH3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We studied a patient with autoimmune haemolytic anaemia and immune thrombocytopenia and identified a germline mutation in SASH3 (c.862C>T;p.Arg288Ter), indicating a recently identified IEI.
    explanation: A patient in whom the autoimmune cytopenias were the presenting illness and the immunodeficiency was found afterwards.
  downstream:
  - target: Autoimmune hemolytic anemia
    causal_link_type: DIRECT
    description: >-
      Antibody-mediated red-cell destruction, one of the two cytopenias that
      together define the Evans syndrome presentation of this disease.
    evidence:
    - reference: PMID:37646304
      reference_title: Evans syndrome caused by a deleterious mutation affecting the adaptor protein SASH3.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We studied a patient with autoimmune haemolytic anaemia and immune thrombocytopenia and identified a germline mutation in SASH3 (c.862C>T;p.Arg288Ter), indicating a recently identified IEI.
      explanation: Names the haemolytic anaemia in a genotyped patient.
  - target: Autoimmune thrombocytopenia
    causal_link_type: DIRECT
    description: >-
      The platelet counterpart of the same process, and the second half of the
      Evans syndrome presentation.
    evidence:
    - reference: PMID:37646304
      reference_title: Evans syndrome caused by a deleterious mutation affecting the adaptor protein SASH3.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Increasing evidence suggests multilineage cytopenias (also known as Evans syndrome) may be caused by inborn errors of immunity (IEI) with immune dysregulation.
      explanation: Frames the multilineage cytopenia, of which the immune thrombocytopenia in this patient is a component, as an inborn-error-of-immunity phenotype.
- name: NK Cell Depletion and Impaired Cytotoxicity
  biological_scale: CELLULAR
  description: >-
    NK cell numbers are reduced in most reported patients, and NK deficiency is
    a recurring feature of the SASH3 cases ascertained through congenital
    neutropenia sequencing. The mechanism is the least settled part of this
    entry. In the mouse, SLy1 in NK cells does not act as a signalling scaffold
    at all: it stabilises the ribosome, and its loss frees ribosomal proteins,
    stabilises p53, and drives NK senescence and exhaustion with reduced
    cytotoxicity. Whether human SASH3 has the same non-signalling role in NK
    cells has not been tested, so the mouse mechanism is recorded here but not
    asserted of patients.
  cell_types:
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  biological_processes:
  - preferred_term: natural killer cell mediated cytotoxicity
    term:
      id: GO:0042267
      label: natural killer cell mediated cytotoxicity
    modifier: DECREASED
  evidence:
  - reference: PMID:40510848
    reference_title: Expanding the phenotypic and genetic landscape of congenital neutropenia through whole-exome and genome sequencing.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: A shared feature among these cases was a tendency toward reduced lymphocyte subsets, particularly NK cells.
    explanation: >-
      The human observation, and marked INDIRECT because of the inference step
      it needs: the sentence is about the immunodeficiency-gene subset of a
      congenital-neutropenia cohort as a whole, not about the SASH3 patient in
      it. SASH3 is named among those genes elsewhere in the same paper, so NK
      reduction in this disease follows from the cohort statement rather than
      being asserted by it.
  - reference: PMID:28123874
    reference_title: Deficiency of the adaptor protein SLy1 results in a natural killer cell ribosomopathy affecting tumor clearance.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "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."
    explanation: The reason this node is drawn as a separate branch rather than downstream of the signalling node. In the mouse the NK role is a different molecular function altogether.
  - reference: PMID:42327758
    reference_title: "SLy1-deficiency results in functional impaired, exhausted and senescent NK cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In brief, we demonstrated that SLy1 is indispensable for adequate numbers of viable, activatable NK cells with an intact cytolytic capacity, and that those phenotypic alterations are p53-mediated."
    explanation: Ties NK number, viability and cytotoxicity to SLy1 loss in the mouse, and attributes them to p53.
  downstream:
  - target: Reduced total natural killer cell count
    causal_link_type: DIRECT
    description: >-
      The measurable phenotype. NK lymphopenia is present in the index cohort
      and in the congenital neutropenia cases, though at least one reported
      patient had a normal NK percentage.
    evidence:
    - reference: PMID:33876203
      reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: These patients also manifested neutropenia and B-cell and natural killer (NK)-cell lymphopenia.
      explanation: NK lymphopenia in the index cohort.
phenotypes:
- category: Clinical
  name: Combined immunodeficiency
  phenotype_term:
    preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  description: >-
    Both the cellular and the humoral arms are affected, which is why the
    2022 IUIS classification places SASH3 deficiency in the table of
    immunodeficiencies affecting cellular and humoral immunity. Severity ranges
    from a presentation indistinguishable from common variable immunodeficiency
    to refractory autoimmune cytopenias, and one variant carrier is
    asymptomatic.
  evidence:
  - reference: PMID:33876203
    reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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, highlighting an important role of SASH3 in human lymphocyte function and survival.
    explanation: The defining statement that this is a combined immunodeficiency.
- category: Clinical
  name: Recurrent sinopulmonary infections
  phenotype_term:
    preferred_term: Recurrent sinopulmonary infections
    term:
      id: HP:0005425
      label: Recurrent sinopulmonary infections
  description: >-
    Recurrent upper and lower respiratory tract infection is the commonest
    presenting complaint, and in the adult case bilateral influenza A pneumonia
    was one of the two episodes that prompted genetic testing.
  evidence:
  - reference: PMID:33876203
    reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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.
    explanation: Recurrent sinopulmonary infection in all four index patients.
- category: Clinical
  name: Recurrent skin infections
  phenotype_term:
    preferred_term: Recurrent skin infections
    term:
      id: HP:0001581
      label: Recurrent skin infections
  description: >-
    Cutaneous and mucosal infection accompanies the respiratory picture.
  evidence:
  - reference: PMID:33876203
    reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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.
    explanation: Cutaneous infection named alongside the sinopulmonary and mucosal infections.
- category: Clinical
  name: Severe varicella zoster infection
  phenotype_term:
    preferred_term: Severe varicella zoster infection
    term:
      id: HP:0032170
      label: Severe varicella zoster infection
  description: >-
    Reported in one adult patient at four years of age. It is recorded here
    because it is the observation that redirected a long-standing common
    variable immunodeficiency diagnosis toward an underlying T-cell defect, not
    because severe VZV is an established feature of the disease; a single case
    cannot establish that.
  evidence:
  - reference: PMID:35464398
    reference_title: "Case Report: X-Linked SASH3 Deficiency Presenting as a Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: The single reported episode and the inference the authors drew from it.
- category: Laboratory
  name: Decreased total CD4+ T cell count
  phenotype_term:
    preferred_term: Decreased total CD4+ T cell count
    term:
      id: HP:5210418
      label: Decreased total CD4+ T cell count
  description: >-
    The most consistent laboratory abnormality in this disease, present in the
    index cohort and in every later case in which lymphocyte subsets were
    reported.
  evidence:
  - reference: PMID:33876203
    reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients exhibited CD4+ T-cell lymphopenia, decreased T-cell proliferation, cell cycle progression, and increased T-cell apoptosis in response to mitogens.
    explanation: CD4+ T-cell lymphopenia in the index cohort.
- category: Laboratory
  name: Decreased total T cell count
  phenotype_term:
    preferred_term: Decreased total T cell count
    term:
      id: HP:0005403
      label: Decreased total T cell count
  description: >-
    Both CD4+ and CD8+ compartments are affected, so total T-cell numbers are
    reduced as well as the CD4+ subset.
  evidence:
  - reference: PMID:40947476
    reference_title: "Osteogenesis imperfecta, intellectual disability and recurrent infections in a male with a pathogenic SASH3 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SASH3 deficiency is typically characterized by three main findings: cytopenia affecting one or more blood cell lineages (including white blood cells such as neutrophils and lymphocytes, red blood cells or platelets), hypogammaglobulinemia and reduced numbers of lymphocyte subsets (T cells, B cells or NK cells)"
    explanation: Summarises reduced lymphocyte subsets, T cells included, as one of the three characteristic findings across the reported cases.
- category: Laboratory
  name: Decreased antigen-specific T cell proliferation
  phenotype_term:
    preferred_term: Decreased antigen-specific T cell proliferation
    term:
      id: HP:0031402
      label: Decreased antigen-specific T cell proliferation
  description: >-
    Patient T cells proliferate poorly on stimulation. This is a functional
    assay result rather than a cell count, and it is what distinguishes the
    disease from a numerical lymphopenia.
  evidence:
  - reference: PMID:33876203
    reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients exhibited CD4+ T-cell lymphopenia, decreased T-cell proliferation, cell cycle progression, and increased T-cell apoptosis in response to mitogens.
    explanation: The proliferative defect measured on mitogen stimulation of patient cells.
