Severe Congenital Neutropenia 1, Autosomal Dominant

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Classifications

Harrison's Part

IUIS Category

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Mappings

MONDO

MONDO:0042490 neutropenia, severe congenital, 1, autosomal dominant

MONDO:0042490 is the gene-anchored SCN1 entity corresponding to OMIM 202700 and to IUIS Table 5's elastase deficiency row. It is the exact concept curated here.

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Inheritance

1

Autosomal dominant HP:0000006

Heterozygous ELANE variants, transmitted dominantly or arising de novo. One parent of a proband is usually affected, and each child of an affected individual has a 50% chance of inheriting the variant. Apparently sporadic families can recur through parental gonadal mosaicism, which is documented for ELANE in the kindred reported by Newburger and colleagues.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:20301705 SUPPORT Human Clinical

"ELANE-related neutropenia is inherited in an autosomal dominant manner. One parent of a proband is usually affected. De novo pathogenic variants have been identified; their frequency is unknown."

States the inheritance mode and records that de novo variants occur at an unknown rate, which is the counselling-relevant qualifier.

PMID:28593997 SUPPORT Human Clinical

"The most frequent pathogenic defects are autosomal dominant mutations in ELANE, which encodes neutrophil elastase, and autosomal recessive mutations in HAX1, whose product contributes to the activation of the granulocyte colony-stimulating factor (G-CSF) signalling pathway."

Independently confirms that the ELANE form of severe congenital neutropenia is the autosomal dominant one, and distinguishes it from the recessive HAX1 form that is not curated here.

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Discussions and Knowledge Gaps

1

What are the cooperating events that convert a CSF3R-mutant clone into myelodysplasia or acute myeloid leukaemia, and can they be detected early enough to guide transplantation?

KNOWLEDGE GAP scn1_csf3r_cooperating_events

Attached to

pathophysiology#Acquisition of Somatic CSF3R Mutations

CSF3R mutation is highly predictive of transformation yet explicitly not necessary, is detectable years in advance, and highly clonal haematopoiesis does not always progress quickly. RUNX1 mutation is the commonest cooperating lesion but arrives late. The clinical question that follows is which surveillance finding should trigger transplantation, and that is not currently answerable: the same finding is compatible with rapid transformation and with years of stability.

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Pathophysiology

8

ELANE Mutation and Neutrophil Elastase Misfolding

The initiating lesion. A heterozygous ELANE mutation yields a neutrophil elastase that fails to fold and traffic correctly. Instead of reaching azurophil granules the mutant protein accumulates in the cytoplasm as a nonfunctional species, and both the regulated and the constitutive secretory routes are impaired. The consequences fall on the granulocytic lineage because elastase is synthesised in neutrophil precursors during primary granule formation. Note that the consequence is not a simple loss of enzyme: cellular elastase activity is reduced in patient neutrophils irrespective of mutation status, while the mutant protein itself is pathogenic through its mislocalisation and the stress response it provokes.

promyelocyte CL:0000836

ELANE hgnc:3309

Genetic context ELANE hgnc:3309 variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE

Recorded as DOMINANT_NEGATIVE rather than LOSS_OF_FUNCTION because the phenotype does not follow from absent enzyme. The mutant allele acts through the misfolded protein it produces: a nonfunctional species accumulating in the cytoplasm that activates the unfolded protein response and kills the precursor, in a protease-independent fashion. A heterozygous null would not be expected to do this, and the mechanism is one of proteotoxicity rather than haploinsufficiency.

neutrophil elastase activity GO:0004252 ↓ DECREASED

Downstream

Endoplasmic Reticulum Stress and Unfolded Protein Response Misfolded elastase accumulating in the secretory pathway triggers the endoplasmic reticulum stress response in granulocytic precursors.

Show evidence (4 references)

PMID:11001877 SUPPORT Human Clinical

"Twenty-two of 25 patients with congenital neutropenia had 18 different heterozygous mutations."

The original demonstration that heterozygous ELANE mutations underlie congenital neutropenia, with the mutational heterogeneity that characterises the gene.

PMID:16551967 SUPPORT In Vitro

"This disruption resulted in cytoplasmic accumulation of a nonfunctional protein, thereby preventing its physiologic transport to azurophil granules."

Establishes the mislocalisation that defines this node: the mutant protein neither folds nor reaches its granule destination.

PMID:16551967 SUPPORT Human Clinical

"Through analysis of primary granulocytes from SCN patients carrying ELA2 mutations, we found an identical pattern of intracellular accumulation of mutant HNE protein in the cytoplasm."

Confirms in patient cells the accumulation pattern first shown in the inducible expression system, so the node is not an artefact of overexpression.

+ 1 more reference

Endoplasmic Reticulum Stress and Unfolded Protein Response

Accumulated mutant elastase activates the unfolded protein response in granulocytic precursors, with induction of BiP/GRP78, XBP1 splicing and CHOP. The magnitude of activation tracks the clinical severity of the causal allele, which is the strongest argument that this branch is on the disease path rather than beside it. The response has also been measured in primary granulocytic precursors taken from patients, not only in expression systems.

promyelocyte CL:0000836

endoplasmic reticulum unfolded protein response GO:0030968 ↑ INCREASED response to endoplasmic reticulum stress GO:0034976 ↑ INCREASED protein folding GO:0006457 ↓ DECREASED

Downstream

Apoptosis of Granulocytic Precursors The unfolded protein response in these cells is not merely adaptive: it induces CHOP and kills the precursor, and it does so without requiring elastase proteolytic activity.

Show evidence (3 references)

PMID:17761833 SUPPORT Human Clinical

"Most strikingly, UPR activation and decreased NE protein expression were detected in primary granulocytic precursors from SCN patients."

Measures the unfolded protein response in patient precursors, which is what grounds this node in human disease rather than in an expression system alone.

PMID:17761833 SUPPORT In Vitro

"The magnitude of UPR activation by a specific ELA2 mutation correlated with its associated clinical phenotype."

A genotype-to-mechanism dose relationship, which is the evidence that distinguishes a causal branch from an incidental stress response.

PMID:16551967 SUPPORT In Vitro

"Moreover, cells expressing mutant HNE protein exhibited a significant increase in apoptosis associated with up-regulation of the master ER chaperone BiP, indicating that disturbance of intracellular trafficking results in activation of the mammalian unfolded protein response."

Independent demonstration of unfolded protein response activation, from a second group using a different expression system.

Apoptosis of Granulocytic Precursors

Accelerated death of promyelocytes and their descendants. This is the step that converts a protein-folding defect into a blood count: granulopoiesis becomes ineffective, precursors are consumed rather than matured, and the marrow shows the arrest that follows.

promyelocyte CL:0000836 neutrophilic myelocyte CL:0000580

apoptotic process GO:0006915 ↑ INCREASED intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress GO:0070059 ↑ INCREASED

Downstream

Myeloid Maturation Arrest at the Promyelocyte Stage Precursor death at the promyelocyte stage is what the marrow shows as an arrest: the maturation pyramid stops at promyelocytes, with few or no later granulocytic forms.

Show evidence (1 reference)

PMID:17761833 SUPPORT In Vitro

"We hypothesize that the ELA2 mutations result in the production of misfolded NE protein, activation of the unfolded protein response (UPR), and ultimately apoptosis of granulocytic precursors."

States precursor apoptosis as the endpoint of the misfolding chain. The source frames it as a hypothesis, which is why the wording here is careful; the same paper then supplies the CHOP and apoptosis measurements that support it.

Myeloid Maturation Arrest at the Promyelocyte Stage

The marrow lesion, and the finding that distinguishes this disease from peripheral causes of neutropenia. The normal maturation pyramid of granulocyte precursors is replaced by an arrest at the promyelocyte stage, characteristically accompanied by marrow eosinophilia and monocytosis.

promyelocyte CL:0000836 myelocyte CL:0002193

granulocyte differentiation GO:0030851 ↓ DECREASED neutrophil differentiation GO:0030223 ↓ DECREASED

Downstream

Profound Persistent Neutropenia An arrested marrow produces no mature neutrophils, so the peripheral count falls and stays low.

Show evidence (2 references)

PMID:21595885 SUPPORT Human Clinical

"patients with severe congenital neutropenia and ELANE mutation: bone marrow myeloid arrest at promyelocyte stage with eosinophilia"

Names the marrow finding for ELANE-mutant severe congenital neutropenia specifically, which is exactly this node.

PMID:21595885 SUPPORT Human Clinical

"Maturation arrest at the promyelocyte stage is often associated with bone marrow hypereosinophilia and monocytosis."

Adds the accompanying marrow features, which matter diagnostically because they are what a reporting haematologist sees alongside the arrest.

Profound Persistent Neutropenia

The defining laboratory state: an absolute neutrophil count persistently below 0.5 x 10^9/L, present from the first weeks of life. Unlike the allelic cyclic disease the deficit is fixed rather than oscillating, and infection risk rises steeply as the count falls, being particularly high below 0.2 x 10^9/L.

neutrophil CL:0000775

Downstream

Impaired Innate Defence and Recurrent Bacterial Infection Neutrophils are the primary cellular defence against pyogenic bacteria, so their absence is the whole of the infectious susceptibility. The relationship is quantitative: risk scales inversely with the count.

Acquisition of Somatic CSF3R Mutations Severe disease requires sustained high-dose G-CSF to maintain a workable count, and it is the patients who respond least well to the largest doses who carry the highest risk of malignant events. The intermediate steps are the chronic proliferative pressure on a stressed progenitor compartment and the selection of clones bearing truncated G-CSF receptors.

Show evidence (2 references)

PMID:20456363 SUPPORT Human Clinical

"Severe congenital neutropenia (SCN) is a genetically heterogeneous disorder of myelopoeisis that is diagnosed clinically on the basis of absolute neutrophil counts (ANC) persistently below the threshold of 0.5"

Gives the clinical case definition and the numerical threshold. The quote stops at the threshold value because the cached text renders the units with an inline superscript.

PMID:21595885 SUPPORT Human Clinical

"Some patients have severe permanent neutropenia and frequent infections early in life, while others have mild intermittent neutropenia."

Records that the ELANE phenotype spans a severity range, of which this entry curates the severe permanent end.

Impaired Innate Defence and Recurrent Bacterial Infection

The infectious arm of the disease. Omphalitis in the newborn period is often the first sign; untreated children then develop diarrhoea, pneumonia and deep abscesses of liver, lung and subcutaneous tissue in the first year, alongside oral ulceration, gingivitis and pharyngitis. Before G-CSF this was the cause of death in most patients.

neutrophil CL:0000775

Downstream

Recurrent Bacterial Infections The clinical expression of this node: omphalitis, skin and perirectal abscess, otitis and pneumonia from the first months of life.

Neonatal Omphalitis Infection of the umbilical stump in the days after birth, frequently the presenting event.

Pneumonia Lower respiratory tract infection, common in untreated infants.

Deep and Cutaneous Abscesses Abscess formation in liver, lung and subcutaneous tissue, reflecting failure to contain pyogenic organisms without neutrophils.

Oral Ulceration Mucosal breakdown of the mouth, part of the oropharyngeal inflammatory picture shared across ELANE-related neutropenia.

Gingivitis Gingival inflammation from bacterial colonisation that neutrophils would otherwise control.

Periodontitis Repeated gingival infection produces cumulative periodontal destruction, described in the congenital neutropenias as chronic periodontal disease that leaves permanent sequelae.

Recurrent Fever Febrile episodes accompanying each infection.

Sepsis Bloodstream infection, historically the usual cause of death and still a steady hazard on treatment.

Show evidence (3 references)

PMID:20301705 SUPPORT Human Clinical

"In congenital neutropenia, omphalitis immediately after birth may be the first sign; in untreated children diarrhea, pneumonia, and deep abscesses in the liver, lungs, and subcutaneous tissues are common in the first year of life."

Enumerates the infections that constitute this node and gives their timing, which is what makes the presentation recognisable in infancy.

PMID:28593997 SUPPORT Human Clinical

"Patients with severe congenital neutropenia are prone to recurrent, often life-threatening infections beginning in their first months of life."

Confirms the severity and the onset window from a disease-primer review.

PMID:20301705 SUPPORT Human Clinical

"Infectious complications are generally more severe in congenital neutropenia than in cyclic neutropenia."

Grades this node against the allelic disorder, which is the clinical distinction that justifies curating the two separately.

Acquisition of Somatic CSF3R Mutations

Mechanism confidence: Provisional

Somatic nonsense mutations in CSF3R truncate the cytoplasmic tail of the G-CSF receptor, removing one to all four tyrosine residues that carry its differentiation signal while leaving the proliferative signal intact. The resulting clone proliferates under G-CSF without maturing. This is recorded as provisional rather than established: the mutations are highly predictive of transformation and appear early, but they are explicitly not a necessary condition, and the authors who described them state that cooperating events remain to be defined.

CSF3R hgnc:2439

Genetic context CSF3R hgnc:2439 variant_origin: SOMATIC functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

Truncating mutations remove the receptor's differentiation-signalling tyrosines while preserving proliferative signalling, so the functional consequence is partial and selective rather than a complete loss of receptor function.

granulocyte colony-stimulating factor signaling pathway GO:0038158 ↕ DYSREGULATED

Downstream

Clonal Evolution to Myelodysplasia and Acute Myeloid Leukaemia The CSF3R-mutant clone acquires further leukaemia-associated mutations, RUNX1 most often, and the combination confers G-CSF-driven proliferation with blocked myeloid differentiation. Single-cell work places the two mutations in the same clone, and sequential sampling places RUNX1 late.

Show evidence (3 references)

PMID:16985178 SUPPORT Human Clinical

"We detected CSF3R nonsense mutations at 17 different nucleotide positions (thereof 10 new mutations) which lead to a loss of 1 to all 4 tyrosine residues in the intracellular domain of the receptor."

