Severe Congenital Neutropenia 9

Mendelian MONDO:0030726 Pathograph 14 Show in embeddings browser Severe Congenital Neutropenia Inborn Error of Immunity

Severe congenital neutropenia 9 (SCN9, CLPB-SCN) is an autosomal dominant disorder of granulopoiesis caused by heterozygous missense variants in CLPB, the ATP-dependent AAA+ disaggregase of the mitochondrial intermembrane space. In the defining series the variants cluster near the ATP-binding pocket of the nucleotide-binding domain, though later carriers also have ankyrin- and D2-domain variants; mutant subunits associate with wild-type CLPB and inhibit its ATPase and disaggregase activity in a dominant-negative manner. Granulocytic precursors expressing the variants die by apoptosis and fail to differentiate, giving a myeloid maturation arrest in the marrow and severe neutropenia with recurrent bacterial infections from infancy. Unlike the other CLPB disorders, most patients have neutropenia alone, without the neurological disease or 3-methylglutaconic aciduria of the recessive form (type VIIB) or of the dominant neurological form (type VIIA). Myelodysplasia has been reported. Treatment is G-CSF, with hematopoietic stem cell transplantation for patients refractory to it. Whether SCN9 and type VIIA are one disorder is an open question.

Ask OpenScientist

Ask a research question about Severe Congenital Neutropenia 9. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
A single heterozygous CLPB missense variant causes the disease. Each child of an affected person has a 50% chance of inheriting it. GeneReviews states that all reported dominant CLPB cases arose de novo; that statement concerns its dominant form with neurological involvement, and the SCN9 sources cited here do not say whether their variants were de novo or inherited.
Autosomal dominant inheritance
Show evidence (4 references)
PMID:27891836 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"CLPB deficiency associated with specific heterozygous CLPB pathogenic variants is inherited in an autosomal dominant manner."
GeneReviews states dominant inheritance for specific heterozygous CLPB variants. Its dominant form is the one with neurological involvement, so this supports SCN9 indirectly.
PMID:27891836 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Each child of an individual with a heterozygous CLPB pathogenic variant has a 50% chance of inheriting the pathogenic variant."
Transmission risk for a heterozygous CLPB variant, from the GeneReviews chapter that does not name SCN9.
PMID:34115842 SUPPORT Human clinical
"Exome sequencing of 104 persons with congenital neutropenia identified heterozygous missense variants of CLPB (caseinolytic peptidase B) in 5 severe congenital neutropenia cases, with 5 more cases identified through additional sequencing efforts or clinical sequencing."
Heterozygous CLPB variants in ten patients with severe congenital neutropenia.
+ 1 more reference
?

Discussions and Knowledge Gaps

2
Are severe congenital neutropenia 9 and 3-methylglutaconic aciduria type VIIA two disorders, or one dominant CLPB disorder with variable neurological expression?
KNOWLEDGE GAP OPEN gap_scn9_vs_mgca7a_boundary
Attached to
disease# phenotypes#Neurological involvement phenotypes#3-Methylglutaconic aciduria
Both are caused by heterozygous CLPB missense variants that inhibit wild-type CLPB dominant-negatively, and R561 is mutated in both. The separating features, neurological disease and 3-methylglutaconic aciduria, occur in some heterozygous patients, and the aciduria was not measured in about half of the published neutropenia cases.
Show evidence (2 references)
PMID:40194906 SUPPORT REVIEW SYNTHESIS Other
"It remains to be established whether the distinction between dominant CLPB deficiency (MGA 7A) and CLPB-SCN is scientifically valid or if these entities represent, in fact, one disorder."
Review stating the boundary is unresolved.
PMID:40194906 SUPPORT REVIEW SYNTHESIS Other
"The distinction based on the lack of 3-MGA-uria in isolated CLPB-related neutropenia needs to be further studied, as this parameter was not assessed in 9 out of 20 published cases, since it had not been linked with neutropenia before."
The biochemical criterion separating the two was often not measured.
Why do variants that severely inhibit wild-type CLPB in vitro produce a relatively mild, often isolated neutropenia that can resolve with age?
KNOWLEDGE GAP OPEN gap_scn9_mild_phenotype
Attached to
pathophysiology#Dominant-Negative Inhibition of CLPB Disaggregase phenotypes#Congenital neutropenia
Mixed-oligomer assays show the variants abolish most disaggregase activity, and myeloid cell models show severely impaired respiration, yet patients usually have neutropenia alone, often responsive to G-CSF, and in one cohort counts normalized with age. Dosage of the mutant subunit in vivo, tissue-specific compensation, and the developmental timing of the marrow defect are untested explanations.
Show evidence (1 reference)
PMID:40194906 SUPPORT REVIEW SYNTHESIS Other
"A perplexing issue is why the SCN-related variants, with such a devastating influence on the ATPase and disaggregase activity on the wild-type protein in vitro, result in a relatively mild phenotype in patients."
Review naming the mismatch between in vitro severity and clinical mildness.
⚙