- category: Laboratory
  name: Decreased total B cell count
  phenotype_term:
    preferred_term: Decreased total B cell count
    term:
      id: HP:0010976
      label: Decreased total B cell count
  description: >-
    Present in the index cohort and marked in the adult common-variable-like
    case, but not universal: one reported patient had a normal B-cell
    percentage with an unambiguous memory-compartment defect.
  evidence:
  - reference: PMID:33876203
    reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These patients also manifested neutropenia and B-cell and natural killer (NK)-cell lymphopenia.
    explanation: B-cell lymphopenia in the index cohort.
- category: Laboratory
  name: Decreased class-switched memory B cell proportion
  phenotype_term:
    preferred_term: Decreased class-switched memory B cell proportion
    term:
      id: HP:0030388
      label: Decreased class-switched memory B cell proportion
  description: >-
    Loss of switched memory B cells is present even where total B-cell numbers
    and IgG are normal, which makes it a more reliable marker of the humoral
    defect than the B-cell count.
  evidence:
  - reference: PMID:40947476
    reference_title: "Osteogenesis imperfecta, intellectual disability and recurrent infections in a male with a pathogenic SASH3 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, further analysis of B cells demonstrated 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%
    explanation: Quantifies the switched memory B-cell reduction in a patient with an otherwise normal B-cell count.
  - reference: PMID:35464398
    reference_title: "Case Report: X-Linked SASH3 Deficiency Presenting as a Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient's immunological phenotype included marked B cell lymphopenia with reduced pre-switch and switch memory B cells, decreased CD4+ and CD8+ naïve T cells, elevated CD4+ and CD8+ TEMRA cells, and abnormal T cell activation and proliferation.
    explanation: The same finding in an independent patient.
- category: Laboratory
  name: Decreased circulating total IgM
  phenotype_term:
    preferred_term: Decreased circulating total IgM
    term:
      id: HP:0002850
      label: Decreased circulating total IgM
  description: >-
    Low IgM is reported both as part of a broader hypogammaglobulinaemia and, in
    one patient, in isolation with normal IgG and IgA.
  evidence:
  - reference: PMID:40947476
    reference_title: "Osteogenesis imperfecta, intellectual disability and recurrent infections in a male with a pathogenic SASH3 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Immunoglobulin levels revealed IgG and IgA within the age-matched normal range, whereas IgM levels were decreased.
    explanation: Isolated low IgM in a genotyped patient.
- category: Laboratory
  name: Reduced total natural killer cell count
  phenotype_term:
    preferred_term: Reduced total natural killer cell count
    term:
      id: HP:0040218
      label: Reduced total natural killer cell count
  description: >-
    NK lymphopenia is reported in the index cohort and is the shared laboratory
    feature of the immunodeficiency-gene cases in a congenital neutropenia
    cohort that included SASH3. It is not universal; one patient had a normal NK
    percentage.
  evidence:
  - reference: PMID:33876203
    reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These patients also manifested neutropenia and B-cell and natural killer (NK)-cell lymphopenia.
    explanation: NK lymphopenia in the index cohort.
  - reference: PMID:40510848
    reference_title: Expanding the phenotypic and genetic landscape of congenital neutropenia through whole-exome and genome sequencing.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: A shared feature among these cases was a tendency toward reduced lymphocyte subsets, particularly NK cells.
    explanation: >-
      Independent cohort evidence for NK reduction among the
      immunodeficiency-gene cases, SASH3 among them. INDIRECT for the same
      reason as on the pathophysiology node: the quoted sentence describes the
      subset, and the claim about SASH3 specifically follows by inference.
- category: Laboratory
  name: Decreased total neutrophil count
  phenotype_term:
    preferred_term: Decreased total neutrophil count
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  description: >-
    Neutropenia is reported in the index cohort and is prominent enough that
    SASH3 has been identified in patients sequenced for suspected congenital
    neutropenia. It sits awkwardly with the rest of this entry: SASH3 expression
    is lymphocyte restricted, so a neutrophil-intrinsic effect is not expected,
    and the alternative, autoimmune destruction, has not been demonstrated in
    these patients. This phenotype is deliberately left unwired in the
    pathograph, and the open question is recorded as a discussion rather than
    resolved by an invented edge.
  evidence:
  - reference: PMID:33876203
    reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These patients also manifested neutropenia and B-cell and natural killer (NK)-cell lymphopenia.
    explanation: Neutropenia in the index cohort.
  - reference: PMID:40510848
    reference_title: Expanding the phenotypic and genetic landscape of congenital neutropenia through whole-exome and genome sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Half of these cases involved genes traditionally associated with hereditary immunodeficiencies (GINS4, CARD11, ADA2, GINS1, LCP1, SASH3, and WAS).
    explanation: SASH3 among the genes returning a molecular diagnosis in a cohort ascertained on congenital neutropenia, which is how prominent the neutropenia can be.
- category: Clinical
  name: Autoimmune hemolytic anemia
  phenotype_term:
    preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  description: >-
    One of the two cytopenias whose combination constitutes the Evans syndrome
    presentation of this disease. Cytopenias are described as refractory in the
    index cohort.
  evidence:
  - reference: PMID:37646304
    reference_title: Evans syndrome caused by a deleterious mutation affecting the adaptor protein SASH3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We studied a patient with autoimmune haemolytic anaemia and immune thrombocytopenia and identified a germline mutation in SASH3 (c.862C>T;p.Arg288Ter), indicating a recently identified IEI.
    explanation: Autoimmune haemolytic anaemia in a genotyped patient.
- category: Clinical
  name: Autoimmune thrombocytopenia
  phenotype_term:
    preferred_term: Autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  description: >-
    Immune thrombocytopenia, the platelet half of the Evans syndrome
    presentation.
  evidence:
  - reference: PMID:37646304
    reference_title: Evans syndrome caused by a deleterious mutation affecting the adaptor protein SASH3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We studied a patient with autoimmune haemolytic anaemia and immune thrombocytopenia and identified a germline mutation in SASH3 (c.862C>T;p.Arg288Ter), indicating a recently identified IEI.
    explanation: Immune thrombocytopenia in the same genotyped patient.
genetic:
- name: SASH3
  gene_term:
    preferred_term: SASH3
    term:
      id: hgnc:15975
      label: SASH3
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Hemizygous germline loss-of-function variants in SASH3 on the X
    chromosome. No cited source in this entry states the cytogenetic band, so
    none is recorded. Four variant types had been reported worldwide as of
    the 2025 case report PMID:40947476, which tabulates them: 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. The gene is also known as SLY1; the mouse
    literature, which is far larger than the human, uses that name.
  evidence:
  - reference: PMID:33876203
    reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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.
    explanation: The gene-disease association as originally established, in four unrelated patients.
  - reference: PMID:35753512
    reference_title: "Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency.
    explanation: The sequencing program in which the association was made, which also reports how rare the diagnosis was within its own cohort.
  - reference: PMID:35464398
    reference_title: "Case Report: X-Linked SASH3 Deficiency Presenting as a Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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*).
    explanation: An independently ascertained hemizygous loss-of-function variant, establishing the association beyond the index cohort.
  - reference: PMID:40947476
    reference_title: "Osteogenesis imperfecta, intellectual disability and recurrent infections in a male with a pathogenic SASH3 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This pathogenic variant was inherited from the mother, who carries the same variant in the heterozygous state.
    explanation: The only reported case in which parental origin was established, confirming maternal carriage and X-linked transmission.
  - reference: PMID:33710696
    reference_title: The emerging and diverse roles of the SLy/SASH1-protein family in health and disease-Overview of three multifunctional proteins.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: The initial characterization of the first member SLy1/SASH3 (SH3 protein expressed in lymphocytes 1) in 2001 was rapidly followed by identification of SLy2/HACS1 (hematopoietic adaptor containing SH3 and SAM domains 1) and SASH1/SLy3 (SAM and SH3 domain containing 1).
    explanation: >-
      Records that SASH3 belongs to a three-member family whose other members,
      SAMSN1 and SASH1, are separate genes with different expression patterns
      and disease associations. Cited here so the gene binding cannot be read
      as covering SASH1, which is ubiquitously expressed and is curated in the
      literature as a tumour suppressor rather than an immunodeficiency gene.
  - reference: PMID:40947476
    reference_title: "Osteogenesis imperfecta, intellectual disability and recurrent infections in a male with a pathogenic SASH3 variant."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    quote_role: BACKGROUND
    snippet: investigated sequence motifs surrounding Arg347, a highly conserved residue from Xenopus to humans, and identified a putative protein-kinase-A-binding motif using a three-dimensional model of SASH3.
    explanation: >-