Describes the molecular lesion annotated on this node: truncation of the receptor's intracellular signalling domain.

PMID:16985178 SUPPORT Human Clinical

"Of 23 patients with CN with signs of malignant transformation, 18 (78%) were shown to harbor a CSF3R mutation, indicating that these mutations, although not a necessary condition, are highly predictive for malignant transformation even if detected in a low percentage of transcripts."

Gives both the strength of the association and the reason this node is marked provisional: the mutation is highly predictive but not necessary.

PMID:16985178 SUPPORT Human Clinical

"Our results strongly suggest that acquisition of a CSF3R mutation is an early event in leukemogenesis that has to be accompanied by cooperating molecular events, which remain to be defined."

Places the event early in the sequence and states explicitly that it is insufficient alone, which is what the PROVISIONAL confidence records.

Clonal Evolution to Myelodysplasia and Acute Myeloid Leukaemia

Mechanism confidence: Established

Severe congenital neutropenia is a preleukaemic bone marrow failure syndrome. A clone bearing a truncated G-CSF receptor expands, acquires RUNX1 mutations and other leukaemia-associated lesions including ASXL1 and chromatin remodellers, and the marrow progresses to myelodysplasia or acute myeloid leukaemia. RUNX1 mutation is far commoner here than in de novo paediatric AML, which is what marks this out as a distinct leukaemogenic route rather than ordinary AML arising in a neutropenic patient.

hematopoietic stem cell CL:0000037

RUNX1 hgnc:10471 CSF3R hgnc:2439

myeloid cell differentiation GO:0030851 ↓ DECREASED

Downstream

Myelodysplastic Syndrome The clone first manifests as myelodysplasia, frequently with monosomy 7.

Acute Myeloid Leukemia Frank leukaemic transformation, the endpoint of the multistep clonal process.

Show evidence (4 references)

PMID:24523240 SUPPORT Human Clinical

"Twenty (64.5%) of the 31 patients had mutations in RUNX1. A majority of patients with RUNX1 mutations (80.5%) also had acquired CSF3R mutations."

Quantifies the two mutations and their co-occurrence in patients who actually transformed, which is the genetic content of this node.

PMID:24523240 SUPPORT Human Clinical

"In contrast to their high frequency in CN patients who developed leukemia or MDS, RUNX1 mutations were found in only 9 of 307 (2.9%) patients with de novo pediatric acute myeloid leukemia."

The contrast with de novo paediatric AML is what supports treating this as a disease-specific route rather than coincidental leukaemia.

PMID:22371884 SUPPORT Human Clinical

"We conclude that progression from SCN to AML is a multistep process, with distinct mutations arising early during the SCN phase and others later in AML development."

Establishes the multistep structure of this node, with early and late lesions separated in time.

+ 1 more reference

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Pathograph

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Phenotypes

13

Blood 4

Profound Persistent Neutropenia OBLIGATE Persistently decreased total neutrophil count HP:0410252

Temporal: CHRONIC

Show evidence (2 references)

PMID:20456363 SUPPORT Human Clinical

"Severe congenital neutropenia (SCN) is a genetically heterogeneous disorder of myelopoeisis that is diagnosed clinically on the basis of absolute neutrophil counts (ANC) persistently below the threshold of 0.5"

The diagnostic criterion itself, which is why this phenotype is marked diagnostic and given an OBLIGATE frequency.

PMID:21595885 SUPPORT Human Clinical

"Neutropenia is said to be severe when below 0.5 G/l"

Confirms the severity threshold in the units used in the European literature.

Myeloid Maturation Arrest at the Promyelocyte Stage Bone marrow arrest at the promyelocytic stage HP:0033607

Show evidence (2 references)

PMID:21595885 SUPPORT Human Clinical

"patients with severe congenital neutropenia and ELANE mutation: bone marrow myeloid arrest at promyelocyte stage with eosinophilia"

Names the finding for ELANE-mutant severe congenital neutropenia, which is exactly the phenotype term bound here.

PMID:28593997 SUPPORT Human Clinical

"Severe congenital neutropenias are a heterogeneous group of rare haematological diseases characterized by impaired maturation of neutrophil granulocytes."

Confirms impaired granulocytic maturation as the characteristic marrow abnormality of this disease group.

Myelodysplastic Syndrome OCCASIONAL Myelodysplasia HP:0002863

Show evidence (2 references)

PMID:20301705 SUPPORT Human Clinical

"After 15 years with granulocyte colony-stimulating factor treatment, the risk of developing myelodysplasia (MDS) or acute myelogenous leukemia (AML) is approximately 15%-25%."

Gives the combined MDS/AML risk figure, which falls in the OCCASIONAL band and is the basis for the frequency recorded here.

PMID:24523240 SUPPORT Human Clinical

"Severe congenital neutropenia (CN) is a preleukemic bone marrow failure syndrome with a 20% risk of evolving into leukemia or myelodysplastic syndrome (MDS)."

An independent estimate of the same combined risk, consistent with the band assigned.

Acute Myeloid Leukemia OCCASIONAL HP:0004808

Show evidence (2 references)

PMID:20456363 SUPPORT Human Clinical

"Long-term, the annual risk of MDS/AML attained a plateau (2.3%/year after 10 years)."

The best long-term hazard estimate, from the largest prospective cohort, and the correction of the earlier and much higher figure.

PMID:20301705 SUPPORT Human Clinical

"After 15 years with granulocyte colony-stimulating factor treatment, the risk of developing myelodysplasia (MDS) or acute myelogenous leukemia (AML) is approximately 15%-25%."

Gives the cumulative risk over fifteen years, which is the figure used for the OCCASIONAL band here.

Head and Neck 3

Oral Ulceration HP:0000155

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"primary hematologic disorders characterized by recurrent fever, skin and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and pharyngitis), and cervical adenopathy"

Names mouth ulcers among the defining clinical characteristics.

Gingivitis HP:0000230

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"primary hematologic disorders characterized by recurrent fever, skin and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and pharyngitis), and cervical adenopathy"

Names gingivitis among the defining clinical characteristics.

Periodontitis HP:0000704

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:21595885 SUPPORT Human Clinical

"Neutropenia can lead to life-threatening pyogenic infections, acute gingivostomatitis and chronic parodontal disease, and each successive infection may leave permanent sequelae."

States chronic periodontal disease as a consequence of the neutropenia and records that damage accumulates, which is what the PROGRESSIVE course annotation asserts.

Immune 4

Recurrent Bacterial Infections VERY_FREQUENT HP:0002718

Temporal: RECURRENT

Show evidence (2 references)

PMID:28593997 SUPPORT Human Clinical

"Patients with severe congenital neutropenia are prone to recurrent, often life-threatening infections beginning in their first months of life."

States that recurrent severe infection is the general rule in this disease, which supports the VERY_FREQUENT band.

PMID:20301705 SUPPORT Human Clinical

"Infectious complications are generally more severe in congenital neutropenia than in cyclic neutropenia."

Grades the severity of the infectious phenotype against the allelic disorder.

Pneumonia HP:0002090

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"in untreated children diarrhea, pneumonia, and deep abscesses in the liver, lungs, and subcutaneous tissues are common in the first year of life"

Names pneumonia among the common infections of untreated infancy in this disease.

Deep and Cutaneous Abscesses HP:0031292

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"deep abscesses in the liver, lungs, and subcutaneous tissues are common in the first year of life"

Names the abscesses and their sites. The bound HPO term covers the cutaneous component; the visceral sites are recorded in the description because HPO has no single term spanning all three.

Sepsis HP:0100806

Show evidence (1 reference)

PMID:16497969 SUPPORT Human Clinical

"In SCN, sepsis mortality was stable at 0.9% per year."

Quantifies the residual sepsis hazard in treated patients, which is what makes this phenotype a continuing rather than a historical concern.

Metabolism 1

Recurrent Fever HP:0001954

Temporal: RECURRENT

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"primary hematologic disorders characterized by recurrent fever, skin and oropharyngeal inflammation"

Names recurrent fever among the defining clinical characteristics.

Prenatal and Birth 1

Neonatal Omphalitis HP:0032435

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"In congenital neutropenia, omphalitis immediately after birth may be the first sign"

Names omphalitis and its timing, and records that it is frequently the first manifestation.

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Genetic Associations

3

ELANE

Gene: ELANE hgnc:3309 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (6 references)

PMID:11001877 SUPPORT Human Clinical

"This study indicates that mutations of the gene encoding neutrophil elastase are probably the most common cause for severe congenital neutropenia as well as the cause for sporadic and autosomal dominant cyclic neutropenia."

Establishes ELANE as the leading cause of severe congenital neutropenia, and in the same sentence states the allelic relationship with cyclic neutropenia.

PMID:11001877 SUPPORT Human Clinical

"In cyclic neutropenia, the mutations appeared to cluster near the active site of the molecule, whereas the opposite face was predominantly affected by the mutations found in congenital neutropenia."

Documents the partial structural separation of the two mutation spectra, which is the strongest genotype-level statement the allelic boundary supports.

PMID:10581030 SUPPORT Human Clinical

"We identified 7 different single-base substitutions in the gene (ELA2) encoding neutrophil elastase"

The original identification of the gene, made in cyclic haematopoiesis a year before the same gene was implicated in congenital neutropenia. Cited here because it is the origin of the allelic relationship this entry has to delimit.

+ 3 more references

CSF3R

Gene: CSF3R hgnc:2439 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:16985178 SUPPORT Human Clinical

"Of 23 patients with CN with signs of malignant transformation, 18 (78%) were shown to harbor a CSF3R mutation, indicating that these mutations, although not a necessary condition, are highly predictive for malignant transformation even if detected in a low percentage of transcripts."

Gives both the frequency among transforming patients and the caveat that the mutation is predictive rather than necessary.

PMID:16985178 SUPPORT Human Clinical

"We could demonstrate that even a highly clonal hematopoiesis did not inevitably show a rapid progression to leukemia."

The observation that keeps this from being read as a deterministic progression, and that matters clinically when a mutation is found on surveillance.

RUNX1

Gene: RUNX1 hgnc:10471 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:24523240 SUPPORT Human Clinical

"A sequential analysis at stages prior to overt leukemia revealed RUNX1 mutations to be late events in leukemic transformation."

Places RUNX1 late in the clonal sequence, which is what distinguishes it from the early CSF3R event.

PMID:24523240 SUPPORT Human Clinical

"Single-cell analyses in 2 patients showed that RUNX1 and CSF3R mutations were present in the same malignant clone."

Establishes that the two lesions are in one clone rather than in parallel populations, which is what makes the cooperativity claim meaningful.

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Medical Actions

4

Granulocyte Colony-Stimulating Factor

Action: colony-stimulating factor therapy Ontology label: Colony-Stimulating Factor Therapy NCIT:C15515

Agent: filgrastim NCIT:C1474

The treatment of choice and the intervention that changed the natural history of this disease. Daily subcutaneous filgrastim raises the neutrophil count, roughly halves infection-related events and shortens antibiotic use. It drives residual granulopoiesis harder rather than correcting the misfolding lesion, so patients remain on it indefinitely, and severe patients need large doses. Common adverse effects are bone pain, headache, rash and asymptomatic splenomegaly; long-term treatment at high dose is associated with the leukaemic risk recorded under progression.

Mechanism Target:

RESTORES Profound Persistent Neutropenia — Pharmacological G-CSF drives the surviving granulocytic compartment to proliferate and mature, raising the circulating count into a protective range in most patients and increasing the proportion of maturing neutrophils in the marrow.

Show evidence (1 reference)

PMID:8490166 SUPPORT Human Clinical

"Examination of BM aspirates showed increased proportions of maturing neutrophils."

Shows the drug acting on the marrow compartment that this node describes, not merely on the peripheral count.

Target Phenotypes: Persistently decreased total neutrophil count HP:0410252 Recurrent bacterial infections HP:0002718

Show evidence (4 references)

PMID:8490166 SUPPORT Human Clinical

"Of the 123 patients enrolled, 120 received filgrastim. On therapy, 108 patients had a median absolute neutrophil count of > or = 1.5 x 10(9)/L."

The randomised trial response rate: 108 of 120 treated patients reached a protective median count.

PMID:8490166 SUPPORT Human Clinical

"Infection-related events were significantly decreased (P < .05) with approximately 50% reduction in the incidence and duration of infection-related events and almost 70% reduction in duration of antibiotic use."

Quantifies the clinical benefit, which is the outcome that matters rather than the count itself.

PMID:8490166 SUPPORT Human Clinical

"Asymptomatic splenic enlargement occurred frequently; adverse events frequently reported were bone pain, headache, and rash, which were generally mild and easily manageable."

The adverse-effect profile from the pivotal trial.

+ 1 more reference

Allogeneic Haematopoietic Stem Cell Transplantation

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

Platform: Cell therapy

The only curative option, and the standard route for patients refractory to high-dose G-CSF or who have transformed. Donor haematopoiesis replaces the ELANE-mutant clone outright. Outcomes are acceptable but not benign: three-year overall survival of 82% with 17% transplant-related mortality in the European series, better in children under ten and with matched donors.

Mechanism Target:

BYPASSES ELANE Mutation and Neutrophil Elastase Misfolding — Transplantation does not correct the mutant allele; it replaces the haematopoietic compartment that expresses it with donor cells, so the whole downstream chain is bypassed rather than interrupted at any one step.

Show evidence (1 reference)

PMID:26185129 SUPPORT Human Clinical

"Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment of severe congenital neutropenia (SCN), but data on outcome are scarce."

States that transplantation is curative, which is the claim that distinguishes bypassing the lesion from treating its output.

Show evidence (4 references)

PMID:26185129 SUPPORT Human Clinical

"The 3-year overall survival (OS) was 82%, and transplant-related mortality (TRM) was 17%."

