G6PC3 Deficiency

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Classifications

Harrison's Part

IUIS Category

ICIMD (Inherited Metabolic Disorders)

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Mappings

MONDO

MONDO:0012930 autosomal recessive severe congenital neutropenia due to G6PC3 deficiency

MONDO:0012930 is the gene-anchored SCN4 entity (relationship RO:0004003 to HGNC:24861 G6PC3; xrefs OMIM:612541, Orphanet:331176) and carries the synonyms "severe congenital neutropenia type 4" and "SCN4". It is the correct anchor for the full G6PC3-deficiency continuum curated here, including the nonsyndromic form.

MONDO:0023124 Dursun syndrome Not Yet Curated

Dursun syndrome is a NARROWER G6PC3-related entity restricted to the familial pulmonary-arterial-hypertension / leukopenia / atrial-septal-defect presentation (Orphanet:178503). This entry previously anchored its disease_term to MONDO:0023124; that was too narrow for an entry describing the whole G6PC3 spectrum and has been corrected to MONDO:0012930, with Dursun syndrome retained here as a narrow match.

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Inheritance

1

Autosomal recessive HP:0000007

G6PC3 deficiency is caused by biallelic pathogenic variants in G6PC3.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:23758768 SUPPORT Human Clinical

"Bi-allelic G6PC3 mutations cause a multi-system autosomal recessive disorder of G6PC3 deficiency"

Review evidence supports autosomal recessive inheritance of G6PC3 deficiency.

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Discussions and Knowledge Gaps

3

By what mechanism does ubiquitous G6PC3 loss produce the specific developmental malformations of this syndrome — atrial septal defect, prominent superficial venous pattern, and urogenital anomalies — rather than a generalised multisystem phenotype, and does 1,5-AG6P accumulation contribute to them at all?

KNOWLEDGE GAP OPEN gap_g6pc3_nonhaematological_mechanism

Attached to

pathophysiology#Ubiquitous G6PC3 loss in non-haematopoietic tissues

The haematological arm of this disease is now mechanistically complete and pharmacologically actionable (1,5-AG6P to hexokinase to glycolysis to neutrophil death, reversed by lowering plasma 1,5-AG). The non-haematological arm is not. G6PC3 is ubiquitously expressed, yet the malformations are anatomically stereotyped, which a simple "enzyme missing everywhere" account does not explain. Nor is it known whether the developmental features share the 1,5-AG6P mechanism — a decisive question, because if they do, early substrate-reduction therapy might be disease-modifying beyond the marrow, whereas if they do not, empagliflozin and HSCT will both leave them untouched.

Proposed experiments

Does 1,5-AG6P accumulate outside the granulocyte lineage?

targeted metabolomics and metabolic flux experiment

exp_g6pc3_metabolite_outside_granulocytes

Measure 1,5-AG6P concentration and glycolytic flux in G6PC3-deficient non-myeloid cells — patient dermal fibroblasts and iPSC-derived endothelial cells and cardiomyocytes — against isogenic corrected controls, to test whether the toxic metabolite accumulates in the tissues that carry the developmental malformations.

Developmental phenotyping of G6PC3-knockout mice with early SGLT2 inhibition

model organism developmental phenotyping experiment

exp_g6pc3_mouse_developmental_phenotype

Determine whether G6PC3-knockout mice reproduce the cardiac, venous, and urogenital anomalies seen in patients, and whether maternal or early-postnatal SGLT2 inhibition alters their incidence or severity.

Non-haematological outcomes in long-term-treated patients

longitudinal clinical cohort study

exp_g6pc3_treated_patient_rephenotyping

Systematically re-phenotype patients on long-term empagliflozin or after HSCT to establish whether either therapy modifies any non-haematological feature, which would discriminate a shared-metabolite mechanism from an independent developmental one.

The leading hypothesis in the literature is that ER stress and increased apoptosis in non-myeloid cells (patient fibroblasts show both) underlie the developmental features, but this has not been shown to cause a specific malformation.

Should SGLT2 inhibition replace G-CSF as first-line therapy in G6PC3 deficiency, and what are the long-term safety and efficacy outcomes in children treated from early life?

OPEN QUESTION OPEN gap_g6pc3_sglt2_long_term_evidence

Attached to

pathophysiology#1,5-AG6P accumulation and hexokinase inhibition

Empagliflozin acts on the causal metabolite while G-CSF only pushes residual granulopoiesis, and the published cases show G-CSF can be tapered or stopped. But the entire G6PC3 evidence base is a handful of treated patients followed for one to a few years, with no randomised comparison, no established paediatric dosing, and no long-term data on growth, bone, or renal outcomes of chronic SGLT2 inhibition begun in infancy. Response also appears to depend on the individual plasma 1,5-AG level, which varies with SGLT5 genotype and with diet, so a uniform first-line recommendation may not be appropriate.

Proposed experiments

Prospective registry of SGLT2-inhibitor-treated G6PC3 and GSD-Ib patients

prospective clinical registry study

exp_g6pc3_sglt2_registry_outcomes

A prospective multi-centre registry study with predefined ANC, infection, growth, bone, and renal endpoints, powered to detect long-term harm as well as benefit in children started on SGLT2 inhibition in early life.

Does baseline plasma 1,5-AG or SGLT5 genotype predict ANC response?

pharmacogenomic response-stratification study

exp_g6pc3_sglt5_response_stratification

Correlate pre-treatment plasma 1,5-AG concentration and SGLT5 genotype with the magnitude of ANC response to empagliflozin across treated patients, to test whether the therapy can be stratified.

Is the neutrophil hypoglycosylation branch (truncated N-/O-glycans, gp91phox hypoglycosylation) a downstream consequence of the glycolytic block caused by 1,5-AG6P, or an independent parallel mechanism of neutrophil dysfunction?

OPEN QUESTION OPEN gap_g6pc3_glycosylation_vs_metabolite

Attached to

pathophysiology#Neutrophil glycosylation and oxidase dysfunction

The glycosylation defect was described before the metabolite-repair mechanism was discovered and led to a proposal that G6PC3 deficiency be classed as a congenital disorder of glycosylation. Reduced glucose-6-phosphate availability could plausibly starve nucleotide-sugar synthesis, which would make glycosylation a downstream effect of the same lesion; alternatively the ER-luminal role of G6PC3 could affect glycosylation directly. The two models are not distinguished, and this entry currently models them as parallel branches converging on neutrophil dysfunction. The distinction is testable and clinically relevant, because substrate reduction should correct a downstream glycosylation defect but not an independent one.

Proposed experiments

Neutrophil glycan profiling before and during SGLT2 inhibition

glycomics profiling experiment

exp_g6pc3_glycan_response_to_empagliflozin

Measure neutrophil N-/O-glycan profiles and gp91phox glycosylation in G6PC3-deficient patients before and during empagliflozin therapy; a correction under substrate reduction would place glycosylation downstream of the metabolite block rather than in a parallel branch.

The GSD-Ib SGLT2 series reported corrected protein glycosylation in 2 of 2 patients tested under empagliflozin (PMID:32294159), which favours the downstream model, but this has not been replicated in G6PC3 deficiency.

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Pathophysiology

7

G6PC3 endoplasmic-reticulum phosphatase deficiency

Biallelic G6PC3 variants reduce ubiquitous endoplasmic-reticulum glucose-6-phosphatase activity. In neutrophils, the critical repair defect is failure to dephosphorylate the glucose analog 1,5-AG6P.

neutrophil CL:0000775

G6PC3 hgnc:24861

glucose-6-phosphatase activity GO:0004346 ↓ DECREASED

endoplasmic reticulum GO:0005783

Downstream

1,5-AG6P accumulation and hexokinase inhibition G6PC3 normally collaborates with G6PT to destroy 1,5-AG6P; deficiency allows this glucose analog phosphate to accumulate and inhibit low-KM hexokinases.

Neutrophil glycosylation and oxidase dysfunction The same loss of ER glucose-6-phosphatase activity is accompanied by a major defect of neutrophil N- and O-glycosylation, including hypoglycosylation of the NADPH-oxidase component gp91phox. This is the second, parallel branch out of the primary enzyme defect. Whether it is a genuinely independent consequence of the ER-luminal lesion or is itself downstream of reduced glucose-6-phosphate availability starving nucleotide-sugar synthesis is unresolved (see discussion gap_g6pc3_glycosylation_vs_metabolite).

Ubiquitous G6PC3 loss in non-haematopoietic tissues G6PC3 is ubiquitously expressed, so the same biallelic loss-of-function that produces the neutrophil lesion is also present in cardiac, vascular, and urogenital tissue, where it underlies the extra-haematological features of the syndrome.

Show evidence (1 reference)

PMID:19118303 SUPPORT Human Clinical

"Sequencing of G6PC3, the candidate gene encoding glucose-6-phosphatase, catalytic subunit 3, revealed a homozygous missense mutation in exon 6 that abolished the enzymatic activity of glucose-6-phosphatase in all affected children in the two families."

The original syndrome paper links G6PC3 variants to loss of glucose-6-phosphatase activity.

1,5-AG6P accumulation and hexokinase inhibition

Granulocytes deficient in G6PC3 accumulate millimolar 1,5-AG6P, inhibiting hexokinase and reducing glucose utilization. This is especially damaging for neutrophils, which depend heavily on glycolysis for effector function. 1,5-AG6P is made by glucose-phosphorylating enzymes from 1,5-anhydroglucitol (1,5-AG), an abundant blood polyol of dietary origin — so the toxic metabolite is continuously regenerated from the circulating pool, which is what makes lowering plasma 1,5-AG a tractable therapeutic target.

neutrophil CL:0000775

glycolytic process GO:0006096 ↓ DECREASED

hexokinase activity GO:0004396 ↓ DECREASED

Downstream

Neutrophil glycolytic block and energy deficit Hexokinase inhibition by 1,5-AG6P blocks the first committed step of glycolysis in cells that depend on it, so glucose utilization falls.

Neutrophil functional defects 1,5-AG6P accumulation decreases neutrophil glucose utilization and can cause neutrophil cell death.

Show evidence (2 references)

PMID:30626647 SUPPORT Human Clinical

"Granulocytes from patients deficient in G6PC3 or G6PT accumulate 1,5AG6P to concentrations (~3 mM) that strongly inhibit hexokinase activity."

Patient granulocyte data directly support 1,5-AG6P accumulation and hexokinase inhibition.

PMID:35506446 SUPPORT Human Clinical

"accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P), an inhibitor of hexokinase made from 1,5-anhydroglucitol (1,5-AG), an abundant polyol present in blood"

Identifies the precursor of the toxic metabolite as the circulating dietary polyol 1,5-AG, which is the basis of the plasma-1,5-AG-lowering therapeutic strategy.

Neutrophil glycolytic block and energy deficit

Myeloid-cell energy metabolism depends primarily on glycolysis, so hexokinase inhibition by accumulated 1,5-AG6P translates directly into an energy deficit in neutrophils and their bone-marrow precursors. This is the step that makes an otherwise ubiquitous enzyme defect present as a neutrophil-selective disease.

neutrophil CL:0000775 granulocyte monocyte progenitor cell CL:0000557

glycolytic process GO:0006096 ↓ DECREASED

bone marrow UBERON:0002371

Downstream

Endoplasmic reticulum stress and increased myeloid apoptosis Impaired glucose flux lowers intracellular glucose and glucose-6-phosphate, provoking an endoplasmic-reticulum stress response and pro-apoptotic signalling in myeloid cells.

Neutrophil functional defects Neutrophil effector functions (chemotaxis, respiratory burst, bactericidal killing) are ATP- and NADPH-expensive and fail when glycolysis and the hexose monophosphate shunt are impaired.

Show evidence (2 references)

PMID:35838821 SUPPORT Human Clinical

"The energy metabolism of myeloid cells depends primarily on glycolysis."

States the glycolytic dependence of myeloid cells that makes hexokinase inhibition selectively damaging to the neutrophil lineage. The cited publication is an investigator-initiated human study of an SGLT2-inhibitor-treated G6PC3 patient, hence HUMAN_CLINICAL, though this particular sentence is its framing of established myeloid physiology.

PMID:33259599 SUPPORT Human Clinical

"demonstrated dramatic impairments in early glycolysis (hexose phosphate levels), hexosemonophosphate shunt (required for the generation of the NADPH), and the total adenylate pool"

Stable-isotope metabolomics in patient neutrophils confirms the glycolytic block and the resulting fall in the adenylate (energy) pool in human G6PC3 deficiency, not only in the mouse model.

