Severe congenital neutropenia type 7 is an autosomal recessive disorder of granulopoiesis caused by biallelic loss-of-function variants in CSF3R, the gene encoding the granulocyte colony-stimulating factor receptor (G-CSFR). The reported pathogenic variants cluster in the extracellular region of the receptor: a missense change near the WSXWS motif that perturbs N-glycosylation and leaves the receptor retained in the endoplasmic reticulum, or frameshift and nonsense variants that truncate the extracellular domain. Either way the cell surface carries little or no functional receptor, G-CSF can no longer drive JAK-STAT3/STAT5 signalling effectively in granulocytic precursors, and the absolute neutrophil count sits below 0.5 x 10^9/L from infancy with recurrent bacterial infection. Two features set SCN7 apart from the common ELANE and HAX1 forms. The bone marrow shows full granulocytic maturation rather than the promyelocyte maturation arrest of those diseases, reflecting G-CSFR-independent granulopoiesis that lets precursors mature but not expand. And because the block is at the receptor rather than upstream of it, recombinant G-CSF is generally ineffective at any dose; GM-CSF, which signals through a separate receptor (CSF2R), stimulates granulopoiesis in several reported patients, and haematopoietic stem cell transplantation is the option for refractory disease. This germline biallelic loss-of-function mechanism is mechanistically distinct from the somatic, truncating CSF3R mutations in the receptor cytoplasmic tail that are acquired on the path to leukaemia in G-CSF-treated ELANE/HAX1 SCN (curated separately under Severe Congenital Neutropenia 1), and from the germline activating CSF3R variants (e.g. T617N) that cause hereditary neutrophilia.
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name: Severe Congenital Neutropenia 7, Autosomal Recessive
category: Mendelian
creation_date: "2026-09-29T21:00:00Z"
synonyms:
- SCN7
- neutropenia, severe congenital, 7, autosomal recessive
- G-CSF receptor deficiency
- CSF3R deficiency
- Severe congenital neutropenia due to CSF3R deficiency
description: >-
Severe congenital neutropenia type 7 is an autosomal recessive disorder of
granulopoiesis caused by biallelic loss-of-function variants in CSF3R, the
gene encoding the granulocyte colony-stimulating factor receptor (G-CSFR).
The reported pathogenic variants cluster in the extracellular region of the
receptor: a missense change near the WSXWS motif that perturbs N-glycosylation
and leaves the receptor retained in the endoplasmic reticulum, or frameshift
and nonsense variants that truncate the extracellular domain. Either way the
cell surface carries little or no functional receptor, G-CSF can no longer
drive JAK-STAT3/STAT5 signalling effectively in granulocytic precursors, and
the absolute
neutrophil count sits below 0.5 x 10^9/L from infancy with recurrent bacterial
infection.
Two features set SCN7 apart from the common ELANE and HAX1 forms. The bone
marrow shows full granulocytic maturation rather than the promyelocyte
maturation arrest of those diseases, reflecting G-CSFR-independent granulopoiesis
that lets precursors mature but not expand. And because the block is at the
receptor rather than upstream of it, recombinant G-CSF is generally
ineffective at any dose; GM-CSF, which signals through a separate receptor
(CSF2R), stimulates granulopoiesis in several reported patients, and
haematopoietic stem cell transplantation is the option for refractory disease.
This germline biallelic loss-of-function mechanism is mechanistically distinct
from the somatic, truncating CSF3R mutations in the receptor cytoplasmic tail
that are acquired on the path to leukaemia in G-CSF-treated ELANE/HAX1 SCN
(curated separately under Severe Congenital Neutropenia 1), and from the
germline activating CSF3R variants (e.g. T617N) that cause hereditary
neutrophilia.
classifications:
harrisons_chapter:
- classification_value: ONCOLOGY_HEMATOLOGY
notes: >-
Disorders of granulocytes: a congenital defect of neutrophil production
presenting as severe congenital neutropenia.
- classification_value: IMMUNE_RHEUMATOLOGIC
notes: >-
An inborn error of immunity (congenital defect of phagocyte number)
presenting with recurrent pyogenic bacterial infection.
iuis_category:
classification_value: phagocyte defect
notes: >-
IUIS 2022 Table 5 (congenital defects of phagocyte number, function, or
both), congenital neutropenias: G-CSF receptor deficiency, gene CSF3R,
autosomal recessive, disturbed stress granulopoiesis. The table prints
OMIM 138971, which is the CSF3R gene MIM; the phenotype MIM for SCN7 is
617014, which is what this entry's disease_term resolves through.
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: "G-CSF receptor deficiency CSF3R AR 138971"
explanation: >-
The IUIS Table 5 row that places this disease among the congenital
neutropenias, naming the gene and the autosomal recessive inheritance.
disease_term:
preferred_term: autosomal recessive severe congenital neutropenia due to CSF3R deficiency
term:
id: MONDO:0014865
label: autosomal recessive severe congenital neutropenia due to CSF3R deficiency
mappings:
mondo_mappings:
- term:
id: MONDO:0014865
label: autosomal recessive severe congenital neutropenia due to CSF3R deficiency
mapping_predicate: skos:exactMatch
mapping_source: MONDO (OMIM:617014, Orphanet:420702)
mapping_justification: >-
MONDO:0014865 is the gene-anchored SCN7 entity (xrefs OMIM:617014,
Orphanet:420702) carrying the synonym SCN7 and the CSF3R deficiency
concept curated here.
parents:
- congenital neutropenia
- inborn error of immunity
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Biallelic loss-of-function CSF3R variants, homozygous in consanguineous
families or compound heterozygous. Heterozygous carrier parents have normal
neutrophil counts.
evidence:
- reference: PMID:24753537
reference_title: Inherited biallelic CSF3R mutations in severe congenital neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the p.Arg308Cys CSF3R variant segregated with the disease phenotype in an autosomal-recessive inheritance pattern"
explanation: >-
Establishes recessive segregation of the causal CSF3R variant in the
index family.
pathophysiology:
- name: Biallelic Loss-of-Function CSF3R Variants
description: >-
Homozygous or compound heterozygous loss-of-function variants in CSF3R,
which encodes the G-CSF receptor. Reported alleles cluster in the
extracellular region: a missense change (p.Arg308Cys) shortly preceding the
conserved WSXWS motif, and frameshift/nonsense variants truncating the
extracellular domain. This is the initiating germline lesion of SCN7 and is
distinct from the somatic cytoplasmic-tail truncations acquired during
leukaemic evolution of other SCN forms.
biological_scale: MOLECULAR
genetic_context:
functional_impact_category: LOSS_OF_FUNCTION
variant_origin: GERMLINE
gene:
preferred_term: CSF3R
term:
id: hgnc:2439
label: CSF3R
description: >-
Biallelic (homozygous or compound heterozygous) germline variants; the
reported pathogenic variants affect the extracellular region of G-CSFR.
genes:
- preferred_term: CSF3R
term:
id: hgnc:2439
label: CSF3R
molecular_functions:
- preferred_term: granulocyte colony-stimulating factor receptor activity
modifier: LOSS_OF_FUNCTION
term:
id: GO:0004902
label: granulocyte colony-stimulating factor receptor activity
downstream:
- target: Deficient Cell-Surface G-CSF Receptor
causal_link_type: DIRECT
evidence:
- reference: PMID:24753537
reference_title: Inherited biallelic CSF3R mutations in severe congenital neutropenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "which resulted in perturbed N-glycosylation and aberrant localization to the cell surface"
explanation: >-
Directly links the extracellular missense variant to defective
receptor glycosylation and surface localization, shown in cell-based
expression studies of the patient variant.
evidence:
- reference: PMID:24753537
reference_title: Inherited biallelic CSF3R mutations in severe congenital neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "recessively inherited loss-of-function mutations in CSF3R, encoding the granulocyte colony-stimulating factor (G-CSF) receptor"
explanation: >-
Names the causal gene and the loss-of-function, recessive nature of the
variants defining this disease.