The outcome figures that set the risk-benefit balance against continued G-CSF.

PMID:26185129 SUPPORT Human Clinical

"In multivariate analysis, transplants performed under the age of 10 years, in recent years, and from HLA-matched related or unrelated donors were associated with a significantly better OS."

Identifies the factors that determine outcome, which is what makes early referral of poor responders a live question.

PMID:20301705 SUPPORT Human Clinical

"HSCT is the only alternative therapy for individuals with congenital neutropenia who are refractory to high-dose G-CSF or who undergo malignant transformation."

States the two indications curated here.

+ 1 more reference

Antimicrobial Prophylaxis and Prompt Treatment of Infection

Action: antibiotic therapy Ontology label: Antibiotic Therapy NCIT:C15620

Agent: trimethoprim-sulfamethoxazole CHEBI:3770

Prophylaxis, usually with trimethoprim-sulfamethoxazole, plus immediate broad-spectrum treatment of any febrile episode. Symptomatic rather than disease-modifying: it addresses the infectious consequences of the neutropenia without touching the granulopoietic defect. Abdominal pain in a neutropenic patient needs assessment for peritonitis and bacteraemia.

Mechanism Target:

INHIBITS Impaired Innate Defence and Recurrent Bacterial Infection — Reduces the bacterial burden the absent neutrophils would otherwise fail to control, and treats established infection before it becomes life-threatening.

Show evidence (1 reference)

PMID:21595885 SUPPORT Human Clinical

"Treatment of severe chronic neutropenia should focus on prevention of infections. It includes antimicrobial prophylaxis, generally with trimethoprim-sulfamethoxazole, and also granulocyte-colony-stimulating factor (G-CSF)."

States that prophylaxis targets the infectious consequence of the neutropenia, and names the agent used.

Show evidence (2 references)

PMID:20301705 SUPPORT Human Clinical

"Immediate treatment with granulocyte colony-stimulating factor (G-CSF) and broad-spectrum antibiotics is important, even lifesaving, when an affected individual has signs of serious infection, which may be caused by both aerobic and anaerobic pathogens."

States the urgency and the spectrum required when infection is suspected.

PMID:21595885 SUPPORT Human Clinical

"Treatment of severe chronic neutropenia should focus on prevention of infections. It includes antimicrobial prophylaxis, generally with trimethoprim-sulfamethoxazole, and also granulocyte-colony-stimulating factor (G-CSF)."

Places antimicrobial prophylaxis alongside G-CSF as standard management.

Dental Hygiene and Periodontal Care

Platform: Behavioral / lifestyle

Good dental hygiene with routine immunisations. Curated separately rather than folded into supportive care because gingivitis and periodontitis are modelled here as phenotypes, and this is the intervention that addresses them.

Mechanism Target:

INHIBITS Impaired Innate Defence and Recurrent Bacterial Infection — Lowers the oral bacterial burden that the neutropenia would otherwise allow to produce gingival and periodontal destruction.

Show evidence (1 reference)

PMID:21595885 SUPPORT Human Clinical

"Neutropenia can lead to life-threatening pyogenic infections, acute gingivostomatitis and chronic parodontal disease, and each successive infection may leave permanent sequelae."

Identifies the oral disease process this intervention is intended to interrupt, and the accumulating damage that makes prevention worthwhile.

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"Prevention of secondary complications: Good dental hygiene; routine immunizations."

States dental hygiene as recommended preventive management in ELANE-related neutropenia.

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Diagnosis

4

Absolute neutrophil count (PRESENT)

A persistently low count below 0.5 x 10^9/L is the entry criterion. Repeated counts distinguish this disease from cyclic neutropenia, where the count oscillates; a single low count establishes neither.

Show evidence (1 reference)

PMID:20456363 SUPPORT Human Clinical

"is diagnosed clinically on the basis of absolute neutrophil counts (ANC) persistently below the threshold of 0.5"

States the clinical diagnostic basis and its threshold.

Bone marrow examination (PRESENT)

Marrow aspirate shows arrest of granulocytic maturation at the promyelocyte stage, often with eosinophilia and monocytosis, establishing a production defect rather than peripheral destruction.

Show evidence (1 reference)

PMID:21595885 SUPPORT Human Clinical

"Bone marrow examination is often necessary to rule out malignant hemopathies, determine cellularity, assess myeloid maturation"

States the diagnostic purposes of marrow examination in congenital neutropenia.

ELANE molecular genetic testing (PRESENT)

A heterozygous pathogenic ELANE variant confirms the diagnosis. A negative result does not exclude severe congenital neutropenia, since ELANE mutations are found in roughly 40 to 50% of cases and several other genes produce the same phenotype.

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"The diagnosis of ELANE-related neutropenia is established in a proband with suggestive clinical findings and the identification of a heterozygous pathogenic variant in ELANE through molecular genetic testing."

States the molecular diagnostic criterion.

Annual bone marrow surveillance with cytogenetics (PRESENT)

Yearly marrow examination with cytogenetics, looking for monosomy 7 and trisomy 21 and for somatic CSF3R and RUNX1 mutations. Listed under diagnosis because it is a monitoring investigation rather than a therapy, and it is required for every patient not transplanted.

Show evidence (2 references)

PMID:28593997 SUPPORT Human Clinical

"Regular clinical assessments (including yearly bone marrow examinations) to monitor treatment course and detect chromosomal abnormalities (for example, monosomy 7 and trisomy 21) as well as somatic pre-leukaemic mutations are recommended."

States the surveillance schedule and exactly what it is looking for.

PMID:20301705 SUPPORT Human Clinical

"Those with congenital neutropenia not undergoing HSCT require surveillance for malignant transformation to MDS/AML."

Establishes who needs surveillance and why, and by implication that transplanted patients leave this pathway.

📈

Progression

3

Neonatal period and infancy

Presentation is early. Omphalitis in the days after birth may be the first sign, followed in untreated children by diarrhoea, pneumonia and deep abscesses during the first year. In the original Swedish description most affected infants died of bacterial infection before their first birthday.

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"In congenital neutropenia, omphalitis immediately after birth may be the first sign; in untreated children diarrhea, pneumonia, and deep abscesses in the liver, lungs, and subcutaneous tissues are common in the first year of life."

Describes the sequence of events that characterises this phase.

Childhood and adult life on G-CSF

With daily subcutaneous G-CSF the neutrophil count rises, infections fall and quality of life improves substantially. Sepsis mortality does not reach zero: it runs at roughly 0.8 to 0.9% per year in the international registry cohort. Oral and periodontal disease continues to need attention.

Show evidence (2 references)

PMID:28593997 SUPPORT Human Clinical

"Daily subcutaneous G-CSF administration is the treatment of choice and leads to a substantial increase in blood neutrophil count, reduction of infections and drastic improvement of quality of life."

States the change in trajectory that defines this phase.

PMID:16497969 SUPPORT Human Clinical

"In SCN, sepsis mortality was stable at 0.9% per year."

Quantifies the residual mortality that persists through this phase despite treatment.

Long-term outcome and malignant transformation

The axis on which this disease diverges completely from its allelic partner. The hazard of myelodysplasia or acute myeloid leukaemia rises over the first decade on G-CSF and then plateaus at about 2.3% per year, giving a cumulative incidence of roughly 22% at fifteen years; GeneReviews puts the fifteen-year risk at 15 to 25%. Cyclic neutropenia carries no recognised risk at all. The earlier and much higher estimate of 8% per year after twelve years was a small-numbers artefact and was corrected by longer follow-up of the same cohort, which is worth stating because the older figure still circulates.

Show evidence (3 references)

PMID:20456363 SUPPORT Human Clinical

"Long-term, the annual risk of MDS/AML attained a plateau (2.3%/year after 10 years)."

The corrected long-term hazard, from extended follow-up of the registry cohort.

PMID:16497969 SUPPORT Human Clinical

"The hazard of MDS/AML increased significantly over time, from 2.9% per year after 6 years to 8.0% per year after 12 years on G-CSF."

The earlier estimate that the 2010 update revised downwards. Recorded so the correction is visible rather than silently applied.

PMID:15642668 SUPPORT Human Clinical

"The cumulative incidence of MDS/AL was 2.7% (SD 1.3%) at 10 years and 8.1% (SD 2.7%) at 20 years."

An independent national registry's cumulative incidence, lower than the international registry's; the two cohorts differ in case mix, since the French figure covers all forms of severe chronic neutropenia.

📊

Prevalence

2

Worldwide (International Neutropenia Registry catchment, approximately 700 million people)

Point Prevalence 0.07 per 100,000 <1 in 1,000,000

Registry-ascertained prevalence of congenital neutropenia as a whole, not of the ELANE form alone; 0.7 per million rising to 1 per million when idiopathic neutropenia is counted. ELANE accounts for roughly half of non-syndromic congenital neutropenia, so the SCN1 figure is lower again. Registry ascertainment is incomplete, so treat this as a floor.

Show evidence (1 reference)

PMID:21595885 SUPPORT Human Clinical

"The prevalence was 0.7 per million inhabitants or 1 per million inhabitants when idiopathic neutropenia was included."

The registry-derived prevalence figure recorded here, with its idiopathic-inclusive variant.

France (French Severe Chronic Neutropenia Registry)

Point Prevalence 0.62 per 100,000 1–9 per 1,000,000

A dedicated national registry finds nearly ten times the prevalence of the Iranian survey of comparable population size, which the review reports as approximately 6.2 per million and takes as the best available floor for congenital neutropenia generally. The quoted span starts mid-sentence and stops before that number because the cached PDF extraction mangles the words "In the French" and renders the exponent broken. Of the French registry patients, 30% had ELANE-related neutropenia, split roughly 20% severe congenital and 10% cyclic.

Show evidence (2 references)

PMID:21595885 SUPPORT Human Clinical

"registry-based study of a population of comparable size, 374 cases had been recorded in December 2006, giving a prevalence nearly 10 times higher"

Establishes that dedicated national ascertainment yields a much higher prevalence than general immunodeficiency surveys, which is why the registry figure is preferred as the floor.

PMID:21595885 SUPPORT Human Clinical

"In the French registry, 30% of patients had ELANE neutropenia"

Gives the ELANE share of a national congenital-neutropenia registry, which is what converts a congenital-neutropenia prevalence into an approximate figure for this entry.

{ }

Source YAML

click to show

name: Severe Congenital Neutropenia 1, Autosomal Dominant
category: Mendelian
creation_date: '2026-09-14T03:20:43Z'
synonyms:
- SCN1
- ELANE-related severe congenital neutropenia
- Elastase deficiency
- Autosomal dominant severe congenital neutropenia
- Congenital neutropenia due to ELANE mutation
description: >-
  An autosomal dominant disorder of granulopoiesis caused by heterozygous ELANE
  mutations, most of them missense. The mutant neutrophil elastase misfolds,
  accumulates in the cytoplasm instead of reaching azurophil granules, and
  provokes endoplasmic reticulum stress with an unfolded protein response in
  granulocytic precursors. Those precursors die, granulopoiesis arrests at the
  promyelocyte stage, and the absolute neutrophil count sits below 0.5 x 10^9/L
  from the first weeks of life. Untreated children present with omphalitis in
  the newborn period and then with pneumonia, deep abscesses and oral
  ulceration; before granulocyte colony-stimulating factor most died of
  bacterial infection in infancy. G-CSF transformed that prognosis and is the
  treatment of choice, but it did not remove the disease's second axis: severe
  congenital neutropenia is a preleukaemic bone marrow failure syndrome, and a
  substantial minority of patients evolve to myelodysplasia or acute myeloid
  leukaemia. The molecular route is somatic acquisition of truncating CSF3R
  mutations in the G-CSF receptor, usually followed by RUNX1 mutations, so
  annual marrow surveillance with cytogenetics is part of care and allogeneic
  transplantation is the option for G-CSF-refractory or transformed disease.