Endoplasmic reticulum stress and increased myeloid apoptosis

G6PC3-deficient neutrophils, myeloid progenitors, and fibroblasts show increased endoplasmic-reticulum stress, increased GSK-3beta activity, and increased susceptibility to apoptosis. Accelerated death of maturing granulocytic precursors is what converts a metabolic lesion into a quantitative neutropenia rather than a purely functional defect.

neutrophil CL:0000775 granulocyte monocyte progenitor cell CL:0000557

response to endoplasmic reticulum stress GO:0034976 ↑ INCREASED apoptotic process GO:0006915 ↑ INCREASED myeloid cell differentiation GO:0030099 ↓ DECREASED

endoplasmic reticulum GO:0005783

Downstream

Severe congenital neutropenia Apoptotic loss of maturing granulocytic precursors produces a late-stage granulopoietic maturation defect in the marrow and profound peripheral neutropenia.

Show evidence (2 references)

PMID:19118303 SUPPORT Human Clinical

"The patients' neutrophils and fibroblasts had increased susceptibility to apoptosis. The myeloid cells showed evidence of increased endoplasmic reticulum stress and increased activity of glycogen synthase kinase 3beta (GSK-3beta)."

The index study directly measured ER stress and apoptotic susceptibility in patient neutrophils, fibroblasts, and myeloid cells.

PMID:34964150 SUPPORT Human Clinical

"caused by an alteration of glucose homeostasis, with increased endoplasmic reticulum stress and cell apoptosis"

A 94-patient literature review frames ER stress and apoptosis downstream of the glucose-homeostasis lesion as the accepted disease mechanism.

Neutrophil glycosylation and oxidase dysfunction

G6PC3 deficiency is also associated with truncated neutrophil N- and O-glycans and hypoglycosylation of gp91phox, the electron-transporting NADPH oxidase component, providing a CDG-like branch of neutrophil dysfunction.

neutrophil CL:0000775

respiratory burst GO:0045730 ↓ DECREASED

Downstream

Neutrophil functional defects Glycolytic impairment and glycosylation defects converge on impaired neutrophil migration, ingestion, bactericidal activity, and superoxide production.

Show evidence (1 reference)

PMID:21385794 SUPPORT Human Clinical

"hypo-glycosylation of gp91(phox), the electron-transporting component of the NADPH oxidase, in all of these patients."

Patient neutrophil data support gp91phox hypoglycosylation as a branch of G6PC3-related neutrophil dysfunction.

Neutrophil functional defects

G6PC3-deficient neutrophils have impaired migration, actin assembly, bactericidal activity, superoxide generation, and survival, leading to severe congenital neutropenia and recurrent bacterial infections.

neutrophil CL:0000775

neutrophil chemotaxis GO:0030593 ↓ DECREASED respiratory burst GO:0045730 ↓ DECREASED neutrophil mediated immunity GO:0002446 ↓ DECREASED apoptotic process GO:0006915 ↑ INCREASED

Downstream

Severe congenital neutropenia Neutrophil death and functional impairment produce the hematologic phenotype of severe congenital neutropenia.

Recurrent bacterial infections Reduced mature neutrophils and impaired neutrophil effector function increase susceptibility to recurrent bacterial infection.

Crohn disease Dysfunctional G6PC3-deficient neutrophils encountering gut bacteria release excess IL-8 and reactive oxygen species and undergo increased apoptosis and secondary necrosis, driving intestinal inflammation. This edge is neutrophil-intrinsic rather than a consequence of low neutrophil numbers, which is why G-CSF does not control the IBD phenotype while HSCT does.

Show evidence (2 references)

PMID:33259599 SUPPORT Human Clinical

"Random and directed migration by the patient's neutrophils was severely diminished."

Patient neutrophil assays support impaired chemotaxis/migration.

PMID:33259599 SUPPORT Human Clinical

"Superoxide anion generation was <25% of control values"

Patient neutrophil assays support defective respiratory burst.

Ubiquitous G6PC3 loss in non-haematopoietic tissues

Unlike the liver/kidney-restricted G6PC1 (glycogen storage disease Ia) and the largely haematopoietic phenotype of G6PT/SLC37A4 (GSD Ib), G6PC3 is ubiquitously expressed. Loss of the enzyme outside the marrow is the presumed basis of the extra-haematological features that distinguish G6PC3 deficiency from other severe congenital neutropenias: a prominent superficial venous pattern, congenital cardiac malformation (most often atrial septal defect), and urogenital anomalies. About three-quarters of reported patients are syndromic in this way. The step from ubiquitous enzyme loss to a specific developmental malformation is NOT mechanistically resolved (see the knowledge-gap discussion attached to this node); ER stress and increased apoptosis in non-myeloid cells such as fibroblasts is the leading, but unproven, explanation.

G6PC3 hgnc:24861

glucose-6-phosphatase activity GO:0004346 ↓ DECREASED

Downstream

Prominent superficial veins Superficial venous angiectasia on trunk and extremities is the most recognizable non-haematological sign of G6PC3 deficiency.

Congenital cardiac defects Congenital structural heart disease arises developmentally and is not a consequence of neutropenia.

Atrial septal defect Atrial septal defect is the specific cardiac lesion that dominates the G6PC3 congenital-heart-disease spectrum, present in just over half of reported patients.

Urogenital anomalies Urogenital malformations are part of the same developmental arm.

Show evidence (2 references)

PMID:23758768 SUPPORT Human Clinical

"G6PC3 deficiency is characterized by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia in many patients, a prominent superficial venous pattern and a high incidence of congenital cardiac defects and uro-genital anomalies."

Establishes the extra-haematological feature set that accompanies the neutropenia in this ubiquitously expressed enzyme deficiency.

PMID:34964150 SUPPORT Human Clinical

"Seventy-five per cent had syndromic features, mainly atrial septal defect in 55% and prominent superficial veins in 62%."

Quantifies how often the non-haematological arm is expressed across the 94 reported patients.

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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

10

Blood 2

Severe congenital neutropenia Decreased total neutrophil count HP:0001875

Show evidence (1 reference)

PMID:23758768 SUPPORT Human Clinical

"G6PC3 deficiency is characterized by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia in many patients, a prominent superficial venous pattern and a high incidence of congenital cardiac defects and uro-genital anomalies."

Review of reported cases identifies severe congenital neutropenia as the cardinal phenotype.

Intermittent thrombocytopenia HP:0001873

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:23758768 SUPPORT Human Clinical

"G6PC3 deficiency is characterized by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia in many patients, a prominent superficial venous pattern and a high incidence of congenital cardiac defects and uro-genital anomalies."

Review of reported cases supports intermittent thrombocytopenia in many patients.

Cardiovascular 3

Congenital cardiac defects Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:19118303 SUPPORT Human Clinical

"structural heart defects, urogenital abnormalities, and venous angiectasia on the trunk and extremities were additional features."

The original syndrome paper reports structural heart defects in syndromic G6PC3 deficiency.

Atrial septal defect FREQUENT HP:0001631

Show evidence (1 reference)

PMID:34964150 SUPPORT Human Clinical

"mainly atrial septal defect in 55%"

55% across 94 reported patients falls in the FREQUENT band (30-79%) and identifies ASD as the predominant cardiac lesion.

Pulmonary hypertension OCCASIONAL Pulmonary arterial hypertension HP:0002092

Show evidence (1 reference)

PMID:23758768 SUPPORT Human Clinical

"Pulmonary hypertension (PHT) has been described in 5/57 patients from three families."

5 of 57 reviewed patients (8.8%) falls in the OCCASIONAL band (5-29%).

Genitourinary 1

Urogenital anomalies Abnormality of the genitourinary system HP:0000119

Show evidence (1 reference)

PMID:19118303 SUPPORT Human Clinical

"structural heart defects, urogenital abnormalities, and venous angiectasia on the trunk and extremities were additional features."

The original syndrome paper reports urogenital abnormalities in syndromic G6PC3 deficiency.

Nervous System 1

Intellectual disability FREQUENT HP:0001249

Show evidence (1 reference)

PMID:25491320 SUPPORT Human Clinical

"including prominent veins (n = 12), cardiac malformations (n = 12), intellectual disability (n = 7), and myopathic syndrome with recurrent painful cramps (n = 1)"

7 of 14 patients (50%) in the French SCN registry cohort with long-term follow-up, which falls in the FREQUENT band (30-79%). The estimate rests on a single 14-patient series and should be treated as provisional.

Other 3

Recurrent bacterial infections VERY_FREQUENT HP:0002718

Temporal: RECURRENT

Show evidence (2 references)

PMID:34964150 SUPPORT Human Clinical

"all presented with at least 1 severe infection prior to age 2"

In the 94-patient literature review every reported patient had at least one severe infection before age 2. That supports a very high frequency band; VERY_FREQUENT rather than OBLIGATE is used because the quantified claim is "at least one severe infection", which is a weaker statement than the recurrent-bacterial-infection phenotype curated here.

PMID:23758768 SUPPORT Human Clinical

"G6PC3 deficiency is characterized by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia in many patients, a prominent superficial venous pattern and a high incidence of congenital cardiac defects and uro-genital anomalies."

Review of reported cases supports recurrent bacterial infections as a characteristic feature.

Prominent superficial veins FREQUENT HP:0001015

Show evidence (2 references)

PMID:34964150 SUPPORT Human Clinical

"prominent superficial veins in 62%"

62% across 94 reported patients falls in the FREQUENT band (30-79%).

PMID:23758768 SUPPORT Human Clinical

"G6PC3 deficiency is characterized by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia in many patients, a prominent superficial venous pattern and a high incidence of congenital cardiac defects and uro-genital anomalies."

Review of reported cases supports prominent superficial veins as a characteristic feature.

Crohn disease OCCASIONAL Crohn's disease HP:0100280

Show evidence (2 references)

PMID:25491320 SUPPORT Human Clinical

"Three patients developed Crohn's disease, and five had chronic diarrhea with steatorrhea."

3 of the 14 French-registry patients (21%) developed Crohn disease, which falls in the OCCASIONAL band (5-29%).

PMID:32930428 SUPPORT Human Clinical

"We conclude that neutrophils in G6PC3 deficiency release pro-inflammatory mediators when exposed to gut bacteria, associated with intestinal inflammation, despite treatment with G-CSF."

Studies in 4 children with G6PC3 deficiency-associated IBD support a neutrophil-intrinsic mechanism for the intestinal inflammation, and explicitly note that it is not corrected by G-CSF.

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Genetic Associations

1

G6PC3

Gene: G6PC3 hgnc:24861 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:19118303 SUPPORT Human Clinical

"We identified seven additional, unrelated patients who had severe congenital neutropenia with syndromic features and distinct biallelic mutations in G6PC3."

The original syndrome paper supports G6PC3 as the causative gene for syndromic severe congenital neutropenia.

PMID:23298686 SUPPORT Human Clinical

"Here, we describe four patients from three families with non-syndromic severe congenital neutropenia and identify four G6PC3 mutations as causative in these cases."

This report extends the G6PC3 causal spectrum to nonsyndromic severe congenital neutropenia.

Variants (1)

Biallelic G6PC3 pathogenic variants

Missense, truncating, frameshift, splice-site, and other pathogenic variants have been reported across the G6PC3 deficiency spectrum.

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Medical Actions

4

Granulocyte colony-stimulating factor (G-CSF)

Action: granulocyte colony-stimulating factor therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: recombinant granulocyte colony-stimulating factor NCIT:C1287

Recombinant G-CSF is the established first-line therapy. It raises the neutrophil count, prevents infection, and improves quality of life. It does NOT address the upstream metabolic lesion: it drives residual granulopoiesis harder rather than removing the 1,5-AG6P hexokinase block, so neutrophil function and the IBD phenotype may remain impaired, and some patients fail to respond even at large doses.

Target Phenotypes: Severe congenital neutropenia HP:0001875

Show evidence (2 references)

PMID:23758768 SUPPORT Human Clinical

"Treatment with G-CSF leads to improvement in neutrophil numbers, prevents infections and improves quality of life."

The disease review states the established benefit of G-CSF in G6PC3 deficiency.

PMID:33259599 SUPPORT Human Clinical

"Administration of granulocyte colony-stimulating factor (G-CSF) resolved the neutropenia and allowed for detailed evaluation of human neutrophil function."

Support is PARTIAL: G-CSF corrected the neutrophil COUNT, but the same study went on to document severely impaired migration, ingestion, bactericidal activity, and superoxide generation in those G-CSF-restored neutrophils — i.e. the qualitative defect persists.