      The structural argument for why the single reported missense substitution behaves like a null. It is a three-dimensional model rather than an experiment, hence COMPUTATIONAL, and the citing paper is restating the index cohort's modelling rather than its own, hence BACKGROUND.
animal_models:
- name: Sly1 knockout mouse
  species: Mouse
  genotype: Sly1 targeted null (Sly1-/-), whole-body
  publication: PMID:19604361
  description: >-
    Complete deletion of the SLy1 protein. This is the model that identified the
    thymocyte survival checkpoint, and the human index cohort was explicitly
    described as recapitulating many of its abnormalities. It substantially
    predates the human disease.
  modeled_mechanisms:
  - target: Thymocyte Survival Failure and Reduced Thymic Output
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Thymic cellularity falls by roughly half, with a block at the
      double-negative to double-positive transition driven by premature
      programmed cell death.
    limitations: >-
      The human block is inferred from in vitro differentiation of patient
      CD34+ cells and from a T-cell receptor alpha rearrangement signature, not
      from thymic tissue, so the staging observed in the mouse has never been
      confirmed in a patient. The mouse is also a complete null, whereas one
      human variant is missense.
    evidence:
    - reference: PMID:19604361
      reference_title: The orphan adapter protein SLY1 as a novel anti-apoptotic protein required for thymocyte development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: 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.
      explanation: Establishes the model as informative for the thymocyte survival node.
    readouts:
    - name: Ribosomal protein S6 phosphorylation and nutrient receptor induction in thymocytes
      target: Thymocyte Survival Failure and Reduced Thymic Output
      direction: DECREASED
      interpretation: >-
        Read as a failure of mTOR complex activation downstream of the pre-T-cell
        receptor and Notch, which is the proposed proximate cause of the
        survival failure in this model.
      evidence:
      - reference: PMID:19604361
        reference_title: The orphan adapter protein SLY1 as a novel anti-apoptotic protein required for thymocyte development.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: SLY1-deficient thymocytes were compromised in inducing nutrient receptor expression and ribosomal protein S6 phosphorylation, indicating a defect in mTOR complex activation.
        explanation: The measurement behind this readout and the authors' interpretation of it.
  - target: Defective T Cell Proliferation and Increased Activation-Induced Apoptosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Differentiated T cells from knockout mice proliferate poorly after
      infection, through dysregulated Foxo1 shuttling and increased expression
      of cell-cycle inhibitory genes.
    limitations: >-
      The Foxo1 mechanism has not been looked for in patients, so the model
      supplies a mechanism for the human proliferative defect that remains
      untested in humans.
    evidence:
    - reference: PMID:26306874
      reference_title: SLy1 regulates T-cell proliferation during Listeria monocytogenes infection in a Foxo1-dependent manner.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The increased susceptibility of SLy1 knock-out (KO) mice was caused by reduced proliferation of differentiated T cells.
      explanation: Attributes the in vivo phenotype to the same proliferative defect seen in patients.
  - target: NK Cell Depletion and Impaired Cytotoxicity
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Knockout mice have reduced NK numbers, viability and cytotoxicity, with
      senescence and exhaustion. The number and function phenotypes match the
      patients; the molecular route does not obviously transfer.
    limitations: >-
      In the mouse the NK phenotype runs through a ribosomal rather than a
      signalling role for SLy1, with p53 stabilisation as the effector. No
      human study has tested whether SASH3 has a ribosomal role in NK cells, so
      the mouse mechanism cannot be carried across; only the direction of the NK
      phenotype is shared.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        The mouse attributes the NK phenotype to ribosomal instability and p53
        accumulation. Whether that pathway operates in human NK cells is
        untested, so the cause the model represents may not be the cause
        operating in patients.
    evidence:
    - reference: PMID:28123874
      reference_title: Deficiency of the adaptor protein SLy1 results in a natural killer cell ribosomopathy affecting tumor clearance.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: In its absence, ribosomal instability results in p53-mediated NK cell senescence and decreased clearance of malignancies.
      explanation: The mouse NK mechanism, and the reason the fidelity of this link is graded LOW.
- name: Sly1 N-terminal deletion mouse
  species: Mouse
  genotype: Sly1 delta/delta, N-terminal 81-amino-acid deletion removing Ser27 and part of the nuclear localisation signal
  publication: PMID:16227612
  description: >-
    A hypomorphic-by-design model expressing a truncated SLy1 that is confined
    to the cytoplasm. It separates the phosphorylation and nuclear-shuttling
    function from the rest of the protein, and it is the source of the humoral
    phenotype data.
  modeled_mechanisms:
  - target: Impaired Germinal Center Reaction and Loss of Class-Switched Memory B Cells
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Reduced lymphoid organ size, loss of marginal-zone B cells, and severely
      impaired antibody responses to both T-dependent and T-independent
      antigens, including the polysaccharide response.
    limitations: >-
      The mouse lesion is at the marginal-zone B-cell transition, with reduced
      Notch target gene expression, whereas the single human histological
      observation is germinal-centre hypoplasia in the spleen. These are
      adjacent but not the same compartment, and no patient has been studied for
      a marginal-zone defect.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Marginal-zone B cells and their dependence on Notch signalling are much
        better defined in mouse spleen than in human, so a marginal-zone lesion
        does not map cleanly onto the human compartment in which germinal-centre
        hypoplasia was seen.
    evidence:
    - reference: PMID:16227612
      reference_title: Impaired immune responses and prolonged allograft survival in Sly1 mutant mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: 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.
      explanation: The humoral phenotype this link asserts the model informs.
    readouts:
    - name: Antigen-specific IgM after pneumococcal polysaccharide immunisation
      target: Impaired Germinal Center Reaction and Loss of Class-Switched Memory B Cells
      direction: DECREASED
      interpretation: >-
        The mouse counterpart of the suboptimal pneumococcal polysaccharide
        vaccine response reported in the adult patient.
      evidence:
      - reference: PMID:18950867
        reference_title: Reduced notch activity is associated with an impaired marginal zone B cell development and function in Sly1 mutant mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Consistent with the loss of MZ B cells, the production of antigen-specific IgM antibodies following immunization with pneumococcal polysaccharides was severely impaired in Sly1(d/d) mice.
        explanation: The specific immunisation experiment behind this readout.
treatments:
- name: Immunoglobulin Replacement Therapy
  description: >-
    Replacement immunoglobulin for the antibody deficiency. It is the standard
    of care for the humoral arm of a combined immunodeficiency with
    hypogammaglobulinaemia and poor specific antibody responses, both of which
    are recorded for this disease in the IUIS table. No published series
    reports outcomes on replacement in SASH3 deficiency specifically, so this
    entry records the indication rather than a genotype-specific efficacy claim.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_mechanisms:
  - target: Impaired Germinal Center Reaction and Loss of Class-Switched Memory B Cells
    description: >-
      Replacement bypasses the germinal centre rather than repairing it: it
      supplies the antibody the reaction fails to produce and does nothing to
      the reaction itself.
  evidence:
  - reference: PMID:35464398
    reference_title: "Case Report: X-Linked SASH3 Deficiency Presenting as a Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Immunoglobulin replacement therapy was not prescribed at that time.
    explanation: >-
      A negative datum, quoted deliberately. This is the only mention of
      immunoglobulin replacement in the SASH3 case literature, and it records
      that a patient with low IgG and IgM was not started on it. It supports the
      indication being considered in these patients; it does not support an
      efficacy claim, and no efficacy claim is made here.
- name: Antimicrobial Prophylaxis
  description: >-
    Prophylactic antimicrobials against the recurrent sinopulmonary, cutaneous
    and mucosal infections. As with immunoglobulin replacement, this is the
    general management of a combined immunodeficiency with this infection
    pattern; no SASH3-specific prophylaxis regimen or outcome has been
    published.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antibiotic prophylaxis
    term:
      id: NCIT:C51993
      label: Antibiotic Prophylaxis
  target_phenotypes:
  - preferred_term: Recurrent sinopulmonary infections
    term:
      id: HP:0005425
      label: Recurrent sinopulmonary infections
  evidence:
  - reference: PMID:33876203
    reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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.
    explanation: Establishes the infection burden this treatment addresses. It does not report prophylaxis, which is why the description states the indication rather than an outcome.
- name: Immunosuppressive Therapy for Autoimmune Cytopenias
  description: >-
    Treatment directed at the immune dysregulation rather than the
    immunodeficiency. The cytopenias are described as refractory in the index