  The same gene causes cyclic neutropenia, curated separately as Cyclic
  Hematopoiesis. That boundary is allelic and imperfect: the two mutation
  spectra differ in tendency but overlap, one S97L allele on a shared paternal
  haplotype has produced both phenotypes in one kindred, and the clinical
  divergence that matters most is not genetic at all. Cyclic neutropenia
  carries no recognised leukaemic risk; this disease does.
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
    notes: >-
      Disorders of granulocytes: a congenital bone marrow failure syndrome with
      granulopoietic maturation arrest, and a recognised preleukaemic state
      evolving to myelodysplasia or acute myeloid leukaemia.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian, autosomal dominant single-gene disorder caused by
      heterozygous ELANE variants, with de novo variants and gonadal mosaicism
      both relevant to counselling.
  iuis_category:
    classification_value: phagocyte defect
    notes: >-
      IUIS 2022 Table 5 (congenital defects of phagocyte number or function),
      section 1 "Congenital Neutropenias", first row: elastase deficiency
      (severe congenital neutropenia 1), gene ELANE, autosomal dominant,
      OMIM 130130, affected cell neutrophil, affected function myeloid
      differentiation, with susceptibility to MDS/leukemia recorded as an
      associated feature. Note the table prints 130130, which is the ELANE
      *gene* MIM; the phenotype MIM for SCN1 is 202700, which is what this
      entry's disease_term resolves through. Both are correct in context. The same table's footnote records that cyclic
      neutropenia was merged into this row in the 2022 update; dismech
      nevertheless curates cyclic hematopoiesis separately, because the
      leukaemic risk that defines this entry's long-term course is absent
      there.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Elastase deficiency (Severe congenital neutropenia [SCN] 1) ELANE AD 130130
      explanation: >-
        The IUIS Table 5 row that places this disease among the congenital
        neutropenias, naming the gene, the inheritance mode and the OMIM entry.
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Removed: Cyclic neutropenia was merged with elastase deficiency
      explanation: >-
        The table footnote recording that IUIS merged cyclic neutropenia into
        this row, which is why the allelic boundary is stated explicitly in this
        entry rather than left implicit.
disease_term:
  preferred_term: severe congenital neutropenia 1, autosomal dominant
  term:
    id: MONDO:0042490
    label: neutropenia, severe congenital, 1, autosomal dominant
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0042490
      label: neutropenia, severe congenital, 1, autosomal dominant
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO (OMIM:202700)
    mapping_justification: >-
      MONDO:0042490 is the gene-anchored SCN1 entity corresponding to OMIM
      202700 and to IUIS Table 5's elastase deficiency row. It is the exact
      concept curated here.
parents:
- congenital neutropenia
- inborn error of immunity
inheritance:
- name: Autosomal dominant
  description: >-
    Heterozygous ELANE variants, transmitted dominantly or arising de novo. One
    parent of a proband is usually affected, and each child of an affected
    individual has a 50% chance of inheriting the variant. Apparently sporadic
    families can recur through parental gonadal mosaicism, which is documented
    for ELANE in the kindred reported by Newburger and colleagues.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:20301705
    reference_title: ELANE-Related Neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ELANE-related neutropenia is inherited in an autosomal dominant manner.
      One parent of a proband is usually affected. De novo pathogenic variants
      have been identified; their frequency is unknown.
    explanation: >-
      States the inheritance mode and records that de novo variants occur at an
      unknown rate, which is the counselling-relevant qualifier.
  - reference: PMID:28593997
    reference_title: Severe congenital neutropenias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most frequent pathogenic defects are autosomal dominant mutations in
      ELANE, which encodes neutrophil elastase, and autosomal recessive
      mutations in HAX1, whose product contributes to the activation of the
      granulocyte colony-stimulating factor (G-CSF) signalling pathway.
    explanation: >-
      Independently confirms that the ELANE form of severe congenital
      neutropenia is the autosomal dominant one, and distinguishes it from the
      recessive HAX1 form that is not curated here.
pathophysiology:
- name: ELANE Mutation and Neutrophil Elastase Misfolding
  biological_scale: MOLECULAR
  description: >-
    The initiating lesion. A heterozygous ELANE mutation yields a neutrophil
    elastase that fails to fold and traffic correctly. Instead of reaching
    azurophil granules the mutant protein accumulates in the cytoplasm as a
    nonfunctional species, and both the regulated and the constitutive
    secretory routes are impaired. The consequences fall on the granulocytic
    lineage because elastase is synthesised in neutrophil precursors during
    primary granule formation. Note that the consequence is not a simple loss
    of enzyme: cellular elastase activity is reduced in patient neutrophils
    irrespective of mutation status, while the mutant protein itself is
    pathogenic through its mislocalisation and the stress response it provokes.
  genes:
  - preferred_term: ELANE
    term:
      id: hgnc:3309
      label: ELANE
  molecular_functions:
  - preferred_term: neutrophil elastase activity
    modifier: DECREASED
    term:
      id: GO:0004252
      label: serine-type endopeptidase activity
  cell_types:
  - preferred_term: promyelocyte
    term:
      id: CL:0000836
      label: promyelocyte
  genetic_context:
    gene:
      preferred_term: ELANE
      term:
        id: hgnc:3309
        label: ELANE
    zygosity: HETEROZYGOUS
    variant_origin: GERMLINE
    functional_impact_category: DOMINANT_NEGATIVE
    description: >-
      Recorded as DOMINANT_NEGATIVE rather than LOSS_OF_FUNCTION because the
      phenotype does not follow from absent enzyme. The mutant allele acts
      through the misfolded protein it produces: a nonfunctional species
      accumulating in the cytoplasm that activates the unfolded protein
      response and kills the precursor, in a protease-independent fashion. A
      heterozygous null would not be expected to do this, and the mechanism is
      one of proteotoxicity rather than haploinsufficiency.
  evidence:
  - reference: PMID:11001877
    reference_title: Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twenty-two of 25 patients with congenital neutropenia had 18 different
      heterozygous mutations.
    explanation: >-
      The original demonstration that heterozygous ELANE mutations underlie
      congenital neutropenia, with the mutational heterogeneity that
      characterises the gene.
  - reference: PMID:16551967
    reference_title: Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This disruption resulted in cytoplasmic accumulation of a nonfunctional
      protein, thereby preventing its physiologic transport to azurophil
      granules.
    explanation: >-
      Establishes the mislocalisation that defines this node: the mutant
      protein neither folds nor reaches its granule destination.
  - reference: PMID:16551967
    reference_title: Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Through analysis of primary granulocytes from SCN patients carrying ELA2
      mutations, we found an identical pattern of intracellular accumulation of
      mutant HNE protein in the cytoplasm.
    explanation: >-
      Confirms in patient cells the accumulation pattern first shown in the
      inducible expression system, so the node is not an artefact of
      overexpression.
  - reference: PMID:23463630
    reference_title: The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cellular elastase activity was reduced in neutrophils from CN/CyN
      patients, irrespective of the mutation status.
    explanation: >-
      Supports the reduced enzymatic activity annotated on this node, and is
      the observation that argues against reading the disease as a simple
      enzyme deficiency, since activity falls even without a detected ELANE
      mutation.
  downstream:
  - target: Endoplasmic Reticulum Stress and Unfolded Protein Response
    causal_link_type: DIRECT
    description: >-
      Misfolded elastase accumulating in the secretory pathway triggers the
      endoplasmic reticulum stress response in granulocytic precursors.
    evidence:
    - reference: PMID:17761833
      reference_title: Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Expression of mutant NE but not wild-type NE strongly induced BiP/GRP78
        mRNA expression and XBP1 mRNA splicing, 2 classic markers of the UPR.
      explanation: >-
        Directly tests the edge: expressing the mutant protein, and not the
        wild-type one, is what induces the stress response.
- name: Endoplasmic Reticulum Stress and Unfolded Protein Response
  biological_scale: CELLULAR
  description: >-
    Accumulated mutant elastase activates the unfolded protein response in
    granulocytic precursors, with induction of BiP/GRP78, XBP1 splicing and
    CHOP. The magnitude of activation tracks the clinical severity of the
    causal allele, which is the strongest argument that this branch is on the
    disease path rather than beside it. The response has also been measured in
    primary granulocytic precursors taken from patients, not only in expression
    systems.
  cell_types:
  - preferred_term: promyelocyte
    term:
      id: CL:0000836
      label: promyelocyte
  biological_processes:
  - preferred_term: endoplasmic reticulum unfolded protein response
    modifier: INCREASED
    term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
  - preferred_term: response to endoplasmic reticulum stress
    modifier: INCREASED
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
  - preferred_term: protein folding
    modifier: DECREASED
    term:
      id: GO:0006457
      label: protein folding
  evidence:
  - reference: PMID:17761833
    reference_title: Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most strikingly, UPR activation and decreased NE protein expression were
      detected in primary granulocytic precursors from SCN patients.
    explanation: >-
      Measures the unfolded protein response in patient precursors, which is
      what grounds this node in human disease rather than in an expression
      system alone.
  - reference: PMID:17761833
    reference_title: Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The magnitude of UPR activation by a specific ELA2 mutation correlated
      with its associated clinical phenotype.
    explanation: >-
      A genotype-to-mechanism dose relationship, which is the evidence that
      distinguishes a causal branch from an incidental stress response.
  - reference: PMID:16551967
    reference_title: Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Moreover, cells expressing mutant HNE protein exhibited a significant
      increase in apoptosis associated with up-regulation of the master ER
      chaperone BiP, indicating that disturbance of intracellular trafficking
      results in activation of the mammalian unfolded protein response.
    explanation: >-
      Independent demonstration of unfolded protein response activation, from a
      second group using a different expression system.
  downstream:
  - target: Apoptosis of Granulocytic Precursors
    causal_link_type: DIRECT
    description: >-
      The unfolded protein response in these cells is not merely adaptive: it
      induces CHOP and kills the precursor, and it does so without requiring
      elastase proteolytic activity.
    evidence:
    - reference: PMID:17761833
      reference_title: Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Consistent with the UPR model, expression of mutant NE in primary human
        granulocytic precursors increased expression of CHOP (DDITS) and induced
        apoptosis in a protease-independent fashion.
      explanation: >-
        States the edge and, in the protease-independent qualifier, rules out
        the competing account in which mutant enzyme activity kills the cell.
- name: Apoptosis of Granulocytic Precursors
  biological_scale: CELLULAR
  description: >-
    Accelerated death of promyelocytes and their descendants. This is the step
    that converts a protein-folding defect into a blood count: granulopoiesis
    becomes ineffective, precursors are consumed rather than matured, and the
    marrow shows the arrest that follows.
  cell_types:
  - preferred_term: promyelocyte
    term:
      id: CL:0000836
      label: promyelocyte
  - preferred_term: neutrophilic myelocyte
    term:
      id: CL:0000580
      label: neutrophilic myelocyte
  biological_processes:
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  - preferred_term: intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
    modifier: INCREASED
    term:
      id: GO:0070059
      label: intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
  evidence:
  - reference: PMID:17761833
    reference_title: Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We hypothesize that the ELA2 mutations result in the production of
      misfolded NE protein, activation of the unfolded protein response (UPR),
      and ultimately apoptosis of granulocytic precursors.
    explanation: >-
      States precursor apoptosis as the endpoint of the misfolding chain. The
      source frames it as a hypothesis, which is why the wording here is
      careful; the same paper then supplies the CHOP and apoptosis measurements
      that support it.
  downstream:
  - target: Myeloid Maturation Arrest at the Promyelocyte Stage
    causal_link_type: DIRECT
    description: >-
      Precursor death at the promyelocyte stage is what the marrow shows as an
      arrest: the maturation pyramid stops at promyelocytes, with few or no
      later granulocytic forms.
    evidence:
    - reference: PMID:28593997
      reference_title: Severe congenital neutropenias.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Severe congenital neutropenias are a heterogeneous group of rare
        haematological diseases characterized by impaired maturation of
        neutrophil granulocytes.
      explanation: >-
        Identifies impaired granulocytic maturation as the defining marrow
        consequence, which is the endpoint this edge asserts.
- name: Myeloid Maturation Arrest at the Promyelocyte Stage
  biological_scale: TISSUE
  description: >-
    The marrow lesion, and the finding that distinguishes this disease from
    peripheral causes of neutropenia. The normal maturation pyramid of
    granulocyte precursors is replaced by an arrest at the promyelocyte stage,
    characteristically accompanied by marrow eosinophilia and monocytosis.
  cell_types:
  - preferred_term: promyelocyte
    term:
      id: CL:0000836
      label: promyelocyte
  - preferred_term: myelocyte
    term:
      id: CL:0002193
      label: myelocyte
  biological_processes:
  - preferred_term: granulocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0030851
      label: granulocyte differentiation
  - preferred_term: neutrophil differentiation
    modifier: DECREASED
    term:
      id: GO:0030223
      label: neutrophil differentiation
  evidence:
  - reference: PMID:21595885
    reference_title: "Congenital neutropenia: diagnosis, molecular bases and patient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients with severe congenital neutropenia and ELANE mutation: bone
      marrow myeloid arrest at promyelocyte stage with eosinophilia
    explanation: >-
      Names the marrow finding for ELANE-mutant severe congenital neutropenia
      specifically, which is exactly this node.
  - reference: PMID:21595885
    reference_title: "Congenital neutropenia: diagnosis, molecular bases and patient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Maturation arrest at the promyelocyte stage is often associated with bone
      marrow hypereosinophilia and monocytosis.
    explanation: >-
      Adds the accompanying marrow features, which matter diagnostically
      because they are what a reporting haematologist sees alongside the
      arrest.
  downstream:
  - target: Profound Persistent Neutropenia
    causal_link_type: DIRECT
    description: >-
      An arrested marrow produces no mature neutrophils, so the peripheral
      count falls and stays low.
    evidence:
    - reference: PMID:20456363
      reference_title: Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        with maturation arrest of neutrophil precursors in the bone marrow
      explanation: >-
        The clinical case definition pairs the persistent peripheral count with
        marrow maturation arrest, which is the pairing this edge asserts.
- name: Profound Persistent Neutropenia
  biological_scale: ORGANISM
  description: >-
    The defining laboratory state: an absolute neutrophil count persistently
    below 0.5 x 10^9/L, present from the first weeks of life. Unlike the
    allelic cyclic disease the deficit is fixed rather than oscillating, and
    infection risk rises steeply as the count falls, being particularly high
    below 0.2 x 10^9/L.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  evidence:
  - reference: PMID:20456363
    reference_title: Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe congenital neutropenia (SCN) is a genetically heterogeneous
      disorder of myelopoeisis that is diagnosed clinically on the basis of
      absolute neutrophil counts (ANC) persistently below the threshold of 0.5
    explanation: >-
      Gives the clinical case definition and the numerical threshold. The quote
      stops at the threshold value because the cached text renders the units
      with an inline superscript.
  - reference: PMID:21595885
    reference_title: "Congenital neutropenia: diagnosis, molecular bases and patient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some patients have severe permanent neutropenia and frequent infections
      early in life, while others have mild intermittent neutropenia.
    explanation: >-
      Records that the ELANE phenotype spans a severity range, of which this
      entry curates the severe permanent end.
  downstream:
  - target: Impaired Innate Defence and Recurrent Bacterial Infection
    causal_link_type: DIRECT
    description: >-
      Neutrophils are the primary cellular defence against pyogenic bacteria,
      so their absence is the whole of the infectious susceptibility. The
      relationship is quantitative: risk scales inversely with the count.
    evidence:
    - reference: PMID:21595885
      reference_title: "Congenital neutropenia: diagnosis, molecular bases and patient management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The risk of infection is roughly inversely proportional to the
        circulating polymorphonuclear neutrophil count and is particularly high
        at counts below 0.2 G/l.
      explanation: >-
        States the dose relationship between the neutrophil count and infection
        risk, which is the edge rather than either node alone.
  - target: Acquisition of Somatic CSF3R Mutations
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Severe disease requires sustained high-dose G-CSF to maintain a workable
      count, and it is the patients who respond least well to the largest doses
      who carry the highest risk of malignant events. The intermediate steps
      are the chronic proliferative pressure on a stressed progenitor
      compartment and the selection of clones bearing truncated G-CSF
      receptors.
    evidence:
    - reference: PMID:16497969
      reference_title: The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In these less-responsive patients, the cumulative incidence of adverse
        events was highest: after 10 years, 40% developed MDS/AML and 14% died
        of sepsis, compared with 11% and 4%, respectively, of more responsive
        patients whose ANC was above the median on doses of G-CSF below the
        median.
      explanation: >-
        Ties malignant risk to the severity of the granulopoietic defect as
        measured by dose requirement and response, which is the link between
        the neutropenia node and the clonal-evolution arm.
- name: Impaired Innate Defence and Recurrent Bacterial Infection
  biological_scale: ORGANISM
  description: >-
    The infectious arm of the disease. Omphalitis in the newborn period is
    often the first sign; untreated children then develop diarrhoea,
    pneumonia and deep abscesses of liver, lung and subcutaneous tissue in the
    first year, alongside oral ulceration, gingivitis and pharyngitis. Before
    G-CSF this was the cause of death in most patients.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  evidence:
  - reference: PMID:20301705
    reference_title: ELANE-Related Neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In congenital neutropenia, omphalitis immediately after birth may be the
      first sign; in untreated children diarrhea, pneumonia, and deep abscesses
      in the liver, lungs, and subcutaneous tissues are common in the first year
      of life.
    explanation: >-
      Enumerates the infections that constitute this node and gives their
      timing, which is what makes the presentation recognisable in infancy.
  - reference: PMID:28593997
    reference_title: Severe congenital neutropenias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with severe congenital neutropenia are prone to recurrent, often
      life-threatening infections beginning in their first months of life.
    explanation: >-
      Confirms the severity and the onset window from a disease-primer review.
  - reference: PMID:20301705
    reference_title: ELANE-Related Neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infectious complications are generally more severe in congenital
      neutropenia than in cyclic neutropenia.
    explanation: >-
      Grades this node against the allelic disorder, which is the clinical
      distinction that justifies curating the two separately.
  downstream:
  - target: Recurrent Bacterial Infections
    causal_link_type: DIRECT
    description: >-
      The clinical expression of this node: omphalitis, skin and perirectal abscess, otitis and pneumonia from the first months of life.
  - target: Neonatal Omphalitis
    causal_link_type: DIRECT
    description: >-
      Infection of the umbilical stump in the days after birth, frequently the
      presenting event.
    evidence:
    - reference: PMID:20301705
      reference_title: ELANE-Related Neutropenia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In congenital neutropenia, omphalitis immediately after birth may be the
        first sign
      explanation: >-
        Places omphalitis as the earliest infectious consequence of the
        neutropenia.
  - target: Pneumonia
    causal_link_type: DIRECT
    description: >-
      Lower respiratory tract infection, common in untreated infants.
    evidence:
    - reference: PMID:20301705
      reference_title: ELANE-Related Neutropenia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        in untreated children diarrhea, pneumonia, and deep abscesses in the
        liver, lungs, and subcutaneous tissues are common in the first year of
        life
      explanation: >-
        Names pneumonia among the infections of untreated infancy.
  - target: Deep and Cutaneous Abscesses
    causal_link_type: DIRECT
    description: >-
      Abscess formation in liver, lung and subcutaneous tissue, reflecting
      failure to contain pyogenic organisms without neutrophils.
    evidence:
    - reference: PMID:20301705
      reference_title: ELANE-Related Neutropenia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        deep abscesses in the liver, lungs, and subcutaneous tissues are common
        in the first year of life
      explanation: >-
        Names the abscesses and their sites as a consequence of untreated
        neutropenia.
  - target: Oral Ulceration
    causal_link_type: DIRECT
    description: >-
      Mucosal breakdown of the mouth, part of the oropharyngeal inflammatory
      picture shared across ELANE-related neutropenia.
    evidence:
    - reference: PMID:20301705
      reference_title: ELANE-Related Neutropenia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        primary hematologic disorders characterized by recurrent fever, skin and
        oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis,
        and pharyngitis), and cervical adenopathy
      explanation: >-
        Names mouth ulceration among the manifestations that follow from the
        neutropenia.
  - target: Gingivitis
    causal_link_type: DIRECT
    description: >-
      Gingival inflammation from bacterial colonisation that neutrophils would
      otherwise control.
    evidence:
    - reference: PMID:20301705
      reference_title: ELANE-Related Neutropenia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        primary hematologic disorders characterized by recurrent fever, skin and
        oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis,
        and pharyngitis), and cervical adenopathy
      explanation: >-
        Names gingivitis among the oropharyngeal manifestations.
  - target: Periodontitis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Repeated gingival infection produces cumulative periodontal destruction,
      described in the congenital neutropenias as chronic periodontal disease
      that leaves permanent sequelae.
    evidence:
    - reference: PMID:21595885
      reference_title: "Congenital neutropenia: diagnosis, molecular bases and patient management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Neutropenia can lead to life-threatening pyogenic infections, acute
        gingivostomatitis and chronic parodontal disease, and each successive
        infection may leave permanent sequelae.
      explanation: >-
        States the progression from repeated acute oral infection to chronic
        periodontal disease with permanent damage, which is what makes this an
        indirect rather than a direct edge.
  - target: Recurrent Fever
    causal_link_type: DIRECT
    description: >-
      Febrile episodes accompanying each infection.
    evidence:
    - reference: PMID:20301705
      reference_title: ELANE-Related Neutropenia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        primary hematologic disorders characterized by recurrent fever, skin and
        oropharyngeal inflammation
      explanation: >-
        Names recurrent fever among the manifestations of ELANE-related
        neutropenia.
  - target: Sepsis
    causal_link_type: DIRECT
    description: >-
      Bloodstream infection, historically the usual cause of death and still a
      steady hazard on treatment.
    evidence:
    - reference: PMID:16497969
      reference_title: The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In SCN, sepsis mortality was stable at 0.9% per year.
      explanation: >-
        Quantifies the sepsis hazard that persists even in a G-CSF-treated
        registry cohort.
- name: Acquisition of Somatic CSF3R Mutations
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Somatic nonsense mutations in CSF3R truncate the cytoplasmic tail of the
    G-CSF receptor, removing one to all four tyrosine residues that carry its
    differentiation signal while leaving the proliferative signal intact. The
    resulting clone proliferates under G-CSF without maturing. This is recorded
    as provisional rather than established: the mutations are highly predictive
    of transformation and appear early, but they are explicitly not a necessary
    condition, and the authors who described them state that cooperating events
    remain to be defined.
  genes:
  - preferred_term: CSF3R
    term:
      id: hgnc:2439
      label: CSF3R
  biological_processes:
  - preferred_term: granulocyte colony-stimulating factor signaling pathway
    modifier: DYSREGULATED
    term:
      id: GO:0038158
      label: granulocyte colony-stimulating factor signaling pathway
  genetic_context:
    gene:
      preferred_term: CSF3R
      term:
        id: hgnc:2439
        label: CSF3R
    variant_origin: SOMATIC
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    description: >-
      Truncating mutations remove the receptor's differentiation-signalling
      tyrosines while preserving proliferative signalling, so the functional
      consequence is partial and selective rather than a complete loss of
      receptor function.
  evidence:
  - reference: PMID:16985178
    reference_title: "Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: Results of a long-term survey."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We detected CSF3R nonsense mutations at 17 different nucleotide positions
      (thereof 10 new mutations) which lead to a loss of 1 to all 4 tyrosine
      residues in the intracellular domain of the receptor.
    explanation: >-
      Describes the molecular lesion annotated on this node: truncation of the
      receptor's intracellular signalling domain.
  - reference: PMID:16985178
    reference_title: "Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: Results of a long-term survey."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 23 patients with CN with signs of malignant transformation, 18 (78%)
      were shown to harbor a CSF3R mutation, indicating that these mutations,
      although not a necessary condition, are highly predictive for malignant
      transformation even if detected in a low percentage of transcripts.
    explanation: >-
      Gives both the strength of the association and the reason this node is
      marked provisional: the mutation is highly predictive but not necessary.
  - reference: PMID:16985178
    reference_title: "Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: Results of a long-term survey."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results strongly suggest that acquisition of a CSF3R mutation is an
      early event in leukemogenesis that has to be accompanied by cooperating
      molecular events, which remain to be defined.
    explanation: >-
      Places the event early in the sequence and states explicitly that it is
      insufficient alone, which is what the PROVISIONAL confidence records.
  downstream:
  - target: Clonal Evolution to Myelodysplasia and Acute Myeloid Leukaemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The CSF3R-mutant clone acquires further leukaemia-associated mutations,
      RUNX1 most often, and the combination confers G-CSF-driven proliferation
      with blocked myeloid differentiation. Single-cell work places the two
      mutations in the same clone, and sequential sampling places RUNX1 late.
    evidence:
    - reference: PMID:24523240
      reference_title: "Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Functional studies demonstrated elevated granulocyte colony-stimulating
        factor (G-CSF)-induced proliferation with diminished myeloid
        differentiation of hematopoietic CD34(+) cells coexpressing mutated
        forms of RUNX1 and CSF3R.
      explanation: >-
        Demonstrates the functional consequence of the two-hit combination,
        which is the mechanism this edge asserts rather than a mere
        co-occurrence.
    - reference: PMID:22371884
      reference_title: Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The sequential gain of 2 CSF3R mutations implicates abnormal G-CSF
        signaling as a driver of leukemic transformation in this case of SCN.
      explanation: >-
        Longitudinal single-patient sequencing implicating aberrant G-CSF
        receptor signalling as the driver of the transition. It is one case, so
        it supports the edge without establishing its generality.
- name: Clonal Evolution to Myelodysplasia and Acute Myeloid Leukaemia
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Severe congenital neutropenia is a preleukaemic bone marrow failure
    syndrome. A clone bearing a truncated G-CSF receptor expands, acquires
    RUNX1 mutations and other leukaemia-associated lesions including ASXL1 and
    chromatin remodellers, and the marrow progresses to myelodysplasia or acute
    myeloid leukaemia. RUNX1 mutation is far commoner here than in de novo
    paediatric AML, which is what marks this out as a distinct leukaemogenic
    route rather than ordinary AML arising in a neutropenic patient.
  genes:
  - preferred_term: RUNX1
    term:
      id: hgnc:10471
      label: RUNX1
  - preferred_term: CSF3R
    term:
      id: hgnc:2439
      label: CSF3R
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  biological_processes:
  - preferred_term: myeloid cell differentiation
    modifier: DECREASED
    term:
      id: GO:0030851
      label: granulocyte differentiation
  evidence:
  - reference: PMID:24523240
    reference_title: "Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twenty (64.5%) of the 31 patients had mutations in RUNX1. A majority of
      patients with RUNX1 mutations (80.5%) also had acquired CSF3R mutations.
    explanation: >-
      Quantifies the two mutations and their co-occurrence in patients who
      actually transformed, which is the genetic content of this node.
  - reference: PMID:24523240
    reference_title: "Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to their high frequency in CN patients who developed leukemia
      or MDS, RUNX1 mutations were found in only 9 of 307 (2.9%) patients with
      de novo pediatric acute myeloid leukemia.
    explanation: >-
      The contrast with de novo paediatric AML is what supports treating this as
      a disease-specific route rather than coincidental leukaemia.
  - reference: PMID:22371884
    reference_title: Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that progression from SCN to AML is a multistep process, with
      distinct mutations arising early during the SCN phase and others later in
      AML development.
    explanation: >-
      Establishes the multistep structure of this node, with early and late
      lesions separated in time.
  - reference: PMID:28593997
    reference_title: Severe congenital neutropenias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Molecular events in the malignant progression include acquired mutations
      in CSF3R (encoding G-CSF receptor) and subsequently in other
      leukaemia-associated genes (such as RUNX1) in a majority of patients.
    explanation: >-
      A review statement of the same sequence, establishing that it applies to
      the majority of transforming patients rather than to selected cases.
  downstream:
  - target: Myelodysplastic Syndrome
    causal_link_type: DIRECT
    description: >-
      The clone first manifests as myelodysplasia, frequently with monosomy 7.
    evidence:
    - reference: PMID:24523240
      reference_title: "Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Severe congenital neutropenia (CN) is a preleukemic bone marrow failure
        syndrome with a 20% risk of evolving into leukemia or myelodysplastic
        syndrome (MDS).
      explanation: >-
        States myelodysplasia as one of the two malignant endpoints of the
        clonal process, with its approximate risk.
  - target: Acute Myeloid Leukemia
    causal_link_type: DIRECT
    description: >-
      Frank leukaemic transformation, the endpoint of the multistep clonal
      process.
    evidence:
    - reference: PMID:22371884
      reference_title: Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The other 9 mutations were only apparent in the AML cells and affected
        known AML-associated genes (RUNX1 and ASXL1) and chromatin remodelers
        (SUZ12 and EP300).
      explanation: >-
        Documents the late lesions present specifically in the leukaemic cells,
        which is the transition this edge records.
phenotypes:
- category: Blood
  name: Profound Persistent Neutropenia
  diagnostic: true
  frequency: OBLIGATE
  description: >-
    An absolute neutrophil count persistently below 0.5 x 10^9/L, present from
    the first weeks of life and, unlike the allelic cyclic disease, not
    oscillating. This is the defining laboratory phenotype.
  phenotype_term:
    preferred_term: Persistently decreased total neutrophil count
    term:
      id: HP:0410252
      label: Persistently decreased total neutrophil count
    temporality: CHRONIC
  evidence:
  - reference: PMID:20456363
    reference_title: Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe congenital neutropenia (SCN) is a genetically heterogeneous
      disorder of myelopoeisis that is diagnosed clinically on the basis of
      absolute neutrophil counts (ANC) persistently below the threshold of 0.5
    explanation: >-
      The diagnostic criterion itself, which is why this phenotype is marked
      diagnostic and given an OBLIGATE frequency.
  - reference: PMID:21595885
    reference_title: "Congenital neutropenia: diagnosis, molecular bases and patient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neutropenia is said to be severe when below 0.5 G/l
    explanation: >-
      Confirms the severity threshold in the units used in the European
      literature.
- category: Blood
  name: Myeloid Maturation Arrest at the Promyelocyte Stage
  diagnostic: true
  description: >-
    The marrow correlate: granulocytic maturation stops at the promyelocyte
    stage, with few later forms, often alongside marrow eosinophilia and
    monocytosis. Demonstrating it is what separates a production defect from
    peripheral destruction.
  phenotype_term:
    preferred_term: Bone marrow arrest at the promyelocytic stage
    term:
      id: HP:0033607
      label: Bone marrow arrest at the promyelocytic stage
  evidence:
  - reference: PMID:21595885
    reference_title: "Congenital neutropenia: diagnosis, molecular bases and patient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients with severe congenital neutropenia and ELANE mutation: bone
      marrow myeloid arrest at promyelocyte stage with eosinophilia
    explanation: >-
      Names the finding for ELANE-mutant severe congenital neutropenia, which is
      exactly the phenotype term bound here.
  - reference: PMID:28593997
    reference_title: Severe congenital neutropenias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe congenital neutropenias are a heterogeneous group of rare
      haematological diseases characterized by impaired maturation of neutrophil
      granulocytes.
    explanation: >-
      Confirms impaired granulocytic maturation as the characteristic marrow
      abnormality of this disease group.
- category: Immune
  name: Recurrent Bacterial Infections
  frequency: VERY_FREQUENT
  description: >-
    Recurrent, often life-threatening pyogenic infection beginning in the first
    months of life, and more severe than in the allelic cyclic disease.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
    temporality: RECURRENT
  evidence:
  - reference: PMID:28593997
    reference_title: Severe congenital neutropenias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with severe congenital neutropenia are prone to recurrent, often
      life-threatening infections beginning in their first months of life.
    explanation: >-
      States that recurrent severe infection is the general rule in this
      disease, which supports the VERY_FREQUENT band.
  - reference: PMID:20301705
    reference_title: ELANE-Related Neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infectious complications are generally more severe in congenital
      neutropenia than in cyclic neutropenia.
    explanation: >-
      Grades the severity of the infectious phenotype against the allelic
      disorder.
- category: Prenatal and Birth
  name: Neonatal Omphalitis
  description: >-
    Infection of the umbilical stump immediately after birth, often the
    presenting sign of the disease.
  phenotype_term:
    preferred_term: Neonatal omphalitis
    term:
      id: HP:0032435
      label: Neonatal omphalitis
  evidence:
  - reference: PMID:20301705
    reference_title: ELANE-Related Neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In congenital neutropenia, omphalitis immediately after birth may be the
      first sign
    explanation: >-
      Names omphalitis and its timing, and records that it is frequently the
      first manifestation.
- category: Respiratory
  name: Pneumonia
  description: >-
    Lower respiratory tract infection, common in the first year of life in
    untreated children.
  phenotype_term:
    preferred_term: Pneumonia
    term:
      id: HP:0002090
      label: Pneumonia
  evidence:
  - reference: PMID:20301705
    reference_title: ELANE-Related Neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in untreated children diarrhea, pneumonia, and deep abscesses in the
      liver, lungs, and subcutaneous tissues are common in the first year of
      life
    explanation: >-
      Names pneumonia among the common infections of untreated infancy in this
      disease.
- category: Integument
  name: Deep and Cutaneous Abscesses
  description: >-
    Abscesses of liver, lung and subcutaneous tissue. Without neutrophils,
    pyogenic organisms are contained poorly and collections form.
  phenotype_term:
    preferred_term: Cutaneous abscess
    term:
      id: HP:0031292
      label: Cutaneous abscess
  evidence:
  - reference: PMID:20301705
    reference_title: ELANE-Related Neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      deep abscesses in the liver, lungs, and subcutaneous tissues are common in
      the first year of life
    explanation: >-
      Names the abscesses and their sites. The bound HPO term covers the
      cutaneous component; the visceral sites are recorded in the description
      because HPO has no single term spanning all three.
- category: Head and Neck
  name: Oral Ulceration
  description: >-
    Painful mouth ulcers, part of the oropharyngeal inflammation that runs
    through ELANE-related neutropenia and often the manifestation that brings
    the patient to a dentist first.
  phenotype_term:
    preferred_term: Oral ulcer
    term:
      id: HP:0000155
      label: Oral ulcer
  evidence:
  - reference: PMID:20301705
    reference_title: ELANE-Related Neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      primary hematologic disorders characterized by recurrent fever, skin and
      oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and
      pharyngitis), and cervical adenopathy
    explanation: >-
      Names mouth ulcers among the defining clinical characteristics.
- category: Head and Neck
  name: Gingivitis
  description: >-
    Gingival inflammation, which in the absence of neutrophils follows from
    ordinary oral bacterial colonisation.
  phenotype_term:
    preferred_term: Gingivitis
    term:
      id: HP:0000230
      label: Gingivitis
  evidence:
  - reference: PMID:20301705
    reference_title: ELANE-Related Neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      primary hematologic disorders characterized by recurrent fever, skin and
      oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and
      pharyngitis), and cervical adenopathy
    explanation: >-
      Names gingivitis among the defining clinical characteristics.
- category: Head and Neck
  name: Periodontitis
  description: >-
    Chronic periodontal disease arising from repeated neutropenic gingival
    infection, capable of leaving permanent tissue loss.
  phenotype_term:
    preferred_term: Periodontitis
    term:
      id: HP:0000704
      label: Periodontitis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:21595885
    reference_title: "Congenital neutropenia: diagnosis, molecular bases and patient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neutropenia can lead to life-threatening pyogenic infections, acute
      gingivostomatitis and chronic parodontal disease, and each successive
      infection may leave permanent sequelae.
    explanation: >-
      States chronic periodontal disease as a consequence of the neutropenia and
      records that damage accumulates, which is what the PROGRESSIVE course
      annotation asserts.
- category: Constitutional
  name: Recurrent Fever
  description: >-
    Febrile episodes accompanying recurrent infection.
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
    temporality: RECURRENT
  evidence:
  - reference: PMID:20301705
    reference_title: ELANE-Related Neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      primary hematologic disorders characterized by recurrent fever, skin and
      oropharyngeal inflammation
    explanation: >-
      Names recurrent fever among the defining clinical characteristics.
- category: Immune
  name: Sepsis
  description: >-
    Bloodstream infection. Historically the usual cause of death in infancy;
    even in a G-CSF-treated registry cohort the annual sepsis mortality is
    close to 1%.
  phenotype_term:
    preferred_term: Sepsis
    term:
      id: HP:0100806
      label: Sepsis
  evidence:
  - reference: PMID:16497969
    reference_title: The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In SCN, sepsis mortality was stable at 0.9% per year.
    explanation: >-
      Quantifies the residual sepsis hazard in treated patients, which is what
      makes this phenotype a continuing rather than a historical concern.
- category: Neoplasm
  name: Myelodysplastic Syndrome
  frequency: OCCASIONAL
  description: >-
    Clonal myelodysplasia, characteristically with monosomy 7, arising on the
    background of the preleukaemic marrow. Reported together with AML in the
    registry literature; the combined risk after 15 years of G-CSF is
    approximately 15 to 25%.
  phenotype_term:
    preferred_term: Myelodysplasia
    term:
      id: HP:0002863
      label: Myelodysplasia
  evidence:
  - reference: PMID:20301705
    reference_title: ELANE-Related Neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After 15 years with granulocyte colony-stimulating factor treatment, the
      risk of developing myelodysplasia (MDS) or acute myelogenous leukemia
      (AML) is approximately 15%-25%.
    explanation: >-
      Gives the combined MDS/AML risk figure, which falls in the OCCASIONAL band
      and is the basis for the frequency recorded here.
  - reference: PMID:24523240
    reference_title: "Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe congenital neutropenia (CN) is a preleukemic bone marrow failure
      syndrome with a 20% risk of evolving into leukemia or myelodysplastic
      syndrome (MDS).
    explanation: >-
      An independent estimate of the same combined risk, consistent with the
      band assigned.
- category: Neoplasm
  name: Acute Myeloid Leukemia
  frequency: OCCASIONAL
  description: >-
    Leukaemic transformation, the endpoint of the CSF3R-to-RUNX1 clonal
    sequence. The annual hazard rises over the first decade on G-CSF and then
    plateaus at about 2.3% per year.
  phenotype_term:
    preferred_term: Acute myeloid leukemia
    term:
      id: HP:0004808
      label: Acute myeloid leukemia
  evidence:
  - reference: PMID:20456363
    reference_title: Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Long-term, the annual risk of MDS/AML attained a plateau (2.3%/year after
      10 years).
    explanation: >-
      The best long-term hazard estimate, from the largest prospective cohort,
      and the correction of the earlier and much higher figure.
  - reference: PMID:20301705
    reference_title: ELANE-Related Neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After 15 years with granulocyte colony-stimulating factor treatment, the
      risk of developing myelodysplasia (MDS) or acute myelogenous leukemia
      (AML) is approximately 15%-25%.
    explanation: >-
      Gives the cumulative risk over fifteen years, which is the figure used for
      the OCCASIONAL band here.
genetic:
- name: ELANE
  gene_term:
    preferred_term: ELANE
    term:
      id: hgnc:3309
      label: ELANE
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  frequency: the most common cause of severe congenital neutropenia
  case_fractions:
  - population: Congenital neutropenia patients screened in the Hannover/SCNIR cohort
    case_fraction_percent: 41.0
    cohort_size: 395
    notes: >-
      Detection rate in a referred, screened cohort. The same screen found 55%
      in cyclic neutropenia, so the ELANE yield is lower in this disease than
      in its allelic partner.
    evidence:
    - reference: PMID:23463630
      reference_title: The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We found 116 different mutations in 162 (41%) CN patients and 26 in 51
        (55%) CyN patients, 69 of them were novel.
      explanation: >-
        Gives the congenital-neutropenia detection rate and its denominator,
        alongside the cyclic comparison.
    - reference: PMID:23463630
      reference_title: The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We screened CN (n = 395) or CyN (n = 92) patients for ELANE mutations
        and investigated the impact of mutations on mRNA expression, protein
        expression, and activity.
      explanation: >-
        Establishes the cohort size recorded here.
  notes: >-
    Heterozygous ELANE variants, predominantly missense, are the commonest
    cause of severe congenital neutropenia. Detection rate depends on the
    cohort: a screen of 395 referred congenital neutropenia patients found
    mutations in 41%, and a French registry-based review puts ELANE behind
    about half of congenital neutropenias that have no extra-haematopoietic
    features and normal adaptive immunity.

    Genotype does not cleanly predict which ELANE phenotype appears. The
    congenital and cyclic mutation spectra differ in tendency, with cyclic
    mutations clustering near the active site and congenital ones on the
    opposite face, but the severity distributions overlap, and one S97L allele
    on a shared paternal haplotype has produced both phenotypes within a single
    kindred. Leukaemic risk correlates with disease severity rather than with
    the presence of an ELANE mutation as such, which is why no specific allele
    is treated here as a leukaemia predictor.
  evidence:
  - reference: PMID:11001877
    reference_title: Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study indicates that mutations of the gene encoding neutrophil
      elastase are probably the most common cause for severe congenital
      neutropenia as well as the cause for sporadic and autosomal dominant
      cyclic neutropenia.
    explanation: >-
      Establishes ELANE as the leading cause of severe congenital neutropenia,
      and in the same sentence states the allelic relationship with cyclic
      neutropenia.
  - reference: PMID:11001877
    reference_title: Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In cyclic neutropenia, the mutations appeared to cluster near the active
      site of the molecule, whereas the opposite face was predominantly affected
      by the mutations found in congenital neutropenia.
    explanation: >-
      Documents the partial structural separation of the two mutation spectra,
      which is the strongest genotype-level statement the allelic boundary
      supports.
  - reference: PMID:10581030
    reference_title: "Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 7 different single-base substitutions in the gene (ELA2)
      encoding neutrophil elastase
    explanation: >-
      The original identification of the gene, made in cyclic haematopoiesis a
      year before the same gene was implicated in congenital neutropenia. Cited
      here because it is the origin of the allelic relationship this entry has
      to delimit.
  - reference: PMID:21595885
    reference_title: "Congenital neutropenia: diagnosis, molecular bases and patient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      About half the forms of congenital neutropenia with no extra-hematopoietic
      manifestations and normal adaptive immunity are due to neutrophil elastase
      (ELANE) mutations.
    explanation: >-
      A registry-based estimate of the ELANE share among non-syndromic
      congenital neutropenias, which is the population this entry covers.
  - reference: PMID:23463630
    reference_title: The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Specific ELANE mutations have limited predictive value for leukemogenesis;
      the risk for leukemia was correlated with disease severity rather than
      with occurrence of an ELANE mutation.
    explanation: >-
      Supports the note that no allele is treated as a leukaemia predictor, and
      locates the risk in disease severity instead.
  - reference: PMID:23463630
    reference_title: The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The frequency of acquired CSF3R mutations, malignant transformation, and
      the need for hematopoietic stem cell transplantation was significantly
      higher in CN patients with ELANE mutation than in ELANE mutation negative
      patients.
    explanation: >-
      Records that within congenital neutropenia the ELANE-mutant group is the
      higher-risk one, which is relevant to how aggressively this entry's
      population is monitored.
- name: CSF3R
  gene_term:
    preferred_term: CSF3R
    term:
      id: hgnc:2439
      label: CSF3R
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    Acquired nonsense mutations truncating the intracellular domain of the
    G-CSF receptor. They are not part of the germline disease; they arise in
    haematopoietic clones during its course and mark the beginning of leukaemic
    evolution. They are detectable in a minority of transcripts long before
    overt transformation, and highly clonal haematopoiesis does not inevitably
    progress quickly.
  evidence:
  - reference: PMID:16985178
    reference_title: "Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: Results of a long-term survey."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 23 patients with CN with signs of malignant transformation, 18 (78%)
      were shown to harbor a CSF3R mutation, indicating that these mutations,
      although not a necessary condition, are highly predictive for malignant
      transformation even if detected in a low percentage of transcripts.
    explanation: >-
      Gives both the frequency among transforming patients and the caveat that
      the mutation is predictive rather than necessary.
  - reference: PMID:16985178
    reference_title: "Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: Results of a long-term survey."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We could demonstrate that even a highly clonal hematopoiesis did not
      inevitably show a rapid progression to leukemia.
    explanation: >-
      The observation that keeps this from being read as a deterministic
      progression, and that matters clinically when a mutation is found on
      surveillance.
- name: RUNX1
  gene_term:
    preferred_term: RUNX1
    term:
      id: hgnc:10471
      label: RUNX1
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    Acquired RUNX1 mutations are the commonest cooperating lesion, found in
    about two thirds of patients who transform, usually in the same clone as a
    CSF3R mutation and arriving late in the sequence.
  evidence:
  - reference: PMID:24523240
    reference_title: "Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A sequential analysis at stages prior to overt leukemia revealed RUNX1
      mutations to be late events in leukemic transformation.
    explanation: >-
      Places RUNX1 late in the clonal sequence, which is what distinguishes it
      from the early CSF3R event.
  - reference: PMID:24523240
    reference_title: "Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Single-cell analyses in 2 patients showed that RUNX1 and CSF3R mutations
      were present in the same malignant clone.
    explanation: >-
      Establishes that the two lesions are in one clone rather than in parallel
      populations, which is what makes the cooperativity claim meaningful.
prevalence:
- population: Worldwide (International Neutropenia Registry catchment, approximately 700 million people)
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.07
  notes: >-
    Registry-ascertained prevalence of congenital neutropenia as a whole, not of
    the ELANE form alone; 0.7 per million rising to 1 per million when
    idiopathic neutropenia is counted. ELANE accounts for roughly half of
    non-syndromic congenital neutropenia, so the SCN1 figure is lower again.
    Registry ascertainment is incomplete, so treat this as a floor.
  evidence:
  - reference: PMID:21595885
    reference_title: "Congenital neutropenia: diagnosis, molecular bases and patient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence was 0.7 per million inhabitants or 1 per million inhabitants
      when idiopathic neutropenia was included.
    explanation: >-
      The registry-derived prevalence figure recorded here, with its
      idiopathic-inclusive variant.
- population: France (French Severe Chronic Neutropenia Registry)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.62
  notes: >-
    A dedicated national registry finds nearly ten times the prevalence of the
    Iranian survey of comparable population size, which the review reports as
    approximately 6.2 per million and takes as the best available floor for
    congenital neutropenia generally. The quoted span starts mid-sentence and
    stops before that number because the cached PDF extraction mangles the
    words "In the French" and renders the exponent broken. Of the French
    registry patients, 30% had ELANE-related neutropenia, split roughly 20%
    severe congenital and 10% cyclic.
  evidence:
  - reference: PMID:21595885
    reference_title: "Congenital neutropenia: diagnosis, molecular bases and patient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      registry-based study of a population of comparable size, 374 cases had been
      recorded in December 2006, giving a prevalence nearly 10 times higher
    explanation: >-
      Establishes that dedicated national ascertainment yields a much higher
      prevalence than general immunodeficiency surveys, which is why the
      registry figure is preferred as the floor.
  - reference: PMID:21595885
    reference_title: "Congenital neutropenia: diagnosis, molecular bases and patient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the French registry, 30% of patients had ELANE neutropenia
    explanation: >-
      Gives the ELANE share of a national congenital-neutropenia registry, which
      is what converts a congenital-neutropenia prevalence into an approximate
      figure for this entry.
progression:
- phase: Neonatal period and infancy
  notes: >-
    Presentation is early. Omphalitis in the days after birth may be the first
    sign, followed in untreated children by diarrhoea, pneumonia and deep
    abscesses during the first year. In the original Swedish description most
    affected infants died of bacterial infection before their first birthday.
  evidence:
  - reference: PMID:20301705
    reference_title: ELANE-Related Neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In congenital neutropenia, omphalitis immediately after birth may be the
      first sign; in untreated children diarrhea, pneumonia, and deep abscesses
      in the liver, lungs, and subcutaneous tissues are common in the first year
      of life.
    explanation: >-
      Describes the sequence of events that characterises this phase.
- phase: Childhood and adult life on G-CSF
  notes: >-
    With daily subcutaneous G-CSF the neutrophil count rises, infections fall
    and quality of life improves substantially. Sepsis mortality does not reach
    zero: it runs at roughly 0.8 to 0.9% per year in the international registry
    cohort. Oral and periodontal disease continues to need attention.
  evidence:
  - reference: PMID:28593997
    reference_title: Severe congenital neutropenias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Daily subcutaneous G-CSF administration is the treatment of choice and
      leads to a substantial increase in blood neutrophil count, reduction of
      infections and drastic improvement of quality of life.
    explanation: >-
      States the change in trajectory that defines this phase.
  - reference: PMID:16497969
    reference_title: The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In SCN, sepsis mortality was stable at 0.9% per year.
    explanation: >-
      Quantifies the residual mortality that persists through this phase despite
      treatment.
- phase: Long-term outcome and malignant transformation
  notes: >-
    The axis on which this disease diverges completely from its allelic
    partner. The hazard of myelodysplasia or acute myeloid leukaemia rises over
    the first decade on G-CSF and then plateaus at about 2.3% per year, giving a
    cumulative incidence of roughly 22% at fifteen years; GeneReviews puts the
    fifteen-year risk at 15 to 25%. Cyclic neutropenia carries no recognised
    risk at all. The earlier and much higher estimate of 8% per year after
    twelve years was a small-numbers artefact and was corrected by longer
    follow-up of the same cohort, which is worth stating because the older
    figure still circulates.
  evidence:
  - reference: PMID:20456363
    reference_title: Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Long-term, the annual risk of MDS/AML attained a plateau (2.3%/year after
      10 years).
    explanation: >-
      The corrected long-term hazard, from extended follow-up of the registry
      cohort.
  - reference: PMID:16497969
    reference_title: The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The hazard of MDS/AML increased significantly over time, from 2.9% per
      year after 6 years to 8.0% per year after 12 years on G-CSF.
    explanation: >-
      The earlier estimate that the 2010 update revised downwards. Recorded so
      the correction is visible rather than silently applied.
  - reference: PMID:15642668
    reference_title: "Analysis of risk factors for myelodysplasias, leukemias and death from infection among patients with congenital neutropenia. Experience of the French Severe Chronic Neutropenia Study Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cumulative incidence of MDS/AL was 2.7% (SD 1.3%) at 10 years and 8.1%
      (SD 2.7%) at 20 years.
    explanation: >-
      An independent national registry's cumulative incidence, lower than the
      international registry's; the two cohorts differ in case mix, since the
      French figure covers all forms of severe chronic neutropenia.
diagnosis:
- name: Absolute neutrophil count
  presence: PRESENT
  description: >-
    A persistently low count below 0.5 x 10^9/L is the entry criterion.
    Repeated counts distinguish this disease from cyclic neutropenia, where the
    count oscillates; a single low count establishes neither.
  evidence:
  - reference: PMID:20456363
    reference_title: Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      is diagnosed clinically on the basis of absolute neutrophil counts (ANC)
      persistently below the threshold of 0.5
    explanation: >-
      States the clinical diagnostic basis and its threshold.
- name: Bone marrow examination
  presence: PRESENT
  description: >-
    Marrow aspirate shows arrest of granulocytic maturation at the promyelocyte
    stage, often with eosinophilia and monocytosis, establishing a production
    defect rather than peripheral destruction.
  evidence:
  - reference: PMID:21595885
    reference_title: "Congenital neutropenia: diagnosis, molecular bases and patient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bone marrow examination is often necessary to rule out malignant
      hemopathies, determine cellularity, assess myeloid maturation
    explanation: >-
      States the diagnostic purposes of marrow examination in congenital
      neutropenia.
- name: ELANE molecular genetic testing
  presence: PRESENT
  description: >-
    A heterozygous pathogenic ELANE variant confirms the diagnosis. A negative
    result does not exclude severe congenital neutropenia, since ELANE
    mutations are found in roughly 40 to 50% of cases and several other genes
    produce the same phenotype.
  evidence:
  - reference: PMID:20301705
    reference_title: ELANE-Related Neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of ELANE-related neutropenia is established in a proband
      with suggestive clinical findings and the identification of a heterozygous
      pathogenic variant in ELANE through molecular genetic testing.
    explanation: >-
      States the molecular diagnostic criterion.
- name: Annual bone marrow surveillance with cytogenetics
  presence: PRESENT
  description: >-
    Yearly marrow examination with cytogenetics, looking for monosomy 7 and
    trisomy 21 and for somatic CSF3R and RUNX1 mutations. Listed under
    diagnosis because it is a monitoring investigation rather than a therapy,
    and it is required for every patient not transplanted.
  evidence:
  - reference: PMID:28593997
    reference_title: Severe congenital neutropenias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Regular clinical assessments (including yearly bone marrow examinations) to
      monitor treatment course and detect chromosomal abnormalities (for example,
      monosomy 7 and trisomy 21) as well as somatic pre-leukaemic mutations are
      recommended.
    explanation: >-
      States the surveillance schedule and exactly what it is looking for.
  - reference: PMID:20301705
    reference_title: ELANE-Related Neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Those with congenital neutropenia not undergoing HSCT require surveillance
      for malignant transformation to MDS/AML.
    explanation: >-
      Establishes who needs surveillance and why, and by implication that
      transplanted patients leave this pathway.
treatments:
- name: Granulocyte Colony-Stimulating Factor
  description: >-
    The treatment of choice and the intervention that changed the natural
    history of this disease. Daily subcutaneous filgrastim raises the neutrophil
    count, roughly halves infection-related events and shortens antibiotic use.
    It drives residual granulopoiesis harder rather than correcting the
    misfolding lesion, so patients remain on it indefinitely, and severe
    patients need large doses. Common adverse effects are bone pain, headache,
    rash and asymptomatic splenomegaly; long-term treatment at high dose is
    associated with the leukaemic risk recorded under progression.
  treatment_term:
    preferred_term: colony-stimulating factor therapy
    term:
      id: NCIT:C15515
      label: Colony-Stimulating Factor Therapy
    therapeutic_agent:
    - preferred_term: filgrastim
      term:
        id: NCIT:C1474
        label: Filgrastim
  target_phenotypes:
  - preferred_term: Persistently decreased total neutrophil count
    term:
      id: HP:0410252
      label: Persistently decreased total neutrophil count
  - preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  target_mechanisms:
  - target: Profound Persistent Neutropenia
    treatment_effect: RESTORES
    description: >-
      Pharmacological G-CSF drives the surviving granulocytic compartment to
      proliferate and mature, raising the circulating count into a protective
      range in most patients and increasing the proportion of maturing
      neutrophils in the marrow.
    evidence:
    - reference: PMID:8490166
      reference_title: A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Examination of BM aspirates showed increased proportions of maturing
        neutrophils.
      explanation: >-
        Shows the drug acting on the marrow compartment that this node
        describes, not merely on the peripheral count.
  evidence:
  - reference: PMID:8490166
    reference_title: A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 123 patients enrolled, 120 received filgrastim. On therapy, 108
      patients had a median absolute neutrophil count of > or = 1.5 x 10(9)/L.
    explanation: >-
      The randomised trial response rate: 108 of 120 treated patients reached a
      protective median count.
  - reference: PMID:8490166
    reference_title: A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infection-related events were significantly decreased (P < .05) with
      approximately 50% reduction in the incidence and duration of
      infection-related events and almost 70% reduction in duration of
      antibiotic use.
    explanation: >-
      Quantifies the clinical benefit, which is the outcome that matters rather
      than the count itself.
  - reference: PMID:8490166
    reference_title: A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Asymptomatic splenic enlargement occurred frequently; adverse events
      frequently reported were bone pain, headache, and rash, which were
      generally mild and easily manageable.
    explanation: >-
      The adverse-effect profile from the pivotal trial.
  - reference: PMID:21595885
    reference_title: "Congenital neutropenia: diagnosis, molecular bases and patient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is usually well tolerated, but potential adverse effects include
      thrombocytopenia, glomerulonephritis, vasculitis and osteoporosis.
    explanation: >-
      Records the less common long-term toxicities that the short trial did not
      capture.
  notes: >-
    The leukaemia association is real but should not be read as simple
    causation. Risk tracks the dose required and the response achieved, so the
    patients at highest risk are those whose disease is most severe, and
    severity is itself a risk factor for transformation independently of
    treatment. The 2010 registry update revised the long-term hazard sharply
    downwards and found it comparable with Fanconi anaemia and dyskeratosis
    congenita rather than higher. What follows clinically is surveillance and
    consideration of early transplantation in poor responders, not withholding
    G-CSF.
- name: Allogeneic Haematopoietic Stem Cell Transplantation
  therapeutic_modality: CELL_THERAPY
  description: >-
    The only curative option, and the standard route for patients refractory to
    high-dose G-CSF or who have transformed. Donor haematopoiesis replaces the
    ELANE-mutant clone outright. Outcomes are acceptable but not benign:
    three-year overall survival of 82% with 17% transplant-related mortality in
    the European series, better in children under ten and with matched donors.
  treatment_term:
    preferred_term: allogeneic hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: ELANE Mutation and Neutrophil Elastase Misfolding
    treatment_effect: BYPASSES
    description: >-
      Transplantation does not correct the mutant allele; it replaces the
      haematopoietic compartment that expresses it with donor cells, so the
      whole downstream chain is bypassed rather than interrupted at any one
      step.
    evidence:
    - reference: PMID:26185129
      reference_title: "Stem cell transplantation in severe congenital neutropenia: an analysis from the European Society for Blood and Marrow Transplantation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Allogeneic hematopoietic stem cell transplantation (HSCT) is the only
        curative treatment of severe congenital neutropenia (SCN), but data on
        outcome are scarce.
      explanation: >-
        States that transplantation is curative, which is the claim that
        distinguishes bypassing the lesion from treating its output.
  evidence:
  - reference: PMID:26185129
    reference_title: "Stem cell transplantation in severe congenital neutropenia: an analysis from the European Society for Blood and Marrow Transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 3-year overall survival (OS) was 82%, and transplant-related mortality
      (TRM) was 17%.
    explanation: >-
      The outcome figures that set the risk-benefit balance against continued
      G-CSF.
  - reference: PMID:26185129
    reference_title: "Stem cell transplantation in severe congenital neutropenia: an analysis from the European Society for Blood and Marrow Transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In multivariate analysis, transplants performed under the age of 10 years,
      in recent years, and from HLA-matched related or unrelated donors were
      associated with a significantly better OS.
    explanation: >-
      Identifies the factors that determine outcome, which is what makes early
      referral of poor responders a live question.
  - reference: PMID:20301705
    reference_title: ELANE-Related Neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HSCT is the only alternative therapy for individuals with congenital
      neutropenia who are refractory to high-dose G-CSF or who undergo malignant
      transformation.
    explanation: >-
      States the two indications curated here.
  - reference: PMID:16497969
    reference_title: The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In less-responsive SCN patients, early hematopoietic stem cell
      transplantation may be a rational option.
    explanation: >-
      The registry authors' own conclusion about which patients should be
      considered for transplantation, based on the risk gradient they measured.
- name: Antimicrobial Prophylaxis and Prompt Treatment of Infection
  description: >-
    Prophylaxis, usually with trimethoprim-sulfamethoxazole, plus immediate
    broad-spectrum treatment of any febrile episode. Symptomatic rather than
    disease-modifying: it addresses the infectious consequences of the
    neutropenia without touching the granulopoietic defect. Abdominal pain in a
    neutropenic patient needs assessment for peritonitis and bacteraemia.
  treatment_term:
    preferred_term: antibiotic therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
    therapeutic_agent:
    - preferred_term: trimethoprim-sulfamethoxazole
      term:
        id: CHEBI:3770
        label: co-trimoxazole
  target_mechanisms:
  - target: Impaired Innate Defence and Recurrent Bacterial Infection
    treatment_effect: INHIBITS
    description: >-
      Reduces the bacterial burden the absent neutrophils would otherwise fail
      to control, and treats established infection before it becomes
      life-threatening.
    evidence:
    - reference: PMID:21595885
      reference_title: "Congenital neutropenia: diagnosis, molecular bases and patient management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Treatment of severe chronic neutropenia should focus on prevention of
        infections. It includes antimicrobial prophylaxis, generally with
        trimethoprim-sulfamethoxazole, and also
        granulocyte-colony-stimulating factor (G-CSF).
      explanation: >-
        States that prophylaxis targets the infectious consequence of the
        neutropenia, and names the agent used.
  evidence:
  - reference: PMID:20301705
    reference_title: ELANE-Related Neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immediate treatment with granulocyte colony-stimulating factor (G-CSF) and
      broad-spectrum antibiotics is important, even lifesaving, when an affected
      individual has signs of serious infection, which may be caused by both
      aerobic and anaerobic pathogens.
    explanation: >-
      States the urgency and the spectrum required when infection is suspected.
  - reference: PMID:21595885
    reference_title: "Congenital neutropenia: diagnosis, molecular bases and patient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment of severe chronic neutropenia should focus on prevention of
      infections. It includes antimicrobial prophylaxis, generally with
      trimethoprim-sulfamethoxazole, and also granulocyte-colony-stimulating
      factor (G-CSF).
    explanation: >-
      Places antimicrobial prophylaxis alongside G-CSF as standard management.
- name: Dental Hygiene and Periodontal Care
  therapeutic_modality: BEHAVIORAL
  description: >-
    Good dental hygiene with routine immunisations. Curated separately rather
    than folded into supportive care because gingivitis and periodontitis are
    modelled here as phenotypes, and this is the intervention that addresses
    them.
  target_mechanisms:
  - target: Impaired Innate Defence and Recurrent Bacterial Infection
    treatment_effect: INHIBITS
    description: >-
      Lowers the oral bacterial burden that the neutropenia would otherwise
      allow to produce gingival and periodontal destruction.
    evidence:
    - reference: PMID:21595885
      reference_title: "Congenital neutropenia: diagnosis, molecular bases and patient management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Neutropenia can lead to life-threatening pyogenic infections, acute
        gingivostomatitis and chronic parodontal disease, and each successive
        infection may leave permanent sequelae.
      explanation: >-
        Identifies the oral disease process this intervention is intended to
        interrupt, and the accumulating damage that makes prevention worthwhile.
  evidence:
  - reference: PMID:20301705
    reference_title: ELANE-Related Neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prevention of secondary complications: Good dental hygiene; routine
      immunizations.
    explanation: >-
      States dental hygiene as recommended preventive management in
      ELANE-related neutropenia.
discussions:
- discussion_id: scn1_csf3r_cooperating_events
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Acquisition of Somatic CSF3R Mutations
  prompt: >-
    What are the cooperating events that convert a CSF3R-mutant clone into
    myelodysplasia or acute myeloid leukaemia, and can they be detected early
    enough to guide transplantation?
  rationale: >-
    CSF3R mutation is highly predictive of transformation yet explicitly not
    necessary, is detectable years in advance, and highly clonal haematopoiesis
    does not always progress quickly. RUNX1 mutation is the commonest
    cooperating lesion but arrives late. The clinical question that follows is
    which surveillance finding should trigger transplantation, and that is not
    currently answerable: the same finding is compatible with rapid
    transformation and with years of stability.
notes: >-
  Scope and naming. Curated as the autosomal dominant ELANE form, matching
  MONDO:0042490 and OMIM 202700. The recessive HAX1 form (Kostmann disease,
  SCN3) and the other congenital neutropenias in IUIS Table 5 are separate
  diseases and are not covered here; G6PC3 deficiency (SCN4) is already curated
  separately. Note that "Kostmann syndrome" in the older literature refers to
  the Swedish recessive kindred, not to this entity, so the name is
  deliberately absent from the synonyms.

  The allelic boundary with cyclic neutropenia. ELANE causes both diseases and
  they overlap genetically: the mutation spectra differ in tendency, with
  cyclic alleles clustering near the active site, but severity distributions
  overlap and one S97L allele on a shared paternal haplotype has produced both
  phenotypes in a single kindred. IUIS merged cyclic neutropenia into the
  elastase-deficiency row in its 2022 update. dismech nevertheless keeps them
  as two entries, because the consequence that dominates management diverges
  completely: this disease is preleukaemic and cyclic neutropenia is not. The
  boundary is documented in the description, in the ELANE genetic notes, and in
  the IUIS classification note. Cyclic neutropenia is curated at
  Cyclic_Hematopoiesis (MONDO:0008090) and is not modelled here as a subtype.

  Mechanism confidence. The misfolding and unfolded protein response chain is
  well supported and, unusually for a mechanism of this kind, has been measured
  in primary granulocytic precursors from patients rather than only in
  expression systems, with the magnitude of activation tracking allele
  severity. It is not unchallenged; the Cyclic_Hematopoiesis entry records a
  study in which a severe congenital neutropenia allele impaired granulocytic
  differentiation without eliciting a detectable unfolded protein response, and
  a transgenic mouse carrying a human SCN allele that does not become
  neutropenic. Those results bear on this disease too and are the reason the
  chain here is stated as the prevailing model rather than as settled.