Empagliflozin (SGLT2 inhibitor) — substrate-reduction repurposing

Action: Pharmacotherapy NCIT:C15986

Agent: empagliflozin CHEBI:82720

Empagliflozin, an SGLT2 inhibitor licensed for type 2 diabetes, is repurposed here as a substrate-reduction therapy. Blocking renal reabsorption of 1,5-anhydroglucitol lowers the plasma 1,5-AG pool, which in turn lowers intra-neutrophil 1,5-AG6P and relieves the hexokinase block — treating the mechanism rather than compensating for its output. This is the same repurposing that works in G6PT/SLC37A4 deficiency (glycogen storage disease type Ib), which shares the identical final metabolic lesion: G6PT and G6PC3 collaborate to destroy 1,5-AG6P, so loss of either produces the same accumulation.

Mechanism Target:

INHIBITS 1,5-AG6P accumulation and hexokinase inhibition — SGLT2 blockade increases urinary excretion of 1,5-anhydroglucitol, depleting the circulating precursor pool so that less 1,5-AG6P is formed inside neutrophils; measured neutrophil 1,5-AG6P falls and hexokinase inhibition is relieved.

Target Phenotypes: Severe congenital neutropenia HP:0001875 Recurrent bacterial infections HP:0002718

Show evidence (3 references)

PMID:35506446 SUPPORT Human Clinical

"Treatment with the SGLT2-inhibitor empagliflozin decreased 1,5-AG in blood and 1,5-AG6P in neutrophils and improved (PT1) or normalized (PT2) neutrophil counts, allowing to stop GCSF."

Direct demonstration in two G6PC3-deficient children that the drug lowers the causal metabolite and corrects the neutrophil count sufficiently to withdraw G-CSF.

PMID:35838821 SUPPORT Human Clinical

"A significant increase in all the hematopoietic cell lineages and substantial improvement in the quality of life was observed."

An independent adult case treated with an SGLT2 inhibitor, showing benefit extending beyond the neutrophil lineage.

PMID:32294159 SUPPORT Human Clinical

"Our discovery that accumulating 1,5-anhydroglucitol-6-phosphate (1,5AG6P) caused neutropenia in a glucose-6-phosphatase 3 (G6PC3)-deficient mouse model and in 2 rare diseases (GSD-Ib and G6PC3 deficiency) led us to repurpose the widely used antidiabetic drug empagliflozin"

Documents the shared 1,5-AG6P mechanism between GSD Ib and G6PC3 deficiency that motivated the repurposing, and the original clinical proof of concept in GSD-Ib.

Allogeneic haematopoietic stem cell transplantation

Action: hematopoietic stem cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Allogeneic HSCT replaces the G6PC3-deficient myeloid compartment and is curative for the haematological and gut-inflammatory disease. It is reserved for patients refractory to G-CSF, with G6PC3-associated IBD refractory to immune suppression, or with myelodysplastic/leukaemic transformation. It does not correct the non-haematopoietic features, since G6PC3 remains deficient in the recipient's other tissues.

Mechanism Target:

RESTORES Neutrophil functional defects — Donor-derived neutrophils carry functional G6PC3, so the metabolic block, the functional defect, and the neutropenia are all corrected in the transplanted haematopoietic compartment.

Show evidence (2 references)

PMID:32930428 SUPPORT Human Clinical

"HSCT led to normalization of neutrophil function and remission of gastrointestinal symptoms."

Shows HSCT corrects the neutrophil functional defect, not only the count, and resolves the IBD phenotype that G-CSF failed to control.

PMID:31157858 SUPPORT Human Clinical

"We show that HSCT resolves G6PC3-associated immunodeficiency and the Crohn's disease phenotype."

An adult case confirming that HSCT resolves both the immunodeficiency and the monogenic Crohn phenotype despite G6PC3 also being expressed non-haematopoietically.

Antibacterial prophylaxis

Action: Pharmacotherapy NCIT:C15986

Agent: antibiotic NCIT:C258

Mildly affected patients whose neutropenia does not reach the severe band may be managed with prophylactic antibiotics rather than G-CSF.

Target Phenotypes: Recurrent bacterial infections HP:0002718

Show evidence (1 reference)

PMID:23758768 SUPPORT Human Clinical

"Mildly affected patients can be managed with prophylactic antibiotics."

The disease review endorses antibiotic prophylaxis as an alternative in mildly affected patients.

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Biochemical Markers

4

Absolute neutrophil count (DECREASED)

Context: The absolute neutrophil count (ANC) is the defining laboratory measurement of the disease. In G6PC3 deficiency the ANC is typically in the severe band (<500/uL) at diagnosis and may fluctuate only marginally, in contrast to the regular oscillation of cyclic neutropenia. It is also the response variable for both G-CSF and empagliflozin therapy.

Pathograph Readouts

Readout Of Endoplasmic reticulum stress and increased myeloid apoptosis Negative Diagnostic

A falling ANC reports the net loss of maturing granulocytic precursors to apoptosis; ANC recovery is the standard endpoint for treatments aimed at the upstream metabolic lesion.

Show evidence (1 reference)

PMID:25491320 SUPPORT Human Clinical

"Neutropenia was profound (<0.5 × 109/l) in almost all cases at diagnosis and could marginally fluctuate."

Establishes the ANC as the primary quantitative disease readout and its typical severity at presentation.

Reference Ranges

Neutrophils [#/volume] in Blood by Automated count 1500.0– cells/uL (adults)

Normal (1500.0– cells/uL) Mild neutropenia (1000.0–1500.0 cells/uL) → Decreased total neutrophil count Moderate neutropenia (500.0–1000.0 cells/uL) → Decreased total neutrophil count Severe neutropenia (–500.0 cells/uL) → Decreased total neutrophil count

Normal: ANC at or above 1,500/uL is not neutropenic.

Mild neutropenia: Mild neutropenia; infection risk is close to background. Some G6PC3 patients sit in this band and can be managed with prophylactic antibiotics alone.

Moderate neutropenia: Moderate neutropenia with intermediate infection risk.

Severe neutropenia: Severe neutropenia; the band occupied by almost all G6PC3-deficient patients at diagnosis and the threshold at which severe pyogenic infection risk rises sharply and G-CSF is indicated.

One-sided interval: chronic neutropenia is diagnosed below 1,500/uL, so only a lower bound is given. Paediatric lower limits are age-dependent and lower in infancy and in individuals of African ancestry (benign ethnic neutropenia); this interval is the adult chronic-neutropenia threshold.

Show evidence (1 reference)

PMID:30078793 SUPPORT Other

"diagnosis of chronic neutropenia is based on recurrent or continuous neutropenia defined by absolute neutrophil count (ANC) less than 1,500/µl for over three or more months"

Source for the 1,500/uL lower bound. Evidence source is OTHER because this is a consensus reference guide rather than a primary study.

Show evidence (1 reference)

PMID:25491320 SUPPORT Human Clinical

"Neutropenia was profound (<0.5 × 109/l) in almost all cases at diagnosis and could marginally fluctuate."

Long-term registry follow-up documents profound neutropenia at diagnosis in nearly all G6PC3 patients.

1,5-anhydroglucitol-6-phosphate (INCREASED)

Context: 1,5-AG6P is the nonclassical phosphorylated glucose analog that accumulates in G6PC3- or G6PT-deficient granulocytes and inhibits low-KM hexokinases.

Pathograph Readouts

Readout Of 1,5-AG6P accumulation and hexokinase inhibition Positive Diagnostic

Increased 1,5-AG6P reports the failed G6PC3/G6PT metabolite-repair reaction.

Show evidence (1 reference)

PMID:30626647 SUPPORT Human Clinical

"Granulocytes from patients deficient in G6PC3 or G6PT accumulate 1,5AG6P to concentrations (~3 mM) that strongly inhibit hexokinase activity."

Patient granulocyte data support 1,5-AG6P as the proximal biochemical readout.

Show evidence (1 reference)

PMID:30626647 SUPPORT Human Clinical

"Granulocytes from patients deficient in G6PC3 or G6PT accumulate 1,5AG6P to concentrations (~3 mM) that strongly inhibit hexokinase activity."

Patient granulocyte data support increased 1,5-AG6P in G6PC3 deficiency.

Plasma 1,5-anhydroglucitol (PRESENT)

Context: 1,5-Anhydroglucitol is an abundant, largely dietary blood polyol and the precursor from which the toxic 1,5-AG6P is generated intracellularly. Plasma 1,5-AG is not itself abnormal in G6PC3 deficiency — it is the pharmacological handle: SGLT2 inhibition blocks its renal reabsorption, lowers the plasma pool, and thereby lowers neutrophil 1,5-AG6P. Interindividual variation in 1,5-AG clearance (e.g. an SGLT5 variant) modifies disease severity.

Pathograph Readouts

Readout Of 1,5-AG6P accumulation and hexokinase inhibition Positive Pharmacodynamic

Plasma 1,5-AG is the upstream substrate pool; lowering it with an SGLT2 inhibitor is the direct pharmacodynamic readout of the therapy and tracks the fall in neutrophil 1,5-AG6P.

Show evidence (1 reference)

PMID:35506446 SUPPORT Human Clinical

"Treatment with the SGLT2-inhibitor empagliflozin decreased 1,5-AG in blood and 1,5-AG6P in neutrophils"

Demonstrates the plasma-1,5-AG to neutrophil-1,5-AG6P pharmacodynamic chain directly in G6PC3-deficient patients.

Show evidence (1 reference)

PMID:35506446 SUPPORT Human Clinical

"which had low blood 1,5-AG levels and only required GCSF during severe infections"

Shows that a low endogenous plasma 1,5-AG level (here from an SGLT5 missense variant increasing urinary clearance) attenuates the disease, confirming plasma 1,5-AG as a severity-determining variable.

Neutrophil gp91phox hypoglycosylation (PRESENT)

Context: Hypoglycosylation of gp91phox/NADPH oxidase is a CDG-like biochemical and cellular readout of G6PC3-related neutrophil dysfunction.

Pathograph Readouts

Readout Of Neutrophil glycosylation and oxidase dysfunction Positive Diagnostic

gp91phox hypoglycosylation reports the glycosylation branch of neutrophil dysfunction.

Show evidence (1 reference)

PMID:21385794 SUPPORT Human Clinical

"hypo-glycosylation of gp91(phox), the electron-transporting component of the NADPH oxidase, in all of these patients."

Patient neutrophil glycomics support gp91phox hypoglycosylation as a mechanistic readout.

Show evidence (1 reference)

PMID:21385794 SUPPORT Human Clinical

"This aberrant neutrophil glycosylation is predicted to have profound effects on the neutrophil function and merit designation of both syndromes as a new class of congenital disorders of glycosylation."

The glycosylation paper supports classifying the glycan abnormality as a CDG-like mechanism.

🔬

Diagnosis

3

Serial absolute neutrophil count

Repeated full blood counts establish persistent rather than cyclic neutropenia. In G6PC3 deficiency the count is typically profound (<500 cells/uL) at diagnosis and fluctuates only marginally, which helps separate it from cyclic neutropenia. See the absolute-neutrophil-count entry under `biochemical` for the reference range and severity bands.

diagnostic procedure NCIT:C18020

Markers: Absolute neutrophil count

Show evidence (1 reference)

PMID:25491320 SUPPORT Human Clinical

"Neutropenia was profound (<0.5 × 109/l) in almost all cases at diagnosis and could marginally fluctuate."

Registry follow-up establishes the expected ANC severity and its near-static behaviour over time.

G6PC3 sequencing

Biallelic pathogenic G6PC3 variants confirm the diagnosis. Because the disorder is clinically indistinguishable from other severe congenital neutropenias when nonsyndromic, G6PC3 should be included in any congenital neutropenia gene panel rather than tested only when syndromic features are present.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:23758768 SUPPORT Human Clinical

"The condition can be diagnosed by sequencing the G6PC3 gene."

The disease review names G6PC3 sequencing as the confirmatory diagnostic test.

PMID:23298686 SUPPORT Human Clinical

"Here, we describe four patients from three families with non-syndromic severe congenital neutropenia and identify four G6PC3 mutations as causative in these cases."

Establishes that G6PC3 disease occurs without syndromic features, so absence of cardiac/venous/urogenital signs does not exclude it.

Echocardiography and renal/pelvic ultrasound at diagnosis

Because congenital cardiac and urogenital malformations are frequent and often clinically silent, imaging of the heart and urinary tract is recommended in every suspected or confirmed case rather than only when symptoms prompt it.

diagnostic imaging NCIT:C17369

Show evidence (1 reference)

PMID:23758768 SUPPORT Human Clinical

"Echocardiogram, renal and pelvic ultrasound scans should be performed in all cases of suspected or confirmed G6PC3 deficiency."