    cohort, and in one reported patient management reached splenectomy. Naming
    specific agents would go beyond what the case literature records, so none
    are named here.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: immunosuppressive therapy
    term:
      id: NCIT:C15261
      label: Immunosuppressive Therapy
  target_mechanisms:
  - target: Breakdown of Peripheral Tolerance and Autoimmune Cytopenias
    description: >-
      Suppresses the autoreactive response, leaving the underlying adaptor
      deficiency untouched.
  evidence:
  - reference: PMID:33876203
    reference_title: SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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.
    explanation: >-
      The word that carries this treatment is "refractory": a cytopenia is
      called refractory only after therapy has been tried and has not held, so
      the index cohort establishes both that immunosuppressive treatment is
      given in this disease and that it is often inadequate. The paper names no
      agent, which is why none is named here.
- name: Splenectomy
  description: >-
    Surgical removal of the spleen as second-line therapy for the refractory
    autoimmune cytopenias, reported in one patient. It removes the principal
    site of antibody-mediated blood-cell destruction; it does nothing to the
    underlying adaptor deficiency, and it adds a lifelong encapsulated-organism
    infection risk to a patient who is already immunodeficient. Recorded here
    because it happened and is documented, not as a recommendation.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: splenectomy
    term:
      id: NCIT:C15328
      label: Splenectomy
  target_mechanisms:
  - target: Breakdown of Peripheral Tolerance and Autoimmune Cytopenias
    description: >-
      Acts on the effector end of this node by removing the site of
      destruction, not on the loss of tolerance that drives it.
  evidence:
  - reference: PMID:37646304
    reference_title: Evans syndrome caused by a deleterious mutation affecting the adaptor protein SASH3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Immunohistochemistry performed after clinically indicated splenectomy revealed severe hypoplasia/absence of germinal centres.
    explanation: >-
      Documents that a splenectomy was performed, and that it was clinically
      indicated rather than diagnostic. The germinal-centre finding it reports
      is curated separately on the germinal-centre pathophysiology node; what
      this item supports is only that the procedure occurred in this disease.
- name: Genetic Counseling
  description: >-
    X-linked inheritance with a demonstrated carrier mother in the one family
    where parental origin was established, and an asymptomatic hemizygous
    brother in another. Counselling therefore has to cover both carrier
    detection in female relatives and the possibility that a hemizygous male
    relative is clinically well.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:40947476
    reference_title: "Osteogenesis imperfecta, intellectual disability and recurrent infections in a male with a pathogenic SASH3 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This pathogenic variant was inherited from the mother, who carries the same variant in the heterozygous state.
    explanation: Documented maternal carrier state, which is the fact counselling turns on.
  - reference: PMID:37646304
    reference_title: Evans syndrome caused by a deleterious mutation affecting the adaptor protein SASH3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The younger brother carries the same SASH3 mutation and shares immunophenotypic features but is currently clinical asymptomatic, indicating heterogeneity of SASH3 deficiency.
    explanation: An asymptomatic hemizygous sibling, which is why counselling cannot promise a predictable phenotype from the genotype.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Only a small number of patients have been reported, and the counts
    overlap: four in the index cohort, five recognised by the 2022 IUIS
    classification, and a handful of single case reports since. No total is
    asserted here, because no source states one. No prevalence or incidence
    estimate exists and none is attempted here. For scale on the denominator, a dedicated sequencing
    program for suspected inborn errors of immunity, covering 1505 individuals
    from 1000 families, returned SASH3 in two of them.
  evidence:
  - reference: PMID:35753512
    reference_title: "Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Specifically, these included individuals with pathogenic variants in GIMAP5 (n = 2) and SASH3 (n = 2).
    explanation: >-
      Two SASH3 diagnoses in a cohort of 1505 individuals from 1000 families
      selected for suspected or known inborn errors of immunity. This is a
      yield within a highly enriched referral population, not a population
      prevalence, and is recorded only as a scale marker.
clinical_burden:
  burden_level: VARIABLE
  rationale: >-
    The reported range runs from an asymptomatic hemizygous brother, through an
    adult carried for decades under a common variable immunodeficiency label
    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 is what drives the most severe presentations. With
    fewer than a dozen reported patients and a median follow-up measured in
    single case reports, any single burden level would overstate what is known.
  evidence:
  - reference: PMID:37646304
    reference_title: Evans syndrome caused by a deleterious mutation affecting the adaptor protein SASH3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The younger brother carries the same SASH3 mutation and shares immunophenotypic features but is currently clinical asymptomatic, indicating heterogeneity of SASH3 deficiency.
    explanation: The authors' own statement of phenotypic heterogeneity, from a family carrying one variant across two very different clinical states.
  - reference: PMID:35464398
    reference_title: "Case Report: X-Linked SASH3 Deficiency Presenting as a Common Variable Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our patient displays a milder phenotype than has been reported previously in these patients, thus expanding the clinical spectrum of this recently identified inborn error of immunity.
    explanation: A second, independent statement that the severity spectrum is wider than the index cohort suggested.
discussions:
- discussion_id: sash3_neutropenia_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What causes the neutropenia in SASH3 deficiency, given that SASH3
    expression is restricted to lymphocytes?
  attaches_to:
  - phenotypes#Decreased total neutrophil count
  rationale: >-
    Neutropenia is reported in the index cohort and is prominent enough that
    SASH3 turns up in cohorts sequenced for suspected congenital neutropenia.
    But the gene is lymphocyte restricted, so a neutrophil-intrinsic effect has
    no obvious basis, and autoimmune destruction, the usual alternative in an
    immune-dysregulation disorder, has not been demonstrated in any reported
    patient. No mouse study has reported neutropenia either. The phenotype is
    therefore deliberately left with no incoming causal edge in this entry: the
    two candidate mechanisms are both untested, and drawing an edge to either
    would assert more than the literature does.
- discussion_id: sash3_nk_role_human_vs_mouse
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does human SASH3 act as a ribosomal stabiliser in NK cells, as mouse SLy1
    does, or does the human NK phenotype arise some other way?
  attaches_to:
  - pathophysiology#NK Cell Depletion and Impaired Cytotoxicity
  rationale: >-
    The mouse work is explicit that SLy1 does something different in NK cells
    than in T and B cells: it is a cytoplasmic ribosomal protein rather than a
    shuttling signalling scaffold, and its loss causes ribosomal instability,
    p53 accumulation, senescence and exhaustion. That is a well-worked-out
    mechanism with a matching phenotype. The human evidence is only that NK
    cells are reduced. Nobody has looked for a ribosomal role for SASH3 in human
    NK cells, so the entry records the NK phenotype as a branch of its own
    rather than placing it downstream of the signalling node, and marks the
    model link LOW fidelity with a CAUSE_UNREPRESENTED divergence.
- discussion_id: sash3_extra_immune_manifestations
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Are the skeletal and neurodevelopmental findings reported in one patient
    with a SASH3 missense variant part of the disease, or coincidental?
  attaches_to:
  - genetic#SASH3
  rationale: >-
    One reported patient had osteogenesis imperfecta, metaphyseal dysplasia,
    intellectual disability, hearing loss, cleft lip and palate and renal
    agenesis alongside the immunological phenotype. Exome sequencing in that
    patient found no pathogenic variant in any gene linked to osteogenesis
    imperfecta or intellectual disability. The reporting authors explicitly
    declined to attribute the skeletal and neurological findings to SASH3, and
    no other patient has had them. This entry follows them: those features are
    not curated as phenotypes of immunodeficiency 102, and this discussion
    records why the decision could go the other way if a second such patient is
    reported.
  evidence:
  - reference: PMID:40947476
    reference_title: "Osteogenesis imperfecta, intellectual disability and recurrent infections in a male with a pathogenic SASH3 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: While immunological features in this case were characterized, further studies are needed to determine the association between the SASH3 variant and the skeletal or neurological manifestations.
    explanation: The reporting authors' own statement that the association is unestablished, which is the basis for excluding these features from the phenotype list.
notes: >-
  Entry-type decision. Curated as a standalone DISEASE. MONDO:0024781 records
  no descendants and a single causal gene (SASH3, hgnc:15975); the label and
  gene appear nowhere else in kb/; and the 2022 IUIS classification lists SASH3
  deficiency as its own entity in the table of immunodeficiencies affecting
  cellular and humoral immunity. There is no parent disease in kb/ for it to
  become a has_subtypes row of, and it is a single-gene entity rather than a
  union, so GROUPING and SUBTYPE were both ruled out.