Pathophysiology

7
Dominant-Negative Inhibition of CLPB Disaggregase
Mutant CLPB subunits associate with wild-type subunits and inhibit both the ATPase and the disaggregase activity of the complex. Subunits carrying recessive-disease variants do not do this, which is why a single dominant allele causes disease while a single recessive allele does not.
CLPB hgnc:30664 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CLPB (hgnc:30664). hgnc:30664 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE
ATP-dependent protein disaggregase activity GO:0140545 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased ATP-dependent protein disaggregase activity (GO:0140545). GO:0140545 is a molecular function from the Gene Ontology. ATP hydrolysis activity GO:0016887 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased ATP hydrolysis activity (GO:0016887). GO:0016887 is a molecular function from the Gene Ontology.
mitochondrial intermembrane space GO:0005758 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves mitochondrial intermembrane space (GO:0005758). GO:0005758 is a cellular component from the Gene Ontology.
Downstream
Intermembrane Space Protein Aggregation
Impaired Mitochondrial Respiration
Show evidence (2 references)
PMID:34115842 SUPPORT In vitro / ex vivo
"These CLPB variants associate with wild-type CLPB and inhibit its adenosine triphosphatase and disaggregase activity in a dominant-negative fashion."
The variants of this disorder bind and inhibit wild-type CLPB.
PMID:36170828 SUPPORT In vitro / ex vivo
"Importantly, SCN-linked subunits sharply inhibit disaggregase activity, whereas MGCA7-linked subunits do not."
Mixed-hexamer experiments show SCN-linked subunits poison wild-type CLPB, unlike recessive-disease subunits.
Intermembrane Space Protein Aggregation
Without disaggregase activity, proteins of the mitochondrial intermembrane space and inner membrane, including the anti-apoptotic protein HAX1, become insoluble.
protein refolding GO:0042026 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein refolding (GO:0042026). GO:0042026 is a biological process from the Gene Ontology.
mitochondrial intermembrane space GO:0005758 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves mitochondrial intermembrane space (GO:0005758). GO:0005758 is a cellular component from the Gene Ontology.
Downstream
HAX1 Insolubility
Show evidence (1 reference)
PMID:32573439 SUPPORT INDIRECT In vitro / ex vivo
"Using Gene Ontology (GO) analysis for cellular component, we found that proteins in the inner mitochondrial membrane and intermembrane space were enriched in the insoluble fraction in the absence of Skd3"
Shown in CLPB knockout cells; the dominant-negative variants are expected to act through the same loss of disaggregase activity.
HAX1 Insolubility
HAX1 is a direct partner and stimulatory cofactor of CLPB and depends on it for solubility. HAX1 deficiency itself causes severe congenital neutropenia (Kostmann syndrome), which links CLPB dysfunction to the neutrophil lineage. HAX1 insolubility has been shown in CLPB-deficient cells, not with the dominant variants of this disorder, and one such variant (R561Q) still binds HAX1.
HAX1 hgnc:16915 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves HAX1 (hgnc:16915). hgnc:16915 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Granulocytic Precursor Apoptosis
Impaired Neutrophil Differentiation
Show evidence (4 references)
PMID:32573439 SUPPORT INDIRECT In vitro / ex vivo
"In wild-type cells, HAX1 remained predominantly soluble (Figure 7d,e). However, when Skd3 was deleted HAX1 became predominantly insoluble (Figure 7d,e). Thus, Skd3 is essential for HAX1 solubility in cells."
CLPB is required for HAX1 solubility; shown in knockout cells.
PMID:42244541 SUPPORT In vitro / ex vivo
"Through biochemical reconstitution, we here find that HAX1 is a direct stimulatory cofactor of CLPB."
HAX1 and CLPB act as one functional unit.
PMID:39644357 SUPPORT INDIRECT In vitro / ex vivo
"We found that CLPB-deficient 32Dcl3 cells showed a decreased mitochondrial membrane potential and increased levels of insoluble HAX1 aggregates in mitochondria, as compared to control cells."
Insoluble HAX1 accumulates in CLPB-deficient mouse myeloblastic cells, the lineage that fails in this disorder.
+ 1 more reference
Impaired Mitochondrial Respiration
In overexpression models, myeloid cells expressing SCN-associated CLPB variants alongside wild-type CLPB show impaired mitochondrial function and severely reduced respiration, without increased sensitivity to endoplasmic reticulum stress. These models may not reflect patient cells. In CLPB-knockout mouse myeloblasts, apoptosis at the onset of differentiation is linked to reactive oxygen species; that link has not been shown with the SCN variants themselves.
cellular respiration GO:0045333 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cellular respiration (GO:0045333). GO:0045333 is a biological process from the Gene Ontology.
Downstream
Mitochondrial ROS Accumulation No source shows that the respiratory defect is the origin of the excess reactive oxygen species; both are reported in CLPB-deficient cells.
Show evidence (3 references)
PMID:34115842 SUPPORT In vitro / ex vivo
"Finally, expression of CLPB variants is associated with impaired mitochondrial function but does not render cells more sensitive to endoplasmic reticulum stress."
Expression of the variants of this disorder impairs mitochondrial function.
PMID:40194906 SUPPORT REVIEW SYNTHESIS Other
"MOLM-13 cells overexpressing selected SCN-related CLPB variants in addition to the native wild-type protein, which were studied as a model of the disease, demonstrated severely impaired respiration"
Review summary of the respiration defect in a myeloid cell model of this disorder.
PMID:40194906 REFUTE REVIEW SYNTHESIS Other
"Neither CLPB knockout nor overexpression of the dominant negative pathogenic CLPB variants accurately reflect the respiratory phenotype of patient cells."
The same review cautions that the overexpression models do not match patient cells.
Mitochondrial ROS Accumulation
CLPB-deficient myeloblasts lose mitochondrial membrane potential and produce excess reactive oxygen species when induced to differentiate, and their apoptosis depends on it: N-acetylcysteine, free fatty acids or citrate protect them. Shown in CLPB-knockout mouse 32Dcl3 cells, not with the dominant SCN variants.
myeloblast CL:0000835 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves myeloblast (CL:0000835). CL:0000835 is a cell type from the Cell Ontology.
reactive oxygen species production GO:1903409 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased reactive oxygen species production, annotated with reactive oxygen species biosynthetic process (GO:1903409). GO:1903409 is a biological process from the Gene Ontology.
Downstream
Granulocytic Precursor Apoptosis
Show evidence (2 references)
PMID:39644357 SUPPORT INDIRECT In vitro / ex vivo
"We found that CLPB-deficient 32Dcl3 cells showed a decreased mitochondrial membrane potential and increased levels of insoluble HAX1 aggregates in mitochondria, as compared to control cells."
Mitochondrial depolarisation in CLPB-deficient myeloblasts.
PMID:39644357 SUPPORT INDIRECT In vitro / ex vivo
"Moreover, we found that increased apoptosis of CLPB-deficient cells is linked to production of reactive oxygen species (ROS)."
Excess ROS production in CLPB-deficient myeloblasts.
Granulocytic Precursor Apoptosis
Granulocytic precursors expressing the variants, or lacking CLPB, die by apoptosis as granulocytic differentiation begins, depleting the neutrophil lineage.
myeloblast CL:0000835 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves myeloblast (CL:0000835). CL:0000835 is a cell type from the Cell Ontology.
apoptotic process GO:0006915 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology.
Experimental models
Human hematopoietic progenitors expressing SCN-associated CLPB variants PRIMARY CELL CULTURE Expression of the variants increases apoptosis of the progenitors.
Downstream
Congenital neutropenia
Show evidence (2 references)
PMID:34115842 SUPPORT In vitro / ex vivo
"Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis."
The variants of this disorder increase apoptosis of human hematopoietic progenitors.
PMID:39644357 SUPPORT INDIRECT In vitro / ex vivo
"CLPB loss did not affect cell proliferation rates in the presence of IL-3 but it increased apoptosis after IL-3 withdrawal and simultaneous induction of cell differentiation with granulocytic colony stimulating factor (G-CSF)."
In mouse myeloblastic cells, loss of CLPB causes apoptosis at the onset of granulocytic differentiation.
Impaired Neutrophil Differentiation
Human hematopoietic progenitors expressing the variants fail to complete granulocytic differentiation, matching the myeloid maturation arrest seen in patient marrow. A mouse myeloblastic model disagrees: there, CLPB-deficient cells that survive differentiate normally.
neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology.
neutrophil differentiation GO:0030223 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neutrophil differentiation (GO:0030223). GO:0030223 is a biological process from the Gene Ontology.
Experimental models
Human hematopoietic progenitors expressing SCN-associated CLPB variants PRIMARY CELL CULTURE Expression of the variants impairs granulocytic differentiation.
Downstream
Myeloid maturation arrest
Congenital neutropenia
Myelodysplasia Transformation in severe congenital neutropenia is attributed to the underlying marrow maturation defect, not to the low neutrophil count as such. No source traces the steps from the CLPB defect to transformation.
Show evidence (2 references)
PMID:34115842 SUPPORT In vitro / ex vivo
"Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis."
The variants of this disorder impair granulocytic differentiation of human progenitors.
PMID:39644357 REFUTE In vitro / ex vivo
"CLPB-deficient cells that survived the stress associated with IL-3 withdrawal/G-CSF treatment expressed the same levels of differentiation markers as control cells."
In this mouse cell model the defect is survival, not differentiation of the cells that survive.
⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Severe Congenital Neutropenia 9 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Blood 3
Congenital neutropenia Severely decreased neutrophil count HP:0025826 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe congenital neutropenia, annotated with Severely decreased neutrophil count (HP:0025826). HP:0025826 is a phenotype from the Human Phenotype Ontology.
Sequelae: Recurrent bacterial infections
Show evidence (3 references)
PMID:34115842 SUPPORT Human clinical
"Exome sequencing of 104 persons with congenital neutropenia identified heterozygous missense variants of CLPB (caseinolytic peptidase B) in 5 severe congenital neutropenia cases, with 5 more cases identified through additional sequencing efforts or clinical sequencing."
Severe congenital neutropenia defines the disorder.
PMID:35499078 SUPPORT Human clinical
"Clinically, 3 of 4 patients (patients 1, 2, and 3) presented with severe neutropenia in the first year, and patient 4 presented with severe neutropenia in the seventh year of life leading to recurrent bacterial infections."
Onset in infancy in most heterozygous patients, later in one.
PMID:41383606 SUPPORT Human clinical
"All patients with heterozygous CLPB changes had neutropenia in childhood, but ANC normalized with age."
Neutropenia in childhood that resolves with age in this cohort.
Myeloid maturation arrest HP:0410253 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myeloid maturation arrest at the promyelocyte stage, annotated with Myeloid maturation arrest (HP:0410253). HP:0410253 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35499078 SUPPORT Human clinical
"Examination of the bone marrow revealed a myeloid maturation arrest at the promyelocyte stage."
Marrow finding in four heterozygous CLPB patients, one of whom also had central nervous system involvement.
Myelodysplasia HP:0002863 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myelodysplastic syndrome, annotated with Myelodysplasia (HP:0002863). HP:0002863 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41383606 SUPPORT Human clinical
"Patient P73 with CLPB, p.Arg599Cys change, developed MDS at the age of 11, underwent HSCT, and survived, but suffered from post-transplant immune thrombocytopenia."
Myelodysplasia in a heterozygous CLPB carrier.
Genitourinary 1
3-Methylglutaconic aciduria HP:0003535 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is 3-Methylglutaconic aciduria (HP:0003535). HP:0003535 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34115842 REFUTE Human clinical
"However, 3-methylglutaconic aciduria was not observed and, other than neutropenia, these clinical features were uncommon in our series."
The organic aciduria was absent in the defining series.
Immune 1
Recurrent bacterial infections HP:0002718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent bacterial infections (HP:0002718). HP:0002718 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35499078 SUPPORT Human clinical
"Clinically, 3 of 4 patients (patients 1, 2, and 3) presented with severe neutropenia in the first year, and patient 4 presented with severe neutropenia in the seventh year of life leading to recurrent bacterial infections."
Neutropenia led to recurrent bacterial infections.
Nervous System 1
Neurological involvement Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:34115842 REFUTE Human clinical
"However, 3-methylglutaconic aciduria was not observed and, other than neutropenia, these clinical features were uncommon in our series."
Neurological features were uncommon in the defining series.
PMID:40194906 REFUTE REVIEW SYNTHESIS Other
"It should be noted that the majority of patients with causative monoallelic CLPB variants reported so far present with isolated neutropenia without other symptoms characteristic of CLPB deficiency"
Most monoallelic patients have neutropenia alone.
PMID:35499078 SUPPORT Human clinical
"Interestingly, only patient 1 showed severe central nervous system involvement associated with neurocognitive developmental delay and spasticity."
One of four heterozygous patients in this series had developmental delay and spasticity.
🧬

Genetic Associations

1
CLPB
Gene: CLPB hgnc:30664 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CLPB (hgnc:30664). hgnc:30664 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 references)
PMID:34115842 SUPPORT Human clinical
"Moreover, the CLPB variants are distinct, consisting of heterozygous variants that cluster near the adenosine triphosphate-binding pocket."
The causal variants are heterozygous and cluster near the ATP-binding pocket.
PMID:35499078 SUPPORT Human clinical
"Surprisingly, we also identify monoallelic CLPB variants (G560R, R561Q, and R620H) associated with severe congenital neutropenia."
Independent heterozygous variants in the ATP-binding domain in a second patient series.
PMID:41383606 SUPPORT Human clinical
"Heterozygous CLPB alterations were located not only in the ATP domain, e.g., p.Arg598Cys, which has been described to affect mitochondrial function and induce apoptosis leading to neutropenia (28, 29), but also in the ankyrin and D2 domains, which turned out to affect CLPB oligomerization (data..."
Not all causal variants are in the ATP-binding domain.
+ 1 more reference
💊

Medical Actions

2
Granulocyte Colony-Stimulating Factor
Action: Colony-Stimulating Factor TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Colony-Stimulating Factor Therapy (NCIT:C15515). NCIT:C15515 is a clinical intervention from the NCI Thesaurus. NCIT:C15515
Agent: granulocyte colony stimulating factor NCIT:C1287 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses granulocyte colony stimulating factor, annotated with Recombinant Granulocyte Colony-Stimulating Factor (NCIT:C1287). NCIT:C1287 is a therapeutic agent from the NCI Thesaurus.
Platform: Other
The neutropenia is often manageable with G-CSF, though some patients are refractory even to high doses. Not all carriers need it: in the Polish cohort none of the CLPB patients received G-CSF.
Target Phenotypes: Neutropenia HP:0001875 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Neutropenia, annotated with Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:40194906 SUPPORT REVIEW SYNTHESIS Other
"frequently consisting of isolated neutropenia that is often manageable with G-CSF"
Review statement that the neutropenia of this disorder usually responds to G-CSF.
PMID:35499078 REFUTE Human clinical
"Patients 2 and 3 were refractory to high doses of G-CSF therapy and were therefore treated with hematopoietic stem cell transplantation."
Two of four heterozygous patients (neither the one with central nervous system involvement) did not respond to high-dose G-CSF.
PMID:27891836 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"granulocyte-colony stimulating factor to increase neutrophil counts to reduce the frequency of infections, especially in individuals with the mild or moderate phenotype"
GeneReviews recommendation for CLPB deficiency; the chapter does not cover this disorder specifically.
+ 1 more reference
Hematopoietic Stem Cell Transplantation
Action: Hematopoietic Cell TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. NCIT:C15431
Platform: Cell therapy
Used for neutropenia refractory to G-CSF and for myelodysplasia.
Mechanism Target:
Granulocytic Precursor Apoptosis — Replaces the hematopoietic compartment carrying the dominant-negative CLPB variant.
Impaired Neutrophil Differentiation — Replaces the hematopoietic compartment carrying the dominant-negative CLPB variant.
Target Phenotypes: Neutropenia HP:0001875 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Neutropenia, annotated with Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology. Myelodysplastic syndrome HP:0002863 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Myelodysplastic syndrome, annotated with Myelodysplasia (HP:0002863). HP:0002863 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:35499078 SUPPORT Human clinical
"Patients 2 and 3 were refractory to high doses of G-CSF therapy and were therefore treated with hematopoietic stem cell transplantation."
Transplantation for G-CSF-refractory disease in two heterozygous patients without central nervous system involvement.
PMID:41383606 SUPPORT Human clinical
"Patient P73 with CLPB, p.Arg599Cys change, developed MDS at the age of 11, underwent HSCT, and survived, but suffered from post-transplant immune thrombocytopenia."
Transplantation for myelodysplasia in a heterozygous carrier.
PMID:27891836 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"consider hematopoietic stem cell transplant in those without severe neurologic disease"
GeneReviews indication for transplantation in CLPB deficiency; this disorder usually lacks neurological disease.
🔬