The disease review makes this an explicit management recommendation at diagnosis.

📊

Prevalence

2

Worldwide

Cases In Literature Ultra Rare

94 patients reported worldwide in the decade after the 2009 gene discovery, from at least 14 countries on 4 continents, with 48% from Middle Eastern countries (consanguinity-enriched). No population-based prevalence estimate exists; the count-in-literature measure is used deliberately rather than a fabricated rate.

Show evidence (1 reference)

PMID:34964150 SUPPORT Human Clinical

"With a total of 94 patients reported in the past decade"

Systematic literature review counting all reported cases from 2009 to 2020.

French Severe Congenital Neutropenia Registry

Unknown Unknown

Share of a severe-congenital-neutropenia population, not a general-population rate: 14 of 605 registry patients (2.3%) carried biallelic G6PC3 variants. Recorded as a genetic-share denominator for differential diagnosis rather than as disease occurrence.

Show evidence (1 reference)

PMID:25491320 SUPPORT Human Clinical

"Among 605 patients included in the French SCN registry, we identified 8 pedigrees that included 14 patients with autosomal recessive G6PC3 mutations."

Gives the numerator and denominator for the G6PC3 share of a national severe-congenital-neutropenia registry.

{ }

Source YAML

click to show

name: G6PC3 Deficiency
category: Mendelian
creation_date: '2026-07-06T02:20:39Z'
synonyms:
- Ubiquitous glucose-6-phosphatase deficiency
- Glucose-6-phosphatase catalytic subunit 3 deficiency
- Severe congenital neutropenia type 4
- Severe congenital neutropenia due to G6PC3 deficiency
- Dursun syndrome
description: >-
  G6PC3 deficiency is an autosomal recessive metabolite-repair/proofreading
  disorder caused by biallelic G6PC3 variants. G6PC3 encodes the ubiquitously
  expressed endoplasmic-reticulum glucose-6-phosphatase catalytic subunit 3.
  The modern metabolite-repair model explains the neutrophil phenotype as
  failure to hydrolyze the nonclassical glucose analog
  1,5-anhydroglucitol-6-phosphate (1,5-AG6P), which accumulates in granulocytes,
  inhibits hexokinase, impairs early glycolysis, and causes neutrophil
  dysfunction and neutropenia.
  A second documented branch is abnormal neutrophil glycosylation affecting
  gp91phox/NADPH oxidase. Clinically, the spectrum ranges from nonsyndromic
  severe congenital neutropenia to syndromic disease with recurrent bacterial
  infections, prominent superficial veins, congenital cardiac defects, and
  urogenital anomalies.
classifications:
  icimd_category:
  - classification_value: metabolite_proofreading
    notes: >-
      ICIMD package WP-031 classifies G6PC3-related ubiquitous
      glucose-6-phosphatase deficiency under Intermediary Metabolism: Others ->
      Disorders of metabolite repair/proofreading, based on failure to eliminate
      the nonclassical metabolite 1,5-AG6P.
  iuis_category:
    classification_value: phagocyte defect
    notes: >-
      IUIS Table 5 (congenital defects of phagocyte number, function, or both).
      G6PC3 deficiency is a congenital defect of phagocyte NUMBER (severe
      congenital neutropenia type 4) that additionally impairs phagocyte
      FUNCTION (chemotaxis, respiratory burst), so it spans both halves of the
      table.
    evidence:
    - reference: PMID:23758768
      reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        G6PC3 deficiency is characterized by severe congenital neutropenia,
        recurrent bacterial infections
      explanation: >-
        Places the disorder in the congenital-neutropenia (phagocyte number)
        branch of the IUIS inborn-errors-of-immunity classification.
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
    notes: >-
      Disorders of granulocytes: severe congenital neutropenia with a
      granulopoietic maturation defect in the bone marrow.
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      Primary immunodeficiency: an inborn error of immunity presenting with
      recurrent pyogenic bacterial infection.
disease_term:
  preferred_term: G6PC3 deficiency (severe congenital neutropenia type 4)
  term:
    id: MONDO:0012930
    label: autosomal recessive severe congenital neutropenia due to G6PC3 deficiency
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0012930
      label: autosomal recessive severe congenital neutropenia due to G6PC3 deficiency
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO (Orphanet:331176, OMIM:612541)
    mapping_justification: >-
      MONDO:0012930 is the gene-anchored SCN4 entity (relationship RO:0004003 to
      HGNC:24861 G6PC3; xrefs OMIM:612541, Orphanet:331176) and carries the
      synonyms "severe congenital neutropenia type 4" and "SCN4". It is the
      correct anchor for the full G6PC3-deficiency continuum curated here,
      including the nonsyndromic form.
  - term:
      id: MONDO:0023124
      label: Dursun syndrome
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO (Orphanet:178503)
    mapping_justification: >-
      Dursun syndrome is a NARROWER G6PC3-related entity restricted to the
      familial pulmonary-arterial-hypertension / leukopenia / atrial-septal-defect
      presentation (Orphanet:178503). This entry previously anchored its
      disease_term to MONDO:0023124; that was too narrow for an entry describing
      the whole G6PC3 spectrum and has been corrected to MONDO:0012930, with
      Dursun syndrome retained here as a narrow match.
parents:
- Severe Congenital Neutropenia
- Inborn Error of Metabolism
- Congenital Disorder of Glycosylation
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    G6PC3 deficiency is caused by biallelic pathogenic variants in G6PC3.
  evidence:
  - reference: PMID:23758768
    reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bi-allelic G6PC3 mutations cause a multi-system autosomal recessive disorder of G6PC3 deficiency
    explanation: Review evidence supports autosomal recessive inheritance of G6PC3 deficiency.
pathophysiology:
- name: G6PC3 endoplasmic-reticulum phosphatase deficiency
  biological_scale: MOLECULAR
  description: >-
    Biallelic G6PC3 variants reduce ubiquitous endoplasmic-reticulum
    glucose-6-phosphatase activity. In neutrophils, the critical repair defect
    is failure to dephosphorylate the glucose analog 1,5-AG6P.
  genes:
  - preferred_term: G6PC3
    term:
      id: hgnc:24861
      label: G6PC3
  molecular_functions:
  - preferred_term: glucose-6-phosphatase activity
    term:
      id: GO:0004346
      label: glucose-6-phosphatase activity
    modifier: DECREASED
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  locations:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence:
  - reference: PMID:19118303
    reference_title: "A syndrome with congenital neutropenia and mutations in G6PC3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequencing of G6PC3, the candidate gene encoding glucose-6-phosphatase, catalytic subunit 3, revealed a homozygous missense mutation in exon 6 that abolished the enzymatic activity of glucose-6-phosphatase in all affected children in the two families.
    explanation: The original syndrome paper links G6PC3 variants to loss of glucose-6-phosphatase activity.
  downstream:
  - target: 1,5-AG6P accumulation and hexokinase inhibition
    description: >-
      G6PC3 normally collaborates with G6PT to destroy 1,5-AG6P; deficiency
      allows this glucose analog phosphate to accumulate and inhibit low-KM
      hexokinases.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30626647
      reference_title: "Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we demonstrate that G6PT and G6PC3 collaborate to destroy 1,5-anhydroglucitol-6-phosphate (1,5AG6P), a close structural analog of glucose-6-phosphate and an inhibitor of low-KM hexokinases
      explanation: Mechanistic experiments define the metabolite-repair substrate of G6PC3/G6PT.
  - target: Neutrophil glycosylation and oxidase dysfunction
    description: >-
      The same loss of ER glucose-6-phosphatase activity is accompanied by a
      major defect of neutrophil N- and O-glycosylation, including
      hypoglycosylation of the NADPH-oxidase component gp91phox. This is the
      second, parallel branch out of the primary enzyme defect. Whether it is a
      genuinely independent consequence of the ER-luminal lesion or is itself
      downstream of reduced glucose-6-phosphate availability starving
      nucleotide-sugar synthesis is unresolved (see discussion
      gap_g6pc3_glycosylation_vs_metabolite).
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced ER-luminal glucose-6-phosphate handling.
    - Impaired nucleotide-sugar availability for glycan assembly.
    - Truncated neutrophil N- and O-glycan structures.
    evidence:
    - reference: PMID:21385794
      reference_title: "G6PC3 mutations are associated with a major defect of glycosylation: a novel mechanism for neutrophil dysfunction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        hypo-glycosylation of gp91(phox), the electron-transporting component of the NADPH oxidase, in all of these patients.
      explanation: >-
        Links G6PC3 mutation directly to a neutrophil glycosylation defect in
        patients, establishing this branch as a consequence of the enzyme
        deficiency.
  - target: Ubiquitous G6PC3 loss in non-haematopoietic tissues
    description: >-
      G6PC3 is ubiquitously expressed, so the same biallelic loss-of-function
      that produces the neutrophil lesion is also present in cardiac, vascular,
      and urogenital tissue, where it underlies the extra-haematological
      features of the syndrome.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23758768
      reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        G6PC3 deficiency is characterized by severe congenital neutropenia,
        recurrent bacterial infections, intermittent thrombocytopenia in many
        patients, a prominent superficial venous pattern and a high incidence of
        congenital cardiac defects and uro-genital anomalies.
      explanation: >-
        Establishes that the same G6PC3 deficiency produces both the
        haematological and the extra-haematological arms of the disease.
- name: 1,5-AG6P accumulation and hexokinase inhibition
  biological_scale: MOLECULAR
  description: >-
    Granulocytes deficient in G6PC3 accumulate millimolar 1,5-AG6P, inhibiting
    hexokinase and reducing glucose utilization. This is especially damaging
    for neutrophils, which depend heavily on glycolysis for effector function.
    1,5-AG6P is made by glucose-phosphorylating enzymes from 1,5-anhydroglucitol
    (1,5-AG), an abundant blood polyol of dietary origin — so the toxic
    metabolite is continuously regenerated from the circulating pool, which is
    what makes lowering plasma 1,5-AG a tractable therapeutic target.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: glycolytic process
    term:
      id: GO:0006096
      label: glycolytic process
    modifier: DECREASED
  molecular_functions:
  - preferred_term: hexokinase activity
    term:
      id: GO:0004396
      label: hexokinase activity
    modifier: DECREASED
  chemical_entities:
  - preferred_term: 1,5-anhydroglucitol-6-phosphate
    description: >-
      Nonclassical phosphorylated glucose analog; no CHEBI identifier was
      identified in the local adapter during WP-031 curation.
    modifier: INCREASED
  evidence:
  - reference: PMID:30626647
    reference_title: "Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Granulocytes from patients deficient in G6PC3 or G6PT accumulate 1,5AG6P to concentrations (~3 mM) that strongly inhibit hexokinase activity.
    explanation: Patient granulocyte data directly support 1,5-AG6P accumulation and hexokinase inhibition.
  - reference: PMID:35506446
    reference_title: "Successful use of empagliflozin to treat neutropenia in two G6PC3-deficient children: Impact of a mutation in SGLT5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P), an inhibitor of
      hexokinase made from 1,5-anhydroglucitol (1,5-AG), an abundant polyol
      present in blood
    explanation: >-
      Identifies the precursor of the toxic metabolite as the circulating
      dietary polyol 1,5-AG, which is the basis of the plasma-1,5-AG-lowering
      therapeutic strategy.
  downstream:
  - target: Neutrophil glycolytic block and energy deficit
    description: >-
      Hexokinase inhibition by 1,5-AG6P blocks the first committed step of
      glycolysis in cells that depend on it, so glucose utilization falls.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30626647
      reference_title: "Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In a model of G6PC3-deficient mouse neutrophils, physiological concentrations of 1,5-anhydroglucitol caused massive accumulation of 1,5AG6P, a decrease in glucose utilization, and cell death.
      explanation: Mouse neutrophil experiments connect 1,5-anhydroglucitol exposure to 1,5-AG6P buildup and reduced glucose use.
  - target: Neutrophil functional defects
    description: >-
      1,5-AG6P accumulation decreases neutrophil glucose utilization and can
      cause neutrophil cell death.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30626647
      reference_title: "Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In a model of G6PC3-deficient mouse neutrophils, physiological concentrations of 1,5-anhydroglucitol caused massive accumulation of 1,5AG6P, a decrease in glucose utilization, and cell death.
      explanation: Mouse neutrophil experiments connect 1,5-anhydroglucitol exposure to 1,5-AG6P buildup, reduced glucose use, and cell death.
- name: Neutrophil glycolytic block and energy deficit
  biological_scale: CELLULAR
  description: >-
    Myeloid-cell energy metabolism depends primarily on glycolysis, so
    hexokinase inhibition by accumulated 1,5-AG6P translates directly into an
    energy deficit in neutrophils and their bone-marrow precursors. This is the
    step that makes an otherwise ubiquitous enzyme defect present as a
    neutrophil-selective disease.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: granulocyte monocyte progenitor cell
    term:
      id: CL:0000557
      label: granulocyte monocyte progenitor cell
  biological_processes:
  - preferred_term: glycolytic process
    term:
      id: GO:0006096
      label: glycolytic process
    modifier: DECREASED
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  evidence:
  - reference: PMID:35838821
    reference_title: "SLGT2 Inhibitor Rescues Myelopoiesis in G6PC3 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The energy metabolism of myeloid cells depends primarily on glycolysis.
    explanation: >-
      States the glycolytic dependence of myeloid cells that makes hexokinase
      inhibition selectively damaging to the neutrophil lineage. The cited
      publication is an investigator-initiated human study of an
      SGLT2-inhibitor-treated G6PC3 patient, hence HUMAN_CLINICAL, though this
      particular sentence is its framing of established myeloid physiology.
  - reference: PMID:33259599
    reference_title: "Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      demonstrated dramatic impairments in early glycolysis (hexose phosphate
      levels), hexosemonophosphate shunt (required for the generation of the
      NADPH), and the total adenylate pool
    explanation: >-
      Stable-isotope metabolomics in patient neutrophils confirms the glycolytic
      block and the resulting fall in the adenylate (energy) pool in human
      G6PC3 deficiency, not only in the mouse model.
  downstream:
  - target: Endoplasmic reticulum stress and increased myeloid apoptosis
    description: >-
      Impaired glucose flux lowers intracellular glucose and glucose-6-phosphate,
      provoking an endoplasmic-reticulum stress response and pro-apoptotic
      signalling in myeloid cells.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced cytoplasmic glucose and glucose-6-phosphate.
    - PERK/BiP-mediated unfolded protein response.
    - GSK-3beta activation and Mcl-1 destabilization.
    evidence:
    - reference: PMID:23758768
      reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        result in reduced enzyme activity, endoplasmic reticulum stress response,
        increased rates of apoptosis of affected cells and dysfunction of neutrophil
      explanation: >-
        The review links reduced G6PC3 enzyme activity to ER stress and
        increased apoptosis as the intermediate steps to neutrophil loss.
  - target: Neutrophil functional defects
    description: >-
      Neutrophil effector functions (chemotaxis, respiratory burst,
      bactericidal killing) are ATP- and NADPH-expensive and fail when
      glycolysis and the hexose monophosphate shunt are impaired.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33259599
      reference_title: "Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In human deficiency of G6PC3, metabolic defects resulting from the enzyme deficiency account for diverse neutrophil functional defects and present a major risk of infection.
      explanation: >-
        Attributes the functional defects of patient neutrophils to the
        metabolic lesion.
- name: Endoplasmic reticulum stress and increased myeloid apoptosis
  biological_scale: CELLULAR
  description: >-
    G6PC3-deficient neutrophils, myeloid progenitors, and fibroblasts show
    increased endoplasmic-reticulum stress, increased GSK-3beta activity, and
    increased susceptibility to apoptosis. Accelerated death of maturing
    granulocytic precursors is what converts a metabolic lesion into a
    quantitative neutropenia rather than a purely functional defect.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: granulocyte monocyte progenitor cell
    term:
      id: CL:0000557
      label: granulocyte monocyte progenitor cell
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    modifier: INCREASED
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  - preferred_term: myeloid cell differentiation
    term:
      id: GO:0030099
      label: myeloid cell differentiation
    modifier: DECREASED
  locations:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence:
  - reference: PMID:19118303
    reference_title: "A syndrome with congenital neutropenia and mutations in G6PC3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients' neutrophils and fibroblasts had increased susceptibility to
      apoptosis. The myeloid cells showed evidence of increased endoplasmic
      reticulum stress and increased activity of glycogen synthase kinase 3beta
      (GSK-3beta).
    explanation: >-
      The index study directly measured ER stress and apoptotic susceptibility
      in patient neutrophils, fibroblasts, and myeloid cells.
  - reference: PMID:34964150
    reference_title: "Severe congenital neutropenia due to G6PC3 deficiency: Case series of five patients and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      caused by an alteration of glucose homeostasis, with increased endoplasmic
      reticulum stress and cell apoptosis
    explanation: >-
      A 94-patient literature review frames ER stress and apoptosis downstream
      of the glucose-homeostasis lesion as the accepted disease mechanism.
  downstream:
  - target: Severe congenital neutropenia
    description: >-
      Apoptotic loss of maturing granulocytic precursors produces a late-stage
      granulopoietic maturation defect in the marrow and profound peripheral
      neutropenia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19118303
      reference_title: "A syndrome with congenital neutropenia and mutations in G6PC3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All index patients were susceptible to bacterial infections and had
        very few mature neutrophils in the bone marrow
      explanation: >-
        Scarcity of mature marrow neutrophils is the histological correlate of
        precursor loss.
    - reference: PMID:25491320
      reference_title: "Clinical spectrum and long-term follow-up of 14 cases with G6PC3 mutations from the French Severe Congenital Neutropenia Registry."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The bone marrow smears exhibited mild late-stage granulopoeitic defects.
      explanation: >-
        The French SCN registry documents the late-stage granulopoietic
        maturation defect in the marrow of G6PC3 patients.
- name: Neutrophil glycosylation and oxidase dysfunction
  biological_scale: MOLECULAR
  conforms_to: "phagocyte_oxidative_burst_failure#Phagocyte NADPH Oxidase Assembly or Activation Failure"
  description: >-
    G6PC3 deficiency is also associated with truncated neutrophil N- and
    O-glycans and hypoglycosylation of gp91phox, the electron-transporting
    NADPH oxidase component, providing a CDG-like branch of neutrophil
    dysfunction.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: respiratory burst
    term:
      id: GO:0045730
      label: respiratory burst
    modifier: DECREASED
  evidence:
  - reference: PMID:21385794
    reference_title: "G6PC3 mutations are associated with a major defect of glycosylation: a novel mechanism for neutrophil dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypo-glycosylation of gp91(phox), the electron-transporting component of the NADPH oxidase, in all of these patients.
    explanation: Patient neutrophil data support gp91phox hypoglycosylation as a branch of G6PC3-related neutrophil dysfunction.
  downstream:
  - target: Neutrophil functional defects
    description: >-
      Glycolytic impairment and glycosylation defects converge on impaired
      neutrophil migration, ingestion, bactericidal activity, and superoxide
      production.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Early glycolysis and hexose monophosphate shunt impairment.
    - gp91phox/NADPH oxidase hypoglycosylation.
    evidence:
    - reference: PMID:33259599
      reference_title: "Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In human deficiency of G6PC3, metabolic defects resulting from the enzyme deficiency account for diverse neutrophil functional defects and present a major risk of infection.
      explanation: Human neutrophil functional testing links G6PC3 metabolic defects to impaired neutrophil function and infection risk.
- name: Neutrophil functional defects
  biological_scale: CELLULAR
  conforms_to: "phagocyte_oxidative_burst_failure#Failed Respiratory Burst and Phagosomal ROS Deficiency"
  description: >-
    G6PC3-deficient neutrophils have impaired migration, actin assembly,
    bactericidal activity, superoxide generation, and survival, leading to
    severe congenital neutropenia and recurrent bacterial infections.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: neutrophil chemotaxis
    term:
      id: GO:0030593
      label: neutrophil chemotaxis
    modifier: DECREASED
  - preferred_term: respiratory burst
    term:
      id: GO:0045730
      label: respiratory burst
    modifier: DECREASED
  - preferred_term: neutrophil mediated immunity
    term:
      id: GO:0002446
      label: neutrophil mediated immunity
    modifier: DECREASED
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:33259599
    reference_title: "Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Random and directed migration by the patient's neutrophils was severely diminished.
    explanation: Patient neutrophil assays support impaired chemotaxis/migration.
  - reference: PMID:33259599
    reference_title: "Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Superoxide anion generation was <25% of control values
    explanation: Patient neutrophil assays support defective respiratory burst.
  downstream:
  - target: Severe congenital neutropenia
    description: Neutrophil death and functional impairment produce the hematologic phenotype of severe congenital neutropenia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30626647
      reference_title: "Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In conclusion, we show that the neutropenia in patients with G6PC3 or G6PT mutations is a metabolite-repair deficiency, caused by a failure to eliminate the nonclassical metabolite 1,5AG6P.
      explanation: The metabolite-repair paper directly states the mechanism for neutropenia in G6PC3 deficiency.
  - target: Recurrent bacterial infections
    description: Reduced mature neutrophils and impaired neutrophil effector function increase susceptibility to recurrent bacterial infection.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19118303
      reference_title: "A syndrome with congenital neutropenia and mutations in G6PC3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All index patients were susceptible to bacterial infections and had very few mature neutrophils in the bone marrow
      explanation: The original syndrome paper links neutrophil scarcity to bacterial infection susceptibility.
  - target: Crohn disease
    description: >-
      Dysfunctional G6PC3-deficient neutrophils encountering gut bacteria
      release excess IL-8 and reactive oxygen species and undergo increased
      apoptosis and secondary necrosis, driving intestinal inflammation. This
      edge is neutrophil-intrinsic rather than a consequence of low neutrophil
      numbers, which is why G-CSF does not control the IBD phenotype while HSCT
      does.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Excess neutrophil IL-8 and reactive oxygen species release on exposure to
      gut bacteria.
    - Increased neutrophil apoptosis and secondary necrosis in the mucosa.
    - Sustained mucosal inflammatory signalling.
    evidence:
    - reference: PMID:32930428
      reference_title: "Neutrophil dysfunction triggers inflammatory bowel disease in G6PC3 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We conclude that neutrophils in G6PC3 deficiency release pro-inflammatory
        mediators when exposed to gut bacteria, associated with intestinal
        inflammation, despite treatment with G-CSF.
      explanation: >-
        States the neutrophil-intrinsic mechanism of the IBD phenotype directly,
        and that it persists under G-CSF — the rationale for HSCT.
- name: Ubiquitous G6PC3 loss in non-haematopoietic tissues
  biological_scale: MOLECULAR
  description: >-
    Unlike the liver/kidney-restricted G6PC1 (glycogen storage disease Ia) and
    the largely haematopoietic phenotype of G6PT/SLC37A4 (GSD Ib), G6PC3 is
    ubiquitously expressed. Loss of the enzyme outside the marrow is the
    presumed basis of the extra-haematological features that distinguish
    G6PC3 deficiency from other severe congenital neutropenias: a prominent
    superficial venous pattern, congenital cardiac malformation (most often
    atrial septal defect), and urogenital anomalies. About three-quarters of
    reported patients are syndromic in this way. The step from ubiquitous
    enzyme loss to a specific developmental malformation is NOT mechanistically
    resolved (see the knowledge-gap discussion attached to this node); ER
    stress and increased apoptosis in non-myeloid cells such as fibroblasts is
    the leading, but unproven, explanation.
  genes:
  - preferred_term: G6PC3
    term:
      id: hgnc:24861
      label: G6PC3
  molecular_functions:
  - preferred_term: glucose-6-phosphatase activity
    term:
      id: GO:0004346
      label: glucose-6-phosphatase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:23758768
    reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      G6PC3 deficiency is characterized by severe congenital neutropenia,
      recurrent bacterial infections, intermittent thrombocytopenia in many
      patients, a prominent superficial venous pattern and a high incidence of
      congenital cardiac defects and uro-genital anomalies.
    explanation: >-
      Establishes the extra-haematological feature set that accompanies the
      neutropenia in this ubiquitously expressed enzyme deficiency.
  - reference: PMID:34964150
    reference_title: "Severe congenital neutropenia due to G6PC3 deficiency: Case series of five patients and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seventy-five per cent had syndromic features, mainly atrial septal defect
      in 55% and prominent superficial veins in 62%.
    explanation: >-
      Quantifies how often the non-haematological arm is expressed across the
      94 reported patients.
  downstream:
  - target: Prominent superficial veins
    description: >-
      Superficial venous angiectasia on trunk and extremities is the most
      recognizable non-haematological sign of G6PC3 deficiency.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:19118303
      reference_title: "A syndrome with congenital neutropenia and mutations in G6PC3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        structural heart defects, urogenital abnormalities, and venous angiectasia on the trunk and extremities were additional features.
      explanation: >-
        Reports venous angiectasia as an intrinsic feature of the G6PC3
        syndrome rather than a consequence of the neutropenia.
  - target: Congenital cardiac defects
    description: >-
      Congenital structural heart disease arises developmentally and is not a
      consequence of neutropenia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:19118303
      reference_title: "A syndrome with congenital neutropenia and mutations in G6PC3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        structural heart defects, urogenital abnormalities, and venous angiectasia on the trunk and extremities were additional features.
      explanation: >-
        Reports structural heart defects as an intrinsic feature of the
        G6PC3 syndrome.
  - target: Atrial septal defect
    description: >-
      Atrial septal defect is the specific cardiac lesion that dominates the
      G6PC3 congenital-heart-disease spectrum, present in just over half of
      reported patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34964150
      reference_title: "Severe congenital neutropenia due to G6PC3 deficiency: Case series of five patients and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Seventy-five per cent had syndromic features, mainly atrial septal defect
        in 55% and prominent superficial veins in 62%.
      explanation: >-
        Identifies ASD as the predominant structural cardiac lesion of the
        syndromic G6PC3 phenotype across 94 reported patients.
  - target: Urogenital anomalies
    description: >-
      Urogenital malformations are part of the same developmental arm.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:19118303
      reference_title: "A syndrome with congenital neutropenia and mutations in G6PC3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        structural heart defects, urogenital abnormalities, and venous angiectasia on the trunk and extremities were additional features.
      explanation: >-
        Reports urogenital abnormalities as an intrinsic feature of the
        G6PC3 syndrome.
phenotypes:
- category: Hematologic
  name: Severe congenital neutropenia
  description: >-
    Persistent severe neutropenia is the core hematologic phenotype and may
    occur with or without additional congenital anomalies.
  phenotype_term:
    preferred_term: Severe congenital neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:23758768
    reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      G6PC3 deficiency is characterized by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia in many patients, a prominent superficial venous pattern and a high incidence of congenital cardiac defects and uro-genital anomalies.
    explanation: Review of reported cases identifies severe congenital neutropenia as the cardinal phenotype.
- category: Immune
  name: Recurrent bacterial infections
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
    temporality: RECURRENT
  evidence:
  - reference: PMID:34964150
    reference_title: "Severe congenital neutropenia due to G6PC3 deficiency: Case series of five patients and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all presented with at least 1 severe infection prior to age 2
    explanation: >-
      In the 94-patient literature review every reported patient had at least
      one severe infection before age 2. That supports a very high frequency
      band; VERY_FREQUENT rather than OBLIGATE is used because the quantified
      claim is "at least one severe infection", which is a weaker statement than
      the recurrent-bacterial-infection phenotype curated here.
  - reference: PMID:23758768
    reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      G6PC3 deficiency is characterized by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia in many patients, a prominent superficial venous pattern and a high incidence of congenital cardiac defects and uro-genital anomalies.
    explanation: Review of reported cases supports recurrent bacterial infections as a characteristic feature.
- category: Hematologic
  name: Intermittent thrombocytopenia
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
    temporality: TRANSIENT
  evidence:
  - reference: PMID:23758768
    reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      G6PC3 deficiency is characterized by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia in many patients, a prominent superficial venous pattern and a high incidence of congenital cardiac defects and uro-genital anomalies.
    explanation: Review of reported cases supports intermittent thrombocytopenia in many patients.
- category: Vascular
  name: Prominent superficial veins
  frequency: FREQUENT
  description: >-
    A prominent superficial venous pattern (venous angiectasia over trunk and
    limbs) is the most distinctive non-haematological sign of G6PC3 deficiency
    and is one of the features that separates it clinically from ELANE-related
    and other severe congenital neutropenias.
  phenotype_term:
    preferred_term: Prominent superficial veins
    term:
      id: HP:0001015
      label: Prominent superficial veins
  evidence:
  - reference: PMID:34964150
    reference_title: "Severe congenital neutropenia due to G6PC3 deficiency: Case series of five patients and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      prominent superficial veins in 62%
    explanation: >-
      62% across 94 reported patients falls in the FREQUENT band (30-79%).
  - reference: PMID:23758768
    reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      G6PC3 deficiency is characterized by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia in many patients, a prominent superficial venous pattern and a high incidence of congenital cardiac defects and uro-genital anomalies.
    explanation: Review of reported cases supports prominent superficial veins as a characteristic feature.
- category: Cardiovascular
  name: Congenital cardiac defects
  phenotype_term:
    preferred_term: Congenital cardiac defects
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:19118303
    reference_title: "A syndrome with congenital neutropenia and mutations in G6PC3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      structural heart defects, urogenital abnormalities, and venous angiectasia on the trunk and extremities were additional features.
    explanation: The original syndrome paper reports structural heart defects in syndromic G6PC3 deficiency.
- category: Genitourinary
  name: Urogenital anomalies
  phenotype_term:
    preferred_term: Urogenital anomalies
    term:
      id: HP:0000119
      label: Abnormality of the genitourinary system
  evidence:
  - reference: PMID:19118303
    reference_title: "A syndrome with congenital neutropenia and mutations in G6PC3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      structural heart defects, urogenital abnormalities, and venous angiectasia on the trunk and extremities were additional features.
    explanation: The original syndrome paper reports urogenital abnormalities in syndromic G6PC3 deficiency.
- category: Cardiovascular
  name: Atrial septal defect
  frequency: FREQUENT
  description: >-
    Atrial septal defect is the single most common congenital cardiac
    malformation in G6PC3 deficiency.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:34964150
    reference_title: "Severe congenital neutropenia due to G6PC3 deficiency: Case series of five patients and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mainly atrial septal defect in 55%
    explanation: >-
      55% across 94 reported patients falls in the FREQUENT band (30-79%) and
      identifies ASD as the predominant cardiac lesion.
- category: Gastrointestinal
  name: Crohn disease
  frequency: OCCASIONAL
  description: >-
    Inflammatory bowel disease with a Crohn-like phenotype occurs in a minority
    of patients and is mechanistically attributed to neutrophil dysfunction —
    the same convergence seen in the related G6PT/SLC37A4 deficiency (GSD Ib).
  phenotype_term:
    preferred_term: Crohn's disease
    term:
      id: HP:0100280
      label: Crohn's disease
  evidence:
  - reference: PMID:25491320
    reference_title: "Clinical spectrum and long-term follow-up of 14 cases with G6PC3 mutations from the French Severe Congenital Neutropenia Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients developed Crohn's disease, and five had chronic diarrhea
      with steatorrhea.
    explanation: >-
      3 of the 14 French-registry patients (21%) developed Crohn disease, which
      falls in the OCCASIONAL band (5-29%).
  - reference: PMID:32930428
    reference_title: "Neutrophil dysfunction triggers inflammatory bowel disease in G6PC3 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that neutrophils in G6PC3 deficiency release pro-inflammatory
      mediators when exposed to gut bacteria, associated with intestinal
      inflammation, despite treatment with G-CSF.
    explanation: >-
      Studies in 4 children with G6PC3 deficiency-associated IBD support a
      neutrophil-intrinsic mechanism for the intestinal inflammation, and
      explicitly note that it is not corrected by G-CSF.
- category: Neurologic
  name: Intellectual disability
  frequency: FREQUENT
  description: >-
    Intellectual disability is reported in a substantial subset of long-term
    follow-up patients; it is not part of the classical syndrome description
    and its mechanism is unknown.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:25491320
    reference_title: "Clinical spectrum and long-term follow-up of 14 cases with G6PC3 mutations from the French Severe Congenital Neutropenia Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including prominent veins (n = 12), cardiac malformations (n = 12),
      intellectual disability (n = 7), and myopathic syndrome with recurrent
      painful cramps (n = 1)
    explanation: >-
      7 of 14 patients (50%) in the French SCN registry cohort with long-term
      follow-up, which falls in the FREQUENT band (30-79%). The estimate rests
      on a single 14-patient series and should be treated as provisional.
- category: Cardiovascular
  name: Pulmonary hypertension
  frequency: OCCASIONAL
  description: >-
    Pulmonary arterial hypertension unrelated to the congenital heart defect
    occurs in a minority of patients and defines the Dursun-syndrome end of the
    G6PC3 spectrum (familial pulmonary arterial hypertension, leukopenia, and
    atrial septal defect).
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: PMID:23758768
    reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pulmonary hypertension (PHT) has been described in 5/57 patients from
      three families.
    explanation: >-
      5 of 57 reviewed patients (8.8%) falls in the OCCASIONAL band (5-29%).
biochemical:
- name: Absolute neutrophil count
  presence: DECREASED
  context: >-
    The absolute neutrophil count (ANC) is the defining laboratory measurement
    of the disease. In G6PC3 deficiency the ANC is typically in the severe band
    (<500/uL) at diagnosis and may fluctuate only marginally, in contrast to the
    regular oscillation of cyclic neutropenia. It is also the response variable
    for both G-CSF and empagliflozin therapy.
  biomarker_term:
    preferred_term: absolute neutrophil count
  readouts:
  - target: Endoplasmic reticulum stress and increased myeloid apoptosis
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      A falling ANC reports the net loss of maturing granulocytic precursors to
      apoptosis; ANC recovery is the standard endpoint for treatments aimed at
      the upstream metabolic lesion.
    evidence:
    - reference: PMID:25491320
      reference_title: "Clinical spectrum and long-term follow-up of 14 cases with G6PC3 mutations from the French Severe Congenital Neutropenia Registry."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Neutropenia was profound (<0.5 × 109/l) in almost all cases at diagnosis
        and could marginally fluctuate.
      explanation: >-
        Establishes the ANC as the primary quantitative disease readout and its
        typical severity at presentation.
  reference_ranges:
  - loinc_term:
      id: LOINC:751-8
      label: Neutrophils [#/volume] in Blood by Automated count
    lower_bound: 1500.0
    unit: cells/uL
    population: adults
    notes: >-
      One-sided interval: chronic neutropenia is diagnosed below 1,500/uL, so
      only a lower bound is given. Paediatric lower limits are age-dependent and
      lower in infancy and in individuals of African ancestry (benign ethnic
      neutropenia); this interval is the adult chronic-neutropenia threshold.
    evidence:
    - reference: PMID:30078793
      reference_title: "[Reference guide for adult chronic neutropenia]."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        diagnosis of chronic neutropenia is based on recurrent or continuous
        neutropenia defined by absolute neutrophil count (ANC) less than
        1,500/µl for over three or more months
      explanation: >-
        Source for the 1,500/uL lower bound. Evidence source is OTHER because
        this is a consensus reference guide rather than a primary study.
    interpretation_bands:
    - name: Normal
      lower_bound: 1500.0
      unit: cells/uL
      abnormal_flag: NORMAL
      interpretation: ANC at or above 1,500/uL is not neutropenic.
    - name: Mild neutropenia
      lower_bound: 1000.0
      upper_bound: 1500.0
      unit: cells/uL
      abnormal_flag: LOW
      severity: MILD
      phenotype_term:
        preferred_term: Neutropenia
        term:
          id: HP:0001875
          label: Decreased total neutrophil count
      interpretation: >-
        Mild neutropenia; infection risk is close to background. Some G6PC3
        patients sit in this band and can be managed with prophylactic
        antibiotics alone.
    - name: Moderate neutropenia
      lower_bound: 500.0
      upper_bound: 1000.0
      unit: cells/uL
      abnormal_flag: LOW
      severity: MODERATE
      phenotype_term:
        preferred_term: Neutropenia
        term:
          id: HP:0001875
          label: Decreased total neutrophil count
      interpretation: Moderate neutropenia with intermediate infection risk.
    - name: Severe neutropenia
      upper_bound: 500.0
      unit: cells/uL
      abnormal_flag: CRITICAL_LOW
      severity: SEVERE
      phenotype_term:
        preferred_term: Severe congenital neutropenia
        term:
          id: HP:0001875
          label: Decreased total neutrophil count
      interpretation: >-
        Severe neutropenia; the band occupied by almost all G6PC3-deficient
        patients at diagnosis and the threshold at which severe pyogenic
        infection risk rises sharply and G-CSF is indicated.
  evidence:
  - reference: PMID:25491320
    reference_title: "Clinical spectrum and long-term follow-up of 14 cases with G6PC3 mutations from the French Severe Congenital Neutropenia Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neutropenia was profound (<0.5 × 109/l) in almost all cases at diagnosis
      and could marginally fluctuate.
    explanation: >-
      Long-term registry follow-up documents profound neutropenia at diagnosis
      in nearly all G6PC3 patients.
- name: 1,5-anhydroglucitol-6-phosphate
  presence: INCREASED
  context: >-
    1,5-AG6P is the nonclassical phosphorylated glucose analog that accumulates
    in G6PC3- or G6PT-deficient granulocytes and inhibits low-KM hexokinases.
  biomarker_term:
    preferred_term: 1,5-anhydroglucitol-6-phosphate
  readouts:
  - target: 1,5-AG6P accumulation and hexokinase inhibition
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased 1,5-AG6P reports the failed G6PC3/G6PT metabolite-repair reaction.
    evidence:
    - reference: PMID:30626647
      reference_title: "Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Granulocytes from patients deficient in G6PC3 or G6PT accumulate 1,5AG6P to concentrations (~3 mM) that strongly inhibit hexokinase activity.
      explanation: Patient granulocyte data support 1,5-AG6P as the proximal biochemical readout.
  evidence:
  - reference: PMID:30626647
    reference_title: "Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Granulocytes from patients deficient in G6PC3 or G6PT accumulate 1,5AG6P to concentrations (~3 mM) that strongly inhibit hexokinase activity.
    explanation: Patient granulocyte data support increased 1,5-AG6P in G6PC3 deficiency.
- name: Plasma 1,5-anhydroglucitol
  presence: PRESENT
  context: >-
    1,5-Anhydroglucitol is an abundant, largely dietary blood polyol and the
    precursor from which the toxic 1,5-AG6P is generated intracellularly. Plasma
    1,5-AG is not itself abnormal in G6PC3 deficiency — it is the pharmacological
    handle: SGLT2 inhibition blocks its renal reabsorption, lowers the plasma
    pool, and thereby lowers neutrophil 1,5-AG6P. Interindividual variation in
    1,5-AG clearance (e.g. an SGLT5 variant) modifies disease severity.
  biomarker_term:
    preferred_term: 1,5-anhydroglucitol
  readouts:
  - target: 1,5-AG6P accumulation and hexokinase inhibition
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: PHARMACODYNAMIC
    interpretation: >-
      Plasma 1,5-AG is the upstream substrate pool; lowering it with an SGLT2
      inhibitor is the direct pharmacodynamic readout of the therapy and tracks
      the fall in neutrophil 1,5-AG6P.
    evidence:
    - reference: PMID:35506446
      reference_title: "Successful use of empagliflozin to treat neutropenia in two G6PC3-deficient children: Impact of a mutation in SGLT5."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Treatment with the SGLT2-inhibitor empagliflozin decreased 1,5-AG in
        blood and 1,5-AG6P in neutrophils
      explanation: >-
        Demonstrates the plasma-1,5-AG to neutrophil-1,5-AG6P pharmacodynamic
        chain directly in G6PC3-deficient patients.
  evidence:
  - reference: PMID:35506446
    reference_title: "Successful use of empagliflozin to treat neutropenia in two G6PC3-deficient children: Impact of a mutation in SGLT5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      which had low blood 1,5-AG levels and only required GCSF during severe
      infections
    explanation: >-
      Shows that a low endogenous plasma 1,5-AG level (here from an SGLT5
      missense variant increasing urinary clearance) attenuates the disease,
      confirming plasma 1,5-AG as a severity-determining variable.
- name: Neutrophil gp91phox hypoglycosylation
  presence: PRESENT
  context: >-
    Hypoglycosylation of gp91phox/NADPH oxidase is a CDG-like biochemical and
    cellular readout of G6PC3-related neutrophil dysfunction.
  readouts:
  - target: Neutrophil glycosylation and oxidase dysfunction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: gp91phox hypoglycosylation reports the glycosylation branch of neutrophil dysfunction.
    evidence:
    - reference: PMID:21385794
      reference_title: "G6PC3 mutations are associated with a major defect of glycosylation: a novel mechanism for neutrophil dysfunction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        hypo-glycosylation of gp91(phox), the electron-transporting component of the NADPH oxidase, in all of these patients.
      explanation: Patient neutrophil glycomics support gp91phox hypoglycosylation as a mechanistic readout.
  evidence:
  - reference: PMID:21385794
    reference_title: "G6PC3 mutations are associated with a major defect of glycosylation: a novel mechanism for neutrophil dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This aberrant neutrophil glycosylation is predicted to have profound effects on the neutrophil function and merit designation of both syndromes as a new class of congenital disorders of glycosylation.
    explanation: The glycosylation paper supports classifying the glycan abnormality as a CDG-like mechanism.
genetic:
- name: G6PC3
  gene_term:
    preferred_term: G6PC3
    term:
      id: hgnc:24861
      label: G6PC3
  relationship_type: CAUSATIVE
  variants:
  - name: Biallelic G6PC3 pathogenic variants
    description: >-
      Missense, truncating, frameshift, splice-site, and other pathogenic
      variants have been reported across the G6PC3 deficiency spectrum.
  features: >-
    G6PC3 encodes the ubiquitously expressed glucose-6-phosphatase catalytic
    subunit 3 / G-6-Pase 3.
  evidence:
  - reference: PMID:19118303
    reference_title: "A syndrome with congenital neutropenia and mutations in G6PC3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified seven additional, unrelated patients who had severe congenital neutropenia with syndromic features and distinct biallelic mutations in G6PC3.
    explanation: The original syndrome paper supports G6PC3 as the causative gene for syndromic severe congenital neutropenia.
  - reference: PMID:23298686
    reference_title: "G6PC3 mutations cause non-syndromic severe congenital neutropenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe four patients from three families with non-syndromic severe congenital neutropenia and identify four G6PC3 mutations as causative in these cases.
    explanation: This report extends the G6PC3 causal spectrum to nonsyndromic severe congenital neutropenia.
diagnosis:
- name: Serial absolute neutrophil count
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Repeated full blood counts establish persistent rather than cyclic
    neutropenia. In G6PC3 deficiency the count is typically profound (<500
    cells/uL) at diagnosis and fluctuates only marginally, which helps separate
    it from cyclic neutropenia. See the absolute-neutrophil-count entry under
    `biochemical` for the reference range and severity bands.
  markers: Absolute neutrophil count
  evidence:
  - reference: PMID:25491320
    reference_title: "Clinical spectrum and long-term follow-up of 14 cases with G6PC3 mutations from the French Severe Congenital Neutropenia Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neutropenia was profound (<0.5 × 109/l) in almost all cases at diagnosis
      and could marginally fluctuate.
    explanation: >-
      Registry follow-up establishes the expected ANC severity and its
      near-static behaviour over time.
- name: G6PC3 sequencing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Biallelic pathogenic G6PC3 variants confirm the diagnosis. Because the
    disorder is clinically indistinguishable from other severe congenital
    neutropenias when nonsyndromic, G6PC3 should be included in any congenital
    neutropenia gene panel rather than tested only when syndromic features are
    present.
  evidence:
  - reference: PMID:23758768
    reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The condition can be diagnosed by sequencing the G6PC3 gene.
    explanation: >-
      The disease review names G6PC3 sequencing as the confirmatory diagnostic
      test.
  - reference: PMID:23298686
    reference_title: "G6PC3 mutations cause non-syndromic severe congenital neutropenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe four patients from three families with non-syndromic severe congenital neutropenia and identify four G6PC3 mutations as causative in these cases.
    explanation: >-
      Establishes that G6PC3 disease occurs without syndromic features, so
      absence of cardiac/venous/urogenital signs does not exclude it.
- name: Echocardiography and renal/pelvic ultrasound at diagnosis
  diagnosis_term:
    preferred_term: diagnostic imaging
    term:
      id: NCIT:C17369
      label: Imaging Procedure
  description: >-
    Because congenital cardiac and urogenital malformations are frequent and
    often clinically silent, imaging of the heart and urinary tract is
    recommended in every suspected or confirmed case rather than only when
    symptoms prompt it.
  evidence:
  - reference: PMID:23758768
    reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Echocardiogram, renal and pelvic ultrasound scans should be performed in
      all cases of suspected or confirmed G6PC3 deficiency.
    explanation: >-
      The disease review makes this an explicit management recommendation at
      diagnosis.
treatments:
- name: Granulocyte colony-stimulating factor (G-CSF)
  description: >-
    Recombinant G-CSF is the established first-line therapy. It raises the
    neutrophil count, prevents infection, and improves quality of life. It does
    NOT address the upstream metabolic lesion: it drives residual granulopoiesis
    harder rather than removing the 1,5-AG6P hexokinase block, so neutrophil
    function and the IBD phenotype may remain impaired, and some patients fail
    to respond even at large doses.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: granulocyte colony-stimulating factor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: recombinant granulocyte colony-stimulating factor
      term:
        id: NCIT:C1287
        label: Recombinant Granulocyte Colony-Stimulating Factor
  target_phenotypes:
  - preferred_term: Severe congenital neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:23758768
    reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with G-CSF leads to improvement in neutrophil numbers, prevents
      infections and improves quality of life.
    explanation: >-
      The disease review states the established benefit of G-CSF in G6PC3
      deficiency.
  - reference: PMID:33259599
    reference_title: "Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Administration of granulocyte colony-stimulating factor (G-CSF) resolved
      the neutropenia and allowed for detailed evaluation of human neutrophil
      function.
    explanation: >-
      Support is PARTIAL: G-CSF corrected the neutrophil COUNT, but the same
      study went on to document severely impaired migration, ingestion,
      bactericidal activity, and superoxide generation in those G-CSF-restored
      neutrophils — i.e. the qualitative defect persists.
  notes: >-
    Some patients fail to respond to G-CSF even in large doses, and mildly
    affected patients may be managed with prophylactic antibiotics alone
    (PMID:23758768). G-CSF corrects the neutrophil count but not the
    qualitative defect, because it drives residual granulopoiesis harder
    rather than relieving the upstream 1,5-AG6P hexokinase block — which is
    also why it is not protein replacement (patients are not G-CSF deficient).
    therapeutic_modality is therefore OTHER; see issue #7457 for the enum gap.
- name: Empagliflozin (SGLT2 inhibitor) — substrate-reduction repurposing
  description: >-
    Empagliflozin, an SGLT2 inhibitor licensed for type 2 diabetes, is
    repurposed here as a substrate-reduction therapy. Blocking renal
    reabsorption of 1,5-anhydroglucitol lowers the plasma 1,5-AG pool, which in
    turn lowers intra-neutrophil 1,5-AG6P and relieves the hexokinase block —
    treating the mechanism rather than compensating for its output. This is the
    same repurposing that works in G6PT/SLC37A4 deficiency (glycogen storage
    disease type Ib), which shares the identical final metabolic lesion: G6PT
    and G6PC3 collaborate to destroy 1,5-AG6P, so loss of either produces the
    same accumulation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: empagliflozin
      term:
        id: CHEBI:82720
        label: empagliflozin
  target_mechanisms:
  - target: 1,5-AG6P accumulation and hexokinase inhibition
    treatment_effect: INHIBITS
    description: >-
      SGLT2 blockade increases urinary excretion of 1,5-anhydroglucitol,
      depleting the circulating precursor pool so that less 1,5-AG6P is formed
      inside neutrophils; measured neutrophil 1,5-AG6P falls and hexokinase
      inhibition is relieved.
  target_phenotypes:
  - preferred_term: Severe congenital neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  - preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:35506446
    reference_title: "Successful use of empagliflozin to treat neutropenia in two G6PC3-deficient children: Impact of a mutation in SGLT5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with the SGLT2-inhibitor empagliflozin decreased 1,5-AG in blood
      and 1,5-AG6P in neutrophils and improved (PT1) or normalized (PT2)
      neutrophil counts, allowing to stop GCSF.
    explanation: >-
      Direct demonstration in two G6PC3-deficient children that the drug lowers
      the causal metabolite and corrects the neutrophil count sufficiently to
      withdraw G-CSF.
  - reference: PMID:35838821
    reference_title: "SLGT2 Inhibitor Rescues Myelopoiesis in G6PC3 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A significant increase in all the hematopoietic cell lineages and
      substantial improvement in the quality of life was observed.
    explanation: >-
      An independent adult case treated with an SGLT2 inhibitor, showing benefit
      extending beyond the neutrophil lineage.
  - reference: PMID:32294159
    reference_title: "Treating neutropenia and neutrophil dysfunction in glycogen storage disease type Ib with an SGLT2 inhibitor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our discovery that accumulating 1,5-anhydroglucitol-6-phosphate (1,5AG6P)
      caused neutropenia in a glucose-6-phosphatase 3 (G6PC3)-deficient mouse
      model and in 2 rare diseases (GSD-Ib and G6PC3 deficiency) led us to
      repurpose the widely used antidiabetic drug empagliflozin
    explanation: >-
      Documents the shared 1,5-AG6P mechanism between GSD Ib and G6PC3
      deficiency that motivated the repurposing, and the original clinical proof
      of concept in GSD-Ib.
  notes: >-
    Off-label use. In the GSD-Ib series no symptomatic hypoglycaemia was
    observed. No dedicated randomised trial exists in G6PC3 deficiency; the
    evidence base is small treated case series.
- name: Allogeneic haematopoietic stem cell transplantation
  description: >-
    Allogeneic HSCT replaces the G6PC3-deficient myeloid compartment and is
    curative for the haematological and gut-inflammatory disease. It is reserved
    for patients refractory to G-CSF, with G6PC3-associated IBD refractory to
    immune suppression, or with myelodysplastic/leukaemic transformation. It
    does not correct the non-haematopoietic features, since G6PC3 remains
    deficient in the recipient's other tissues.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Neutrophil functional defects
    treatment_effect: RESTORES
    description: >-
      Donor-derived neutrophils carry functional G6PC3, so the metabolic block,
      the functional defect, and the neutropenia are all corrected in the
      transplanted haematopoietic compartment.
  evidence:
  - reference: PMID:32930428
    reference_title: "Neutrophil dysfunction triggers inflammatory bowel disease in G6PC3 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HSCT led to normalization of neutrophil function and remission of
      gastrointestinal symptoms.
    explanation: >-
      Shows HSCT corrects the neutrophil functional defect, not only the count,
      and resolves the IBD phenotype that G-CSF failed to control.
  - reference: PMID:31157858
    reference_title: "Remission of Inflammatory Bowel Disease in Glucose-6-Phosphatase 3 Deficiency by Allogeneic Haematopoietic Stem Cell Transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show that HSCT resolves G6PC3-associated immunodeficiency and the
      Crohn's disease phenotype.
    explanation: >-
      An adult case confirming that HSCT resolves both the immunodeficiency and
      the monogenic Crohn phenotype despite G6PC3 also being expressed
      non-haematopoietically.
  notes: >-
    One French-registry patient who developed myelodysplasia and acute myeloid
    leukaemia at age 14 was cured by chemotherapy and HSCT (PMID:25491320).
- name: Antibacterial prophylaxis
  description: >-
    Mildly affected patients whose neutropenia does not reach the severe band
    may be managed with prophylactic antibiotics rather than G-CSF.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: antibiotic
      term:
        id: NCIT:C258
        label: Antibiotic
  target_phenotypes:
  - preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:23758768
    reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mildly affected patients can be managed with prophylactic antibiotics.
    explanation: >-
      The disease review endorses antibiotic prophylaxis as an alternative in
      mildly affected patients.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    94 patients reported worldwide in the decade after the 2009 gene discovery,
    from at least 14 countries on 4 continents, with 48% from Middle Eastern
    countries (consanguinity-enriched). No population-based prevalence estimate
    exists; the count-in-literature measure is used deliberately rather than a
    fabricated rate.
  evidence:
  - reference: PMID:34964150
    reference_title: "Severe congenital neutropenia due to G6PC3 deficiency: Case series of five patients and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      With a total of 94 patients reported in the past decade
    explanation: >-
      Systematic literature review counting all reported cases from 2009 to
      2020.
- population: French Severe Congenital Neutropenia Registry
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Share of a severe-congenital-neutropenia population, not a general-population
    rate: 14 of 605 registry patients (2.3%) carried biallelic G6PC3 variants.
    Recorded as a genetic-share denominator for differential diagnosis rather
    than as disease occurrence.
  evidence:
  - reference: PMID:25491320
    reference_title: "Clinical spectrum and long-term follow-up of 14 cases with G6PC3 mutations from the French Severe Congenital Neutropenia Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among 605 patients included in the French SCN registry, we identified 8
      pedigrees that included 14 patients with autosomal recessive G6PC3
      mutations.
    explanation: >-
      Gives the numerator and denominator for the G6PC3 share of a national
      severe-congenital-neutropenia registry.
discussions:
- discussion_id: gap_g6pc3_nonhaematological_mechanism
  prompt: >-
    By what mechanism does ubiquitous G6PC3 loss produce the specific
    developmental malformations of this syndrome — atrial septal defect,
    prominent superficial venous pattern, and urogenital anomalies — rather than
    a generalised multisystem phenotype, and does 1,5-AG6P accumulation
    contribute to them at all?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Ubiquitous G6PC3 loss in non-haematopoietic tissues
  rationale: >-
    The haematological arm of this disease is now mechanistically complete and
    pharmacologically actionable (1,5-AG6P to hexokinase to glycolysis to
    neutrophil death, reversed by lowering plasma 1,5-AG). The
    non-haematological arm is not. G6PC3 is ubiquitously expressed, yet the
    malformations are anatomically stereotyped, which a simple "enzyme missing
    everywhere" account does not explain. Nor is it known whether the
    developmental features share the 1,5-AG6P mechanism — a decisive question,
    because if they do, early substrate-reduction therapy might be
    disease-modifying beyond the marrow, whereas if they do not, empagliflozin
    and HSCT will both leave them untouched.
  proposed_experiments:
  - experiment_id: exp_g6pc3_metabolite_outside_granulocytes
    name: Does 1,5-AG6P accumulate outside the granulocyte lineage?
    description: >-
      Measure 1,5-AG6P concentration and glycolytic flux in G6PC3-deficient
      non-myeloid cells — patient dermal fibroblasts and iPSC-derived
      endothelial cells and cardiomyocytes — against isogenic corrected
      controls, to test whether the toxic metabolite accumulates in the tissues
      that carry the developmental malformations.
    experiment_type:
      preferred_term: targeted metabolomics and metabolic flux experiment
  - experiment_id: exp_g6pc3_mouse_developmental_phenotype
    name: Developmental phenotyping of G6PC3-knockout mice with early SGLT2 inhibition
    description: >-
      Determine whether G6PC3-knockout mice reproduce the cardiac, venous, and
      urogenital anomalies seen in patients, and whether maternal or
      early-postnatal SGLT2 inhibition alters their incidence or severity.
    experiment_type:
      preferred_term: model organism developmental phenotyping experiment
  - experiment_id: exp_g6pc3_treated_patient_rephenotyping
    name: Non-haematological outcomes in long-term-treated patients
    description: >-
      Systematically re-phenotype patients on long-term empagliflozin or after
      HSCT to establish whether either therapy modifies any non-haematological
      feature, which would discriminate a shared-metabolite mechanism from an
      independent developmental one.
    experiment_type:
      preferred_term: longitudinal clinical cohort study
  notes: >-
    The leading hypothesis in the literature is that ER stress and increased
    apoptosis in non-myeloid cells (patient fibroblasts show both) underlie the
    developmental features, but this has not been shown to cause a specific
    malformation.
- discussion_id: gap_g6pc3_sglt2_long_term_evidence
  prompt: >-
    Should SGLT2 inhibition replace G-CSF as first-line therapy in G6PC3
    deficiency, and what are the long-term safety and efficacy outcomes in
    children treated from early life?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#1,5-AG6P accumulation and hexokinase inhibition
  rationale: >-
    Empagliflozin acts on the causal metabolite while G-CSF only pushes residual
    granulopoiesis, and the published cases show G-CSF can be tapered or
    stopped. But the entire G6PC3 evidence base is a handful of treated patients
    followed for one to a few years, with no randomised comparison, no
    established paediatric dosing, and no long-term data on growth, bone, or
    renal outcomes of chronic SGLT2 inhibition begun in infancy. Response also
    appears to depend on the individual plasma 1,5-AG level, which varies with
    SGLT5 genotype and with diet, so a uniform first-line recommendation may not
    be appropriate.
  proposed_experiments:
  - experiment_id: exp_g6pc3_sglt2_registry_outcomes
    name: Prospective registry of SGLT2-inhibitor-treated G6PC3 and GSD-Ib patients
    description: >-
      A prospective multi-centre registry study with predefined ANC, infection,
      growth, bone, and renal endpoints, powered to detect long-term harm as
      well as benefit in children started on SGLT2 inhibition in early life.
    experiment_type:
      preferred_term: prospective clinical registry study
  - experiment_id: exp_g6pc3_sglt5_response_stratification
    name: Does baseline plasma 1,5-AG or SGLT5 genotype predict ANC response?
    description: >-
      Correlate pre-treatment plasma 1,5-AG concentration and SGLT5 genotype
      with the magnitude of ANC response to empagliflozin across treated
      patients, to test whether the therapy can be stratified.
    experiment_type:
      preferred_term: pharmacogenomic response-stratification study
- discussion_id: gap_g6pc3_glycosylation_vs_metabolite
  prompt: >-
    Is the neutrophil hypoglycosylation branch (truncated N-/O-glycans,
    gp91phox hypoglycosylation) a downstream consequence of the glycolytic block
    caused by 1,5-AG6P, or an independent parallel mechanism of neutrophil
    dysfunction?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Neutrophil glycosylation and oxidase dysfunction
  rationale: >-
    The glycosylation defect was described before the metabolite-repair
    mechanism was discovered and led to a proposal that G6PC3 deficiency be
    classed as a congenital disorder of glycosylation. Reduced
    glucose-6-phosphate availability could plausibly starve nucleotide-sugar
    synthesis, which would make glycosylation a downstream effect of the same
    lesion; alternatively the ER-luminal role of G6PC3 could affect
    glycosylation directly. The two models are not distinguished, and this entry
    currently models them as parallel branches converging on neutrophil
    dysfunction. The distinction is testable and clinically relevant, because
    substrate reduction should correct a downstream glycosylation defect but not
    an independent one.
  proposed_experiments:
  - experiment_id: exp_g6pc3_glycan_response_to_empagliflozin
    name: Neutrophil glycan profiling before and during SGLT2 inhibition
    description: >-
      Measure neutrophil N-/O-glycan profiles and gp91phox glycosylation in
      G6PC3-deficient patients before and during empagliflozin therapy; a
      correction under substrate reduction would place glycosylation downstream
      of the metabolite block rather than in a parallel branch.
    experiment_type:
      preferred_term: glycomics profiling experiment
  notes: >-
    The GSD-Ib SGLT2 series reported corrected protein glycosylation in 2 of 2
    patients tested under empagliflozin (PMID:32294159), which favours the
    downstream model, but this has not been replicated in G6PC3 deficiency.
notes: >-
  WP-031 placement decision: curate a G6PC3 Deficiency entry rather than only a
  Dursun syndrome entry because independent sources describe a broader G6PC3
  deficiency continuum, including nonsyndromic severe congenital neutropenia and
  syndromic disease with cardiac/urogenital/venous findings. The package code is
  12.2.07.01; the current ICIMD enum exposes the broader
  metabolite_proofreading value.