  Naming. The file follows the Immunodeficiency_NNN convention used by the
  other 39 numbered immunodeficiency entries in kb/disorders/, with SASH3
  deficiency carried as a synonym. The closest precedent is
  Immunodeficiency_105, which likewise keeps the MONDO-style numbered name and carries its gene-based alias (CD45
  deficiency) as a synonym rather than in the filename.

  GeneReviews. There is no GeneReviews chapter for SASH3 deficiency or
  immunodeficiency 102. Verified offline against the committed Bookshelf index
  with `just check-genereviews`, not asserted from memory.

  Evidence balance. The SLy1 literature begins with the protein's initial
  characterization in 2001 and the first mutant mouse in 2005, against a human
  disease literature that begins in 2021, and the mouse literature is the
  larger of the two. Every mouse-derived claim in this entry is graded
  MODEL_ORGANISM and is paired with a human observation on the same node; no human phenotype rests on mouse evidence alone. Where a
  human case report restates a mouse or index-cohort finding rather than
  producing it, the evidence item carries quote_role: BACKGROUND.

  Mucosal infection is not curated as a phenotype, and not for want of
  looking. PMID:33876203 gives the infection pattern as "recurrent
  sinopulmonary, cutaneous, and mucosal infections"; the first two are curated
  and the third has no HPO term that fits. Searched
  `runoak -i ols:hp search "mucosal infection"` (returns only HP:0020342
  Unusual stomatitis), `search "Recurrent mucocutaneous infection"` (no hits),
  `search "t~mucosal"` (morphology terms only), and the is-a descendants of
  HP:0002719 Recurrent infections, whose only mucosal members are site-specific
  (HP:0004798 Recurrent infection of the gastrointestinal tract, HP:0031123
  Recurrent gastroenteritis, HP:0009098 Chronic oral candidiasis). Binding any
  of those would assert a site the index cohort does not name, and
  HP:0002728 Recurrent mucocutaneous candidiasis would assert an organism no
  source reports. No term beats a bad one, so none is bound.