Diagnosis

2
Molecular genetic testing
Exome or genome sequencing, or a congenital neutropenia gene panel that includes CLPB, identifies the heterozygous variant. Neurological features and urinary organic acids help place a case relative to type VIIA.
Show evidence (2 references)
PMID:34115842 SUPPORT Human clinical
"Together, these data show that heterozygous CLPB variants are a new and relatively common cause of congenital neutropenia and should be considered in the evaluation of patients with congenital neutropenia."
Recommends testing CLPB in the evaluation of congenital neutropenia.
PMID:27891836 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"identification of one of several specific heterozygous CLPB pathogenic variants associated with autosomal dominant CLPB deficiency on molecular genetic testing"
GeneReviews diagnostic criterion for dominant CLPB deficiency. The chapter does not name SCN9, so this supports it indirectly.
Blood count surveillance
Regular white blood cell count with differential, as GeneReviews recommends for CLPB deficiency.
Show evidence (1 reference)
PMID:27891836 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"measure white blood cell count with differential"
GeneReviews surveillance recommendation for CLPB deficiency.
📊

Prevalence

1
Polish national congenital neutropenia cohort
Cases/families reported in the literature
No population prevalence is available. In the Polish nationwide screening campaign, CLPB variants accounted for 10% of genetically diagnosed congenital neutropenia (10 of about 102 patients), the same share as SBDS; the exome series that defined the disorder called heterozygous CLPB variants a relatively common cause of congenital neutropenia.
Show evidence (2 references)
PMID:41383606 SUPPORT Human clinical
"CLPB-related neutropenia also accounted for 10% of cases, followed by defects in the TCIRG1 (eight cases), CXCR4 (seven cases), and SRP72 genes (seven cases)."
Share of genetically diagnosed congenital neutropenia attributable to CLPB in Poland.
PMID:34115842 SUPPORT Human clinical
"Together, these data show that heterozygous CLPB variants are a new and relatively common cause of congenital neutropenia and should be considered in the evaluation of patients with congenital neutropenia."
The defining series describes the cause as relatively common within congenital neutropenia.
🧫

Experimental Models

1
Human hematopoietic progenitors expressing SCN-associated CLPB variants PRIMARY_CELL_CULTURE
Human hematopoietic progenitor cells expressing heterozygous CLPB variants from SCN patients, or with CLPB knocked out, differentiated toward granulocytes.
Publication
PMID:34115842
Pathograph links
Granulocytic Precursor Apoptosis recapitulates fidelity: moderate observes: cellular Expression of the variants increases apoptosis of the progenitors.
Limitations: The variants are expressed alongside endogenous CLPB rather than from the native locus, so their dosage relative to wild type is not the patients'.
Show evidence (1 reference)
PMID:34115842 SUPPORT In vitro / ex vivo
"Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis."
The progenitor model reproduces precursor apoptosis.
Impaired Neutrophil Differentiation recapitulates fidelity: moderate observes: cellular Expression of the variants impairs granulocytic differentiation.
Limitations: The variants are expressed alongside endogenous CLPB rather than from the native locus, so their dosage relative to wild type is not the patients'.
Show evidence (1 reference)
PMID:34115842 SUPPORT In vitro / ex vivo
"Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis."
The progenitor model reproduces impaired differentiation.
{ }