  The clonal-evolution arm is marked PROVISIONAL at the CSF3R node and
  ESTABLISHED at the transformation node, which is deliberate. That
  transformation happens, and that it involves CSF3R and RUNX1 mutations in a
  majority of patients, is not in doubt. What is provisional is the causal role
  of the CSF3R mutation itself: it is highly predictive but not necessary, and
  the group that characterised it says the cooperating events remain to be
  defined.

  Prevalence. Recorded from registry ascertainment for congenital neutropenia
  as a whole, because no cleanly quotable ELANE-specific rate was found in the
  cached sources. The commonly repeated figure of one in 200,000 to 250,000
  births is not recorded here: it did not appear in any cached reference in a
  form that could be quoted, and a curated number without a verifiable quote is
  worse than none. The two registry rows differ by nearly tenfold, which is
  ascertainment rather than biology, and both should be read as floors.

  Ontology notes. HPO distinguishes persistent from cyclic neutropenia
  (HP:0410252 versus HP:0040289), so the two allelic entries bind different
  defining phenotypes, and HP:0033607 gives the promyelocyte-stage marrow
  arrest exactly. Filgrastim has no CHEBI term, so the therapeutic agent binds
  to NCIT. Trimethoprim-sulfamethoxazole binds to the CHEBI combination term
  co-trimoxazole rather than to either component.

  A quoting note. Two snippets are drawn from the cached full text of
  PMID:20456363 and PMID:21595885 rather than from abstracts, and in both cases
  the quoted span stops short of a numeric unit that the cached rendering
  breaks across a line (an inline superscript in the first, a broken exponent
  in the second). The explanations say so rather than silently truncating.

  Known extension points: clinical_trials, for which no SCN1-specific
  registered trial was screened in this pass; computational_models, given the
  substantial mathematical modelling literature on granulopoiesis in this
  disease and its cyclic partner; animal_models, where the G193X Elane mouse is
  already recorded on the Cyclic_Hematopoiesis entry and would need
  SCN-specific framing rather than a copied link; and histopathology of the
  marrow beyond the maturation-arrest phenotype.

  Provenance. Curated directly from PubMed and the cached reference set rather
  than from a deep-research report. Every snippet was fetched with
  just fetch-reference and verified as an exact substring of the cached text.
references:
- reference: PMID:8490166
  title: "A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia."
- reference: PMID:10581030
  title: "Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis."
- reference: PMID:11001877
  title: "Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia."
- reference: PMID:15642668
  title: "Analysis of risk factors for myelodysplasias, leukemias and death from infection among patients with congenital neutropenia. Experience of the French Severe Chronic Neutropenia Study Group."
- reference: PMID:16497969
  title: "The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy."
- reference: PMID:16551967
  title: "Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response."
- reference: PMID:16985178
  title: "Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: Results of a long-term survey."
- reference: PMID:17761833
  title: "Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis."
- reference: PMID:20301705
  title: "ELANE-Related Neutropenia."
  tags:
  - GeneReviews
- reference: PMID:20456363
  title: "Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy."
- reference: PMID:21595885
  title: "Congenital neutropenia: diagnosis, molecular bases and patient management."
- reference: PMID:22371884
  title: "Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia."
- reference: PMID:23463630
  title: "The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia."
- reference: PMID:24523240
  title: "Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis."
- reference: PMID:26185129
  title: "Stem cell transplantation in severe congenital neutropenia: an analysis from the European Society for Blood and Marrow Transplantation."
- reference: PMID:28593997
  title: "Severe congenital neutropenias."
- reference: PMID:35748970
  title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."

📚

References & Deep Research

References

17

PMID:8490166

A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia.

No top-level findings curated for this source.

PMID:10581030

Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis.

No top-level findings curated for this source.

PMID:11001877

Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.

No top-level findings curated for this source.

PMID:15642668

Analysis of risk factors for myelodysplasias, leukemias and death from infection among patients with congenital neutropenia. Experience of the French Severe Chronic Neutropenia Study Group.

No top-level findings curated for this source.

PMID:16497969

The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy.

No top-level findings curated for this source.

PMID:16551967

Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response.

No top-level findings curated for this source.

PMID:16985178

Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: Results of a long-term survey.

No top-level findings curated for this source.

PMID:17761833

Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis.

No top-level findings curated for this source.

PMID:20301705

ELANE-Related Neutropenia.

No top-level findings curated for this source.

PMID:20456363

Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy.

No top-level findings curated for this source.

PMID:21595885

Congenital neutropenia: diagnosis, molecular bases and patient management.

No top-level findings curated for this source.

PMID:22371884

Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia.

No top-level findings curated for this source.

PMID:23463630

The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia.

No top-level findings curated for this source.

PMID:24523240

Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis.

No top-level findings curated for this source.

PMID:26185129

Stem cell transplantation in severe congenital neutropenia: an analysis from the European Society for Blood and Marrow Transplantation.

No top-level findings curated for this source.

PMID:28593997

Severe congenital neutropenias.

No top-level findings curated for this source.

PMID:35748970

Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee.

No top-level findings curated for this source.

Severe Congenital Neutropenia 1, Autosomal Dominant

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