  Orphanet prevalence is deliberately not curated. MONDO:0024781 xrefs
  Orphanet:653751, and the deep-research report states Orphanet classifies this
  disease as <1/1,000,000. That could not be verified here: `just
  fetch-reference ORPHA:653751` fails with "No source found", because ORPHA
  records are built from the Orphadata bulk XML rather than fetched per
  identifier, and that build is not present in this worktree. The prevalence
  record therefore stays CASES_IN_LITERATURE / ULTRA_RARE on evidence that is
  cached and quotable, rather than importing an unverified band from a report.

  Treatments. No published series reports treatment outcomes in SASH3
  deficiency. Four of the five treatments curated here record standard
  management of a combined immunodeficiency with this phenotype, and each says
  so; none makes a genotype-specific efficacy claim. The fifth, splenectomy, is
  the one procedure a published patient actually underwent, and is recorded as
  a documented event rather than a recommendation. Haematopoietic stem cell transplantation is
  deliberately absent: it is the obvious curative candidate for a combined
  immunodeficiency, but no reported SASH3 patient has been described as
  transplanted. The cached text of all five human SASH3 papers (PMID:33876203,
  PMID:35464398, PMID:37646304, PMID:40947476, PMID:40510848) was searched for
  transplant, HSCT and stem cell with no hit; the only hit anywhere in the
  cited set is a cohort-wide actionability tally in PMID:35753512 that is not
  about these patients. Asserting transplantation here would be inventing a
  treatment record. Note that PMID:33876203 is cached abstract-only, so absence
  there is weaker than in the four full texts.