Source YAML

click to show 
name: Severe Congenital Neutropenia 9
creation_date: "2026-10-20T19:40:00Z"
category: Mendelian
description: >-
  Severe congenital neutropenia 9 (SCN9, CLPB-SCN) is an autosomal dominant
  disorder of granulopoiesis caused by heterozygous missense variants in CLPB,
  the ATP-dependent AAA+ disaggregase of the mitochondrial intermembrane space.
  In the defining series the variants cluster near the ATP-binding pocket of
  the nucleotide-binding domain, though later carriers also have ankyrin- and
  D2-domain variants; mutant subunits associate with wild-type CLPB and inhibit its ATPase
  and disaggregase activity in a dominant-negative manner. Granulocytic
  precursors expressing the variants die by apoptosis and fail to
  differentiate, giving a myeloid maturation arrest in the marrow and severe
  neutropenia with recurrent bacterial infections from infancy. Unlike the
  other CLPB disorders, most patients have neutropenia alone, without the
  neurological disease or 3-methylglutaconic aciduria of the recessive form
  (type VIIB) or of the dominant neurological form (type VIIA). Myelodysplasia
  has been reported. Treatment is G-CSF, with hematopoietic stem cell
  transplantation for patients refractory to it. Whether SCN9 and type VIIA are
  one disorder is an open question.
disease_term:
  preferred_term: neutropenia, severe congenital, 9, autosomal dominant
  term:
    id: MONDO:0030726
    label: neutropenia, severe congenital, 9, autosomal dominant
synonyms:
- SCN9
- CLPB-SCN
- CLPB-related severe congenital neutropenia
- Autosomal dominant severe congenital neutropenia due to CLPB variants
parents:
- Severe Congenital Neutropenia
- Inborn Error of Immunity
notes: >-
  Scope: this entry covers heterozygous CLPB variants with neutropenia as the
  main or only feature, OMIM 619813 (MONDO:0030726). The dominant CLPB disorder
  with neurological involvement and 3-methylglutaconic aciduria, OMIM 619835,
  is curated as 3-methylglutaconic_Aciduria_Type_VIIA, and the recessive form,
  OMIM 616271, as 3-methylglutaconic_Aciduria_Type_VIIB. The boundary between
  the two dominant disorders is unsettled; it is recorded as a knowledge gap in
  both entries. Some sources pool all monoallelic patients (PMID:41719910) or
  report heterozygous patients with and without neurological disease together
  (PMID:35499078); where they are cited, the description says so. The only
  ClinGen gene-disease validity record for CLPB in
  cache/clingen/gene_validity.csv is for Leigh syndrome (MONDO:0009723), a
  different disease, so no gene_disease_validity assertion is recorded.
  The GeneReviews CLPB Deficiency chapter (PMID:27891836) covers biallelic
  disease and the dominant form it describes with neurological involvement;
  it does not name this disorder. Its management guidance is cited here as
  indirect support.
references:
- reference: PMID:27891836
  title: CLPB Deficiency.
  tags:
  - GeneReviews
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    A single heterozygous CLPB missense variant causes the disease. Each
    child of an affected person has a 50% chance of inheriting it.
    GeneReviews states that all reported dominant CLPB cases arose de novo;
    that statement concerns its dominant form with neurological involvement,
    and the SCN9 sources cited here do not say whether their variants were
    de novo or inherited.
  evidence:
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "CLPB deficiency associated with specific heterozygous CLPB pathogenic variants is inherited in an autosomal dominant manner."
    explanation: >-
      GeneReviews states dominant inheritance for specific heterozygous CLPB
      variants. Its dominant form is the one with neurological involvement, so
      this supports SCN9 indirectly.
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "Each child of an individual with a heterozygous CLPB pathogenic variant has a 50% chance of inheriting the pathogenic variant."
    explanation: Transmission risk for a heterozygous CLPB variant, from the GeneReviews chapter that does not name SCN9.
  - reference: PMID:34115842
    reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing of 104 persons with congenital neutropenia identified heterozygous missense variants of CLPB (caseinolytic peptidase B) in 5 severe congenital neutropenia cases, with 5 more cases identified through additional sequencing efforts or clinical sequencing."
    explanation: Heterozygous CLPB variants in ten patients with severe congenital neutropenia.
  - reference: PMID:41383606
    reference_title: "The genetic landscape of congenital neutropenia in Poland: summary of the nationwide screening campaign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten patients were carriers of heterozygous CLPB variants, including known p.Arg297Trp and p.Arg598Cys changes, associated with isolated dominant neutropenia and a novel p.Arg599Cys variant located as well in the ATPase domain."
    explanation: A national cohort with ten further heterozygous carriers with dominant neutropenia.
prevalence:
- population: Polish national congenital neutropenia cohort
  measure_type: CASES_IN_LITERATURE
  notes: >-
    No population prevalence is available. In the Polish nationwide screening
    campaign, CLPB variants accounted for 10% of genetically diagnosed
    congenital neutropenia (10 of about 102 patients), the same share as SBDS;
    the exome series that defined the disorder called heterozygous CLPB
    variants a relatively common cause of congenital neutropenia.
  evidence:
  - reference: PMID:41383606
    reference_title: "The genetic landscape of congenital neutropenia in Poland: summary of the nationwide screening campaign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CLPB-related neutropenia also accounted for 10% of cases, followed by defects in the TCIRG1 (eight cases), CXCR4 (seven cases), and SRP72 genes (seven cases)."
    explanation: Share of genetically diagnosed congenital neutropenia attributable to CLPB in Poland.
  - reference: PMID:34115842
    reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Together, these data show that heterozygous CLPB variants are a new and relatively common cause of congenital neutropenia and should be considered in the evaluation of patients with congenital neutropenia."
    explanation: The defining series describes the cause as relatively common within congenital neutropenia.
genetic:
- name: CLPB
  gene_term:
    preferred_term: CLPB
    term:
      id: hgnc:30664
      label: CLPB
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    In the defining series and the Care-for-Rare patients, the heterozygous
    missense variants cluster near the ATP-binding pocket of the C-terminal
    nucleotide-binding domain (p.Arg561Gln, p.Gly560Arg, p.Arg620His;
    PMID:35499078). The Polish carriers include ATPase-domain variants
    (p.Arg598Cys, p.Arg599Cys) and also variants in the ankyrin and D2
    domains, among them p.Arg297Trp (PMID:41383606). The arginine finger R561
    is the most frequently mutated residue across monoallelic CLPB disease.
  evidence:
  - reference: PMID:34115842
    reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, the CLPB variants are distinct, consisting of heterozygous variants that cluster near the adenosine triphosphate-binding pocket."
    explanation: The causal variants are heterozygous and cluster near the ATP-binding pocket.
  - reference: PMID:35499078
    reference_title: HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surprisingly, we also identify monoallelic CLPB variants (G560R, R561Q, and R620H) associated with severe congenital neutropenia."
    explanation: Independent heterozygous variants in the ATP-binding domain in a second patient series.
  - reference: PMID:41383606
    reference_title: "The genetic landscape of congenital neutropenia in Poland: summary of the nationwide screening campaign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous CLPB alterations were located not only in the ATP domain, e.g., p.Arg598Cys, which has been described to affect mitochondrial function and induce apoptosis leading to neutropenia (28, 29), but also in the ankyrin and D2 domains, which turned out to affect CLPB oligomerization (data not shown)."
    explanation: Not all causal variants are in the ATP-binding domain.
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Mutations of this residue have been reported in nine unrelated patients, the largest number for any CLPB amino acid."
    explanation: >-
      R561 is the most frequently mutated residue in monoallelic CLPB disease.
      The count pools both dominant disorders, including R561W carriers with
      3-methylglutaconic aciduria.
pathophysiology:
- name: Dominant-Negative Inhibition of CLPB Disaggregase
  description: >-
    Mutant CLPB subunits associate with wild-type subunits and inhibit both the
    ATPase and the disaggregase activity of the complex. Subunits carrying
    recessive-disease variants do not do this, which is why a single dominant
    allele causes disease while a single recessive allele does not.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CLPB
    term:
      id: hgnc:30664
      label: CLPB
  molecular_functions:
  - preferred_term: ATP-dependent protein disaggregase activity
    term:
      id: GO:0140545
      label: ATP-dependent protein disaggregase activity
    modifier: DECREASED
  - preferred_term: ATP hydrolysis activity
    term:
      id: GO:0016887
      label: ATP hydrolysis activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: mitochondrial intermembrane space
    term:
      id: GO:0005758
      label: mitochondrial intermembrane space
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
  evidence:
  - reference: PMID:34115842
    reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These CLPB variants associate with wild-type CLPB and inhibit its adenosine triphosphatase and disaggregase activity in a dominant-negative fashion."
    explanation: The variants of this disorder bind and inhibit wild-type CLPB.
  - reference: PMID:36170828
    reference_title: "Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Importantly, SCN-linked subunits sharply inhibit disaggregase activity, whereas MGCA7-linked subunits do not."
    explanation: Mixed-hexamer experiments show SCN-linked subunits poison wild-type CLPB, unlike recessive-disease subunits.
  downstream:
  - target: Intermembrane Space Protein Aggregation
    causal_link_type: DIRECT
  - target: Impaired Mitochondrial Respiration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Intermembrane Space Protein Aggregation
  description: >-
    Without disaggregase activity, proteins of the mitochondrial intermembrane
    space and inner membrane, including the anti-apoptotic protein HAX1,
    become insoluble.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: protein refolding
    term:
      id: GO:0042026
      label: protein refolding
    modifier: DECREASED
  cellular_components:
  - preferred_term: mitochondrial intermembrane space
    term:
      id: GO:0005758
      label: mitochondrial intermembrane space
  evidence:
  - reference: PMID:32573439
    reference_title: Skd3 (human ClpB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Using Gene Ontology (GO) analysis for cellular component, we found that proteins in the inner mitochondrial membrane and intermembrane space were enriched in the insoluble fraction in the absence of Skd3"
    explanation: >-
      Shown in CLPB knockout cells; the dominant-negative variants are expected
      to act through the same loss of disaggregase activity.
  downstream:
  - target: HAX1 Insolubility
    causal_link_type: DIRECT
- name: HAX1 Insolubility
  description: >-
    HAX1 is a direct partner and stimulatory cofactor of CLPB and depends on it
    for solubility. HAX1 deficiency itself causes severe congenital neutropenia
    (Kostmann syndrome), which links CLPB dysfunction to the neutrophil lineage.
    HAX1 insolubility has been shown in CLPB-deficient cells, not with the
    dominant variants of this disorder, and one such variant (R561Q) still
    binds HAX1.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: HAX1
    term:
      id: hgnc:16915
      label: HAX1
  evidence:
  - reference: PMID:32573439
    reference_title: Skd3 (human ClpB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "In wild-type cells, HAX1 remained predominantly soluble (Figure 7d,e). However, when Skd3 was deleted HAX1 became predominantly insoluble (Figure 7d,e). Thus, Skd3 is essential for HAX1 solubility in cells."
    explanation: CLPB is required for HAX1 solubility; shown in knockout cells.
  - reference: PMID:42244541
    reference_title: HAX1 drives assembly and activation of the mitochondrial intermembrane space chaperone CLPB.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Through biochemical reconstitution, we here find that HAX1 is a direct stimulatory cofactor of CLPB."
    explanation: HAX1 and CLPB act as one functional unit.
  - reference: PMID:39644357
    reference_title: Mitochondrial CLPB is a pro-survival factor at the onset of granulocytic differentiation of mouse myeloblastic cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "We found that CLPB-deficient 32Dcl3 cells showed a decreased mitochondrial membrane potential and increased levels of insoluble HAX1 aggregates in mitochondria, as compared to control cells."
    explanation: Insoluble HAX1 accumulates in CLPB-deficient mouse myeloblastic cells, the lineage that fails in this disorder.
  - reference: PMID:35499078
    reference_title: HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "While the R561Q mutant is competent for HAX1 binding (Figure 2G)"
    explanation: At least one SCN variant does not lose HAX1 binding, so the HAX1 step is not shown for every variant.
  downstream:
  - target: Granulocytic Precursor Apoptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Impaired Neutrophil Differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35499078
      reference_title: HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "we defined a potentially novel functional CLPB/HAX1/(PRKD2)/HSP27 axis with critical importance for the differentiation of neutrophil granulocytes and, thus, elucidated molecular and metabolic mechanisms underlying congenital neutropenia in patients with HAX1 deficiency as well as bi- and monoallelic mutations in CLPB."
      explanation: Places the CLPB/HAX1 axis upstream of neutrophil differentiation, including in monoallelic CLPB patients.
- name: Impaired Mitochondrial Respiration
  description: >-
    In overexpression models, myeloid cells expressing SCN-associated CLPB
    variants alongside wild-type CLPB show impaired mitochondrial function and
    severely reduced respiration, without increased sensitivity to endoplasmic
    reticulum stress. These models may not reflect patient cells. In
    CLPB-knockout mouse myeloblasts, apoptosis at the onset of differentiation
    is linked to reactive oxygen species; that link has not been shown with
    the SCN variants themselves.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: cellular respiration
    term:
      id: GO:0045333
      label: cellular respiration
    modifier: DECREASED
  evidence:
  - reference: PMID:34115842
    reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Finally, expression of CLPB variants is associated with impaired mitochondrial function but does not render cells more sensitive to endoplasmic reticulum stress."
    explanation: Expression of the variants of this disorder impairs mitochondrial function.
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "MOLM-13 cells overexpressing selected SCN-related CLPB variants in addition to the native wild-type protein, which were studied as a model of the disease, demonstrated severely impaired respiration"
    explanation: Review summary of the respiration defect in a myeloid cell model of this disorder.
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: REFUTE
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Neither CLPB knockout nor overexpression of the dominant negative pathogenic CLPB variants accurately reflect the respiratory phenotype of patient cells."
    explanation: The same review cautions that the overexpression models do not match patient cells.
  downstream:
  - target: Mitochondrial ROS Accumulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      No source shows that the respiratory defect is the origin of the excess
      reactive oxygen species; both are reported in CLPB-deficient cells.
- name: Mitochondrial ROS Accumulation
  description: >-
    CLPB-deficient myeloblasts lose mitochondrial membrane potential and
    produce excess reactive oxygen species when induced to differentiate, and
    their apoptosis depends on it: N-acetylcysteine, free fatty acids or
    citrate protect them. Shown in CLPB-knockout mouse 32Dcl3 cells, not with
    the dominant SCN variants.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: myeloblast
    term:
      id: CL:0000835
      label: myeloblast
  biological_processes:
  - preferred_term: reactive oxygen species production
    term:
      id: GO:1903409
      label: reactive oxygen species biosynthetic process
    modifier: INCREASED
  evidence:
  - reference: PMID:39644357
    reference_title: Mitochondrial CLPB is a pro-survival factor at the onset of granulocytic differentiation of mouse myeloblastic cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "We found that CLPB-deficient 32Dcl3 cells showed a decreased mitochondrial membrane potential and increased levels of insoluble HAX1 aggregates in mitochondria, as compared to control cells."
    explanation: Mitochondrial depolarisation in CLPB-deficient myeloblasts.
  - reference: PMID:39644357
    reference_title: Mitochondrial CLPB is a pro-survival factor at the onset of granulocytic differentiation of mouse myeloblastic cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Moreover, we found that increased apoptosis of CLPB-deficient cells is linked to production of reactive oxygen species (ROS)."
    explanation: Excess ROS production in CLPB-deficient myeloblasts.
  downstream:
  - target: Granulocytic Precursor Apoptosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39644357
      reference_title: Mitochondrial CLPB is a pro-survival factor at the onset of granulocytic differentiation of mouse myeloblastic cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "N-acetylcysteine, exogenous free fatty acids, or exogenous citrate protected CLPB-deficient 32Dcl3 cells from apoptosis at the onset of differentiation."
      explanation: >-
        The antioxidant N-acetylcysteine rescues the apoptosis, so ROS is on
        the path to precursor death. Shown in knockout mouse cells; the rescue
        is preclinical.
- name: Granulocytic Precursor Apoptosis
  description: >-
    Granulocytic precursors expressing the variants, or lacking CLPB, die by
    apoptosis as granulocytic differentiation begins, depleting the neutrophil
    lineage.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: myeloblast
    term:
      id: CL:0000835
      label: myeloblast
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:34115842
    reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis."
    explanation: The variants of this disorder increase apoptosis of human hematopoietic progenitors.
  - reference: PMID:39644357
    reference_title: Mitochondrial CLPB is a pro-survival factor at the onset of granulocytic differentiation of mouse myeloblastic cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "CLPB loss did not affect cell proliferation rates in the presence of IL-3 but it increased apoptosis after IL-3 withdrawal and simultaneous induction of cell differentiation with granulocytic colony stimulating factor (G-CSF)."
    explanation: In mouse myeloblastic cells, loss of CLPB causes apoptosis at the onset of granulocytic differentiation.
  downstream:
  - target: Congenital neutropenia
    causal_link_type: DIRECT
- name: Impaired Neutrophil Differentiation
  description: >-
    Human hematopoietic progenitors expressing the variants fail to complete
    granulocytic differentiation, matching the myeloid maturation arrest seen
    in patient marrow. A mouse myeloblastic model disagrees: there,
    CLPB-deficient cells that survive differentiate normally.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: neutrophil differentiation
    term:
      id: GO:0030223
      label: neutrophil differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:34115842
    reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis."
    explanation: The variants of this disorder impair granulocytic differentiation of human progenitors.
  - reference: PMID:39644357
    reference_title: Mitochondrial CLPB is a pro-survival factor at the onset of granulocytic differentiation of mouse myeloblastic cells.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "CLPB-deficient cells that survived the stress associated with IL-3 withdrawal/G-CSF treatment expressed the same levels of differentiation markers as control cells."
    explanation: In this mouse cell model the defect is survival, not differentiation of the cells that survive.
  downstream:
  - target: Myeloid maturation arrest
    causal_link_type: DIRECT
  - target: Congenital neutropenia
    causal_link_type: DIRECT
  - target: Myelodysplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Transformation in severe congenital neutropenia is attributed to the
      underlying marrow maturation defect, not to the low neutrophil count as
      such. No source traces the steps from the CLPB defect to transformation.
phenotypes:
- name: Congenital neutropenia
  description: >-
    Severe neutropenia, presenting in the first year of life in most patients
    and later in childhood in some. In the Polish cohort neutrophil counts
    normalized with age in all heterozygous carriers.
  category: Hematological
  phenotype_term:
    preferred_term: Severe congenital neutropenia
    term:
      id: HP:0025826
      label: Severely decreased neutrophil count
  evidence:
  - reference: PMID:34115842
    reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing of 104 persons with congenital neutropenia identified heterozygous missense variants of CLPB (caseinolytic peptidase B) in 5 severe congenital neutropenia cases, with 5 more cases identified through additional sequencing efforts or clinical sequencing."
    explanation: Severe congenital neutropenia defines the disorder.
  - reference: PMID:35499078
    reference_title: HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, 3 of 4 patients (patients 1, 2, and 3) presented with severe neutropenia in the first year, and patient 4 presented with severe neutropenia in the seventh year of life leading to recurrent bacterial infections."
    explanation: Onset in infancy in most heterozygous patients, later in one.
  - reference: PMID:41383606
    reference_title: "The genetic landscape of congenital neutropenia in Poland: summary of the nationwide screening campaign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients with heterozygous CLPB changes had neutropenia in childhood, but ANC normalized with age."
    explanation: Neutropenia in childhood that resolves with age in this cohort.
  sequelae:
  - target: Recurrent bacterial infections
    causal_link_type: DIRECT
- name: Recurrent bacterial infections
  category: Immunological
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:35499078
    reference_title: HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, 3 of 4 patients (patients 1, 2, and 3) presented with severe neutropenia in the first year, and patient 4 presented with severe neutropenia in the seventh year of life leading to recurrent bacterial infections."
    explanation: Neutropenia led to recurrent bacterial infections.
- name: Myeloid maturation arrest
  description: Bone marrow shows arrest of myeloid maturation at the promyelocyte stage.
  category: Hematological
  phenotype_term:
    preferred_term: Myeloid maturation arrest at the promyelocyte stage
    term:
      id: HP:0410253
      label: Myeloid maturation arrest
  evidence:
  - reference: PMID:35499078
    reference_title: HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Examination of the bone marrow revealed a myeloid maturation arrest at the promyelocyte stage."
    explanation: Marrow finding in four heterozygous CLPB patients, one of whom also had central nervous system involvement.
- name: Myelodysplasia
  description: >-
    Myelodysplastic syndrome was reported in one heterozygous carrier
    (p.Arg599Cys) at 11 years of age, treated by stem cell transplantation.
  category: Neoplasm
  phenotype_term:
    preferred_term: Myelodysplastic syndrome
    term:
      id: HP:0002863
      label: Myelodysplasia
  evidence:
  - reference: PMID:41383606
    reference_title: "The genetic landscape of congenital neutropenia in Poland: summary of the nationwide screening campaign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient P73 with CLPB, p.Arg599Cys change, developed MDS at the age of 11, underwent HSCT, and survived, but suffered from post-transplant immune thrombocytopenia."
    explanation: Myelodysplasia in a heterozygous CLPB carrier.
- name: Neurological involvement
  description: >-
    Uncommon. Most patients have isolated neutropenia; a minority of
    heterozygous patients have developmental delay or spasticity. Where they
    do, the case sits on the unsettled boundary with type VIIA.
  category: Neurological
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:34115842
    reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "However, 3-methylglutaconic aciduria was not observed and, other than neutropenia, these clinical features were uncommon in our series."
    explanation: Neurological features were uncommon in the defining series.
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: REFUTE
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "It should be noted that the majority of patients with causative monoallelic CLPB variants reported so far present with isolated neutropenia without other symptoms characteristic of CLPB deficiency"
    explanation: Most monoallelic patients have neutropenia alone.
  - reference: PMID:35499078
    reference_title: HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, only patient 1 showed severe central nervous system involvement associated with neurocognitive developmental delay and spasticity."
    explanation: One of four heterozygous patients in this series had developmental delay and spasticity.
- name: 3-Methylglutaconic aciduria
  description: >-
    Not observed in the defining series, which is one of the features used to
    separate this disorder from type VIIA. It was not measured in about half of
    published cases.
  category: Metabolic
  phenotype_term:
    preferred_term: 3-Methylglutaconic aciduria
    term:
      id: HP:0003535
      label: 3-Methylglutaconic aciduria
  evidence:
  - reference: PMID:34115842
    reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "However, 3-methylglutaconic aciduria was not observed and, other than neutropenia, these clinical features were uncommon in our series."
    explanation: The organic aciduria was absent in the defining series.
diagnosis:
- name: Molecular genetic testing
  description: >-
    Exome or genome sequencing, or a congenital neutropenia gene panel that
    includes CLPB, identifies the heterozygous variant. Neurological features
    and urinary organic acids help place a case relative to type VIIA.
  evidence:
  - reference: PMID:34115842
    reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Together, these data show that heterozygous CLPB variants are a new and relatively common cause of congenital neutropenia and should be considered in the evaluation of patients with congenital neutropenia."
    explanation: Recommends testing CLPB in the evaluation of congenital neutropenia.
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "identification of one of several specific heterozygous CLPB pathogenic variants associated with autosomal dominant CLPB deficiency on molecular genetic testing"
    explanation: >-
      GeneReviews diagnostic criterion for dominant CLPB deficiency. The
      chapter does not name SCN9, so this supports it indirectly.
- name: Blood count surveillance
  description: >-
    Regular white blood cell count with differential, as GeneReviews
    recommends for CLPB deficiency.
  evidence:
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "measure white blood cell count with differential"
    explanation: GeneReviews surveillance recommendation for CLPB deficiency.
treatments:
- name: Granulocyte Colony-Stimulating Factor
  description: >-
    The neutropenia is often manageable with G-CSF, though some patients are
    refractory even to high doses. Not all carriers need it: in the Polish
    cohort none of the CLPB patients received G-CSF.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Colony-Stimulating Factor Therapy
    term:
      id: NCIT:C15515
      label: Colony-Stimulating Factor Therapy
    therapeutic_agent:
    - preferred_term: granulocyte colony stimulating factor
      term:
        id: NCIT:C1287
        label: Recombinant Granulocyte Colony-Stimulating Factor
  target_phenotypes:
  - preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "frequently consisting of isolated neutropenia that is often manageable with G-CSF"
    explanation: Review statement that the neutropenia of this disorder usually responds to G-CSF.
  - reference: PMID:35499078
    reference_title: HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients 2 and 3 were refractory to high doses of G-CSF therapy and were therefore treated with hematopoietic stem cell transplantation."
    explanation: Two of four heterozygous patients (neither the one with central nervous system involvement) did not respond to high-dose G-CSF.
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "granulocyte-colony stimulating factor to increase neutrophil counts to reduce the frequency of infections, especially in individuals with the mild or moderate phenotype"
    explanation: GeneReviews recommendation for CLPB deficiency; the chapter does not cover this disorder specifically.
  - reference: PMID:41383606
    reference_title: "The genetic landscape of congenital neutropenia in Poland: summary of the nationwide screening campaign."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with variants in the CLPB and TCIRG1 genes did not receive G-CSF treatment."
    explanation: The Polish CLPB patients were managed without G-CSF, so the cohort gives no response data.
- name: Hematopoietic Stem Cell Transplantation
  description: >-
    Used for neutropenia refractory to G-CSF and for myelodysplasia.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: Hematopoietic Cell Transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_phenotypes:
  - preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  - preferred_term: Myelodysplastic syndrome
    term:
      id: HP:0002863
      label: Myelodysplasia
  target_mechanisms:
  - target: Granulocytic Precursor Apoptosis
    description: Replaces the hematopoietic compartment carrying the dominant-negative CLPB variant.
  - target: Impaired Neutrophil Differentiation
    description: Replaces the hematopoietic compartment carrying the dominant-negative CLPB variant.
  evidence:
  - reference: PMID:35499078
    reference_title: HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients 2 and 3 were refractory to high doses of G-CSF therapy and were therefore treated with hematopoietic stem cell transplantation."
    explanation: Transplantation for G-CSF-refractory disease in two heterozygous patients without central nervous system involvement.
  - reference: PMID:41383606
    reference_title: "The genetic landscape of congenital neutropenia in Poland: summary of the nationwide screening campaign."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient P73 with CLPB, p.Arg599Cys change, developed MDS at the age of 11, underwent HSCT, and survived, but suffered from post-transplant immune thrombocytopenia."
    explanation: Transplantation for myelodysplasia in a heterozygous carrier.
  - reference: PMID:27891836
    reference_title: CLPB Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "consider hematopoietic stem cell transplant in those without severe neurologic disease"
    explanation: GeneReviews indication for transplantation in CLPB deficiency; this disorder usually lacks neurological disease.
experimental_models:
- name: Human hematopoietic progenitors expressing SCN-associated CLPB variants
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Human hematopoietic progenitor cells expressing heterozygous CLPB variants
    from SCN patients, or with CLPB knocked out, differentiated toward
    granulocytes.
  publication: PMID:34115842
  modeled_mechanisms:
  - target: Granulocytic Precursor Apoptosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Expression of the variants increases apoptosis of the progenitors.
    limitations: >-
      The variants are expressed alongside endogenous CLPB rather than from
      the native locus, so their dosage relative to wild type is not the
      patients'.
    evidence:
    - reference: PMID:34115842
      reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis."
      explanation: The progenitor model reproduces precursor apoptosis.
  - target: Impaired Neutrophil Differentiation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Expression of the variants impairs granulocytic differentiation.
    limitations: >-
      The variants are expressed alongside endogenous CLPB rather than from
      the native locus, so their dosage relative to wild type is not the
      patients'.
    evidence:
    - reference: PMID:34115842
      reference_title: Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis."
      explanation: The progenitor model reproduces impaired differentiation.
discussions:
- discussion_id: gap_scn9_vs_mgca7a_boundary
  prompt: >-
    Are severe congenital neutropenia 9 and 3-methylglutaconic aciduria type
    VIIA two disorders, or one dominant CLPB disorder with variable
    neurological expression?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - disease#
  - phenotypes#Neurological involvement
  - phenotypes#3-Methylglutaconic aciduria
  rationale: >-
    Both are caused by heterozygous CLPB missense variants that inhibit
    wild-type CLPB dominant-negatively, and R561 is mutated in both. The
    separating features, neurological disease and 3-methylglutaconic aciduria,
    occur in some heterozygous patients, and the aciduria was not measured in
    about half of the published neutropenia cases.
  evidence:
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "It remains to be established whether the distinction between dominant CLPB deficiency (MGA 7A) and CLPB-SCN is scientifically valid or if these entities represent, in fact, one disorder."
    explanation: Review stating the boundary is unresolved.
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The distinction based on the lack of 3-MGA-uria in isolated CLPB-related neutropenia needs to be further studied, as this parameter was not assessed in 9 out of 20 published cases, since it had not been linked with neutropenia before."
    explanation: The biochemical criterion separating the two was often not measured.
- discussion_id: gap_scn9_mild_phenotype
  prompt: >-
    Why do variants that severely inhibit wild-type CLPB in vitro produce a
    relatively mild, often isolated neutropenia that can resolve with age?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Dominant-Negative Inhibition of CLPB Disaggregase
  - phenotypes#Congenital neutropenia
  rationale: >-
    Mixed-oligomer assays show the variants abolish most disaggregase activity,
    and myeloid cell models show severely impaired respiration, yet patients
    usually have neutropenia alone, often responsive to G-CSF, and in one
    cohort counts normalized with age. Dosage of the mutant subunit in vivo,
    tissue-specific compensation, and the developmental timing of the marrow
    defect are untested explanations.
  evidence:
  - reference: PMID:40194906
    reference_title: CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "A perplexing issue is why the SCN-related variants, with such a devastating influence on the ATPase and disaggregase activity on the wild-type protein in vitro, result in a relatively mild phenotype in patients."
    explanation: Review naming the mismatch between in vitro severity and clinical mildness.
📚

References & Deep Research

References

1
PMID:27891836
CLPB Deficiency.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Severe_Congenital_Neutropenia_9 · 2026-10-20T20:17:35Z · View source

New entry for autosomal dominant severe congenital neutropenia 9 (CLPB-SCN; MONDO:0030726, OMIM 619813), claimed in #15046. Scoped against 3-methylglutaconic_Aciduria_Type_VIIA (OMIM 619835, dominant CLPB with neurological involvement) and VIIB (recessive); the open question of whether SCN9 and VIIA are one disorder is a KNOWLEDGE_GAP in both entries. Main sources: the defining series PMID:34115842 (abstract only), the Polish national cohort PMID:41383606 (CLPB 10% of genetically diagnosed CN, counts normalised with age, one MDS case), the Care-for-Rare heterozygous patients in PMID:35499078 (one of four with CNS disease, noted wherever it is cited), and the 2025 review PMID:40194906. Mechanistic nodes reuse the knockout and reconstitution papers (PMID:32573439, PMID:42244541, PMID:39644357) marked INDIRECT. Myelodysplasia hangs off the marrow maturation node, not the neutrophil count, matching the change made to VIIA in #15048. GeneReviews (PMID:27891836) covers CLPB deficiency but not this disorder by name; it is tagged and its management lines are cited as INDIRECT. Deep research: falcon is not configured here, so the run used --fallback and openscientist wrote the report. Unlike the VIIA run it was on target: 18/18 references resolved, 18/18 quotes matched, preflight-dr PASS. It added no CLPB-specific source beyond those already cited; its general SCN transplant papers (PMID:15640815, PMID:15489867) and its NCIT:C15847 (resolves to Non-Ionizing Radiotherapy) were not used. A pre-PR self-review led to: narrowing the variant-clustering claim (the Polish carriers include ankyrin- and D2-domain variants, p.Arg297Trp among them); a REFUTE caveat that overexpression models do not reflect patient respiration; attribution notes on PMID:35499078 items; the R561 count explained as pooled; HP:0025826 Severely decreased neutrophil count for the phenotype; a REFUTE noting R561Q still binds HAX1; and PMID:39644357 insoluble-HAX1 evidence. Validation: just validate and validate-disorders pass; count-verified-snippets 47/47; check-genereviews TAGGED; entity-ref, causal-target, duplicate-key, enum, snippet-grading, coarse-phenotype and block-scalar checks pass; model-scale-audit 2/2 aligned. The deep-research report also cited PMID:41560087, a de novo p.R561W case with white-matter disease and a movement disorder. It was left out of this entry because that case belongs with type VIIA (where it is cited), not SCN9. Review round 1 on #15057 (changes requested). Added a Mitochondrial ROS Accumulation node (GO:1903409, INCREASED) between impaired respiration and precursor apoptosis, from PMID:39644357 (knockout mouse myeloblasts: lower membrane potential, ROS-linked apoptosis, rescue by N-acetylcysteine, free fatty acids or citrate), all marked INDIRECT; the respiration node no longer calls that step untested. Added GeneReviews diagnosis and genetic-counselling lines (autosomal dominant, 50% transmission) as INDIRECT items; the inheritance description notes that GeneReviews' all-de-novo statement concerns its neurological dominant form and that the SCN9 sources do not say whether their variants were de novo. count-verified-snippets 53/53.

OpenScientist ▸
Key Findings
openscientist-autonomous 18 citations 2026-10-20T20:01:30.174795

Key Findings

Finding 1 — SCN9 is caused by heterozygous dominant-negative CLPB variants (autosomal dominant)

SCN9 maps to MONDO:0030726 ("Neutropenia, severe congenital, 9, autosomal dominant"), cross-referenced to OMIM:619813, UMLS:C5676954, and GARD:0025625, with material basis in germline mutation in CLPB (HGNC:30664). The defining study, Warren et al. 2022 (Blood), used exome sequencing of 104 persons with congenital neutropenia to identify heterozygous missense CLPB variants in 5 severe congenital neutropenia cases, with 5 additional cases identified through supplementary sequencing — 10 total. The variants are not scattered but cluster near the adenosine-triphosphate–binding pocket of CLPB.

"Exome sequencing of 104 persons with congenital neutropenia identified heterozygous missense variants of CLPB (caseinolytic peptidase B) in 5 severe congenital neutropenia cases, with 5 more cases identified through additional sequencing efforts or clinical sequencing." — PMID: 34115842

"the CLPB variants are distinct, consisting of heterozygous variants that cluster near the adenosine triphosphate-binding pocket" — PMID: 34115842

This dominant form is molecularly and clinically distinct from the biallelic CLPB disease (OMIM 616271, 3-MGA-uria type VII, autosomal recessive).

Finding 2 — Mechanism: dominant-negative CLPB impairs mitochondrial disaggregase activity, blocking granulopoiesis and increasing apoptosis

CLPB (SKD3) is an AAA+ ATPase disaggregase/refoldase residing in the mitochondrial intermembrane space (IMS). SCN9 variants physically associate with wild-type CLPB and inhibit both its ATPase and disaggregase activities in a dominant-negative fashion. Both genetic loss of CLPB and expression of the variant protein impair granulocytic differentiation of human hematopoietic progenitors and increase apoptosis.

"These CLPB variants associate with wild-type CLPB and inhibit its adenosine triphosphatase and disaggregase activity in a dominant-negative fashion." — PMID: 34115842

"Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis." — PMID: 34115842

A key mechanistic link is to HAX1, the protein mutated in SCN3 (Kostmann disease). CLPB maintains the solubility of HAX1, and HAX1 in turn acts as a direct stimulatory cofactor that oligomerizes and activates CLPB — tying two distinct neutropenia genes into one IMS proteostasis axis.

"loss of function in either gene causes severe congenital neutropenia as well as neuropathology and causes many proteins in the IMS and its bounding membranes to become insoluble" — PMID: 42244541

In CLPB-deficient myeloblasts, the downstream picture is reduced mitochondrial membrane potential, insoluble HAX1 aggregates, and ROS-driven apoptosis precisely at the onset of G-CSF-induced differentiation (PMID: 39644357). Monoallelic variants disturb refoldase activity (and to a lesser extent ATPase activity) dominant-negatively (PMID: 34140661).

Finding 3 — SCN9 phenotype is typically isolated severe neutropenia, lacking the neuro/metabolic features of biallelic disease

In Warren et al. 2022, heterozygous CLPB carriers had severe congenital neutropenia but — unlike biallelic disease — 3-methylglutaconic aciduria was not observed, and syndromic features (cataracts, neurological disease) were uncommon.

"3-methylglutaconic aciduria was not observed and, other than neutropenia, these clinical features were uncommon in our series" — PMID: 34115842

By contrast, the biallelic recessive syndrome (OMIM 616271) spans a neurological phenotype from nonprogressive intellectual disability to prenatal encephalopathy:

"a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early death" — PMID: 25597510

A subset of monoallelic (de novo) cases do show some neurodevelopmental involvement (seizures, developmental delay), indicating a phenotypic spectrum rather than a clean dichotomy (PMID: 34140661).

Finding 4 — Zygosity predicts outcome: monoallelic disease is milder with better survival

Heath et al. 2026 assembled a cohort of 63 individuals (41 biallelic, 22 monoallelic) and quantified the zygosity-outcome relationship.

"Death occurred in 66% of biallelic and 23% of monoallelic individuals, with earlier median age at death in biallelic cases (6 months vs 2.4 years). Biallelic cases had significantly higher DBI scores and poorer survival (4-year survival: 50% vs 82%)." — PMID: 41719910

Notably, structural predictions (nonsense-mediated decay or ankyrin-repeat-domain disruption) were stronger predictors of survival than zygosity or age of onset alone, and stop/stop genotypes conferred greater disease burden than missense combinations. Early onset (<12 months) correlated with more severe progression.

Finding 5 — Treatment: G-CSF maintains counts and reduces infections; HSCT is definitive; antioxidant/metabolic rescue is experimental

In a CLPB-neutropenia case report, intermittent G-CSF successfully maintained protective neutrophil counts and cut respiratory infections:

"Administration of granulocyte colony-stimulating factor successfully maintained neutrophil counts above 0.5 × 109/L and significantly reduced the frequency of respiratory tract infections." — PMID: 41560087

Across congenital neutropenia syndromes, G-CSF responders retain residual risk of bone marrow failure, MDS, and AML (PMID: 38589208); HSCT is the only curative option for transformation or G-CSF non-response (PMID: 15640815; PMID: 15489867). Mechanistic rescue experiments identify candidate metabolic strategies:

"N-acetylcysteine, exogenous free fatty acids, or exogenous citrate protected CLPB-deficient 32Dcl3 cells from apoptosis at the onset of differentiation" — PMID: 39644357

Finding 6 — Model systems: zebrafish morphant, CLPB-KO 32Dcl3 myeloblasts, cross-species orthology

The zebrafish clpb morphant recapitulates the CNS phenotype of the recessive syndrome, with rescue specificity establishing variant pathogenicity:

"Suppression of clpb in zebrafish embryos induced a central nervous system phenotype that was consistent with cerebellar and cerebral atrophy that could be rescued by wild-type, but not mutant, human CLPB mRNA" — PMID: 25597510

The most neutropenia-relevant model is the CRISPR CLPB-knockout of the IL-3-dependent mouse 32D clone 3 (32Dcl3) myeloblastic line, which reproduces the differentiation/apoptosis defect:

"we used 32D clone 3 (32Dcl3) cells, an interleukin-3 (IL-3)-dependent mouse myeloblastic cell line model, to investigate the effects of CLPB knockout on myeloblast-to-neutrophil differentiation" — PMID: 39644357

Finding 7 — Inheritance & population genetics: AD via de novo dominant-negative missense; CLPB is LoF-tolerant

SCN9 arises through de novo monoallelic missense variants acting dominant-negatively:

"we identified one of four different de novo monoallelic missense variants in CLPB. We show that these variants disturb refoldase and to a lesser extent ATPase activity of CLPB in a dominant-negative manner" — PMID: 34140661

Critically, gnomAD constraint metrics exclude haploinsufficiency: pLI ≈ 2.4×10⁻⁵, observed/expected LoF = 40/78.4 (oe_lof 0.51, LOEUF 0.66), missense Z = 1.53 — i.e., heterozygous loss-of-function is tolerated. This confirms that disease requires a poison (dominant-negative) allele, not simple gene-dosage reduction. The biallelic form shows a Greenlandic founder cohort:

"Four of the individuals were of Greenlandic descent, and one was North American" — PMID: 25597511

Finding 8 — Diagnostics & anatomy: severe neonatal neutropenia with marrow maturation arrest; diagnosis by NGS/WES

Severe congenital neutropenia is defined hematologically by myeloid maturation arrest:

"characterized by a maturation arrest of myelopoiesis at the promyelocyte/myelocyte stage of development. This arrest results in severe neutropenia with absolute neutrophil counts (ANC) less than 0.2 x 10(9)/l associated with severe systemic bacterial infections from early infancy" — PMID: 10994541

Molecular diagnosis of CLPB-SCN relies on NGS gene panels / whole-exome or whole-genome sequencing; CLPB is now routinely included on congenital neutropenia panels (PMID: 40510848; PMID: 41383606), and reanalysis of previously negative exomes can reveal CLPB (PMID: 41560087).

Finding 9 — Downstream consequences & complications: IMS proteostasis collapse, infection susceptibility, MDS/AML risk

CLPB loss triggers stress-specific IMS protein aggregation that cripples mitochondrial quality control:

"CLPB deficiency impeding SPY complex function by virtue of protein aggregation in the intermembrane space" — PMID: 38270563

Clinically, the neutropenia drives recurrent severe bacterial infections, and like other SCN subtypes carries malignant transformation risk:

"neutropenia that can develop into leukemia" — PMID: 25597510

Finding 10 — Official HPO phenotype frequencies for SCN9

The HPO disease annotation for OMIM:619813 (source PMID 34115842, n≈10) formalizes the phenotype frequencies, with the 0/5 for 3-MGA-uria confirming the metabolic hallmark of biallelic disease is absent in SCN9.

"3-methylglutaconic aciduria was not observed and, other than neutropenia, these clinical features were uncommon in our series" — PMID: 34115842

HPO term ID Frequency in SCN9
Myeloid maturation arrest HP:0410253 10/10 (100%)
Infantile onset HP:0003593 5/10
Childhood onset HP:0011463 4/10
Congenital onset HP:0003577 1/10
Cataract HP:0000518 2/10 (20%)
Splenomegaly HP:0001744 2/10
Seizure HP:0001250 2/10
Global developmental delay HP:0001263 1/10
3-Methylglutaconic aciduria HP:0003535 0/5 (0%)
Autosomal dominant inheritance HP:0000006 —

Full Section-by-Section Report

1. Disease Information

SCN9 is a rare Mendelian disorder of granulopoiesis producing severe, persistent neutropenia from early infancy, caused by heterozygous dominant-negative variants in CLPB. Key identifiers: MONDO:0030726, OMIM:619813, UMLS:C5676954, GARD:0025625. It falls under the broader ICD-10 category D70 (neutropenia) / ICD-11 4B00.0 (congenital neutropenia); MeSH maps to "Congenital Bone Marrow Failure Syndromes" / "Neutropenia." Synonyms/alternative names: Severe congenital neutropenia type 9; autosomal dominant CLPB-related neutropenia; CLPB-associated congenital neutropenia (monoallelic form). The information is derived primarily from aggregated disease-level resources (OMIM, Orphanet, HPO) and from small published case series/cohorts (Warren 2022, Wortmann 2021, Heath 2026) rather than from EHR.

2. Etiology

Primary cause — genetic: heterozygous (monoallelic) missense variants in CLPB/SKD3 that cluster near the ATP-binding pocket and act in a dominant-negative manner (PMID: 34115842; PMID: 34140661). Many arise de novo. Genetic risk factors: the causal variant is the sole established risk factor; no susceptibility loci or modifier genes are established for the dominant form, though structural impact (NMD vs ankyrin-domain disruption) modifies severity in the broader CLPB spectrum (PMID: 41719910). Environmental risk/protective factors: none identified — this is a monogenic disorder. Gene–environment interactions: none established; infection exposure determines clinical severity of complications but does not cause the disease.

3. Phenotypes

The core phenotype is a laboratory/hematologic abnormality — severe neutropenia (ANC often <0.2–0.5×10⁹/L) with bone-marrow myeloid maturation arrest (HP:0410253, 100%) — manifesting clinically as recurrent severe bacterial infections (HP:0002718) from early infancy. Onset is congenital/infantile (HP:0003593/HP:0003577). Severity is severe; course is chronic and lifelong but stabilizable with G-CSF. Non-hematologic features (cataract HP:0000518 20%; splenomegaly HP:0001744; seizure HP:0001250) occur at low frequency; 3-MGA-uria (HP:0003535) is characteristically absent (0/5). Quality-of-life impact: chronic infection susceptibility, repeated hospitalization, need for lifelong G-CSF injections and infection prophylaxis; well-managed patients can achieve good functional status, but transformation to MDS/AML is a severe QoL and survival threat.

4. Genetic / Molecular Information

Causal gene: CLPB (SKD3), HGNC:30664, OMIM gene 616254, Entrez 81570, Ensembl ENSG00000162129, UniProt Q9H078, locus 11q13.4 (GRCh38 chr11:72,285,495–72,434,680). Pathogenic variants: heterozygous missense variants near the ATP-binding pocket (dominant SCN9); biallelic missense/frameshift/nonsense (recessive 3-MGA-uria VII). Example recessive variants: c.1016delT (p.L339Rfs5), c.1087A>G (p.R363G) (PMID: 37906145); p.Arg408Gly abolishes ATPase function (PMID: 25597510). Classification: pathogenic/likely pathogenic per ACMG. Allele frequency: ultra-rare; gnomAD shows CLPB is LoF-tolerant (oe_lof 0.51, LOEUF 0.66), excluding haploinsufficiency. Origin: germline. Functional consequence: dominant-negative (SCN9) vs loss-of-function (recessive disease). Modifier genes: none validated; structural class of the variant is the main severity modifier. Epigenetic/chromosomal abnormalities:* none described.

5. Environmental Information

Not applicable as a cause — SCN9 is monogenic. Environmental triggers of complications include bacterial and viral pathogens (recurrent sepsis, respiratory/skin/oral infections; EBV reactivation has been reported in the CLPB/VPS45 neutropenia spectrum). No toxins, lifestyle, or occupational exposures contribute to disease causation.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

  1. A heterozygous dominant-negative missense variant in CLPB (near the ATP-binding pocket) leads to a mutant CLPB subunit that is translated and imported into the mitochondrial IMS.
  2. The mutant subunit co-assembles with wild-type CLPB into mixed oligomers and inhibits the complex's ATPase and disaggregase/refoldase activity (dominant-negative poisoning) — demonstrated biochemically (PMID: 34115842).
  3. Loss of disaggregase activity results in failure to maintain solubility of IMS clients — notably HAX1 aggregation — and impairment of the proteolytic SPY complex (STOML2–PARL–YME1L1) (PMID: 42244541; PMID: 38270563).
  4. IMS proteostasis collapse leads to reduced mitochondrial membrane potential and ROS accumulation in myeloid precursors (PMID: 39644357).
  5. ROS/stress triggers apoptosis specifically at the onset of G-CSF–induced granulocytic differentiation, i.e., CLPB is a pro-survival factor at this checkpoint (PMID: 39644357).
  6. Precursor apoptosis produces myeloid maturation arrest at the promyelocyte/myelocyte stage → severe peripheral neutropenia → recurrent bacterial infections from infancy.
  7. Branch (downstream, inferred): chronic proliferative stress on the marrow contributes to clonal evolution and MDS/AML transformation risk, as in other SCN subtypes.

Molecular pathways: mitochondrial protein quality control / disaggregation; HAX1–CLPB axis; SPY proteolytic complex. Cellular processes: apoptosis (GO:0006915), response to ROS (GO:0000302), neutrophil differentiation (GO:0030223), protein refolding/disaggregation (GO:0042026). Protein dysfunction: dominant-negative impairment of an AAA+ ATPase disaggregase. Cell types: neutrophil (CL:0000775), promyelocyte (CL:0000836), granulocyte-monocyte progenitor (CL:0000557), hematopoietic stem cell (CL:0000037). Subcellular: mitochondrial intermembrane space (GO:0005758). CLPB assembles into homo-tetradecamers (apo) / homo-dodecamers (substrate-bound) with an essential N-terminal ankyrin-repeat domain (PMID: 36745679).

7. Anatomical Structures Affected

Organ level: bone marrow (UBERON:0002371) and blood (UBERON:0000178) are primary; spleen (splenomegaly in some) secondary. Body system: hematopoietic/immune. Cell level: neutrophils and their myeloid precursors (promyelocytes, GMPs, HSCs). Subcellular: mitochondria, specifically the intermembrane space (GO:0005758). Lateralization: not applicable (systemic hematologic disease). In the biallelic form, additional organs are involved — CNS (UBERON:0000955, brain atrophy), lens/eye (cataract), and ovary (premature ovarian insufficiency, PMID: 36074910).

8. Temporal Development

Onset: congenital/neonatal to infantile; neutropenia detectable from early infancy. Onset pattern: chronic from birth. Progression: generally stable neutropenia maintainable with G-CSF; risk of progression to marrow failure or MDS/AML over time. Early onset (<12 months) predicts more severe progression across the CLPB spectrum (PMID: 41719910). Course: chronic, lifelong. Remission: treatment-induced count normalization with G-CSF; no spontaneous cure. Critical period: the onset of granulocytic differentiation is the vulnerable checkpoint (where CLPB-dependent apoptosis occurs), and infancy is the window of greatest infection risk.

9. Inheritance and Population

Inheritance: autosomal dominant (SCN9, OMIM 619813), frequently de novo, dominant-negative (PMID: 34140661). Penetrance: myeloid maturation arrest appears fully penetrant (100%) in reported carriers; expressivity variable for non-hematologic features. Epidemiology: ultra-rare — dozens of families worldwide; the largest CLPB cohort assembled only 63 individuals across both zygosity forms (PMID: 41719910). Founder effects: a Greenlandic founder cohort exists for the biallelic form (PMID: 25597511); consanguinity enriches the recessive disease. Carrier frequency: not established (dominant form typically de novo). Sex ratio: both sexes affected, no strong skew. Age distribution: presents in infancy.