  MONDO re-anchoring (2026-07-31): the entry previously carried
  disease_term MONDO:0023124 (Dursun syndrome, Orphanet:178503), which is a
  NARROWER G6PC3 entity restricted to the familial pulmonary arterial
  hypertension / leukopenia / atrial septal defect presentation. The correct
  anchor for the full continuum curated here is MONDO:0012930, "autosomal
  recessive severe congenital neutropenia due to G6PC3 deficiency" (SCN4;
  OMIM:612541, Orphanet:331176, RO:0004003 to HGNC:24861 G6PC3). MONDO:0023124
  is retained under mappings as a skos:narrowMatch.


  Adjacent-disease guardrail (named-entity confusion): G6PC3 deficiency must not
  be conflated with G6PC1 deficiency (glycogen storage disease type Ia, von
  Gierke) or with SLC37A4/G6PT deficiency (GSD type Ib). All three affect
  glucose-6-phosphate handling, but they are distinct diseases with distinct
  genes. The relationship with GSD Ib is nonetheless real and mechanistically
  informative rather than incidental: G6PT and G6PC3 collaborate to destroy
  1,5-AG6P, so loss of either produces the same neutrophil metabolite
  accumulation, the same neutropenia and neutrophil dysfunction, and responds to
  the same SGLT2-inhibitor substrate-reduction therapy. GSD Ib additionally has
  the hepatic/renal glycogen-storage phenotype that G6PC3 deficiency lacks.


  Not curated for want of a verifiable quotable source, rather than because they
  are absent from the disease: growth retardation, endocrine abnormalities,
  minor facial dysmorphism, myelokathexis, lymphopenia, thymic hypoplasia, and
  the reported myelodysplasia/AML transformation (a single French-registry
  patient). These are listed in PMID:23758768 as parts of the extended spectrum
  and are candidates for a follow-up curation pass with per-feature evidence.

G6PC3 Deficiency

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