  Deep research. research/Immunodeficiency_102-deep-research-claude_code.md was
  generated after the entry was drafted and is committed alongside it, so it is
  a cross-check rather than a source: no claim in this entry was taken from it.
  It reports 16/16 references verified with a 0.0 confabulation rate, and
  `just preflight-dr` returns WARN only because CD4 is mentioned 17 times
  against SASH3's 67 — CD4 here is the lymphopenic cell population, not a rival
  disease gene, and the report's OMIM (301082) matches MONDO's. The cross-check
  changed nothing about the phenotype list or the causal chain, both of which it
  reproduces independently. Two things came out of it: splenectomy was promoted
  to its own treatment, and the two cohort-level PMID:40510848 items were marked
  directness: INDIRECT. Its Xq26.1 band and its Orphanet prevalence class were
  both declined as unverifiable here, for the reasons given above.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Entry-type decision. Curated as a standalone DISEASE. MONDO:0024781 records no descendants and a single causal gene (SASH3, hgnc:15975); the label and gene appear nowhere else in kb/; and the 2022 IUIS classification lists SASH3 deficiency as its own entity in the table of immunodeficiencies affecting cellular and humoral immunity. There is no parent disease in kb/ for it to become a has_subtypes row of, and it is a single-gene entity rather than a union, so GROUPING and SUBTYPE were both ruled out. Naming. The file follows the Immunodeficiency_NNN convention used by the other 39 numbered immunodeficiency entries in kb/disorders/, with SASH3 deficiency carried as a synonym. The closest precedent is Immunodeficiency_105, which likewise keeps the MONDO-style numbered name and carries its gene-based alias (CD45 deficiency) as a synonym rather than in the filename. GeneReviews. There is no GeneReviews chapter for SASH3 deficiency or immunodeficiency 102. Verified offline against the committed Bookshelf index with `just check-genereviews`, not asserted from memory. Evidence balance. The SLy1 literature begins with the protein's initial characterization in 2001 and the first mutant mouse in 2005, against a human disease literature that begins in 2021, and the mouse literature is the larger of the two. Every mouse-derived claim in this entry is graded MODEL_ORGANISM and is paired with a human observation on the same node; no human phenotype rests on mouse evidence alone. Where a human case report restates a mouse or index-cohort finding rather than producing it, the evidence item carries quote_role: BACKGROUND. Mucosal infection is not curated as a phenotype, and not for want of looking. PMID:33876203 gives the infection pattern as "recurrent sinopulmonary, cutaneous, and mucosal infections"; the first two are curated and the third has no HPO term that fits. Searched `runoak -i ols:hp search "mucosal infection"` (returns only HP:0020342 Unusual stomatitis), `search "Recurrent mucocutaneous infection"` (no hits), `search "t~mucosal"` (morphology terms only), and the is-a descendants of HP:0002719 Recurrent infections, whose only mucosal members are site-specific (HP:0004798 Recurrent infection of the gastrointestinal tract, HP:0031123 Recurrent gastroenteritis, HP:0009098 Chronic oral candidiasis). Binding any of those would assert a site the index cohort does not name, and HP:0002728 Recurrent mucocutaneous candidiasis would assert an organism no source reports. No term beats a bad one, so none is bound. Orphanet prevalence is deliberately not curated. MONDO:0024781 xrefs Orphanet:653751, and the deep-research report states Orphanet classifies this disease as <1/1,000,000. That could not be verified here: `just fetch-reference ORPHA:653751` fails with "No source found", because ORPHA records are built from the Orphadata bulk XML rather than fetched per identifier, and that build is not present in this worktree. The prevalence record therefore stays CASES_IN_LITERATURE / ULTRA_RARE on evidence that is cached and quotable, rather than importing an unverified band from a report. Treatments. No published series reports treatment outcomes in SASH3 deficiency. Four of the five treatments curated here record standard management of a combined immunodeficiency with this phenotype, and each says so; none makes a genotype-specific efficacy claim. The fifth, splenectomy, is the one procedure a published patient actually underwent, and is recorded as a documented event rather than a recommendation. Haematopoietic stem cell transplantation is deliberately absent: it is the obvious curative candidate for a combined immunodeficiency, but no reported SASH3 patient has been described as transplanted. The cached text of all five human SASH3 papers (PMID:33876203, PMID:35464398, PMID:37646304, PMID:40947476, PMID:40510848) was searched for transplant, HSCT and stem cell with no hit; the only hit anywhere in the cited set is a cohort-wide actionability tally in PMID:35753512 that is not about these patients. Asserting transplantation here would be inventing a treatment record. Note that PMID:33876203 is cached abstract-only, so absence there is weaker than in the four full texts. Deep research. research/Immunodeficiency_102-deep-research-claude_code.md was generated after the entry was drafted and is committed alongside it, so it is a cross-check rather than a source: no claim in this entry was taken from it. It reports 16/16 references verified with a 0.0 confabulation rate, and `just preflight-dr` returns WARN only because CD4 is mentioned 17 times against SASH3's 67 — CD4 here is the lymphopenic cell population, not a rival disease gene, and the report's OMIM (301082) matches MONDO's. The cross-check changed nothing about the phenotype list or the causal chain, both of which it reproduces independently. Two things came out of it: splenectomy was promoted to its own treatment, and the two cohort-level PMID:40510848 items were marked directness: INDIRECT. Its Xq26.1 band and its Orphanet prevalence class were both declined as unverifiable here, for the reasons given above.

Review round 1: add deep-research baseline, splenectomy, directness marks · 2026-09-19T09:00:05Z · View source

Addresses the CHANGES_REQUESTED review on PR #12284. Blocking item: no deep-research artifact existed for this entry. Generated research/Immunodeficiency_102-deep-research-claude_code.md plus its citations sidecar with the claude_code provider (253s, 4 web searches, 16/16 references verified, 0.0 confabulation rate). just preflight-dr returns WARN only because CD4 is mentioned 17 times against SASH3's 67; CD4 is the lymphopenic cell population here rather than a rival disease gene, and the report's OMIM 301082 matches MONDO's, so disease identity is confirmed. The artifact was generated after the entry was drafted and is a cross-check, not a source: it independently reproduces the same 14 phenotypes with identical HPO ids and the same seven-node causal chain, so it confirmed completeness rather than changing it. Two changes did come out of it: splenectomy promoted from an awkward evidence item inside the immunosuppression treatment to its own Treatment bound to NCIT:C15328 Splenectomy, verified reachable from NCIT:C25218, with therapeutic_modality SURGERY and a target_mechanisms link to the tolerance node describing it as acting on the effector end rather than the cause; and the reviewer's suggestion 2, directness INDIRECT on the two cohort-level PMID:40510848 evidence items, whose quoted sentence describes the immunodeficiency-gene subset of a congenital-neutropenia cohort rather than the SASH3 patient in it. The gene-list snippet on the neutropenia phenotype is direct and stays unmarked. Reviewer suggestion 3, a mucosal-infection phenotype, was searched and declined: no HPO term fits. Recorded the exact queries run in notes per the dismech-terms rule that a negative-existence claim must be re-runnable. Also declined the report's Xq26.1 cytogenetic band and its Orphanet prevalence class as unverifiable in this worktree, both recorded with the reason. Validation after the round: 82/82 snippets verified, schema and terms clean, entity refs, causal targets, enum values, duplicate keys, qualifier terms, folded hyphens and the snippet gates all clean, gene binding still SASH3.

Claude Code ▸

Research Report: Immunodeficiency 102 (IMD102; SASH3 Deficiency)

claude-fable-5, claude-haiku-4-5-20251001, claude-opus-5 10 citations 2026-09-19T01:53:23.109013

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.

Resource	Identifier
MONDO	MONDO:0024781 (immunodeficiency 102)
OMIM (phenotype)	#301082 (IMMUNODEFICIENCY 102; IMD102) — note 301083 is a different disease (CNSHA9)
OMIM (gene)	*300441 (SASH3)
Orphanet	ORPHA:653751 — "X-linked combined immunodeficiency due to SASH3 deficiency"
ICD-10	D81.8 (other combined immunodeficiencies)
HGNC	hgnc:15975 (SASH3)
UniProt	O75995 (SASH3_HUMAN, 380 aa, ~41.6 kDa)
IUIS 2022	Table 1, "Immunodeficiencies affecting cellular and humoral immunity" (PMID:35748970)

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).