10. Diagnostics

Hematology: CBC showing severe neutropenia (ANC <0.2–0.5×10⁹/L); bone marrow aspirate showing promyelocyte/myelocyte maturation arrest (PMID: 10994541). Genetic testing (definitive): NGS congenital-neutropenia gene panels, WES, or WGS, now including CLPB; reanalysis of prior negative exomes is warranted (PMID: 40510848; PMID: 41383606; PMID: 41560087). Supportive discriminators: urine organic acids (3-MGA — normal in SCN9, elevated in biallelic disease; CHEBI:1890), slit-lamp exam (cataract), neuro-exam/MRI (recessive syndrome). Differential diagnosis: other SCN genes — ELANE (SCN1), GFI1 (SCN2), HAX1 (SCN3/Kostmann), G6PC3 (SCN4), VPS45 (SCN5), CSF3R (SCN7), SRP54 (SCN8), JAGN1, WAS — plus Shwachman-Diamond and cyclic neutropenia. Screening: no population newborn screening; cascade family genetic testing applies once a variant is known.

11. Outcome / Prognosis

Survival: monoallelic (SCN9) ~82% 4-year survival vs ~50% biallelic; death in 23% monoallelic vs 66% biallelic; median age at death 2.4 years (monoallelic) vs 6 months (biallelic) (PMID: 41719910). Morbidity: recurrent infections, hospitalizations; complications include sepsis, oral/periodontal and respiratory infections, hypersplenism, and MDS/AML transformation. Recovery potential: neutropenia is controllable (not curable) with G-CSF; HSCT can cure. Prognostic factors: zygosity, variant structural class (NMD/ankyrin-domain disruption > zygosity as predictor), age of onset (<12 months worse), disease burden index.

12. Treatment

Pharmacotherapy: G-CSF / filgrastim (NCIT:C1705-class) is first-line, maintaining ANC >0.5×10⁹/L and reducing infections (PMID: 41560087); pathogen-directed antibiotics (NCIT:C15847) for infections. Advanced therapeutics: allogeneic HSCT (NCIT:C15431) is the only curative option, indicated for G-CSF non-response, marrow failure, or MDS/AML (PMID: 15640815; PMID: 15489867). Experimental/metabolic: N-acetylcysteine (NCIT:C291), free fatty acids, or citrate rescued CLPB-deficient myeloblasts from apoptosis in vitro (PMID: 39644357) — candidate antioxidant/metabolic strategies not yet clinically validated. Supportive care: infection prophylaxis, prompt treatment of febrile episodes, dental/periodontal care. Pharmacogenomics / gene therapy / RNA therapy: none established.

13. Prevention

No primary prevention exists for this monogenic disease. Secondary prevention: early genetic diagnosis enabling prompt G-CSF and infection surveillance; routine monitoring for MDS/AML (serial CBC, marrow exams). Tertiary prevention: infection prophylaxis, timely HSCT before leukemic progression. Genetic counseling: autosomal dominant recurrence risk (often de novo); prenatal/preimplantation testing possible once the familial variant is known. Immunization/public health/environmental interventions: not applicable to disease causation (standard vaccination and infection control apply to the immunocompromised patient).

14. Other Species / Natural Disease

CLPB is evolutionarily conserved in the ClpB/Hsp100 AAA+ disaggregase family, with a bacterial ClpB homolog. Orthologs (NCBI Gene): mouse Clpb (GeneID 20480), rat Clpb (65041), zebrafish clpb (100331587); human CLPB Entrez 81570. No naturally occurring companion-animal or wildlife disease is documented (no OMIA entry noted). No zoonotic potential. The deep conservation of the disaggregase mechanism underpins the utility of zebrafish and rodent/cellular models.

15. Model Organisms

Zebrafish: morpholino clpb knockdown produces cerebellar/cerebral atrophy, rescued by wild-type but not mutant human CLPB mRNA — validating variant pathogenicity (PMID: 25597510). Cellular: CRISPR CLPB-knockout of IL-3-dependent mouse 32Dcl3 myeloblasts recapitulates the neutropenia-relevant defect — reduced mitochondrial membrane potential, insoluble HAX1 aggregates, ROS-driven apoptosis at G-CSF-induced differentiation (PMID: 39644357). Biochemical reconstitution: purified human CLPB + HAX1 systems (PMID: 42244541) and cryo-EM structural models (PMID: 36745679). Phenotype recapitulation: zebrafish captures the neurological (recessive) phenotype; 32Dcl3 captures the myeloid differentiation defect. Limitations: no dedicated mouse model of the dominant SCN9 phenotype is yet reported; morphant models have known off-target caveats.

Mechanistic Model / Interpretation

 Heterozygous dominant-negative CLPB missense variant (near ATP-binding pocket)
         │
         ▼
   Mutant subunit co-assembles with WT CLPB in mitochondrial IMS
         │  (dominant-negative poisoning — demonstrated)
         ▼
     ↓ CLPB ATPase & disaggregase/refoldase activity
         │
    ┌────────────┴─────────────┐
    ▼                          ▼
   HAX1 aggregation          Impaired SPY complex
   (insoluble IMS clients)   (STOML2–PARL–YME1L1)
    └────────────┬─────────────┘
         ▼
     ↓ mitochondrial membrane potential → ROS accumulation
         │
         ▼
   Apoptosis at ONSET of G-CSF-induced granulocytic differentiation
         │
         ▼
   Myeloid maturation arrest (promyelocyte/myelocyte)  ──► SEVERE NEUTROPENIA
         │                                        │
         ▼                                        ▼
 Recurrent bacterial infections (infancy)        MDS/AML risk (downstream, inferred)

Zygosity–mechanism–outcome synthesis:

Feature Monoallelic (SCN9, AD) Biallelic (3-MGA-uria VII, AR)
OMIM 619813 616271
Mechanism Dominant-negative missense Loss of function (biallelic)
Neutropenia Yes (100% maturation arrest) Yes
3-MGA-uria Absent (0/5) Characteristic
Cataracts / CNS / movement disorder Uncommon Frequent
4-year survival ~82% ~50%
Median age at death 2.4 years 6 months

The unifying insight is that CLPB sits at the heart of a mitochondrial IMS proteostasis network linking it to HAX1 (SCN3/Kostmann) — explaining why two genetically distinct congenital neutropenias converge on the same disaggregase pathway. gnomAD LoF-tolerance proves that one functional allele suffices for neutrophil production; disease in SCN9 therefore requires an actively interfering allele, and the poisoned oligomer tips neutrophil precursors into ROS-driven apoptosis at their most vulnerable differentiation checkpoint.

Evidence Base

PMID Title / Focus Role in this report
34115842 Heterozygous variants of CLPB are a cause of severe congenital neutropenia Defining paper; dominant-negative mechanism, phenotype, HPO frequencies
34140661 Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency De novo dominant-negative inheritance; refoldase>ATPase defect
41719910 From genotype to outcome: zygosity-specific insights in 63 cases Quantitative survival/outcome by zygosity
39644357 Mitochondrial CLPB is a pro-survival factor at onset of granulocytic differentiation 32Dcl3 model; ROS apoptosis; NAC/FFA/citrate rescue
42244541 HAX1 drives assembly and activation of CLPB CLPB–HAX1 axis; IMS insolubility
38270563 CLPB dysfunction impacts the proteolytic SPY complex Downstream IMS proteostasis collapse
25597510 CLPB mutations cause 3-MGA-uria, brain atrophy... Biallelic phenotype; zebrafish model; leukemia risk
25597511 CLPB variants — AR mitochondrial disorder Greenlandic founder effect
41560087 CLPB deficiency-associated congenital neutropenia: case report G-CSF efficacy; exome reanalysis
10994541 Severe congenital neutropenia: diagnosis & therapy SCN diagnostic definition
36745679 Structural characterization of human CLPB disaggregase Oligomerization; ankyrin domain
38589208 Clinicopathological features of congenital neutropenia syndromes MDS/AML risk; differential diagnosis
15640815, 15489867 HSCT in SCN Curative transplant evidence
40510848, 41383606 WES/WGS & national neutropenia screening Genetic diagnostic approach
36074910 POI in CLPB deficiency Adult/ovarian complication (biallelic)

Limitations and Knowledge Gaps

  1. Very small sample sizes. The disease rests on ~10 heterozygous cases (Warren 2022) and a combined cohort of 63 across both zygosity forms (Heath 2026). HPO frequencies (e.g., cataract 2/10) have wide confidence intervals.
  2. No dedicated dominant-model organism. Mechanistic data derive from CLPB-knockout cell lines and morphant zebrafish that model loss of function/recessive phenotypes, not the dominant-negative SCN9 state specifically.
  3. Spectrum vs dichotomy. Some monoallelic cases show neurodevelopmental features, blurring the clean "isolated neutropenia" picture; genotype–phenotype rules remain incompletely defined.
  4. No validated epidemiologic prevalence/incidence for SCN9 specifically (ultra-rare; registry data limited).
  5. Metabolic/antioxidant rescue is in vitro only — NAC, FFA, and citrate have not been tested clinically.
  6. Leukemic transformation risk is extrapolated from SCN broadly; CLPB-specific transformation rates are not quantified.

Proposed Follow-up Experiments / Actions

  1. Generate a knock-in mouse carrying a human SCN9 dominant-negative CLPB missense allele to establish an in-vivo dominant model and quantify neutrophil, survival, and MDS/AML outcomes.
  2. Prospective natural-history registry for CLPB-neutropenia to firm up prevalence, penetrance, transformation rates, and genotype–phenotype correlations (expanding the Heath 2026 cohort).
  3. Preclinical trial of antioxidant/metabolic rescue (N-acetylcysteine, citrate, free fatty acids) in CLPB-deficient primary human CD34⁺ progenitors and the knock-in mouse, moving toward a pilot clinical study.
  4. Structural/biochemical dissection of how each variant class (ATP-pocket missense vs ankyrin-domain disruption) poisons the oligomer, to build a variant-to-severity predictor usable in counseling.
  5. Longitudinal MDS/AML surveillance protocol specific to CLPB-SCN, correlating clonal markers (e.g., CSF3R/RUNX1 mutations) with transformation.
  6. Systematic HAX1–CLPB interaction mapping in patient-derived cells to test whether HAX1 stabilization can bypass the CLPB defect therapeutically.

Evidence source types represented: human clinical (cohorts/case reports), model organism (zebrafish), in vitro (32Dcl3 knockout, biochemical reconstitution, cryo-EM), and computational (gnomAD constraint, structural prediction).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 18
Resolved 18
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 18
Quoted claims found in source 18
Quoted claims not found in source 0
References weighed for topical relevance 18
On topic 13
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 33
Resolved 29
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 4
Terms whose name was checked 13
Terms named correctly 10
Terms named as a different term 1
Terms whose name is worth a second look 2

Terms the report names something else

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

  • NCIT:C15847 (1 mention) - the report calls it "antibiotics"; NCIT calls it Non-Ionizing Radiotherapy

Terms whose name is worth a second look

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

  • HP:0002718 (1 mention) - the report calls it "recurrent severe bacterial infections"; HP calls it Recurrent bacterial infections
  • NCIT:C15431 (1 mention) - the report calls it "allogeneic HSCT"; NCIT calls it Hematopoietic Cell Transplantation, and lists "HSCT" among its other names

Prefixes with no resolver

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