- reference: PMID:42482462
reference_title: "Crohn's Disease Phenotype in a Patient With Severe Congenital Neutropenia Caused by CSF3R Variants: Exploring the Pathogenesis and Effects of Thalidomide Treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These variants usually affect the extracellular domain of G‐CSFR, unlike somatic CSF3R variants, which usually affect the cytoplasmic region of G‐CSFR"
explanation: >-
Records that the germline SCN7 variants sit in the extracellular domain,
contrasting them with the cytoplasmic-tail somatic variants of leukaemic
evolution.
- name: Deficient Cell-Surface G-CSF Receptor
description: >-
Little or no functional G-CSFR reaches the plasma membrane. Extracellular
missense variants such as p.Arg308Cys disrupt N-glycosylation and the
receptor is retained in the endoplasmic reticulum; truncating variants
abolish surface expression outright. Flow cytometry of patient neutrophils
shows markedly reduced surface receptor.
biological_scale: MOLECULAR
molecular_functions:
- preferred_term: granulocyte colony-stimulating factor receptor activity
modifier: LOSS_OF_FUNCTION
term:
id: GO:0004902
label: granulocyte colony-stimulating factor receptor activity
biological_processes:
- preferred_term: protein N-linked glycosylation
modifier: ABNORMAL
term:
id: GO:0006487
label: protein N-linked glycosylation
downstream:
- target: Reduced G-CSF/JAK-STAT Signaling in Granulocytic Precursors
causal_link_type: DIRECT
evidence:
- reference: PMID:24753537
reference_title: Inherited biallelic CSF3R mutations in severe congenital neutropenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The p.Arg308Cys mutation in CSF3R leads to altered G-CSF receptor glycosylation and surface expression and abrogated downstream signaling"
explanation: >-
States that the surface-expression defect abrogates the receptor's
downstream signalling, the next step in the chain.
evidence:
- reference: PMID:24753537
reference_title: Inherited biallelic CSF3R mutations in severe congenital neutropenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "which resulted in perturbed N-glycosylation and aberrant localization to the cell surface"
explanation: >-
Describes the glycosylation and surface-localization defect underlying the
cell-surface receptor deficiency.
- name: Reduced G-CSF/JAK-STAT Signaling in Granulocytic Precursors
description: >-
Too little surface receptor remains to transduce the G-CSF signal, so the
Janus kinase / STAT3 and STAT5 cascade it normally drives runs far below
normal rather than being wholly abolished. Patient and mutant-receptor cells
show reduced STAT3/STAT5 phosphorylation on G-CSF stimulation, and
hypomorphic alleles retain partial signalling.
biological_scale: MOLECULAR
cell_types:
- preferred_term: neutrophil progenitor cell
term:
id: CL:0000834
label: neutrophil progenitor cell
biological_processes:
- preferred_term: granulocyte colony-stimulating factor signaling pathway
modifier: DECREASED
term:
id: GO:0038158
label: granulocyte colony-stimulating factor signaling pathway
- preferred_term: cell surface receptor signaling pathway via JAK-STAT
modifier: DECREASED
term:
id: GO:0007259
label: cell surface receptor signaling pathway via JAK-STAT
downstream:
- target: Impaired Granulocytic Proliferation and Survival
causal_link_type: DIRECT
- target: Preserved Bone Marrow Granulocytic Maturation
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Maturation persists despite this loss of signal rather than because of it.
G-CSFR signalling is required for adequate neutrophil production but is
dispensable for terminal maturation, so the precursors that remain go on
maturing fully while their numbers fall.
evidence:
- reference: PMID:36316822
reference_title: A congenital CSF3R mutation in chronic neutropenia reveals a vital role for a cytokine receptor extracellular hinge motif in the response to granulocyte colony-stimulating factor.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the di-proline hinge motif in the extracellular cytokine receptor homology domain of CSF3R is critical for adequate neutrophil production, but dispensable for in vivo terminal neutrophil maturation"
explanation: >-
Sources the asymmetry this edge asserts: the same receptor defect that
cuts neutrophil production leaves terminal maturation intact, which is
why maturation survives the reduced signal instead of failing with it.
evidence:
- reference: PMID:24753537
reference_title: Inherited biallelic CSF3R mutations in severe congenital neutropenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Cells expressing the mutant receptor showed reduced phosphorylation of STAT3 and STAT5, but signal transduction was not completely abrogated"
explanation: >-
Demonstrates the reduced JAK-STAT signalling produced by the mutant
receptor, with residual activity for the hypomorphic allele.
- reference: PMID:24753537
reference_title: Inherited biallelic CSF3R mutations in severe congenital neutropenia.
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
snippet: "relies on Janus kinase activation for signal transduction through signal transducer and activator of transcription 3 and 5 (STAT3 and STAT5)"
explanation: >-
States the JAK-STAT3/STAT5 pathway that G-CSFR normally uses, the
signalling that is lost here.
- name: Impaired Granulocytic Proliferation and Survival
description: >-
Loss of the pro-proliferative, pro-survival G-CSF signal reduces expansion
of granulocytic progenitors and increases apoptosis of maturing neutrophils,
so neutrophil output falls. What is lost here is the number of precursors,
not their capacity to mature, which is why the marrow stays hypoplastic
rather than arrested.
biological_scale: CELLULAR
cell_types:
- preferred_term: neutrophil progenitor cell
term:
id: CL:0000834
label: neutrophil progenitor cell
biological_processes:
- preferred_term: granulocytic precursor proliferation
modifier: DECREASED
term:
id: GO:0008283
label: cell population proliferation
- preferred_term: neutrophil apoptotic process
modifier: INCREASED
term:
id: GO:0001781
label: neutrophil apoptotic process
downstream:
- target: Profound Peripheral Neutropenia
causal_link_type: DIRECT
evidence:
- reference: PMID:8934575
reference_title: Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "G-CSFR-deficient mice have decreased numbers of phenotypically normal circulating neutrophils. Hematopoietic progenitors are decreased in the bone marrow, and the expansion and terminal differentiation of these progenitors into granulocytes is impaired."
explanation: >-
The G-CSFR-knockout mouse shows the impaired progenitor expansion this
node asserts. The same sentence also reports impaired terminal
differentiation, which is a mouse finding the human marrows do not
reproduce; that divergence is recorded on the model link rather than
claimed here.
- reference: PMID:8934575
reference_title: Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Neutrophils isolated from G-CSFR-deficient mice have an increased susceptibility to apoptosis, suggesting that the G-CSFR may also regulate neutrophil survival."
explanation: >-
Supports the increased-apoptosis component of this node.
- name: Preserved Bone Marrow Granulocytic Maturation
description: >-
Unlike ELANE- and HAX1-related SCN, which arrest at the promyelocyte stage,
SCN7 marrow shows full granulocytic maturation. G-CSFR-independent pathways
permit precursors to mature even though their numbers are low, which is the
morphologic hallmark distinguishing this disease and a diagnostic clue.
biological_scale: TISSUE
cell_types:
- preferred_term: neutrophil
term:
id: CL:0000775
label: neutrophil
biological_processes:
- preferred_term: neutrophil differentiation
term:
id: GO:0030223
label: neutrophil differentiation
evidence:
- reference: PMID:24753537
reference_title: Inherited biallelic CSF3R mutations in severe congenital neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Despite peripheral SCN, all patients had morphologic evidence of full myeloid cell maturation in bone marrow"
explanation: >-
Documents preserved marrow maturation in the patients, the distinguishing
feature this node captures.
- reference: PMID:24753537
reference_title: Inherited biallelic CSF3R mutations in severe congenital neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "This is in contrast to inherited SCN with mutations in ELANE or HAX1, which show a characteristic myeloid maturation arrest at the promyelocyte-to-myelocyte differentiation step and generally respond to rhG-CSF treatment"
explanation: >-
States the contrast with the maturation arrest of ELANE/HAX1 SCN that
makes preserved maturation diagnostically informative.
- reference: PMID:36316822
reference_title: A congenital CSF3R mutation in chronic neutropenia reveals a vital role for a cytokine receptor extracellular hinge motif in the response to granulocyte colony-stimulating factor.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the di-proline hinge motif in the extracellular cytokine receptor homology domain of CSF3R is critical for adequate neutrophil production, but dispensable for in vivo terminal neutrophil maturation"
explanation: >-
Independently shows that G-CSFR is required for neutrophil production but
not for terminal maturation, the basis for preserved marrow maturation.
- name: Profound Peripheral Neutropenia
description: >-
An absolute neutrophil count persistently below 0.5 x 10^9/L from infancy,
the defining laboratory feature and the direct cause of the clinical
infection burden. Some hypomorphic-allele patients have milder counts.
biological_scale: ORGANISM
cell_types:
- preferred_term: neutrophil
term:
id: CL:0000775
label: neutrophil
downstream:
- target: Severely decreased neutrophil count
- target: Recurrent bacterial infections
- target: Recurrent tonsillitis
- target: Recurrent otitis media
- target: Recurrent pneumonia
- target: Oral ulcer
- target: Recurrent fever
evidence:
- reference: PMID:34778134
reference_title: "Efficacy of Low-Dose rhGM-CSF Treatment in a Patient With Severe Congenital Neutropenia Due to CSF3R Deficiency: Case Report of a Novel Biallelic CSF3R Mutation and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient presented with recurrent suppurative tonsillitis and decreased absolute neutrophil count <0.5 × 109/L."
explanation: >-
Documents the sub-0.5 x 10^9/L neutrophil count and the infection it
produces in a genetically confirmed SCN7 patient.
phenotypes:
- category: Laboratory
name: Severely decreased neutrophil count
description: >-
Absolute neutrophil count persistently below 0.5 x 10^9/L, present from
infancy.
phenotype_term:
preferred_term: Severely decreased neutrophil count
term:
id: HP:0025826
label: Severely decreased neutrophil count
frequency: VERY_FREQUENT
evidence:
- reference: PMID:34778134
reference_title: "Efficacy of Low-Dose rhGM-CSF Treatment in a Patient With Severe Congenital Neutropenia Due to CSF3R Deficiency: Case Report of a Novel Biallelic CSF3R Mutation and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient presented with recurrent suppurative tonsillitis and decreased absolute neutrophil count <0.5 × 109/L."
explanation: >-
Reports the sub-0.5 x 10^9/L absolute neutrophil count in a confirmed
SCN7 patient.
- category: Clinical
name: Recurrent bacterial infections
description: >-
Recurrent, potentially life-threatening bacterial infections from infancy,
the consequence of profound neutropenia.
phenotype_term:
preferred_term: Recurrent bacterial infections
term:
id: HP:0002718
label: Recurrent bacterial infections
frequency: VERY_FREQUENT
evidence:
- reference: PMID:24753537
reference_title: Inherited biallelic CSF3R mutations in severe congenital neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Severe congenital neutropenia (SCN) is characterized by low numbers of peripheral neutrophil granulocytes and a predisposition to life-threatening bacterial infections."
explanation: >-
Defines the disease by predisposition to life-threatening bacterial
infection, the phenotype curated here.
- reference: PMID:34778134
reference_title: "Efficacy of Low-Dose rhGM-CSF Treatment in a Patient With Severe Congenital Neutropenia Due to CSF3R Deficiency: Case Report of a Novel Biallelic CSF3R Mutation and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "all presented repeated infection and required long-term antibiotic treatments"
explanation: >-
Records recurrent infection across the reported SCN7 patient series.
- category: Clinical
name: Recurrent tonsillitis
description: Recurrent suppurative tonsillitis.
phenotype_term:
preferred_term: Recurrent tonsillitis
term:
id: HP:0011110
label: Recurrent tonsillitis
evidence:
- reference: PMID:34778134
reference_title: "Efficacy of Low-Dose rhGM-CSF Treatment in a Patient With Severe Congenital Neutropenia Due to CSF3R Deficiency: Case Report of a Novel Biallelic CSF3R Mutation and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient presented with recurrent suppurative tonsillitis and decreased absolute neutrophil count <0.5 × 109/L."
explanation: >-
Reports recurrent suppurative tonsillitis as the presenting infection.
- category: Clinical
name: Recurrent otitis media
description: Recurrent otitis media among the bacterial infections of SCN7.
phenotype_term:
preferred_term: Recurrent otitis media
term:
id: HP:0000403
label: Recurrent otitis media
evidence:
- reference: PMID:42482462
reference_title: "Crohn's Disease Phenotype in a Patient With Severe Congenital Neutropenia Caused by CSF3R Variants: Exploring the Pathogenesis and Effects of Thalidomide Treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "clinical manifestations include recurrent fevers and various types of infections, such as otitis media, tonsillitis, and pneumonia"
explanation: >-
Lists otitis media among the recurrent infections in CSF3R-associated SCN.
- category: Clinical
name: Recurrent pneumonia
description: Recurrent pneumonia among the bacterial infections of SCN7.
phenotype_term:
preferred_term: Recurrent pneumonia
term:
id: HP:0006532
label: Recurrent pneumonia
evidence:
- reference: PMID:42482462
reference_title: "Crohn's Disease Phenotype in a Patient With Severe Congenital Neutropenia Caused by CSF3R Variants: Exploring the Pathogenesis and Effects of Thalidomide Treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "clinical manifestations include recurrent fevers and various types of infections, such as otitis media, tonsillitis, and pneumonia"
explanation: >-
Lists pneumonia among the recurrent infections in CSF3R-associated SCN.
- category: Clinical
name: Oral ulcer
description: Recurrent oral ulceration, a common feature of severe neutropenia.
phenotype_term:
preferred_term: Oral ulcer
term:
id: HP:0000155
label: Oral ulcer
evidence:
- reference: PMID:42482462
reference_title: "Crohn's Disease Phenotype in a Patient With Severe Congenital Neutropenia Caused by CSF3R Variants: Exploring the Pathogenesis and Effects of Thalidomide Treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "recurrent fever, infections, oral ulcers, diarrhea, and juvenile idiopathic arthritis"
explanation: >-
Lists oral ulcers among the reported manifestations of inherited biallelic
CSF3R variants.
- category: Clinical
name: Recurrent fever
description: Recurrent fevers accompanying infections.
phenotype_term:
preferred_term: Recurrent fever
term:
id: HP:0001954
label: Recurrent fever
evidence:
- reference: PMID:42482462
reference_title: "Crohn's Disease Phenotype in a Patient With Severe Congenital Neutropenia Caused by CSF3R Variants: Exploring the Pathogenesis and Effects of Thalidomide Treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "recurrent fever, infections, oral ulcers, diarrhea, and juvenile idiopathic arthritis"
explanation: >-
Lists recurrent fever among the reported manifestations.
- category: Clinical
name: Juvenile idiopathic arthritis
description: >-
Reported in a minority of patients with inherited biallelic CSF3R variants.
phenotype_term:
preferred_term: Juvenile idiopathic arthritis
term:
id: HP:0005681
label: Juvenile rheumatoid arthritis
frequency: VERY_RARE
evidence:
- reference: PMID:42482462
reference_title: "Crohn's Disease Phenotype in a Patient With Severe Congenital Neutropenia Caused by CSF3R Variants: Exploring the Pathogenesis and Effects of Thalidomide Treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "recurrent fever, infections, oral ulcers, diarrhea, and juvenile idiopathic arthritis"
explanation: >-
Lists juvenile idiopathic arthritis among the reported manifestations of
biallelic CSF3R variants.
- category: Clinical
name: Crohn's disease
description: >-
An inflammatory bowel disease phenotype reported in a single SCN7 patient,
consistent with the protective role of neutrophils in the gut demonstrated
in Csf3r-null mice.
phenotype_term:
preferred_term: Crohn's disease
term:
id: HP:0100280
label: Crohn's disease
frequency: VERY_RARE
evidence:
- reference: PMID:42482462
reference_title: "Crohn's Disease Phenotype in a Patient With Severe Congenital Neutropenia Caused by CSF3R Variants: Exploring the Pathogenesis and Effects of Thalidomide Treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This study describes a case of severe congenital neutropenia (SCN) harboring biallelic CSF3R variants and presenting with a novel inflammatory bowel disease (IBD) phenotype that responded remarkably to thalidomide."
explanation: >-
The report is the first description of an IBD (Crohn's disease) phenotype
in a biallelic-CSF3R SCN patient; recorded here as a rare, single-case
feature.
genetic:
- name: CSF3R
gene_term:
preferred_term: CSF3R
term:
id: hgnc:2439
label: CSF3R
relationship_type: CAUSATIVE
variant_origin: GERMLINE
frequency: a rare cause of severe congenital neutropenia (SCN type 7)
case_fractions:
- population: Turkish Severe Congenital Neutropenia Registry (216 patients)
case_fraction_percent: 2.9
cohort_size: 216
notes: >-
Biallelic CSF3R accounted for 6 of 216 registry patients in a population
with high consanguinity, where HAX1 (36%) dominated. CSF3R is a rare
subtype even where recessive SCN is common.
evidence:
- reference: PMID:31321910
reference_title: "Homozygous c.130-131 ins A (pW44X) mutation in the HAX1 gene as the most common cause of congenital neutropenia in Turkey: Report from the Turkish Severe Congenital Neutropenia Registry."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Biallelic mutations of G6PC3 (n = 9, 4.3%), CSF3R (n = 6, 2.9%), and JAGN1 (n = 2, 1%) were also observed."
explanation: >-
Gives the CSF3R share of a national SCN registry and its denominator.
variants:
- name: p.Arg308Cys (c.922C>T)
description: >-
An extracellular missense variant near the WSXWS motif; reported
homozygous in a consanguineous family, perturbing N-glycosylation and
surface localization of the receptor.
- name: Extracellular truncating variants
description: >-
Compound heterozygous frameshift/nonsense variants (e.g. c.948_963del
p.Gly316fs and c.1245del p.Gly415fs) truncating the extracellular domain
and abolishing surface expression.
notes: >-
All reported pathogenic SCN7 variants lie in the extracellular region of
G-CSFR, distinguishing them from the somatic cytoplasmic-tail truncations
acquired during leukaemic evolution of ELANE/HAX1 SCN, and from the germline
activating variants (e.g. T617N) that cause hereditary neutrophilia. A third
entity shares the extracellular location and must still be kept separate:
rare heterozygous extracellular CSF3R variants, somatic or arising de novo
in meiosis, leave the receptor hyporesponsive to G-CSF and act in a
dominant-negative fashion against the wild-type allele. Those are
single-allele dominant-negative cases, not the biallelic recessive disease
curated here, even though both localise to the extracellular domain and
both present with G-CSF hyporesponsiveness.
evidence:
- reference: PMID:33108454
reference_title: Heterozygous germ line CSF3R variants as risk alleles for development of hematologic malignancies.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "biallelic germ line hypomorphic variants in CSF3R are a rare cause of severe congenital neutropenia, a hypoproliferative condition"
explanation: >-
States that biallelic germline hypomorphic CSF3R variants cause severe
congenital neutropenia.
- reference: PMID:33108454
reference_title: Heterozygous germ line CSF3R variants as risk alleles for development of hematologic malignancies.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Acquired activating heterozygous variants in CSF3R are the main cause of chronic neutrophilic leukemia, a hyperproliferative disorder."
explanation: >-
Contrasts the recessive loss-of-function mechanism of SCN7 with the
acquired activating CSF3R variants of chronic neutrophilic leukemia.
- reference: PMID:24753537
reference_title: Inherited biallelic CSF3R mutations in severe congenital neutropenia.
supports: SUPPORT
evidence_source: OTHER
quote_role: BACKGROUND
snippet: "These mutants are characterized by hyporesponsiveness to rhG-CSF and act in a dominant-negative fashion by interfering with proper function of the wild-type (WT) G-CSFR"
explanation: >-
Triot's introduction, restating the separate heterozygous extracellular
entity that this entry is careful not to fold into SCN7: those variants
are dominant-negative against the wild-type allele rather than recessive.
- reference: PMID:14528102
reference_title: Deletional mutation of the external domain of the human granulocyte colony-stimulating factor receptor in a patient with severe chronic neutropenia refractory to granulocyte colony-stimulating factor.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Coexpression of the mutant receptor inhibited the wild-type response in Ba/F3 cells"
explanation: >-
The primary demonstration that a heterozygous extracellular G-CSFR
deletion interferes with the wild-type receptor, which is what makes that
mechanism dominant-negative and not the biallelic loss curated here.
- reference: PMID:10449521
reference_title: Novel point mutation in the extracellular domain of the granulocyte colony-stimulating factor (G-CSF) receptor in a case of severe congenital neutropenia hyporesponsive to G-CSF treatment.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "When this mutant G-CSF-R was expressed in myeloid cells, it was defective in both proliferation and survival signaling."
explanation: >-
Shows that a heterozygous extracellular G-CSFR point mutation is itself
signalling-defective, the functional basis of the G-CSF hyporesponsiveness
that these single-allele cases share with SCN7.
prevalence:
- population: Worldwide (reported cases)
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
An ultra-rare SCN subtype: as of November 2024, 18 CSF3R variants in 18
patients had been reported globally. Severe congenital neutropenia overall
has an incidence of roughly 1/200,000, of which CSF3R is a small fraction.
evidence:
- reference: PMID:42482462
reference_title: "Crohn's Disease Phenotype in a Patient With Severe Congenital Neutropenia Caused by CSF3R Variants: Exploring the Pathogenesis and Effects of Thalidomide Treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "To date, 18 kinds of variants in CSF3R associated with SCN have been identified globally in 18 patients"
explanation: >-
Quantifies the total reported case count, supporting the ultra-rare class.
- reference: PMID:34778134
reference_title: "Efficacy of Low-Dose rhGM-CSF Treatment in a Patient With Severe Congenital Neutropenia Due to CSF3R Deficiency: Case Report of a Novel Biallelic CSF3R Mutation and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SCN is a group of rare congenital hematologic diseases caused by germline mutations with an incidence rate of ~1/200,000"
explanation: >-
Gives the overall SCN incidence against which CSF3R is a rare subtype.
diagnosis:
- name: Absolute neutrophil count
presence: PRESENT
description: >-
A persistent absolute neutrophil count below 0.5 x 10^9/L from infancy is
the entry criterion, as for all severe congenital neutropenia.
evidence:
- reference: PMID:34778134
reference_title: "Efficacy of Low-Dose rhGM-CSF Treatment in a Patient With Severe Congenital Neutropenia Due to CSF3R Deficiency: Case Report of a Novel Biallelic CSF3R Mutation and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient presented with recurrent suppurative tonsillitis and decreased absolute neutrophil count <0.5 × 109/L."
explanation: >-
Illustrates the sub-0.5 x 10^9/L count that defines the disease.
- name: Bone marrow examination
presence: PRESENT
description: >-
Marrow shows full granulocytic maturation rather than the promyelocyte
maturation arrest of ELANE/HAX1 SCN, which is a diagnostic pointer toward a
receptor-level defect.
evidence:
- reference: PMID:24753537
reference_title: Inherited biallelic CSF3R mutations in severe congenital neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Despite peripheral SCN, all patients had morphologic evidence of full myeloid cell maturation in bone marrow"
explanation: >-
States the preserved marrow maturation that distinguishes SCN7 on
aspirate.
- name: CSF3R molecular genetic testing
presence: PRESENT
description: >-
Identification of biallelic loss-of-function CSF3R variants, usually by
whole-exome or targeted sequencing with parental segregation, confirms the
diagnosis.
evidence:
- reference: PMID:24753537
reference_title: Inherited biallelic CSF3R mutations in severe congenital neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the p.Arg308Cys CSF3R variant segregated with the disease phenotype in an autosomal-recessive inheritance pattern"
explanation: >-
Molecular confirmation of biallelic CSF3R variants segregating recessively.
- name: G-CSF receptor signalling assay
presence: PRESENT
description: >-
Flow cytometry shows reduced surface G-CSFR and blunted STAT3 phosphorylation
after G-CSF, while GM-CSF still triggers STAT3 phosphorylation, functionally
confirming a receptor-level block.
evidence:
- reference: PMID:42482462
reference_title: "Crohn's Disease Phenotype in a Patient With Severe Congenital Neutropenia Caused by CSF3R Variants: Exploring the Pathogenesis and Effects of Thalidomide Treatment."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "After rhGM‐CSF stimulation, neutrophils from both the control and the patient displayed STAT3 phosphorylation, whereas only the control neutrophils did so following rhG‐CSF stimulation"
explanation: >-
The functional signature: G-CSF fails to phosphorylate STAT3 in patient
neutrophils while GM-CSF succeeds, localizing the defect to the G-CSF
receptor.
treatments:
- name: GM-CSF (sargramostim)
action_category: THERAPEUTIC
therapeutic_modality: PROTEIN_REPLACEMENT
description: >-
Recombinant GM-CSF stimulates granulopoiesis through its own receptor
(CSF2R), bypassing the defective G-CSF receptor, and has raised neutrophil
counts and prevented infection in several reported SCN7 patients who were
refractory to G-CSF.
treatment_term:
preferred_term: colony-stimulating factor therapy
term:
id: NCIT:C15515
label: Colony-Stimulating Factor Therapy
therapeutic_agent:
- preferred_term: sargramostim
term:
id: CHEBI:749544
label: sargramostim
target_phenotypes:
- preferred_term: Severely decreased neutrophil count
term:
id: HP:0025826
label: Severely decreased neutrophil count
target_mechanisms:
- target: Profound Peripheral Neutropenia
treatment_effect: BYPASSES
description: >-
GM-CSF acts through CSF2R rather than the defective G-CSFR, so it can
drive granulopoiesis despite the receptor block.
evidence:
- reference: PMID:34778134
reference_title: "Efficacy of Low-Dose rhGM-CSF Treatment in a Patient With Severe Congenital Neutropenia Due to CSF3R Deficiency: Case Report of a Novel Biallelic CSF3R Mutation and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "however, after rhGM-CSF (5 μg/kg, Topleucon, Amoytop Biotech, Xiamen, China) injection, ANC increased from 0.19 to 1.95 × 109/L"
explanation: >-
Shows GM-CSF raising the neutrophil count where G-CSF failed, acting on
this node.
evidence:
- reference: PMID:34778134
reference_title: "Efficacy of Low-Dose rhGM-CSF Treatment in a Patient With Severe Congenital Neutropenia Due to CSF3R Deficiency: Case Report of a Novel Biallelic CSF3R Mutation and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a small proportion of SCN patients with G-CSF receptor deficiency (i.e., due to biallelic loss-of-function mutations in the CSF3R gene) are refractory to G-CSF but respond to granulocyte macrophage colony-stimulating factor (GM-CSF) treatment"
explanation: >-
States the rationale for GM-CSF as the treatment for G-CSF-refractory
CSF3R deficiency.
- reference: PMID:34778134
reference_title: "Efficacy of Low-Dose rhGM-CSF Treatment in a Patient With Severe Congenital Neutropenia Due to CSF3R Deficiency: Case Report of a Novel Biallelic CSF3R Mutation and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The responsiveness to rhGM-CSF of patients with CSF3R mutations can be attributed to granulocyte stimulation by GM-CSF and the activation of CSF2R"
explanation: >-
Names CSF2R as the receptor GM-CSF uses to bypass the G-CSFR defect.
- reference: PMID:34778134
reference_title: "Efficacy of Low-Dose rhGM-CSF Treatment in a Patient With Severe Congenital Neutropenia Due to CSF3R Deficiency: Case Report of a Novel Biallelic CSF3R Mutation and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "110 μg/kg/d (unresponsive) | 6–3 μg/kg/d biw | c.998-2A>T (p.W547*) | Regular rhGM-CSF for 12 years | Klimiankou et al."
explanation: >-
The literature-table row for the index GM-CSF case, originally reported by
Klimiankou and colleagues: unresponsive to G-CSF even at 110 ug/kg/day,
then held on regular GM-CSF for twelve years. It is the longest documented
GM-CSF course in this disease and the observation the treatment rests on.
Quoted from the review that tabulates it because the original letter has
no retrievable abstract (see notes).
- name: Recombinant G-CSF (generally ineffective)
action_category: THERAPEUTIC
therapeutic_modality: PROTEIN_REPLACEMENT
description: >-
Recombinant G-CSF, the mainstay for other SCN types, is generally
ineffective in SCN7 because the defect is in the G-CSF receptor itself;
patients typically fail to respond even at very high doses. A minority with
hypomorphic alleles show partial responses. It is usually tried first but is
not a durable option.
treatment_term:
preferred_term: colony-stimulating factor therapy
term:
id: NCIT:C15515
label: Colony-Stimulating Factor Therapy
therapeutic_agent:
- preferred_term: filgrastim
term:
id: CHEBI:749461
label: filgrastim
evidence:
- reference: PMID:24753537
reference_title: Inherited biallelic CSF3R mutations in severe congenital neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "None of the patients responded to treatment with recombinant human G-CSF"
explanation: >-
Documents the non-response to G-CSF that defines the clinical management
problem in SCN7.
- name: Hematopoietic cell transplantation
action_category: THERAPEUTIC
description: >-
Allogeneic haematopoietic stem cell transplantation is the option for
patients refractory to both G-CSF and GM-CSF.
treatment_term:
preferred_term: hematopoietic cell transplantation
term:
id: NCIT:C15431
label: Hematopoietic Cell Transplantation
therapeutic_modality: CELL_THERAPY
evidence:
- reference: PMID:34778134
reference_title: "Efficacy of Low-Dose rhGM-CSF Treatment in a Patient With Severe Congenital Neutropenia Due to CSF3R Deficiency: Case Report of a Novel Biallelic CSF3R Mutation and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hematopoietic stem cell transplantation can serve as a treatment option"
explanation: >-
States HSCT as a treatment option for refractory disease.
- name: Antimicrobial management
action_category: THERAPEUTIC
description: >-
Prompt antibiotics for infections and long-term antimicrobial support are
part of care, as for all severe congenital neutropenia.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:34778134
reference_title: "Efficacy of Low-Dose rhGM-CSF Treatment in a Patient With Severe Congenital Neutropenia Due to CSF3R Deficiency: Case Report of a Novel Biallelic CSF3R Mutation and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "all presented repeated infection and required long-term antibiotic treatments"
explanation: >-
Records the reliance on long-term antibiotics across the reported series.
animal_models:
- name: Csf3r-null mouse
species: Mouse
genotype: Csf3r homozygous null
background: Targeted homozygous null mutation of the murine G-CSFR gene
publication: PMID:8934575
description: >-
G-CSFR-deficient mice are neutropenic, with reduced haematopoietic
progenitors in the marrow, impaired expansion and impaired terminal
differentiation of those progenitors into granulocytes, and neutrophils that
are more prone to apoptosis.
modeled_mechanisms:
- target: Profound Peripheral Neutropenia
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: ORGANISM
description: >-
The knockout reproduces the circulating neutropenia of receptor loss.
limitations: >-
A whole-gene knockout models complete receptor loss; several human alleles
are hypomorphic missense variants with residual signalling.
evidence:
- reference: PMID:8934575
reference_title: Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "These data confirm a role for the G-CSFR as a major regulator of granulopoiesis in vivo"
explanation: >-
Establishes that G-CSFR loss produces the neutropenia phenotype in vivo.
- target: Impaired Granulocytic Proliferation and Survival
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: >-
Reduced progenitor expansion and increased neutrophil apoptosis, the
cellular mechanism of the neutropenia.
divergences:
- divergence_type: SPECIES_MISMATCH
materiality: QUALIFYING
description: >-
Mouse and human diverge on maturation, not on cell number. In the
knockout the terminal differentiation of granulocytic progenitors is
itself impaired, whereas the reported human SCN7 marrows show full
granulocytic maturation with only the numbers reduced. The model is
therefore informative for the proliferation and survival deficit this
node describes, but it overstates the differentiation block relative to
the human disease and should not be read as evidence for the preserved
maturation curated elsewhere in this entry.
readouts:
- name: Bone marrow granulocytic progenitor number
target: Impaired Granulocytic Proliferation and Survival
direction: DECREASED
interpretation: Structural correlate of impaired progenitor expansion.
evidence:
- reference: PMID:8934575
reference_title: Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Hematopoietic progenitors are decreased in the bone marrow, and the expansion and terminal differentiation of these progenitors into granulocytes is impaired."
explanation: Reports the reduced progenitors and impaired differentiation.
evidence:
- reference: PMID:8934575
reference_title: Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Neutrophils isolated from G-CSFR-deficient mice have an increased susceptibility to apoptosis, suggesting that the G-CSFR may also regulate neutrophil survival."
explanation: >-
Supports the increased-apoptosis component modelled here.
- name: csf3r zebrafish mutant
species: Zebrafish
genotype: Biallelic csf3r CRISPR/Cas9 mutant
publication: PMID:28281657
description: >-
A CRISPR/Cas9 csf3r mutant with a persistent, stable reduction in neutrophil
numbers, presented by its authors as a model of human CSF3R-dependent
congenital neutropenia.
modeled_mechanisms:
- target: Profound Peripheral Neutropenia
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: ORGANISM
description: >-
Stable, life-long neutrophil deficiency from biallelic csf3r loss.
limitations: >-
A teleost model; neutrophil biology and infection spectrum differ from
human, and the model captures the deficiency rather than the human
infection phenotype.
evidence:
- reference: PMID:28281657
reference_title: A GCSFR/CSF3R zebrafish mutant models the persistent basal neutrophil deficiency of severe congenital neutropenia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Biallelic csf3r mutant embryos are viable and have normal early survival, despite a substantial reduction of their neutrophil population size, and normal macrophage abundance."
explanation: >-
Reports the selective neutrophil deficiency recapitulating the human
phenotype.
evidence:
- reference: PMID:28281657
reference_title: A GCSFR/CSF3R zebrafish mutant models the persistent basal neutrophil deficiency of severe congenital neutropenia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "These csf3r mutants are a new animal model of human CSF3R-dependent congenital neutropenia."
explanation: >-
The authors position the mutant as a model of human CSF3R-dependent
congenital neutropenia.
discussions:
- discussion_id: scn7_severity_and_gmcsf_response
kind: KNOWLEDGE_GAP
prompt: >-
What determines the wide severity range of SCN7, from neutropenia
unresponsive to high-dose G-CSF to mild neutropenia needing no treatment,
and can genotype predict responsiveness to GM-CSF?
attaches_to:
- genetic#CSF3R
- treatments#GM-CSF (sargramostim)
rationale: >-
Reported patients span severe G-CSF-refractory disease to mild, untreated
neutropenia, and GM-CSF response is not uniform; the small case count and
allele heterogeneity leave the genotype-phenotype and genotype-response
relationships unresolved.
notes: >-
SCN7 is defined by germline biallelic loss-of-function of the G-CSF receptor.
This is mechanistically distinct from two other CSF3R associations that must
not be conflated with it: the somatic, cytoplasmic-tail truncating CSF3R
mutations acquired by ELANE/HAX1 SCN clones on the path to MDS/AML (curated in
Severe Congenital Neutropenia 1), and the germline activating CSF3R variants
such as T617N that cause hereditary neutrophilia. The distinguishing clinical
clues to SCN7 among the SCNs are full granulocytic maturation on marrow
aspirate and non-response to G-CSF with response to GM-CSF. No GeneReviews
chapter exists for CSF3R deficiency / SCN7 (checked against the committed
Bookshelf index over the entry name and synonyms).
The original report of GM-CSF response in this disease (Klimiankou et al.,
Blood 2015, PMID:26324699) is listed under references but carries no evidence
item of its own: PubMed holds no abstract for it and neither the PMID nor the
DOI fetch returns quotable text, so that case is evidenced here through the
2021 review that tabulates it.
Infection was fatal in one of the four children in the originally reported
families, who died at three months of age. That outcome is not curated as a
phenotype because HPO files Death in infancy (HP:0001522) under mortality
rather than under phenotypic abnormality, so it falls outside the
PhenotypeTerm enum; the life-threatening character of the infections is
carried by the Recurrent bacterial infections phenotype instead.
Deep-research provenance: OpenScientist was run twice for this slug and
returned a report about JAGN1 deficiency (SCN6) both times rather than CSF3R,
so neither run was committed. The committed report is the claude_code run,
which preflight-dr confirms is on this disease (CSF3R the top gene, no JAGN1,
OMIM 617014 matching MONDO:0014865). The entry was curated from primary
literature and cross-checked against that report.
references:
- reference: PMID:24753537
title: Inherited biallelic CSF3R mutations in severe congenital neutropenia.
- reference: PMID:26324699
title: "GM-CSF stimulates granulopoiesis in a congenital neutropenia patient with loss-of-function biallelic heterozygous CSF3R mutations."
- reference: PMID:34778134
title: "Efficacy of Low-Dose rhGM-CSF Treatment in a Patient With Severe Congenital Neutropenia Due to CSF3R Deficiency: Case Report of a Novel Biallelic CSF3R Mutation and Literature Review."
- reference: PMID:42482462
title: "Crohn's Disease Phenotype in a Patient With Severe Congenital Neutropenia Caused by CSF3R Variants: Exploring the Pathogenesis and Effects of Thalidomide Treatment."
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Record notes
SCN7 is defined by germline biallelic loss-of-function of the G-CSF receptor. This is mechanistically distinct from two other CSF3R associations that must not be conflated with it: the somatic, cytoplasmic-tail truncating CSF3R mutations acquired by ELANE/HAX1 SCN clones on the path to MDS/AML (curated in Severe Congenital Neutropenia 1), and the germline activating CSF3R variants such as T617N that cause hereditary neutrophilia. The distinguishing clinical clues to SCN7 among the SCNs are full granulocytic maturation on marrow aspirate and non-response to G-CSF with response to GM-CSF. No GeneReviews chapter exists for CSF3R deficiency / SCN7 (checked against the committed Bookshelf index over the entry name and synonyms). The original report of GM-CSF response in this disease (Klimiankou et al., Blood 2015, PMID:26324699) is listed under references but carries no evidence item of its own: PubMed holds no abstract for it and neither the PMID nor the DOI fetch returns quotable text, so that case is evidenced here through the 2021 review that tabulates it. Infection was fatal in one of the four children in the originally reported families, who died at three months of age. That outcome is not curated as a phenotype because HPO files Death in infancy (HP:0001522) under mortality rather than under phenotypic abnormality, so it falls outside the PhenotypeTerm enum; the life-threatening character of the infections is carried by the Recurrent bacterial infections phenotype instead. Deep-research provenance: OpenScientist was run twice for this slug and returned a report about JAGN1 deficiency (SCN6) both times rather than CSF3R, so neither run was committed. The committed report is the claude_code run, which preflight-dr confirms is on this disease (CSF3R the top gene, no JAGN1, OMIM 617014 matching MONDO:0014865). The entry was curated from primary literature and cross-checked against that report.
Create: Severe Congenital Neutropenia 7, Autosomal Recessive (CSF3R deficiency) · 2026-09-29T21:12:19Z · View source
Curated de novo the autosomal recessive SCN7 / G-CSF receptor deficiency entry (MONDO:0014865, gene CSF3R hgnc:2439) entirely from independently verified primary literature. Deep research took three runs to land on this disease. OpenScientist was run twice: the first report was about JAGN1 deficiency (SCN6, OMIM 616022) rather than CSF3R, and after clearing that query from the deep-research-client cache (issue #11748) the second OpenScientist run again asserted JAGN1 as the SCN7 gene, though it had at least picked up the right OMIM. preflight-dr against MONDO:0014865 caught both (run 1: CSF3R x2 vs JAGN1 x48, OMIM 616022; run 2: CSF3R x14 vs JAGN1 x48). Neither OpenScientist report is committed. `--fallback` could not switch provider because OpenScientist does not fail, it returns the wrong disease; Edison/falcon then refused the stored key with a 403, so the run that produced the committed report is claude_code. preflight-dr confirms that one is on this disease: CSF3R the top gene at 16 mentions, JAGN1 absent, report OMIM 617014 matching the MONDO xref, with only STAT3 flagged as a second gene, which is this disease's own signalling effector. Its own reference validation is 10/10 verified with 0 unresolved; its `needs_review: true` is set only because 2 of the quotes it composed did not match their sources, and none of its quoted material was reused here. The entry was cross-checked against it; its causal chain, its G-CSF-refractory/GM-CSF-responsive treatment branch and its preserved-marrow-maturation distinction all agree with what was already curated. Pathophysiology modelled as a causal chain: biallelic extracellular LOF CSF3R variants -> deficient cell-surface G-CSFR (N-glycosylation defect / ER retention or truncation) -> absent G-CSF JAK-STAT3/STAT5 signalling -> impaired granulocytic proliferation/survival with increased apoptosis -> profound peripheral neutropenia, plus a branch to preserved bone-marrow granulocytic maturation (the morphologic feature distinguishing SCN7 from ELANE/HAX1 maturation arrest). Key references verified against fetched cache: Triot 2014 (PMID:24753537, the defining biallelic-CSF3R report; full maturation, G-CSF non-response), Zhou 2021 (PMID:34778134, GM-CSF response, SCN7 label, case-series table), the 2026 Crohn/thalidomide review (PMID:42482462, extracellular vs cytoplasmic variant contrast, phenotype spectrum, 18 patients), Sippel/di-proline hinge (PMID:36316822), Csf3r-/- mouse (PMID:8934575), csf3r zebrafish (PMID:28281657), heterozygous-germline-risk paper (PMID:33108454, LOF-vs-activating contrast), Turkish registry (PMID:31321910, 6/216 case fraction), and IUIS 2022 (PMID:35748970) for classification. Distinction from somatic cytoplasmic-tail CSF3R (leukemic evolution of SCN1) and germline activating T617N hereditary neutrophilia stated explicitly in description and notes. Klimiankou 2015 (PMID:26324699) and Sprenkeler 2020 (PMID:32966608) were fetched but had no quotable PubMed abstract (content unavailable) so were not cited. No GeneReviews chapter exists (verified offline and --online over name+synonyms). All gates pass: validate, validate-terms, 45/45 snippets verified, entity-refs, causal-targets, duplicate-keys, qualifier-terms, coarse-phenotypes; 7/9 phenotypes causally connected (JIA and Crohn left unwired as immune-dysregulation features not directly downstream of neutropenia). Review round 1 (ai4c-reviewer, PR #13177). Replaced the off-target OpenScientist bundle as described above. Removed the contradiction between the proliferation node and its neighbour: the node bound GO:0002318 myeloid progenitor cell differentiation DECREASED while the adjacent node asserts maturation is preserved, so the differentiation binding was replaced with GO:0008283 cell population proliferation DECREASED, GO having no granulocyte-progenitor proliferation term. Rewrote the Csf3r-null mouse description, which had claimed no maturation arrest "mirroring the human SCN7 marrow" where PMID:8934575 reports terminal differentiation is impaired; the human/mouse difference is now a SPECIES_MISMATCH divergence on the model link. Gave the signalling-to-preserved-maturation edge its own evidence and wording that says maturation persists despite the lost signal rather than because of it. Renamed the signalling node from Absent to Reduced, since its own evidence says transduction is not completely abrogated, and softened the GO:0038158 modifier from LOSS_OF_FUNCTION to DECREASED to match. Added therapeutic_modality PROTEIN_REPLACEMENT to the two recombinant-cytokine treatments, moved both precursor cell bindings from GMP to CL:0000834 neutrophil progenitor cell, and regraded the PMID:24753537 cell-based summary sentence from HUMAN_CLINICAL to IN_VITRO. Added the dominant-negative heterozygous extracellular CSF3R variants that Triot's introduction describes, with the primary demonstrations (PMID:14528102, PMID:10449521), kept explicitly separate from this biallelic recessive disease. Added the original Klimiankou GM-CSF case through the review table that reproduces it, and listed PMID:26324699 under references; that letter has no retrievable abstract by PMID or DOI even with --force, so it carries no evidence item and the reason is recorded in notes. Also fixed the CI gate `check_gene_activity_grounding`, which flagged CSF3R as newly wired into the pathograph without a molecular function on its landing node: bound GO:0004902 granulocyte colony-stimulating factor receptor activity with modifier LOSS_OF_FUNCTION on the lesion node, matching that node's own functional_impact_category. Considered and rejected adding a Death in infancy phenotype that the on-target report surfaced: HP:0001522 sits in HPO's mortality branch, outside the PhenotypeTerm enum, and binding a substitute would have overstated; the reason is recorded in notes.
Still researching. I have the Triot 2014 paper, the Zhou 2021 case report and review, and the mouse knockout, so I'm writing the report now.
Verification status. Everything cited below with a PMID or URL was seen in this session's searches, except the items in the closing "Unverified" list. I did not open the ClinGen, gnomAD, OMIM, OMIA or MGI records. Values there are marked "not verified" and need a lookup before curation. CURIEs were not looked up in OAK, so treat all suggested ontology terms as leads only.
Overview. SCN7 is an autosomal recessive primary immunodeficiency caused by biallelic loss-of-function variants in CSF3R, which encodes the G-CSF receptor. It presents in infancy or early childhood with recurrent bacterial infections and profound peripheral neutropenia. Bone marrow shows full myeloid maturation, and neutropenia is typically refractory to recombinant human G-CSF (rhG-CSF). Some patients respond to GM-CSF. - Sources: LOVD disease entry; NORD/MONDO entry; Triot 2014, PMID:24753537.
Identifiers. - OMIM #617014 (per LOVD). - The template gives MONDO:0014865. The search hit for that ID returned the NORD page titled "autosomal recessive severe congenital neutropenia due to CSF3R deficiency". The label match is plausible but I did not confirm the ID-to-label pairing in MONDO itself. Check it with OAK before binding. - DOID:0112129, "severe congenital neutropenia 7" (Glycosmos). - Orphanet, ICD-10/11 and MeSH: not verified.
Synonyms. SCN7; neutropenia, severe congenital, 7, autosomal recessive; autosomal recessive SCN due to CSF3R deficiency; G-CSFR-deficient congenital neutropenia.
Data source. The evidence is aggregated, published case and family reports (about 13 biallelic cases per the 2021 review). It is not EHR-derived.
Frequencies are qualitative because n≈13 in the literature. Suggested HP terms are leads, not verified.
| Phenotype | Notes | Suggested HP |
|---|---|---|
| Severe neutropenia | ANC <0.5×10⁹/L; onset in infancy (birth to 5 months in reported cases). Family A ANC ranged 420–2180/µL; Family B 200–1000/µL. Present in all affected. | Neutropenia; Severe congenital neutropenia |
| Recurrent bacterial infections | Pneumonia, otitis media, urinary tract infection, suppurative tonsillitis (15–30 episodes between ages 1 and 2 on rhG-CSF in one patient, PMID:34778134) | Recurrent bacterial infections; Recurrent pneumonia; Recurrent otitis media |
| Fever | Multiple hospitalizations (PMID:24753537) | Fever |
| Normal bone marrow maturation | "all patients had morphologic evidence of full myeloid cell maturation in bone marrow" | No specific term; describe in text |
| Death in infancy | One patient died at 3 months of suspected aspiration pneumonia (PMID:24753537) | Death in infancy |
| Dextrocardia | One patient. Likely incidental and not established as part of the disease. | Dextrocardia |
Phenotype range: "from severe neutropenia unresponsive to high-dose rhG-CSF treatment… to mild neutropenia that does not require active treatment" (PMID:34778134). A homozygous p.R440* patient was reported untreated with a mild phenotype (PMID:34778134). Quality-of-life data: none found.
Gene. CSF3R (G-CSF receptor) at 1p34.3. The HGNC ID was not verified; look it up, using the lowercase hgnc: form.
Reported variants.
| Variant | Genotype | Consequence and response | Source |
|---|---|---|---|
| c.922C>T, p.Arg308Cys | Homozygous (Family A, Turkish, consanguineous) | Altered N-glycosylation, ER retention, reduced STAT3/STAT5 phosphorylation; refractory to rhG-CSF | PMID:24753537 |
| c.948_963del (p.Gly316fsTer322) plus c.1245del (p.Gly415fsTer432) | Compound heterozygous (Family B, Spanish) | Frameshift, premature stop; refractory to rhG-CSF | PMID:24753537 |
| c.690delC (p.Met231Cysfs*32) plus c.64+5G>A | Compound heterozygous | Refractory to rhG-CSF; responded to low-dose GM-CSF | PMID:34778134 |
| c.998-2A>T plus p.W547* | Compound heterozygous | Unresponsive to G-CSF up to 110 µg/kg/d; GM-CSF response sustained for 12 years | Review in PMID:34778134 |
| c.610-611delinsAG (p.Q204R) | Homozygous | Unresponsive to G-CSF; GM-CSF responsive | Review in PMID:34778134; PMID:30499904 |
| c.1318C>T (p.R440*) | Homozygous | Mild phenotype, untreated | Review in PMID:34778134 |
A hypomorphic biallelic allele responding to G-CSF has also been reported (PMID:30028820; title only, not read).
Functional consequence. Loss of function, with partial function retained for p.Arg308Cys. ClinVar/ACMG classification and gnomAD frequencies: not verified. Origin is germline. Epigenetic and chromosomal abnormalities: none reported.
Compensation. Heterozygous parents showed elevated CSF3R mRNA with normal protein levels, which the authors interpret as a genetic compensation mechanism rather than nonsense-mediated decay (PMID:34778134).
No environmental or lifestyle factors are established. The pathogen exposure that matters is opportunistic and ordinary bacterial flora (organisms were not systematically reported in the sources I read). No specific infectious agent defines the disease, so an infectious_agent block is not applicable.
Causal chain. 1. Biallelic CSF3R variants (missense affecting folding, or frameshift/splice/nonsense truncations) reduce functional G-CSFR. Demonstrated. 2. For p.Arg308Cys: abnormal N-glycosylation (EndoH-sensitive, unlike wild type), retention around the nucleus co-localizing with calnexin (ER), and no proper plasma-membrane localization. Demonstrated in vitro. Leads to reduced cell-surface receptor. 3. Reduced receptor number or function lowers G-CSF-driven STAT3/STAT5 phosphorylation. "Cells expressing the mutant receptor showed reduced phosphorylation of STAT3 and STAT5, but signal transduction was not completely abrogated." Demonstrated in vitro. 4. Impaired G-CSF signaling results in reduced neutrophil output or release and survival. Mouse data support this: G-CSFR-deficient mice have "decreased numbers of phenotypically normal circulating neutrophils", decreased marrow progenitors, and impaired expansion and terminal differentiation (Liu 1996, Immunity 5:491; MGI/RIKEN PMID 8934575, seen via search snippet only). Inferred for humans. 5. Maturation still proceeds, so bone marrow appears morphologically normal while circulating neutrophils are low. This distinguishes SCN7 from maturation-arrest forms of SCN (ELANE, HAX1). Demonstrated morphologically; the mechanism of peripheral deficit is inferred. 6. Neutropenia leads to impaired innate antibacterial defense, then recurrent bacterial infections, and in the worst cases death in infancy. Clinical observation. 7. Branch on treatment. rhG-CSF cannot act through a defective receptor and fails even at high dose ("up to 110 μg/kg/day", PMID:34778134). GM-CSF acts through CSF2R, bypassing G-CSFR, and can raise neutrophils ("granulocyte stimulation by GM-CSF and the activation of CSF2R"). Demonstrated in case reports.
Cell types (CL leads). Granulocyte-monocyte progenitor, myeloid progenitor, neutrophil (CL:0000775), hematopoietic stem cell. GO leads. Granulocyte colony-stimulating factor signaling pathway; neutrophil differentiation / granulocyte differentiation; STAT3/STAT5-mediated signaling; positive regulation of neutrophil apoptotic process (regulation of survival). Protein processing in the ER and glycosylation are relevant for the missense allele. Cellular components. ER (calnexin co-localization), plasma membrane. Immune involvement. Isolated neutrophil-lineage immunodeficiency. Omics, single-cell, and functional-genomics data: none found.
NCIT:C15986; therapeutic agent filgrastim (look up a code).PROTEIN_REPLACEMENT or SMALL_MOLECULE, and the classification needs a curator decision.NCIT:C15747.NCIT:C15240).Orthologs exist in mouse and other vertebrates (a zebrafish gene page appeared in search results; not verified). No naturally occurring animal disease was found; OMIA was not checked.
modeled_mechanisms target: the neutrophil production deficit node, RECAPITULATES or PARTIALLY_RECAPITULATES.just fetch-reference and just count-verified-snippets.Checked with linkml-reference-validator 0.3.0rc3.
| Outcome | Count |
|---|---|
| References checked | 10 |
| Resolved | 10 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 2 |
| Quoted claims found in source | 0 |
| Quoted claims not found in source | 2 |
| References weighed for topical relevance | 10 |
| On topic | 9 |
| Off topic | 0 |
Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:
PMID:24753537: "We describe a novel genetic SCN type in 2 unrelated families associated with recessively inherited biallelic CSF3R mutations."PMID:34778134: "from severe neutropenia unresponsive to high-dose rhG-CSF treatment… to mild neutropenia that does not require active treatment"Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 9 |
| Resolved | 9 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 0 |
Every term resolved, and every label the report gave matched.