Phenotype	HPO	Type / notes	Frequency
Combined immunodeficiency	HP:0005387	Defining; IUIS Table 1 entity	All symptomatic patients
Recurrent sinopulmonary infections	HP:0005425	Presenting complaint	Very frequent
Recurrent skin infections	HP:0001581	Cellulitis requiring admission reported	Frequent
Autoimmune hemolytic anemia	HP:0001890	Refractory; Evans syndrome presentation	Frequent
Autoimmune thrombocytopenia	HP:0001973	Refractory; splenectomy in one case	Frequent
Severe varicella zoster infection	HP:0032170	Single adult case, age 4	One patient
Decreased total CD4+ T cell count	HP:5210418	Most consistent lab abnormality	Near-universal
Decreased total T cell count	HP:0005403	Both CD4+ and CD8+ affected	Frequent
Decreased antigen-specific T cell proliferation	HP:0031402	Functional,

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.

Resource	Identifier
MONDO	MONDO:0024781 (immunodeficiency 102)
OMIM (phenotype)	#301082 (IMMUNODEFICIENCY 102; IMD102) — note 301083 is a different disease (CNSHA9)
OMIM (gene)	*300441 (SASH3)
Orphanet	ORPHA:653751 — "X-linked combined immunodeficiency due to SASH3 deficiency"
ICD-10	D81.8 (other combined immunodeficiencies)
HGNC	hgnc:15975 (SASH3)
UniProt	O75995 (SASH3_HUMAN, 380 aa, ~41.6 kDa)
IUIS 2022	Table 1, "Immunodeficiencies affecting cellular and humoral immunity" (PMID:35748970)

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).

Phenotype	HPO	Type / notes	Frequency
Combined immunodeficiency	HP:0005387	Defining; IUIS Table 1 entity	All symptomatic patients
Recurrent sinopulmonary infections	HP:0005425	Presenting complaint	Very frequent
Recurrent skin infections	HP:0001581	Cellulitis requiring admission reported	Frequent
Autoimmune hemolytic anemia	HP:0001890	Refractory; Evans syndrome presentation	Frequent
Autoimmune thrombocytopenia	HP:0001973	Refractory; splenectomy in one case	Frequent
Severe varicella zoster infection	HP:0032170	Single adult case, age 4	One patient
Decreased total CD4+ T cell count	HP:5210418	Most consistent lab abnormality	Near-universal
Decreased total T cell count	HP:0005403	Both CD4+ and CD8+ affected	Frequent
Decreased antigen-specific T cell proliferation	HP:0031402	Functional, mitogen/TCR stimulation	Consistent
Decreased total B cell count	HP:0010976	Not universal — one patient normal	Frequent
Decreased class-switched memory B cell proportion	HP:0030388	More reliable than B-cell count	Consistent
Decreased circulating total IgM	HP:0002850	Sometimes isolated (normal IgG/IgA)	Frequent
Reduced total natural killer cell count	HP:0040218	Not universal	Frequent
Decreased total neutrophil count	HP:0001875	Mechanistically unexplained (see §6)	Frequent

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

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.
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.
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).

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.
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

Concept	Term
Signalling adaptor activity (lost)	GO:0035591
T cell receptor signaling pathway (↓)	GO:0050852
B cell receptor signaling pathway (↓)	GO:0050853
Intracellular signal transduction (↓)	GO:0035556
T cell differentiation in thymus (↓)	GO:0033077
Thymocyte apoptotic process (↑)	GO:0070242
T cell proliferation (↓)	GO:0042098
Cell cycle (↓)	GO:0007049
Positive regulation of apoptotic process (↑)	GO:0043065
Germinal center formation (↓)	GO:0002467
Isotype switching (↓)	GO:0045190
Immunoglobulin production (↓)	GO:0002377
NK cell mediated cytotoxicity (↓)	GO:0042267
Regulation of immune response (dysregulated)	GO:0050776

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.

Treatment	NCIT	Modality	Evidence status
Immunoglobulin replacement therapy	NCIT:C62710	PROTEIN_REPLACEMENT	Indication only. The single mention in the SASH3 literature is a negative datum — "Immunoglobulin replacement therapy was not prescribed at that time" (PMID:35464398) — in a patient with low IgG and IgM. No efficacy data exist.
Antimicrobial prophylaxis	NCIT:C51993	SMALL_MOLECULE	Indication only, from the documented infection burden. No SASH3-specific regimen or outcome published.
Immunosuppressive therapy for autoimmune cytopenias	NCIT:C15261	—	The index cohort's cytopenias are described as refractory, which establishes both that immunosuppression is given and that it is often inadequate. No agent is named in any publication, so none should be recommended by name.
Splenectomy	NCIT:C15329	SURGERY	Performed in one patient as second-line therapy for immune cytopenia (PMID:37646304).
Genetic counseling	NCIT:C15240	BEHAVIORAL	Must cover carrier detection in female relatives and the documented possibility that a hemizygous male relative is clinically well.

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

PMID	Year	Journal	Role
33876203	2021	Blood	Index cohort — 4 unrelated males, 3 variants; defines the disease
35464398	2022	Front Immunol	Adult CVID-like presentation, p.Gln169*
35748970	2022	J Clin Immunol	IUIS 2022 classification — places SASH3 in Table 1
35753512	2022	J Allergy Clin Immunol	1,000-family exome program; 2 SASH3 diagnoses
37646304	2023	Br J Haematol	Evans syndrome, p.Arg288*; splenic histology; asymptomatic brother
40510848	2025	HemaSphere	Congenital neutropenia WES/WGS cohort including SASH3
40947476	2025	Hum Genome Var	p.Arg347Cys; maternal carriage; variant table; extra-immune findings
16227612	2005	Mol Cell Biol	Sly1Δ/Δ mouse — humoral phenotype
18950867	2009	Mol Immunol	Notch/marginal-zone B cells in Sly1 mutant mice
19604361	2009	BMC Immunol	Sly1 KO — thymocyte anti-apoptotic role
26306874	2015	Eur J Immunol	Foxo1-dependent T-cell proliferation
28123874	2016	Oncoimmunology	NK ribosomopathy
33710696	2021	FASEB J	SLy/SASH family review
36401605	2023	Eur J Immunol	DN thymocyte proliferation; p53 tumour protection
42327758	2026	Front Immunol	NK exhaustion/senescence, p53-mediated

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

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	16
Resolved	16
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	2
Quoted claims found in source	2
Quoted claims not found in source	0
References weighed for topical relevance	16
On topic	14
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	56
Resolved	53
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	3
Terms whose name was checked	35
Terms named correctly	26
Terms named as a different term	1
Terms whose name is worth a second look	8

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.

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Research Report: Immunodeficiency 102 (IMD102; SASH3 Deficiency)

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Evidence Base Summary and Caveats

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver