Familial Erythrocytosis 5

Mendelian MONDO:0033483 Pathograph 21 Show in embeddings browser Hereditary Erythrocytosis Congenital Secondary Erythrocytosis

Familial erythrocytosis 5 (ECYT5) is an autosomal dominant erythrocytosis caused by germline variants in EPO, the gene encoding erythropoietin itself. It is the form of hereditary erythrocytosis in which the lesion sits in the hormone rather than in its receptor (ECYT1, EPOR) or in the oxygen-sensing machinery that controls EPO transcription (VHL, EGLN1 and EPAS1). Two classes of EPO variant have been reported and they reach the same endpoint by different molecular routes. A single-nucleotide deletion in exon 2 (c.32delG) interrupts translation of the canonical EPO transcript but shifts the reading frame of a normally noncoding transcript initiated from an alternative promoter in intron 1, so that this second transcript starts to produce biologically active erythropoietin; a neighboring exon 2 deletion, c.19delC, behaves the same way when tested in transfected cells. Separately, noncoding variants in the EPO promoter and in intron 1 act on regulatory elements that are strongly hypoxia responsive, raising EPO transcription and yielding circulating erythropoietin with a hepatic rather than renal glycosylation pattern and with increased erythropoietin receptor signaling activity in vitro. In both routes the shared downstream path is excess or hyperactive erythropoietin acting on EPOR on erythroid progenitors, increased erythroid output and a raised red cell mass, presenting as a longstanding isolated erythrocytosis with high hematocrit and hemoglobin and, in the kindred where this was looked for, without leukocytosis, thrombocytosis or splenomegaly. Serum erythropoietin is not a reliable discriminator here: in the reported noncoding-variant families it is low to normal, or only moderately raised for the degree of erythrocytosis, so a concentration that is inappropriately normal rather than frankly elevated is what points to the diagnosis. Reported management is repeated phlebotomy; current guidance for JAK2-unmutated erythrocytosis in general is phlebotomy for symptom control with cytoreductive therapy avoided, alongside low-dose aspirin and cardiovascular risk reduction.

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1
Inheritance
9
Pathophys.
3
Phenotypes
4
Gaps
21
Pathograph
1
Genes
6
Variants
2
Medical Actions
1
Models
10
References
1
Deep Research
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Classifications

Harrison's Part
ONCOLOGY HEMATOLOGY GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal dominant HP:0000006
A single heterozygous EPO variant is sufficient. The c.32delG exon 2 deletion cosegregated with erythrocytosis in a family with a logarithm of the odds score of 3.3, and the c.-136G>A promoter variant segregated with the phenotype across a five-generation kindred, affected members being heterozygous and unaffected relatives negative.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:29514032 SUPPORT Human Clinical
"We identified a mutation in EPO that cosegregated with disease with a logarithm of the odds (LOD) score of 3.3 in a family with autosomal dominant erythrocytosis."
Linkage of an EPO variant to erythrocytosis in a family transmitting the trait as an autosomal dominant.
PMID:41574959 SUPPORT Human Clinical
"We studied nine affected and 13 non-affected relatives from a five-generation kindred with autosomal dominant familial erythrocytosis"
A second, independent EPO-variant family in which the trait is transmitted as an autosomal dominant over five generations.
PMID:41574959 SUPPORT Human Clinical
"The mutation segregated with the erythrocytosis phenotype in 15 examined family members"
Cosegregation of the heterozygous promoter variant with the phenotype in the examined relatives.
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Discussions and Knowledge Gaps

4
Which tissue produces the excess erythropoietin in carriers of noncoding EPO variants, and is the hepatic glycosylation signature evidence of hepatocyte origin or only of a non-renal one?
KNOWLEDGE GAP epo_producing_tissue_unidentified
Attached to
pathophysiology#Increased EPO Transcription from Hypoxia-Responsive Regulatory Elements pathophysiology#Hepatic-Type Erythropoietin Glycosylation
Both reported noncoding series infer the producing tissue from the charge of circulating erythropoietin rather than from the tissue itself. The glycosylation argument establishes that the hormone is not renal; reading it as hepatic is a further step, and a promoter variant could instead switch on transcription in several non-renal tissues. The two groups also disagree on which carbohydrate change the isoelectric shift reflects, which matters because sialylation and sulfation have different consequences for clearance and activity. A mouse carrying one of these alleles, or spatial transcriptomics on patient tissue, would settle it, and neither exists. The one mouse line curated here drives erythropoietin from a transgene, so it has nothing to say about which tissue a variant allele switches on.
Show evidence (1 reference)
PMID:41574959 SUPPORT Human Clinical
"the direct identification of the EPO producing tissue is currently lacking"
The authors state the gap for their own variant and, in the same passage, for the earlier noncoding series.
Are the exon 2 frameshift and the noncoding regulatory EPO variants one disease, given that one was described as producing excess erythropoietin and the other as producing a normal amount of hyperactive erythropoietin?
KNOWLEDGE GAP two_routes_one_entity
Attached to
disease#Familial Erythrocytosis 5 pathophysiology#EPO Exon 2 Frameshift Deletion pathophysiology#EPO Noncoding Regulatory Variant
The OMIM concept ECYT5 was created for the exon 2 frameshift family and the noncoding variants arrived later. They share the gene, the dominant transmission and the clinical picture, which is why they are curated together here, but the lesion differs in kind: a reading-frame rescue of an alternative transcript versus activation of a cis-regulatory element. The laboratory phenotypes differ too, with circulating hormone described as frankly increased in the one account and inside the reference interval in the other. If the two diverge on natural history or management they would be better carried as subtypes, which is the shape to revisit once more families are reported.
Show evidence (2 references)
PMID:29514032 SUPPORT Human Clinical
"initiates excess production of erythropoietin from what is normally a noncoding EPO mRNA"
The exon 2 route is described as producing excess hormone.
PMID:40305710 SUPPORT Human Clinical
"erythrocytosis that was associated with circulating EPO levels within the normal range"
The noncoding route presents with normal circulating concentrations, the contrast this gap is about.
Does an erythropoietin-driven red cell mass at the hematocrit human EPO-variant carriers actually reach cause the organ and endothelial damage the tg6 mouse develops, or is that damage a property of the degree the model exaggerates?
HUMAN MODEL MISMATCH mouse_organ_damage_at_supraphysiological_hematocrit
Attached to
animal_models#Mouse pathophysiology#Increased Red Cell Mass
This is a mismatch rather than an absence, which is why it is typed HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP. The model evidence is good and it is consistent across four studies: chronic erythropoietin-driven erythrocytosis in the tg6 mouse produces hepatic, renal, neuronal and muscular degeneration with a reduced lifespan, reduced brain vessel density with endothelial activation, and near-abolition of the endothelial glycocalyx. What is uncertain is whether any of it transfers. The model runs at a hematocrit of 0.85 to 0.89 and the reported patients sit between roughly 0.50 and 0.63, and the model's own authors attribute the damage to the degree of erythrocytosis rather than to erythropoietin itself, so the one variable that would decide the question is the one that does not match. The human side is empty rather than negative: no cohort of EPO-variant carriers has been followed for vascular or end-organ outcomes, which is also why this entry curates no thrombotic or hyperviscosity phenotype. A tg6 arm held at a patient-range hematocrit, or an outcome study in the known kindreds, would resolve it; neither has been reported.
Show evidence (3 references)
PMID:16690772 SUPPORT Model Organism
"Taken together, chronically increased Epo levels inducing excessive erythrocytosis leads to multiple organ degeneration and reduced life expectancy."
The model finding whose transfer to human ECYT5 is the open question.
PMID:16254128 SUPPORT Model Organism
"We propose that chronic excessive erythrocytosis and sustained high hematocrit cause endothelial damage, which may, ultimately, increase susceptibility to vascular disease."
The authors tie the damage to sustained high hematocrit, which is the quantity that differs between the model and patients.
PMID:21859826 SUPPORT Model Organism
"In a transgenic mouse (tg6) model exhibiting systemic Hct levels of about 0.85 the glycocalyx/ESL was nearly abolished."
A third endothelial finding, reported at the model's hematocrit of about 0.85 rather than at a patient-range value.
If the c.-136G>A promoter variant does not work by creating a bound HIF response element, which transcription factor mediates its effect?
KNOWLEDGE GAP promoter_variant_transcription_factor
Attached to
pathophysiology#Increased EPO Transcription from Hypoxia-Responsive Regulatory Elements
The variant creates a predicted hypoxia response element and behaves like one in reporter assays, where added HIF-2 alpha augments it, yet chromatin immunoprecipitation at the native locus did not detect HIF-1 or HIF-2 binding. The authors cannot exclude a technical failure in this GC-rich region, and they offer predicted KLF-family and SOX18 sites as alternatives, with only KLF9 enrichment confirmed and no evidence that KLF9 acts on erythropoiesis. The node is therefore established at the level of output and not of the factor involved.
Show evidence (1 reference)
PMID:41574959 SUPPORT In Vitro
"However, ChIP experiments failed to confirm direct HIF-2 or HIF-1 binding to the mutated EPO promoter"
The negative binding result that leaves the mediating factor open.
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Pathophysiology

9
EPO Exon 2 Frameshift Deletion
A heterozygous single-nucleotide deletion in exon 2 of EPO: c.32delG in the index family and c.19delC in a second report. The deletion frameshifts the canonical transcript, truncating the erythropoietin signal peptide and terminating translation after a novel peptide, so the canonical transcript no longer yields the hormone.
EPO hgnc:3415 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EPO (hgnc:3415). hgnc:3415 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: GAIN_OF_FUNCTION
Downstream
Translation of Erythropoietin from the Intron 1 P2 Transcript The same frameshift that destroys the canonical reading frame brings the alternative intron 1 transcript into frame with the erythropoietin coding sequence.
Show evidence (1 reference)
PMID:31350093 SUPPORT REVIEW SYNTHESIS Other
"The deletion causes a frameshift that truncates the EPO signal peptide and generates a novel peptide which is terminated after an additional 51 amino acids"
States what the exon 2 deletion does to the canonical erythropoietin reading frame.
EPO Noncoding Regulatory Variant
A heterozygous variant in the EPO main promoter (c.-252C>T, c.-136G>A) or in intron 1 (c.14-26A>G, c.14-28T>C). The protein sequence is unchanged; the variants fall in cis-regulatory elements of the gene.
EPO hgnc:3415 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EPO (hgnc:3415). hgnc:3415 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: GAIN_OF_FUNCTION
Downstream
Increased EPO Transcription from Hypoxia-Responsive Regulatory Elements
Show evidence (1 reference)
PMID:41713879 SUPPORT BACKGROUND Human Clinical
"while the amino acid sequence of the protein was not affected, although regulatory elements appeared to be impacted"
States that this variant class leaves the protein sequence intact and acts on regulatory elements.
Translation of Erythropoietin from the Intron 1 P2 Transcript
EPO carries a second promoter, P2, inside intron 1, whose transcripts are normally noncoding. With the exon 2 frameshift the downstream start codon of the P2 transcript comes into frame with the erythropoietin coding sequence and initiates translation of biologically active hormone, with a shortened signal peptide and a novel amino terminus.
translation of erythropoietin from the alternative P2 transcript GO:0042446 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased translation of erythropoietin from the alternative P2 transcript, annotated with hormone biosynthetic process (GO:0042446). GO:0042446 is a biological process from the Gene Ontology.
Downstream
Excess Bioactive Circulating Erythropoietin
Show evidence (3 references)
PMID:31350093 SUPPORT REVIEW SYNTHESIS In Vitro
"In addition to the expected transcripts derived from the canonical promoter P1 upstream of exon 1 they discovered unexpected EPO mRNA transcripts which originate from an alternative promoter (P2) in intron 1"
Establishes the alternative intron 1 promoter transcript that this node is about.
PMID:31350093 SUPPORT REVIEW SYNTHESIS In Vitro
"Cells transfected with ΔG P2 produced more EPO than those transfected with wild-type P1 cDNA and the EPO was biologically active"
Transfection shows the mutant P2 transcript produces more erythropoietin than the wild-type canonical transcript, and that it is bioactive.
PMID:31350093 SUPPORT REVIEW SYNTHESIS In Vitro
"The P2 transcripts with the ΔC mutation produced high amounts of biologically active EPO, demonstrating that the EPO ΔC causes erythrocytosis by the same mechanism as the EPO ΔG mutation"
The second exon 2 deletion acts through the same P2 route, so this node covers both alleles.
Increased EPO Transcription from Hypoxia-Responsive Regulatory Elements
The noncoding variants raise EPO transcription from cis-regulatory elements of the gene. For c.-136G>A, CRISPR-edited hepatoma cells carry more EPO mRNA and protein in normoxia with a further rise in hypoxia, and the mutant promoter drives more reporter activity. Which transcription factor mediates this is unsettled: the variant creates a predicted hypoxia response element, but chromatin immunoprecipitation at the native locus did not confirm HIF-1 or HIF-2 binding.
hepatocyte-like erythropoietin-producing cell CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte-like erythropoietin-producing cell, annotated with hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
EPO transcription from a variant cis-regulatory element GO:0045944 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased EPO transcription from a variant cis-regulatory element, annotated with positive regulation of transcription by RNA polymerase II (GO:0045944). GO:0045944 is a biological process from the Gene Ontology.
Downstream
Hepatic-Type Erythropoietin Glycosylation Carriers of these variants have circulating erythropoietin with a non-renal glycosylation pattern, read as a shift in the tissue producing the hormone. The producing tissue has not been identified directly.
Excess Bioactive Circulating Erythropoietin In the c.-136G>A family circulating erythropoietin is not frankly high but is moderately increased for the degree of erythrocytosis, so this node is reached in a quantitatively milder form than by the exon 2 route.
Show evidence (3 references)
PMID:41574959 SUPPORT In Vitro
"the mutant promoter increased transcription of EPO mRNA and its translated protein even under normoxia, with further augmentation during hypoxia"
Direct transcriptional gain of function for the promoter variant in an edited erythropoietin-producing cell line.
PMID:41574959 SUPPORT In Vitro
"Hypoxia induced a 2.7-fold increase in EPO production in mutant cells compared to wild-type Hep3B cells"
Quantifies the increase in secreted erythropoietin from the edited cells under hypoxia.
PMID:41574959 REFUTE In Vitro
"However, ChIP experiments failed to confirm direct HIF-2 or HIF-1 binding to the mutated EPO promoter"
Contradicts the simplest reading of this node, that the variant works by creating a bound HIF response element.
Hepatic-Type Erythropoietin Glycosylation
Erythropoietin from carriers of the noncoding variants runs as a more basic set of isoforms on isoelectric focusing, matching hepatic rather than renal erythropoietin. Which carbohydrate change this reflects is disputed, with reduced sialylation and reduced N-glycan sulfation both proposed. The profile is stable over years in a given patient.
Downstream
Increased Erythropoietin Receptor Signaling in Erythroid Progenitors Erythropoietin purified from patient plasma signals more strongly through its receptor than wild-type hormone, which the authors attribute to the liver-type glycosylation.
Show evidence (2 references)
PMID:41713879 SUPPORT Human Clinical
"Plasma EPO profile from all the patients showed a basic profile"
Confirms the basic isoform profile in every noncoding-variant patient examined by an independent laboratory.
PMID:41574959 SUPPORT Human Clinical
"The IEF profile of EPO c.-136 G>A shows a shift in the distribution of EPO isoforms toward the basic region, compared to endogenous EPO from non-affected family members"
The same basic shift in the promoter-variant kindred, against unaffected relatives as the internal comparison.
Excess Bioactive Circulating Erythropoietin
More biologically active erythropoietin reaching the marrow than the red cell mass warrants. The two variant classes differ in how this presents in the laboratory: the exon 2 route was described as excess production, while in the noncoding families circulating concentrations stay inside the reference interval and the excess is one of activity rather than amount. What is raised is the hormone's own action: in the noncoding families the protein sequence is unchanged, and erythropoietin purified from patient plasma signals more strongly through its receptor than wild-type hormone, which is a quantitative increase in an otherwise normal activity rather than a new one.
EPO hgnc:3415 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EPO (hgnc:3415). hgnc:3415 is a gene from the HUGO Gene Nomenclature Committee.
erythropoietin hormone activity GO:0005179 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased erythropoietin hormone activity, annotated with hormone activity (GO:0005179). GO:0005179 is a molecular function from the Gene Ontology.
Animal models
tg6 human EPO-overexpressing transgenic mouse Mouse recapitulates Constitutive, hypoxia-independent erythropoietin excess, which is the node this entry's two variant classes converge on.
Downstream
Increased Erythropoietin Receptor Signaling in Erythroid Progenitors
Show evidence (3 references)
PMID:40305710 SUPPORT In Vitro
"EPO that was purified from patient plasma and umbilical-cord blood samples showed enhanced EPO receptor signaling activity in vitro"
Grounds the molecular function on this node: hormone taken from patients acts more strongly on its receptor than wild-type hormone does.
PMID:40305710 SUPPORT Human Clinical
"We identified six families with erythrocytosis that was associated with circulating EPO levels within the normal range"
Records that in the noncoding-variant families the concentration is normal, so this node must be read as excess activity rather than excess measured hormone.
PMID:41123216 SUPPORT REVIEW SYNTHESIS Other
"EPO mutations which produce hyperactive, hepatic-like Epo were identified."
A current review of the field summarizes the EPO-variant mechanism as hyperactive hormone.
Increased Erythropoietin Receptor Signaling in Erythroid Progenitors
Erythropoietin receptor signaling in marrow erythroid progenitors is driven above its normal set point. Unlike ECYT1 the receptor itself is intact, so the excess sits on the ligand side: hormone from patients, or from cells carrying the promoter variant, produces a stronger response in erythropoietin-dependent reporter cells than wild-type hormone. No progenitor culture from an EPO-variant patient has been reported, so the cell type here is the one erythropoietin is known to act on rather than one assayed in these families.
erythroid progenitor cell CL:0000038 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythroid progenitor cell (CL:0000038). CL:0000038 is a cell type from the Cell Ontology.
erythropoietin-mediated signaling pathway GO:0038162 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased erythropoietin-mediated signaling pathway (GO:0038162). GO:0038162 is a biological process from the Gene Ontology.
Downstream
Increased Erythroid Output
Show evidence (2 references)
PMID:41713879 SUPPORT BACKGROUND In Vitro
"This specific form of EPO was associated with a higher activation of EPOR signaling in vitro and could thus be involved in the development of erythrocytosis."
States the increased receptor activation by patient erythropoietin and its proposed role in the erythrocytosis.
PMID:41574959 SUPPORT In Vitro
"the supernatant from EPO c.-136 G>A mutant clones induced a stronger proliferative response in EPO-dependent Ba/F3-EPOR cells than supernatant from wild-type cells"
Receptor-dependent proliferation assay showing stronger signaling from the mutant clones' secreted hormone.
Increased Erythroid Output
Sustained receptor signaling expands the erythron and raises erythrocyte production. No marrow or progenitor-culture study of an EPO-variant patient has been reported, so this node rests on the established physiology of erythropoietin rather than on a measurement in these families.
erythrocyte differentiation GO:0030218 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased erythrocyte differentiation (GO:0030218). GO:0030218 is a biological process from the Gene Ontology.
Downstream
Increased Red Cell Mass
Show evidence (1 reference)
PMID:41713879 SUPPORT INDIRECT BACKGROUND Other
"Its erythropoietic activity is due to the activation of antiapoptotic signaling pathways in erythroid progenitors in the bone marrow"
Supplies the physiological step from receptor signaling to erythroid output; background in this paper, not a measurement in these patients.
Increased Red Cell Mass
An expanded circulating erythrocyte compartment, the clinical endpoint of the chain, reflected in a raised hematocrit and hemoglobin. White cell and platelet counts are not raised and there is no splenomegaly, which separates the picture from polycythemia vera.
Animal models
tg6 human EPO-overexpressing transgenic mouse Mouse recapitulates Erythropoietin-driven expansion of the red cell compartment, reached through the same hormonal route as in patients.
Downstream
Polycythemia
Increased Hematocrit
Increased Circulating Hemoglobin Concentration
Show evidence (1 reference)
PMID:41574959 SUPPORT Human Clinical
"No splenomegaly, leukocytosis, thrombocytosis, arterial hypoxia, or abnormalities in oxygen affinity (p50) were observed"
Confirms that the expansion is confined to the erythroid lineage in the promoter-variant family.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Familial Erythrocytosis 5 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

3
Polycythemia Hematological HP:0001901 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polycythemia (HP:0001901). HP:0001901 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40305710 SUPPORT Human Clinical
"We identified six families with erythrocytosis that was associated with circulating EPO levels within the normal range"
Erythrocytosis is the phenotype that defined the six noncoding-variant families.
PMID:41574959 SUPPORT Human Clinical
"The mutation segregated with the erythrocytosis phenotype in 15 examined family members"
Erythrocytosis tracks with the variant across the examined relatives.
Increased Hematocrit Hematological HP:0001899 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased hematocrit (HP:0001899). HP:0001899 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41574959 SUPPORT Human Clinical
"males had a mean HCT of 55.7% (normal range: 42%-51%)"
Mean hematocrit above the reference interval in affected men of the promoter-variant kindred.
PMID:41713879 SUPPORT Human Clinical
"high hematological values (males: hematocrit (%) 55.8-63.0; hemoglobin (HGB) (g/dL): 18.2-20.8; females: hematocrit (%) 54.0-55.0, HGB (g/dL) 17.7-18.1)"
Source for the reported hematocrit range in noncoding-variant patients.
Increased Circulating Hemoglobin Concentration Hematological HP:0001900 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating hemoglobin concentration (HP:0001900). HP:0001900 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41713879 SUPPORT Human Clinical
"hemoglobin (HGB) (g/dL): 18.2-20.8; females: hematocrit (%) 54.0-55.0, HGB (g/dL) 17.7-18.1"
Reported hemoglobin concentrations in the noncoding-variant patients.
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Genetic Associations

1
EPO variants
Gene: EPO hgnc:3415 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EPO (hgnc:3415). hgnc:3415 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (5 references)
PMID:29514032 SUPPORT Human Clinical
"This mutation, a single-nucleotide deletion (c.32delG), introduces a frameshift in exon 2 that interrupts translation of the main EPO messenger RNA (mRNA) transcript but initiates excess production of erythropoietin from what is normally a noncoding EPO mRNA transcribed from an alternative..."
Identifies the causal exon 2 deletion and states its consequence for erythropoietin production.
PMID:31350093 SUPPORT REVIEW SYNTHESIS Other
"Familial erythrocytosis caused by mutations in the EPO gene has now been designated as ECYT5 in the MIM classification"
Establishes that EPO-gene familial erythrocytosis is the concept labeled ECYT5, which is the identity of this entry.
PMID:31350093 SUPPORT REVIEW SYNTHESIS Human Clinical
"a father and daughter with a single C nucleotide deletion (ΔC) of unknown significance located in EPO exon 2"
Source for the second exon 2 deletion, c.19delC, and for its report in two relatives.
+ 2 more references
Variants (6)
c.32delG
The sentinel allele. A single G deletion in exon 2 that truncates the erythropoietin signal peptide and frameshifts the normally noncoding intron 1 transcript into the erythropoietin coding frame.
c.19delC
A single C deletion in exon 2, 13 nucleotides upstream of c.32delG, reported in a father and daughter and originally of unknown significance. Transfected constructs carrying it produced high amounts of biologically active erythropoietin, the same mechanism as c.32delG.
c.-136G>A
A 5-prime untranslated region promoter variant that increases EPO transcription and secretion in CRISPR-edited Hep3B cells and is associated with a non-renal circulating erythropoietin glycosylation profile in carriers.
c.-252C>T
A variant in the main EPO promoter, one of three noncoding variants found in families with erythrocytosis and normal-range circulating erythropoietin.
c.14-26A>G
An intron 1 variant from the same series of noncoding EPO variants.
c.14-28T>C
A second intron 1 variant from the same series of noncoding EPO variants.
💊

Medical Actions

2
Therapeutic phlebotomy
Action: phlebotomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is phlebotomy (NCIT:C28221). NCIT:C28221 is a clinical intervention from the NCI Thesaurus. Ontology label: Phlebotomy NCIT:C28221
Platform: Other
Repeated phlebotomy is what the reported EPO-variant patients received, at intervals of a few months. It lowers the red cell mass and so relieves hyperviscosity symptoms without touching the cause. No trial has been run in this disease; the practice follows general guidance for JAK2-unmutated erythrocytosis, which also advises against cytoreductive therapy.
Mechanism Target:
INHIBITS Increased Red Cell Mass — Phlebotomy removes circulating erythrocytes, so it acts only on the last node of the chain and leaves the erythropoietin drive intact.
Show evidence (2 references)
PMID:41713879 SUPPORT Human Clinical
"They were treated by repeated phlebotomies every couple of months."
Records the treatment actually given to patients carrying noncoding EPO variants.
PMID:41123216 SUPPORT REVIEW SYNTHESIS Other
"Cytoreductive therapy should be avoided. Phlebotomy should be considered for symptom control."
Current guidance for JAK2-unmutated erythrocytosis, the class this disease falls in.
Low-dose aspirin and cardiovascular risk reduction
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: aspirin CHEBI:15365 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses aspirin, annotated with acetylsalicylic acid (CHEBI:15365). CHEBI:15365 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Low-dose aspirin with cardiovascular risk-factor optimization is advised for JAK2-unmutated erythrocytosis in general. There is no ECYT5-specific evidence, and the thrombotic risk of EPO-variant erythrocytosis has not been quantified in a cohort, so this row records inherited guidance rather than a result in this disease.
Show evidence (1 reference)
PMID:41123216 SUPPORT REVIEW SYNTHESIS Other
"Cardiovascular risk optimization and low-dose aspirin are advised, while the role of HIF2A inhibitors remains unclear."
The source of the recommendation, stated for JAK2-unmutated erythrocytosis as a class rather than for EPO variants specifically.
🔬

Diagnosis

3
Serum erythropoietin measurement
Erythropoietin is measured in every erythrocytosis workup, but in ECYT5 it does not behave as it does in the other secondary erythrocytoses. In the noncoding-variant families it is low to normal, and in the promoter-variant kindred it is only moderately raised for the hematocrit while staying inside the reference interval. A concentration that is not suppressed, in a patient whose red cell mass should have suppressed it, is the finding that argues against ECYT1 and for a drive on the hormone side.
serum erythropoietin measurement NCIT:C74855 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:41713879 SUPPORT Human Clinical
"EPO concentration in blood were in the low to normal range"
Records the measured erythropoietin range in noncoding-variant patients, which is what makes this test a weak discriminator here.
PMID:41123216 SUPPORT REVIEW SYNTHESIS Other
"Serum erythropoietin (Epo) levels are variably informative."
Current guidance states the limited discriminating value of the measurement in JAK2-unmutated erythrocytosis.
Erythropoietin isoelectric focusing profile
Isoelectric focusing of plasma or urine erythropoietin separates charge isoforms. In EPO noncoding-variant carriers the profile shifts to the basic region, matching non-renal hormone, and it is stable over years. This is a research assay borrowed from antidoping laboratories rather than a routine diagnostic test, and those laboratories have shown the pattern does not meet current criteria for recombinant erythropoietin, so it should not be read as doping.
erythropoietin isoelectric focusing profile NCIT:C74855 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:41713879 SUPPORT Human Clinical
"The specific basic profiles from patients were stable over time, remaining unchanged over several years"
Establishes the reproducibility of the profile, which is what would make it usable as a marker.
PMID:41713879 SUPPORT Human Clinical
"It is highly unlikely that these EPO mutations, only identified in erythrocytosis patients yet, could lead to an adverse analytical finding."
Supports the caveat that the basic profile is not an antidoping finding.
EPO sequencing including noncoding regions
Four of the six reported alleles lie outside the coding sequence, so an exome or panel restricted to coding exons can miss the diagnosis. Sequencing of the EPO promoter and intron 1 is what established both reported noncoding series.
germline EPO sequencing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:41574959 SUPPORT Human Clinical
"underscores the diagnostic value of sequencing EPO regulatory regions in patients with JAK2-negative erythrocytosis with normal or moderately elevated EPO levels"
States the diagnostic case for sequencing the regulatory regions of EPO.
PMID:41123216 SUPPORT REVIEW SYNTHESIS Other
"In cases with negative workup but high clinical suspicion, an expanded next generation sequencing panel for hereditary erythrocytosis is recommended."
Supports extending sequencing when the standard workup is negative, which is the situation EPO noncoding variants create.
🐁

Animal Models

1
tg6 human EPO-overexpressing transgenic mouse
The tg6 line carries a human EPO transgene expressed independently of oxygen tension, so erythropoietin drive is permanently uncoupled from the hypoxia signal that normally gates it. That is the same uncoupling the EPO variants produce in patients, which is why the model is informative here; the model reaches it by a transgene rather than by an EPO allele, and at a far higher hematocrit than patients carry. Beyond the red cell mass the model also develops hepatic, renal, neuronal and muscular degeneration, a reduced lifespan, endothelial activation with reduced brain vessel density, and near-loss of the endothelial glycocalyx. None of those is a reported feature of human ECYT5 and none is curated as a phenotype of this disease; see the HUMAN_MODEL_MISMATCH discussion.
Species
Mouse
Genotype
Transgenic for human EPO under a constitutive, hypoxia-independent promoter (line tg6)
Publication
PMID:16690772
Pathograph links
Excess Bioactive Circulating Erythropoietin recapitulates fidelity: moderate observes: organism Constitutive, hypoxia-independent erythropoietin excess, which is the node this entry's two variant classes converge on.
Limitations: The excess is produced by a human EPO transgene rather than by a regulatory or coding EPO variant, and plasma erythropoietin is raised roughly twelve-fold, far beyond the normal-range or modestly raised concentrations reported in patients.
Divergences from the human mechanism
cause unrepresented qualifying
The disease lesion is absent. Erythropoietin excess is imposed by a transgene, so nothing in the model corresponds to the exon 2 frameshift or to the promoter and intron 1 variants, and the model can say nothing about how either lesion produces the excess.
other qualifying
The degree is supraphysiological. Plasma erythropoietin is about twelve-fold elevated and hematocrit reaches 0.85 to 0.89, where reported patients sit between roughly 0.50 and 0.63, so the model exaggerates whatever is dose-dependent. The taxonomy has no value for a supraphysiological level of an otherwise correctly modelled quantity.
species mismatch qualifying
Murine erythropoiesis and vasculature, carrying a human EPO transgene.
Readouts
Plasma erythropoietin concentration
Direction: INCREASED
Interpretation: Confirms that the model reproduces circulating hormone excess.
Show evidence (1 reference)
PMID:18256329 SUPPORT Model Organism
"pregnant human erythropoietin-overexpressing (plasma levels elevated 12-fold) mice (termed tg6 mice) suffering from excessive erythrocytosis generally abort at midgestation unless their hematocrit of 0.85 is drastically lowered"
States the measured degree of plasma erythropoietin elevation in the line.
Show evidence (1 reference)
PMID:16690772 SUPPORT Model Organism
"transgenic mouse line (tg6) that constitutively overexpresses erythropoietin (Epo) in a hypoxia-independent manner, thereby reaching hematocrit levels of up to 0.89"
Establishes the model as hypoxia-independent erythropoietin excess, which is what makes it informative for this node.
Increased Red Cell Mass recapitulates fidelity: moderate observes: organism Erythropoietin-driven expansion of the red cell compartment, reached through the same hormonal route as in patients.
Limitations: Hematocrit reaches 0.85 to 0.89, above the range reported in EPO-variant patients, so the model's downstream organ and vascular findings cannot be read as the expected course of human ECYT5.
Divergences from the human mechanism
other invalidating
The red cell mass is far above the patient range, which is the variable the model's own authors tie the organ damage to. Any claim about consequences carried from this model to patients is therefore invalid at this degree, although the existence of the expansion itself is faithful.
Readouts
Hematocrit
Direction: INCREASED
Interpretation: The direct measure of the node, and the variable the model's organ pathology tracks with.
Show evidence (1 reference)
PMID:16690772 SUPPORT Model Organism
"thereby reaching hematocrit levels of up to 0.89"
The measured hematocrit in the line.
Show evidence (1 reference)
PMID:16690772 SUPPORT Model Organism
"Taken together, chronically increased Epo levels inducing excessive erythrocytosis leads to multiple organ degeneration and reduced life expectancy."
The authors' own summary, which attributes the outcome to erythropoietin driven excessive erythrocytosis.
The line was built to study excessive erythrocytosis generically, and its own authors frame it as a model for polycythemia vera, chronic mountain sickness and erythropoietin doping rather than for a hereditary EPO variant. It is cited here for the hormone-excess and red-cell-mass nodes only. No knock-in mouse carrying a patient EPO allele has been reported.
{ }

Source YAML

click to show 
name: Familial Erythrocytosis 5
creation_date: "2026-10-15T17:00:00Z"
category: Mendelian
categories:
- Disorder of Erythropoietin Production
parents:
- Hereditary Erythrocytosis
- Congenital Secondary Erythrocytosis
synonyms:
- ECYT5
- EPO familial polycythemia
- erythrocytosis, familial, 5
- familial erythrocytosis type 5
- familial polycythemia caused by mutation in EPO
- EPO-related erythrocytosis
description: >-
  Familial erythrocytosis 5 (ECYT5) is an autosomal dominant erythrocytosis
  caused by germline variants in EPO, the gene encoding erythropoietin itself.
  It is the form of hereditary erythrocytosis in which the lesion sits in the
  hormone rather than in its receptor (ECYT1, EPOR) or in the oxygen-sensing
  machinery that controls EPO transcription (VHL, EGLN1 and EPAS1). Two classes
  of EPO variant have been reported and they reach the same endpoint by
  different molecular routes. A single-nucleotide deletion in exon 2 (c.32delG)
  interrupts translation of the canonical EPO transcript but shifts the reading
  frame of a normally noncoding transcript initiated from an alternative
  promoter in intron 1, so that this second transcript starts to produce
  biologically active erythropoietin; a neighboring exon 2 deletion, c.19delC,
  behaves the same way when tested in transfected cells. Separately, noncoding
  variants in the EPO promoter and in intron 1 act on regulatory elements that
  are strongly hypoxia responsive, raising EPO transcription and yielding
  circulating erythropoietin with a hepatic rather than renal glycosylation
  pattern and with increased erythropoietin receptor signaling activity in
  vitro. In both routes the shared downstream path is excess or hyperactive
  erythropoietin acting on EPOR on erythroid progenitors, increased erythroid
  output and a raised red cell mass, presenting as a longstanding isolated
  erythrocytosis with high hematocrit and hemoglobin and, in the kindred where
  this was looked for, without leukocytosis, thrombocytosis or splenomegaly.
  Serum erythropoietin is not a reliable
  discriminator here: in the reported noncoding-variant families it is low to
  normal, or only moderately raised for the degree of erythrocytosis, so a
  concentration that is inappropriately normal rather than frankly elevated is
  what points to the diagnosis. Reported management is repeated phlebotomy;
  current guidance for JAK2-unmutated erythrocytosis in general is phlebotomy
  for symptom control with cytoreductive therapy avoided, alongside low-dose
  aspirin and cardiovascular risk reduction.
disease_term:
  preferred_term: erythrocytosis, familial, 5
  term:
    id: MONDO:0033483
    label: erythrocytosis, familial, 5
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    A single heterozygous EPO variant is sufficient. The c.32delG exon 2
    deletion cosegregated with erythrocytosis in a family with a logarithm of
    the odds score of 3.3, and the c.-136G>A promoter variant segregated with
    the phenotype across a five-generation kindred, affected members being
    heterozygous and unaffected relatives negative.
  evidence:
  - reference: PMID:29514032
    reference_title: A Gain-of-Function Mutation in EPO in Familial Erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a mutation in EPO that cosegregated with disease with a logarithm of the odds (LOD) score of 3.3 in a family with autosomal dominant erythrocytosis."
    explanation: >-
      Linkage of an EPO variant to erythrocytosis in a family transmitting the
      trait as an autosomal dominant.
  - reference: PMID:41574959
    reference_title: Autosomal Dominant Erythrocytosis Caused by Non-Renal Erythropoietin (EPO) Due to EPO c.-136 G>A Germline Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We studied nine affected and 13 non-affected relatives from a five-generation kindred with autosomal dominant familial erythrocytosis"
    explanation: >-
      A second, independent EPO-variant family in which the trait is transmitted
      as an autosomal dominant over five generations.
  - reference: PMID:41574959
    reference_title: Autosomal Dominant Erythrocytosis Caused by Non-Renal Erythropoietin (EPO) Due to EPO c.-136 G>A Germline Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation segregated with the erythrocytosis phenotype in 15 examined family members"
    explanation: >-
      Cosegregation of the heterozygous promoter variant with the phenotype in
      the examined relatives.
genetic:
- name: EPO variants
  gene_term:
    preferred_term: EPO
    term:
      id: hgnc:3415
      label: EPO
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Heterozygous germline variants in EPO. Two kinds have been reported: single
    nucleotide deletions in exon 2, which act by bringing a normally noncoding
    intron 1 transcript into the erythropoietin reading frame, and noncoding
    variants in the main promoter and in intron 1, which increase transcription
    from hypoxia-responsive regulatory elements. Both act as gain of function
    with respect to erythropoietin output or activity, and in both the lesion
    is extrinsic to the erythroid progenitor.
  notes: >-
    The OMIM designation ECYT5 was created for the exon 2 frameshift family. The
    noncoding promoter and intron 1 variants were reported later and are curated
    here under the same concept because the gene, the mode of transmission and
    the clinical picture are the same; no nosology has formally placed them. See
    the discussion on whether the two routes are one disease entity.
  variants:
  - name: c.32delG
    description: >-
      The sentinel allele. A single G deletion in exon 2 that truncates the
      erythropoietin signal peptide and frameshifts the normally noncoding
      intron 1 transcript into the erythropoietin coding frame.
  - name: c.19delC
    description: >-
      A single C deletion in exon 2, 13 nucleotides upstream of c.32delG,
      reported in a father and daughter and originally of unknown significance.
      Transfected constructs carrying it produced high amounts of biologically
      active erythropoietin, the same mechanism as c.32delG.
  - name: c.-136G>A
    description: >-
      A 5-prime untranslated region promoter variant that increases EPO
      transcription and secretion in CRISPR-edited Hep3B cells and is associated
      with a non-renal circulating erythropoietin glycosylation profile in
      carriers.
  - name: c.-252C>T
    description: >-
      A variant in the main EPO promoter, one of three noncoding variants found
      in families with erythrocytosis and normal-range circulating
      erythropoietin.
  - name: c.14-26A>G
    description: >-
      An intron 1 variant from the same series of noncoding EPO variants.
  - name: c.14-28T>C
    description: >-
      A second intron 1 variant from the same series of noncoding EPO variants.
  evidence:
  - reference: PMID:29514032
    reference_title: A Gain-of-Function Mutation in EPO in Familial Erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mutation, a single-nucleotide deletion (c.32delG), introduces a frameshift in exon 2 that interrupts translation of the main EPO messenger RNA (mRNA) transcript but initiates excess production of erythropoietin from what is normally a noncoding EPO mRNA transcribed from an alternative promoter located in intron 1."
    explanation: >-
      Identifies the causal exon 2 deletion and states its consequence for
      erythropoietin production.
  - reference: PMID:31350093
    reference_title: "Update on mutations in the HIF: EPO pathway and their role in erythrocytosis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Familial erythrocytosis caused by mutations in the EPO gene has now been designated as ECYT5 in the MIM classification"
    explanation: >-
      Establishes that EPO-gene familial erythrocytosis is the concept labeled
      ECYT5, which is the identity of this entry.
  - reference: PMID:31350093
    reference_title: "Update on mutations in the HIF: EPO pathway and their role in erythrocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "a father and daughter with a single C nucleotide deletion (ΔC) of unknown significance located in EPO exon 2"
    explanation: >-
      Source for the second exon 2 deletion, c.19delC, and for its report in two
      relatives.
  - reference: PMID:40305710
    reference_title: Identification of Hepatic-like EPO as a Cause of Polycythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three novel variants were identified in the noncoding regions of EPO."
    explanation: >-
      Source for the noncoding class of EPO variants, found across six
      erythrocytosis families.
  - reference: PMID:41713879
    reference_title: Detection of a Distinct Erythropoietin (EPO) Profile After Isoelectric Focusing in Patients With Familial Erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The only mutations detected were in noncoding parts of the EPO gene"
    explanation: >-
      Names the variant class carried by the patients whose erythropoietin was
      profiled, quoted from this paper's account of the earlier genetic report.
pathophysiology:
- name: EPO Exon 2 Frameshift Deletion
  biological_scale: MOLECULAR
  description: >-
    A heterozygous single-nucleotide deletion in exon 2 of EPO: c.32delG in the
    index family and c.19delC in a second report. The deletion frameshifts the
    canonical transcript, truncating the erythropoietin signal peptide and
    terminating translation after a novel peptide, so the canonical transcript
    no longer yields the hormone.
  genes:
  - preferred_term: EPO
    term:
      id: hgnc:3415
      label: EPO
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: GAIN_OF_FUNCTION
  evidence:
  - reference: PMID:31350093
    reference_title: "Update on mutations in the HIF: EPO pathway and their role in erythrocytosis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The deletion causes a frameshift that truncates the EPO signal peptide and generates a novel peptide which is terminated after an additional 51 amino acids"
    explanation: >-
      States what the exon 2 deletion does to the canonical erythropoietin
      reading frame.
  downstream:
  - target: Translation of Erythropoietin from the Intron 1 P2 Transcript
    causal_link_type: DIRECT
    description: >-
      The same frameshift that destroys the canonical reading frame brings the
      alternative intron 1 transcript into frame with the erythropoietin coding
      sequence.
    evidence:
    - reference: PMID:29514032
      reference_title: A Gain-of-Function Mutation in EPO in Familial Erythrocytosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "introduces a frameshift in exon 2 that interrupts translation of the main EPO messenger RNA (mRNA) transcript but initiates excess production of erythropoietin from what is normally a noncoding EPO mRNA transcribed from an alternative promoter located in intron 1"
      explanation: >-
        The discovery report attributes the switch to the intron 1 transcript
        directly to the exon 2 frameshift.
- name: EPO Noncoding Regulatory Variant
  biological_scale: MOLECULAR
  description: >-
    A heterozygous variant in the EPO main promoter (c.-252C>T, c.-136G>A) or in
    intron 1 (c.14-26A>G, c.14-28T>C). The protein sequence is unchanged; the
    variants fall in cis-regulatory elements of the gene.
  genes:
  - preferred_term: EPO
    term:
      id: hgnc:3415
      label: EPO
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: GAIN_OF_FUNCTION
  evidence:
  - reference: PMID:41713879
    reference_title: Detection of a Distinct Erythropoietin (EPO) Profile After Isoelectric Focusing in Patients With Familial Erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "while the amino acid sequence of the protein was not affected, although regulatory elements appeared to be impacted"
    explanation: >-
      States that this variant class leaves the protein sequence intact and acts
      on regulatory elements.
  downstream:
  - target: Increased EPO Transcription from Hypoxia-Responsive Regulatory Elements
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40305710
      reference_title: Identification of Hepatic-like EPO as a Cause of Polycythemia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Experiments with reporter assays and iPSC-derived hepatocyte-like cells showed that the variants targeted previously uncharacterized regulatory elements of the gene, which, when the variants were present, showed high responsiveness to hypoxia."
      explanation: >-
        Reporter assays and patient-derived hepatocyte-like cells tie the
        noncoding variants to activation of hypoxia-responsive regulatory
        elements.
- name: Translation of Erythropoietin from the Intron 1 P2 Transcript
  biological_scale: MOLECULAR
  description: >-
    EPO carries a second promoter, P2, inside intron 1, whose transcripts are
    normally noncoding. With the exon 2 frameshift the downstream start codon of
    the P2 transcript comes into frame with the erythropoietin coding sequence
    and initiates translation of biologically active hormone, with a shortened
    signal peptide and a novel amino terminus.
  biological_processes:
  - preferred_term: translation of erythropoietin from the alternative P2 transcript
    modifier: INCREASED
    term:
      id: GO:0042446
      label: hormone biosynthetic process
  evidence:
  - reference: PMID:31350093
    reference_title: "Update on mutations in the HIF: EPO pathway and their role in erythrocytosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "In addition to the expected transcripts derived from the canonical promoter P1 upstream of exon 1 they discovered unexpected EPO mRNA transcripts which originate from an alternative promoter (P2) in intron 1"
    explanation: >-
      Establishes the alternative intron 1 promoter transcript that this node is
      about.
  - reference: PMID:31350093
    reference_title: "Update on mutations in the HIF: EPO pathway and their role in erythrocytosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "Cells transfected with ΔG P2 produced more EPO than those transfected with wild-type P1 cDNA and the EPO was biologically active"
    explanation: >-
      Transfection shows the mutant P2 transcript produces more erythropoietin
      than the wild-type canonical transcript, and that it is bioactive.
  - reference: PMID:31350093
    reference_title: "Update on mutations in the HIF: EPO pathway and their role in erythrocytosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "The P2 transcripts with the ΔC mutation produced high amounts of biologically active EPO, demonstrating that the EPO ΔC causes erythrocytosis by the same mechanism as the EPO ΔG mutation"
    explanation: >-
      The second exon 2 deletion acts through the same P2 route, so this node
      covers both alleles.
  downstream:
  - target: Excess Bioactive Circulating Erythropoietin
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29514032
      reference_title: A Gain-of-Function Mutation in EPO in Familial Erythrocytosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "initiates excess production of erythropoietin from what is normally a noncoding EPO mRNA"
      explanation: >-
        The discovery report states that the alternative transcript is what
        produces the excess hormone.
- name: Increased EPO Transcription from Hypoxia-Responsive Regulatory Elements
  biological_scale: MOLECULAR
  description: >-
    The noncoding variants raise EPO transcription from cis-regulatory elements
    of the gene. For c.-136G>A, CRISPR-edited hepatoma cells carry more EPO mRNA
    and protein in normoxia with a further rise in hypoxia, and the mutant
    promoter drives more reporter activity. Which transcription factor mediates
    this is unsettled: the variant creates a predicted hypoxia response element,
    but chromatin immunoprecipitation at the native locus did not confirm HIF-1
    or HIF-2 binding.
  biological_processes:
  - preferred_term: EPO transcription from a variant cis-regulatory element
    modifier: INCREASED
    term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
  cell_types:
  - preferred_term: hepatocyte-like erythropoietin-producing cell
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:41574959
    reference_title: Autosomal Dominant Erythrocytosis Caused by Non-Renal Erythropoietin (EPO) Due to EPO c.-136 G>A Germline Mutation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the mutant promoter increased transcription of EPO mRNA and its translated protein even under normoxia, with further augmentation during hypoxia"
    explanation: >-
      Direct transcriptional gain of function for the promoter variant in an
      edited erythropoietin-producing cell line.
  - reference: PMID:41574959
    reference_title: Autosomal Dominant Erythrocytosis Caused by Non-Renal Erythropoietin (EPO) Due to EPO c.-136 G>A Germline Mutation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Hypoxia induced a 2.7-fold increase in EPO production in mutant cells compared to wild-type Hep3B cells"
    explanation: >-
      Quantifies the increase in secreted erythropoietin from the edited cells
      under hypoxia.
  - reference: PMID:41574959
    reference_title: Autosomal Dominant Erythrocytosis Caused by Non-Renal Erythropoietin (EPO) Due to EPO c.-136 G>A Germline Mutation.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "However, ChIP experiments failed to confirm direct HIF-2 or HIF-1 binding to the mutated EPO promoter"
    explanation: >-
      Contradicts the simplest reading of this node, that the variant works by
      creating a bound HIF response element.
  downstream:
  - target: Hepatic-Type Erythropoietin Glycosylation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Carriers of these variants have circulating erythropoietin with a
      non-renal glycosylation pattern, read as a shift in the tissue producing
      the hormone. The producing tissue has not been identified directly.
    evidence:
    - reference: PMID:40305710
      reference_title: Identification of Hepatic-like EPO as a Cause of Polycythemia.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "EPO samples from all the patients showed a modified isoelectric-focusing profile, identical to hepatic EPO that is expressed in premature neonates and in patients with acquired erythrocytosis associated with liver diseases."
      explanation: >-
        The hormone circulating in variant carriers carries the hepatic rather
        than the renal glycosylation signature.
  - target: Excess Bioactive Circulating Erythropoietin
    causal_link_type: DIRECT
    description: >-
      In the c.-136G>A family circulating erythropoietin is not frankly high but
      is moderately increased for the degree of erythrocytosis, so this node is
      reached in a quantitatively milder form than by the exon 2 route.
    evidence:
    - reference: PMID:41574959
      reference_title: Autosomal Dominant Erythrocytosis Caused by Non-Renal Erythropoietin (EPO) Due to EPO c.-136 G>A Germline Mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "these patients demonstrated moderately increased EPO levels for their elevated HCT but remaining within the normal range"
      explanation: >-
        Erythropoietin is inappropriately normal rather than suppressed, which is
        what a continuing drive from the variant allele predicts.
- name: Hepatic-Type Erythropoietin Glycosylation
  biological_scale: MOLECULAR
  description: >-
    Erythropoietin from carriers of the noncoding variants runs as a more basic
    set of isoforms on isoelectric focusing, matching hepatic rather than renal
    erythropoietin. Which carbohydrate change this reflects is disputed, with
    reduced sialylation and reduced N-glycan sulfation both proposed. The
    profile is stable over years in a given patient.
  evidence:
  - reference: PMID:41713879
    reference_title: Detection of a Distinct Erythropoietin (EPO) Profile After Isoelectric Focusing in Patients With Familial Erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma EPO profile from all the patients showed a basic profile"
    explanation: >-
      Confirms the basic isoform profile in every noncoding-variant patient
      examined by an independent laboratory.
  - reference: PMID:41574959
    reference_title: Autosomal Dominant Erythrocytosis Caused by Non-Renal Erythropoietin (EPO) Due to EPO c.-136 G>A Germline Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The IEF profile of EPO c.-136 G>A shows a shift in the distribution of EPO isoforms toward the basic region, compared to endogenous EPO from non-affected family members"
    explanation: >-
      The same basic shift in the promoter-variant kindred, against unaffected
      relatives as the internal comparison.
  downstream:
  - target: Increased Erythropoietin Receptor Signaling in Erythroid Progenitors
    causal_link_type: DIRECT
    description: >-
      Erythropoietin purified from patient plasma signals more strongly through
      its receptor than wild-type hormone, which the authors attribute to the
      liver-type glycosylation.
    evidence:
    - reference: PMID:40305710
      reference_title: Identification of Hepatic-like EPO as a Cause of Polycythemia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "EPO that was purified from patient plasma and umbilical-cord blood samples showed enhanced EPO receptor signaling activity in vitro, which suggests a potential gain of function linked to the liver-type glycosylation of EPO."
      explanation: >-
        Links the altered glycosylation to stronger receptor signaling, the step
        this edge asserts.
- name: Excess Bioactive Circulating Erythropoietin
  biological_scale: ORGANISM
  description: >-
    More biologically active erythropoietin reaching the marrow than the red
    cell mass warrants. The two variant classes differ in how this presents in
    the laboratory: the exon 2 route was described as excess production, while
    in the noncoding families circulating concentrations stay inside the
    reference interval and the excess is one of activity rather than amount.
    What is raised is the hormone's own action: in the noncoding families the
    protein sequence is unchanged, and erythropoietin purified from patient
    plasma signals more strongly through its receptor than wild-type hormone,
    which is a quantitative increase in an otherwise normal activity rather
    than a new one.
  genes:
  - preferred_term: EPO
    term:
      id: hgnc:3415
      label: EPO
  molecular_functions:
  - preferred_term: erythropoietin hormone activity
    modifier: INCREASED
    term:
      id: GO:0005179
      label: hormone activity
  evidence:
  - reference: PMID:40305710
    reference_title: Identification of Hepatic-like EPO as a Cause of Polycythemia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "EPO that was purified from patient plasma and umbilical-cord blood samples showed enhanced EPO receptor signaling activity in vitro"
    explanation: >-
      Grounds the molecular function on this node: hormone taken from patients
      acts more strongly on its receptor than wild-type hormone does.
  - reference: PMID:40305710
    reference_title: Identification of Hepatic-like EPO as a Cause of Polycythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified six families with erythrocytosis that was associated with circulating EPO levels within the normal range"
    explanation: >-
      Records that in the noncoding-variant families the concentration is normal,
      so this node must be read as excess activity rather than excess measured
      hormone.
  - reference: PMID:41123216
    reference_title: "JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "EPO mutations which produce hyperactive, hepatic-like Epo were identified."
    explanation: >-
      A current review of the field summarizes the EPO-variant mechanism as
      hyperactive hormone.
  downstream:
  - target: Increased Erythropoietin Receptor Signaling in Erythroid Progenitors
    causal_link_type: DIRECT
- name: Increased Erythropoietin Receptor Signaling in Erythroid Progenitors
  biological_scale: CELLULAR
  description: >-
    Erythropoietin receptor signaling in marrow erythroid progenitors is driven
    above its normal set point. Unlike ECYT1 the receptor itself is intact, so
    the excess sits on the ligand side: hormone from patients, or from cells
    carrying the promoter variant, produces a stronger response in
    erythropoietin-dependent reporter cells than wild-type hormone. No
    progenitor culture from an EPO-variant patient has been reported, so the
    cell type here is the one erythropoietin is known to act on rather than one
    assayed in these families.
  cell_types:
  - preferred_term: erythroid progenitor cell
    term:
      id: CL:0000038
      label: erythroid progenitor cell
  biological_processes:
  - preferred_term: erythropoietin-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0038162
      label: erythropoietin-mediated signaling pathway
  evidence:
  - reference: PMID:41713879
    reference_title: Detection of a Distinct Erythropoietin (EPO) Profile After Isoelectric Focusing in Patients With Familial Erythrocytosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "This specific form of EPO was associated with a higher activation of EPOR signaling in vitro and could thus be involved in the development of erythrocytosis."
    explanation: >-
      States the increased receptor activation by patient erythropoietin and its
      proposed role in the erythrocytosis.
  - reference: PMID:41574959
    reference_title: Autosomal Dominant Erythrocytosis Caused by Non-Renal Erythropoietin (EPO) Due to EPO c.-136 G>A Germline Mutation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the supernatant from EPO c.-136 G>A mutant clones induced a stronger proliferative response in EPO-dependent Ba/F3-EPOR cells than supernatant from wild-type cells"
    explanation: >-
      Receptor-dependent proliferation assay showing stronger signaling from the
      mutant clones' secreted hormone.
  downstream:
  - target: Increased Erythroid Output
    causal_link_type: DIRECT
- name: Increased Erythroid Output
  biological_scale: TISSUE
  description: >-
    Sustained receptor signaling expands the erythron and raises erythrocyte
    production. No marrow or progenitor-culture study of an EPO-variant patient
    has been reported, so this node rests on the established physiology of
    erythropoietin rather than on a measurement in these families.
  biological_processes:
  - preferred_term: erythrocyte differentiation
    modifier: INCREASED
    term:
      id: GO:0030218
      label: erythrocyte differentiation
  evidence:
  - reference: PMID:41713879
    reference_title: Detection of a Distinct Erythropoietin (EPO) Profile After Isoelectric Focusing in Patients With Familial Erythrocytosis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Its erythropoietic activity is due to the activation of antiapoptotic signaling pathways in erythroid progenitors in the bone marrow"
    explanation: >-
      Supplies the physiological step from receptor signaling to erythroid
      output; background in this paper, not a measurement in these patients.
  downstream:
  - target: Increased Red Cell Mass
    causal_link_type: DIRECT
- name: Increased Red Cell Mass
  biological_scale: ORGANISM
  description: >-
    An expanded circulating erythrocyte compartment, the clinical endpoint of the
    chain, reflected in a raised hematocrit and hemoglobin. White cell and
    platelet counts are not raised and there is no splenomegaly, which separates
    the picture from polycythemia vera.
  evidence:
  - reference: PMID:41574959
    reference_title: Autosomal Dominant Erythrocytosis Caused by Non-Renal Erythropoietin (EPO) Due to EPO c.-136 G>A Germline Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No splenomegaly, leukocytosis, thrombocytosis, arterial hypoxia, or abnormalities in oxygen affinity (p50) were observed"
    explanation: >-
      Confirms that the expansion is confined to the erythroid lineage in the
      promoter-variant family.
  downstream:
  - target: Polycythemia
    causal_link_type: DIRECT
  - target: Increased Hematocrit
    causal_link_type: DIRECT
  - target: Increased Circulating Hemoglobin Concentration
    causal_link_type: DIRECT
phenotypes:
- name: Polycythemia
  category: Hematological
  description: >-
    An isolated, longstanding erythrocytosis is the presenting and defining
    feature. It is the phenotype on which both reported series were assembled,
    and in the promoter-variant kindred it tracked with the variant across the
    examined relatives.
  phenotype_term:
    preferred_term: Polycythemia
    term:
      id: HP:0001901
      label: Polycythemia
  evidence:
  - reference: PMID:40305710
    reference_title: Identification of Hepatic-like EPO as a Cause of Polycythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified six families with erythrocytosis that was associated with circulating EPO levels within the normal range"
    explanation: >-
      Erythrocytosis is the phenotype that defined the six noncoding-variant
      families.
  - reference: PMID:41574959
    reference_title: Autosomal Dominant Erythrocytosis Caused by Non-Renal Erythropoietin (EPO) Due to EPO c.-136 G>A Germline Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation segregated with the erythrocytosis phenotype in 15 examined family members"
    explanation: >-
      Erythrocytosis tracks with the variant across the examined relatives.
- name: Increased Hematocrit
  category: Hematological
  description: >-
    Hematocrit values reported in affected adults run from the low fifties to the
    low sixties per cent in men and in the mid fifties in women, against
    sex-specific reference intervals.
  phenotype_term:
    preferred_term: Increased hematocrit
    term:
      id: HP:0001899
      label: Increased hematocrit
  evidence:
  - reference: PMID:41574959
    reference_title: Autosomal Dominant Erythrocytosis Caused by Non-Renal Erythropoietin (EPO) Due to EPO c.-136 G>A Germline Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "males had a mean HCT of 55.7% (normal range: 42%-51%)"
    explanation: >-
      Mean hematocrit above the reference interval in affected men of the
      promoter-variant kindred.
  - reference: PMID:41713879
    reference_title: Detection of a Distinct Erythropoietin (EPO) Profile After Isoelectric Focusing in Patients With Familial Erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high hematological values (males: hematocrit (%) 55.8-63.0; hemoglobin (HGB) (g/dL): 18.2-20.8; females: hematocrit (%) 54.0-55.0, HGB (g/dL) 17.7-18.1)"
    explanation: >-
      Source for the reported hematocrit range in noncoding-variant patients.
- name: Increased Circulating Hemoglobin Concentration
  category: Hematological
  description: >-
    Hemoglobin concentrations above the reference interval accompany the raised
    hematocrit, reported between roughly 18 and 21 g/dL in affected men and
    around 18 g/dL in affected women.
  phenotype_term:
    preferred_term: Increased circulating hemoglobin concentration
    term:
      id: HP:0001900
      label: Increased circulating hemoglobin concentration
  evidence:
  - reference: PMID:41713879
    reference_title: Detection of a Distinct Erythropoietin (EPO) Profile After Isoelectric Focusing in Patients With Familial Erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hemoglobin (HGB) (g/dL): 18.2-20.8; females: hematocrit (%) 54.0-55.0, HGB (g/dL) 17.7-18.1"
    explanation: >-
      Reported hemoglobin concentrations in the noncoding-variant patients.
diagnosis:
- name: Serum erythropoietin measurement
  description: >-
    Erythropoietin is measured in every erythrocytosis workup, but in ECYT5 it
    does not behave as it does in the other secondary erythrocytoses. In the
    noncoding-variant families it is low to normal, and in the promoter-variant
    kindred it is only moderately raised for the hematocrit while staying inside
    the reference interval. A concentration that is not suppressed, in a patient
    whose red cell mass should have suppressed it, is the finding that argues
    against ECYT1 and for a drive on the hormone side.
  diagnosis_term:
    preferred_term: serum erythropoietin measurement
    term:
      id: NCIT:C74855
      label: Erythropoietin Measurement
  evidence:
  - reference: PMID:41713879
    reference_title: Detection of a Distinct Erythropoietin (EPO) Profile After Isoelectric Focusing in Patients With Familial Erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EPO concentration in blood were in the low to normal range"
    explanation: >-
      Records the measured erythropoietin range in noncoding-variant patients,
      which is what makes this test a weak discriminator here.
  - reference: PMID:41123216
    reference_title: "JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Serum erythropoietin (Epo) levels are variably informative."
    explanation: >-
      Current guidance states the limited discriminating value of the measurement
      in JAK2-unmutated erythrocytosis.
- name: Erythropoietin isoelectric focusing profile
  description: >-
    Isoelectric focusing of plasma or urine erythropoietin separates charge
    isoforms. In EPO noncoding-variant carriers the profile shifts to the basic
    region, matching non-renal hormone, and it is stable over years. This is a
    research assay borrowed from antidoping laboratories rather than a routine
    diagnostic test, and those laboratories have shown the pattern does not meet
    current criteria for recombinant erythropoietin, so it should not be read as
    doping.
  diagnosis_term:
    preferred_term: erythropoietin isoelectric focusing profile
    term:
      id: NCIT:C74855
      label: Erythropoietin Measurement
  evidence:
  - reference: PMID:41713879
    reference_title: Detection of a Distinct Erythropoietin (EPO) Profile After Isoelectric Focusing in Patients With Familial Erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The specific basic profiles from patients were stable over time, remaining unchanged over several years"
    explanation: >-
      Establishes the reproducibility of the profile, which is what would make it
      usable as a marker.
  - reference: PMID:41713879
    reference_title: Detection of a Distinct Erythropoietin (EPO) Profile After Isoelectric Focusing in Patients With Familial Erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is highly unlikely that these EPO mutations, only identified in erythrocytosis patients yet, could lead to an adverse analytical finding."
    explanation: >-
      Supports the caveat that the basic profile is not an antidoping finding.
- name: EPO sequencing including noncoding regions
  description: >-
    Four of the six reported alleles lie outside the coding sequence, so an exome
    or panel restricted to coding exons can miss the diagnosis. Sequencing of the
    EPO promoter and intron 1 is what established both reported noncoding series.
  diagnosis_term:
    preferred_term: germline EPO sequencing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:41574959
    reference_title: Autosomal Dominant Erythrocytosis Caused by Non-Renal Erythropoietin (EPO) Due to EPO c.-136 G>A Germline Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "underscores the diagnostic value of sequencing EPO regulatory regions in patients with JAK2-negative erythrocytosis with normal or moderately elevated EPO levels"
    explanation: >-
      States the diagnostic case for sequencing the regulatory regions of EPO.
  - reference: PMID:41123216
    reference_title: "JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "In cases with negative workup but high clinical suspicion, an expanded next generation sequencing panel for hereditary erythrocytosis is recommended."
    explanation: >-
      Supports extending sequencing when the standard workup is negative, which
      is the situation EPO noncoding variants create.
treatments:
- name: Therapeutic phlebotomy
  description: >-
    Repeated phlebotomy is what the reported EPO-variant patients received, at
    intervals of a few months. It lowers the red cell mass and so relieves
    hyperviscosity symptoms without touching the cause. No trial has been run in
    this disease; the practice follows general guidance for JAK2-unmutated
    erythrocytosis, which also advises against cytoreductive therapy.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: phlebotomy
    term:
      id: NCIT:C28221
      label: Phlebotomy
  target_mechanisms:
  - target: Increased Red Cell Mass
    treatment_effect: INHIBITS
    description: >-
      Phlebotomy removes circulating erythrocytes, so it acts only on the last
      node of the chain and leaves the erythropoietin drive intact.
  evidence:
  - reference: PMID:41713879
    reference_title: Detection of a Distinct Erythropoietin (EPO) Profile After Isoelectric Focusing in Patients With Familial Erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They were treated by repeated phlebotomies every couple of months."
    explanation: >-
      Records the treatment actually given to patients carrying noncoding EPO
      variants.
  - reference: PMID:41123216
    reference_title: "JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Cytoreductive therapy should be avoided. Phlebotomy should be considered for symptom control."
    explanation: >-
      Current guidance for JAK2-unmutated erythrocytosis, the class this disease
      falls in.
- name: Low-dose aspirin and cardiovascular risk reduction
  description: >-
    Low-dose aspirin with cardiovascular risk-factor optimization is advised for
    JAK2-unmutated erythrocytosis in general. There is no ECYT5-specific
    evidence, and the thrombotic risk of EPO-variant erythrocytosis has not been
    quantified in a cohort, so this row records inherited guidance rather than a
    result in this disease.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: aspirin
      term:
        id: CHEBI:15365
        label: acetylsalicylic acid
  evidence:
  - reference: PMID:41123216
    reference_title: "JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Cardiovascular risk optimization and low-dose aspirin are advised, while the role of HIF2A inhibitors remains unclear."
    explanation: >-
      The source of the recommendation, stated for JAK2-unmutated erythrocytosis
      as a class rather than for EPO variants specifically.
animal_models:
- name: tg6 human EPO-overexpressing transgenic mouse
  species: Mouse
  genotype: Transgenic for human EPO under a constitutive, hypoxia-independent promoter (line tg6)
  publication: PMID:16690772
  description: >-
    The tg6 line carries a human EPO transgene expressed independently of
    oxygen tension, so erythropoietin drive is permanently uncoupled from the
    hypoxia signal that normally gates it. That is the same uncoupling the EPO
    variants produce in patients, which is why the model is informative here;
    the model reaches it by a transgene rather than by an EPO allele, and at a
    far higher hematocrit than patients carry. Beyond the red cell mass the
    model also develops hepatic, renal, neuronal and muscular degeneration, a
    reduced lifespan, endothelial activation with reduced brain vessel density,
    and near-loss of the endothelial glycocalyx. None of those is a reported
    feature of human ECYT5 and none is curated as a phenotype of this disease;
    see the HUMAN_MODEL_MISMATCH discussion.
  modeled_mechanisms:
  - target: Excess Bioactive Circulating Erythropoietin
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Constitutive, hypoxia-independent erythropoietin excess, which is the node
      this entry's two variant classes converge on.
    limitations: >-
      The excess is produced by a human EPO transgene rather than by a
      regulatory or coding EPO variant, and plasma erythropoietin is raised
      roughly twelve-fold, far beyond the normal-range or modestly raised
      concentrations reported in patients.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        The disease lesion is absent. Erythropoietin excess is imposed by a
        transgene, so nothing in the model corresponds to the exon 2 frameshift
        or to the promoter and intron 1 variants, and the model can say nothing
        about how either lesion produces the excess.
    - divergence_type: OTHER
      materiality: QUALIFYING
      description: >-
        The degree is supraphysiological. Plasma erythropoietin is about
        twelve-fold elevated and hematocrit reaches 0.85 to 0.89, where
        reported patients sit between roughly 0.50 and 0.63, so the model
        exaggerates whatever is dose-dependent. The taxonomy has no value for a
        supraphysiological level of an otherwise correctly modelled quantity.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Murine erythropoiesis and vasculature, carrying a human EPO transgene.
    readouts:
    - name: Plasma erythropoietin concentration
      target: Excess Bioactive Circulating Erythropoietin
      direction: INCREASED
      interpretation: Confirms that the model reproduces circulating hormone excess.
      evidence:
      - reference: PMID:18256329
        reference_title: Abortion in mice with excessive erythrocytosis is due to impaired arteriogenesis of the uterine arcade.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "pregnant human erythropoietin-overexpressing (plasma levels elevated 12-fold) mice (termed tg6 mice) suffering from excessive erythrocytosis generally abort at midgestation unless their hematocrit of 0.85 is drastically lowered"
        explanation: States the measured degree of plasma erythropoietin elevation in the line.
    evidence:
    - reference: PMID:16690772
      reference_title: Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "transgenic mouse line (tg6) that constitutively overexpresses erythropoietin (Epo) in a hypoxia-independent manner, thereby reaching hematocrit levels of up to 0.89"
      explanation: >-
        Establishes the model as hypoxia-independent erythropoietin excess, which
        is what makes it informative for this node.
  - target: Increased Red Cell Mass
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Erythropoietin-driven expansion of the red cell compartment, reached
      through the same hormonal route as in patients.
    limitations: >-
      Hematocrit reaches 0.85 to 0.89, above the range reported in EPO-variant
      patients, so the model's downstream organ and vascular findings cannot be
      read as the expected course of human ECYT5.
    divergences:
    - divergence_type: OTHER
      materiality: INVALIDATING
      description: >-
        The red cell mass is far above the patient range, which is the variable
        the model's own authors tie the organ damage to. Any claim about
        consequences carried from this model to patients is therefore invalid at
        this degree, although the existence of the expansion itself is faithful.
    readouts:
    - name: Hematocrit
      target: Increased Red Cell Mass
      direction: INCREASED
      interpretation: >-
        The direct measure of the node, and the variable the model's organ
        pathology tracks with.
      evidence:
      - reference: PMID:16690772
        reference_title: Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "thereby reaching hematocrit levels of up to 0.89"
        explanation: The measured hematocrit in the line.
    evidence:
    - reference: PMID:16690772
      reference_title: Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Taken together, chronically increased Epo levels inducing excessive erythrocytosis leads to multiple organ degeneration and reduced life expectancy."
      explanation: >-
        The authors' own summary, which attributes the outcome to erythropoietin
        driven excessive erythrocytosis.
  notes: >-
    The line was built to study excessive erythrocytosis generically, and its
    own authors frame it as a model for polycythemia vera, chronic mountain
    sickness and erythropoietin doping rather than for a hereditary EPO
    variant. It is cited here for the hormone-excess and red-cell-mass nodes
    only. No knock-in mouse carrying a patient EPO allele has been reported.
discussions:
- discussion_id: epo_producing_tissue_unidentified
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Increased EPO Transcription from Hypoxia-Responsive Regulatory Elements
  - pathophysiology#Hepatic-Type Erythropoietin Glycosylation
  prompt: >-
    Which tissue produces the excess erythropoietin in carriers of noncoding EPO
    variants, and is the hepatic glycosylation signature evidence of hepatocyte
    origin or only of a non-renal one?
  rationale: >-
    Both reported noncoding series infer the producing tissue from the charge of
    circulating erythropoietin rather than from the tissue itself. The
    glycosylation argument establishes that the hormone is not renal; reading it
    as hepatic is a further step, and a promoter variant could instead switch on
    transcription in several non-renal tissues. The two groups also disagree on
    which carbohydrate change the isoelectric shift reflects, which matters
    because sialylation and sulfation have different consequences for clearance
    and activity. A mouse carrying one of these alleles, or spatial
    transcriptomics on patient tissue, would settle it, and neither exists. The
    one mouse line curated here drives erythropoietin from a transgene, so it
    has nothing to say about which tissue a variant allele switches on.
  evidence:
  - reference: PMID:41574959
    reference_title: Autosomal Dominant Erythrocytosis Caused by Non-Renal Erythropoietin (EPO) Due to EPO c.-136 G>A Germline Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the direct identification of the EPO producing tissue is currently lacking"
    explanation: >-
      The authors state the gap for their own variant and, in the same passage,
      for the earlier noncoding series.
- discussion_id: two_routes_one_entity
  kind: KNOWLEDGE_GAP
  attaches_to:
  - disease#Familial Erythrocytosis 5
  - pathophysiology#EPO Exon 2 Frameshift Deletion
  - pathophysiology#EPO Noncoding Regulatory Variant
  prompt: >-
    Are the exon 2 frameshift and the noncoding regulatory EPO variants one
    disease, given that one was described as producing excess erythropoietin and
    the other as producing a normal amount of hyperactive erythropoietin?
  rationale: >-
    The OMIM concept ECYT5 was created for the exon 2 frameshift family and the
    noncoding variants arrived later. They share the gene, the dominant
    transmission and the clinical picture, which is why they are curated
    together here, but the lesion differs in kind: a reading-frame rescue of an
    alternative transcript versus activation of a cis-regulatory element. The
    laboratory phenotypes differ too, with circulating hormone described as
    frankly increased in the one account and inside the reference interval in the
    other. If the two diverge on natural history or management they would be
    better carried as subtypes, which is the shape to revisit once more families
    are reported.
  evidence:
  - reference: PMID:29514032
    reference_title: A Gain-of-Function Mutation in EPO in Familial Erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "initiates excess production of erythropoietin from what is normally a noncoding EPO mRNA"
    explanation: >-
      The exon 2 route is described as producing excess hormone.
  - reference: PMID:40305710
    reference_title: Identification of Hepatic-like EPO as a Cause of Polycythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "erythrocytosis that was associated with circulating EPO levels within the normal range"
    explanation: >-
      The noncoding route presents with normal circulating concentrations, the
      contrast this gap is about.
- discussion_id: mouse_organ_damage_at_supraphysiological_hematocrit
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - animal_models#Mouse
  - pathophysiology#Increased Red Cell Mass
  prompt: >-
    Does an erythropoietin-driven red cell mass at the hematocrit human
    EPO-variant carriers actually reach cause the organ and endothelial damage
    the tg6 mouse develops, or is that damage a property of the degree the model
    exaggerates?
  rationale: >-
    This is a mismatch rather than an absence, which is why it is typed
    HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP. The model evidence is good
    and it is consistent across four studies: chronic erythropoietin-driven
    erythrocytosis in the tg6 mouse produces hepatic, renal, neuronal and
    muscular degeneration with a reduced lifespan, reduced brain vessel density
    with endothelial activation, and near-abolition of the endothelial
    glycocalyx. What is uncertain is whether any of it transfers. The model runs
    at a hematocrit of 0.85 to 0.89 and the reported patients sit between
    roughly 0.50 and 0.63, and the model's own authors attribute the damage to
    the degree of erythrocytosis rather than to erythropoietin itself, so the
    one variable that would decide the question is the one that does not match.
    The human side is empty rather than negative: no cohort of EPO-variant
    carriers has been followed for vascular or end-organ outcomes, which is also
    why this entry curates no thrombotic or hyperviscosity phenotype. A tg6
    arm held at a patient-range hematocrit, or an outcome study in the known
    kindreds, would resolve it; neither has been reported.
  evidence:
  - reference: PMID:16690772
    reference_title: "Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Taken together, chronically increased Epo levels inducing excessive erythrocytosis leads to multiple organ degeneration and reduced life expectancy."
    explanation: >-
      The model finding whose transfer to human ECYT5 is the open question.
  - reference: PMID:16254128
    reference_title: Chronic excessive erythrocytosis induces endothelial activation and damage in mouse brain.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We propose that chronic excessive erythrocytosis and sustained high hematocrit cause endothelial damage, which may, ultimately, increase susceptibility to vascular disease."
    explanation: >-
      The authors tie the damage to sustained high hematocrit, which is the
      quantity that differs between the model and patients.
  - reference: PMID:21859826
    reference_title: Excessive erythrocytosis compromises the blood-endothelium interface in erythropoietin-overexpressing mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In a transgenic mouse (tg6) model exhibiting systemic Hct levels of about 0.85 the glycocalyx/ESL was nearly abolished."
    explanation: >-
      A third endothelial finding, reported at the model's hematocrit of about
      0.85 rather than at a patient-range value.
- discussion_id: promoter_variant_transcription_factor
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Increased EPO Transcription from Hypoxia-Responsive Regulatory Elements
  prompt: >-
    If the c.-136G>A promoter variant does not work by creating a bound HIF
    response element, which transcription factor mediates its effect?
  rationale: >-
    The variant creates a predicted hypoxia response element and behaves like one
    in reporter assays, where added HIF-2 alpha augments it, yet chromatin
    immunoprecipitation at the native locus did not detect HIF-1 or HIF-2
    binding. The authors cannot exclude a technical failure in this GC-rich
    region, and they offer predicted KLF-family and SOX18 sites as alternatives,
    with only KLF9 enrichment confirmed and no evidence that KLF9 acts on
    erythropoiesis. The node is therefore established at the level of output and
    not of the factor involved.
  evidence:
  - reference: PMID:41574959
    reference_title: Autosomal Dominant Erythrocytosis Caused by Non-Renal Erythropoietin (EPO) Due to EPO c.-136 G>A Germline Mutation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, ChIP experiments failed to confirm direct HIF-2 or HIF-1 binding to the mutated EPO promoter"
    explanation: >-
      The negative binding result that leaves the mediating factor open.
notes: >-
  Lump and split. The entry covers both reported classes of causal EPO variant
  under the single MONDO concept, with the case for splitting recorded as a
  knowledge gap rather than acted on. The noncoding series is described by its
  own authors as a cause of secondary erythrocytosis, which is consistent with
  the lesion being extrinsic to the erythroid progenitor, and is why this entry
  sits beside the oxygen-sensing erythrocytoses rather than beside ECYT1.
  Thrombotic risk is deliberately not curated as a phenotype. Hyperviscosity and
  vascular complications are the expected consequence of a raised red cell mass
  and are mentioned in passing in the sources, but no cohort has reported
  vascular event rates in EPO-variant carriers, so no phenotype row is written
  for them. Headache, pruritus, erythromelalgia and visual disturbance are left
  out for the same reason and a sharper one: the sources that name them are
  describing polycythemia vera or erythrocytosis as a class, not EPO-variant
  carriers, and importing them here would attribute another disease's symptom
  list to this one. The tg6 mouse's organ and endothelial damage is left out
  too; it is recorded against the model, with the transfer question typed as a
  HUMAN_MODEL_MISMATCH discussion.
  No GeneReviews chapter covers EPO-related erythrocytosis. A search of the
  committed Bookshelf index and a live PubMed title search over this entry's
  name, disease term and synonyms return no chapter. The nearest chapter,
  Primary Familial and Congenital Erythrocytosis, is about EPOR; it defines its
  own subject as erythrocytosis in the absence of disorders causing secondary
  erythrocytosis, which excludes this disease, so it is not a baseline here and
  is deliberately not cited. The EPOR entry in this knowledge base carries it.
  Serum erythropoietin in the exon 2 frameshift family is not recorded here: the
  cached record for PMID:29514032 is abstract only and the abstract does not give
  that family's concentrations, so the entry states only what the noncoding
  families' measurements show.
references:
- reference: PMID:29514032
  title: A Gain-of-Function Mutation in EPO in Familial Erythrocytosis.
- reference: PMID:40305710
  title: Identification of Hepatic-like EPO as a Cause of Polycythemia.
- reference: PMID:41574959
  title: Autosomal Dominant Erythrocytosis Caused by Non-Renal Erythropoietin (EPO) Due to EPO c.-136 G>A Germline Mutation.
- reference: PMID:41713879
  title: Detection of a Distinct Erythropoietin (EPO) Profile After Isoelectric Focusing in Patients With Familial Erythrocytosis.
- reference: PMID:31350093
  title: "Update on mutations in the HIF: EPO pathway and their role in erythrocytosis."
- reference: PMID:41123216
  title: "JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management."
- reference: PMID:16690772
  title: "Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration."
- reference: PMID:16254128
  title: Chronic excessive erythrocytosis induces endothelial activation and damage in mouse brain.
- reference: PMID:21859826
  title: Excessive erythrocytosis compromises the blood-endothelium interface in erythropoietin-overexpressing mice.
- reference: PMID:18256329
  title: Abortion in mice with excessive erythrocytosis is due to impaired arteriogenesis of the uterine arcade.
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
📚

References & Deep Research

References

10
PMID:29514032
A Gain-of-Function Mutation in EPO in Familial Erythrocytosis.
No top-level findings curated for this source.
PMID:40305710
Identification of Hepatic-like EPO as a Cause of Polycythemia.
No top-level findings curated for this source.
PMID:41574959
Autosomal Dominant Erythrocytosis Caused by Non-Renal Erythropoietin (EPO) Due to EPO c.-136 G>A Germline Mutation.
No top-level findings curated for this source.
PMID:41713879
Detection of a Distinct Erythropoietin (EPO) Profile After Isoelectric Focusing in Patients With Familial Erythrocytosis.
No top-level findings curated for this source.
PMID:31350093
Update on mutations in the HIF: EPO pathway and their role in erythrocytosis.
No top-level findings curated for this source.
PMID:41123216
JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management.
No top-level findings curated for this source.
PMID:16690772
Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration.
No top-level findings curated for this source.
PMID:16254128
Chronic excessive erythrocytosis induces endothelial activation and damage in mouse brain.
No top-level findings curated for this source.
PMID:21859826
Excessive erythrocytosis compromises the blood-endothelium interface in erythropoietin-overexpressing mice.
No top-level findings curated for this source.
PMID:18256329
Abortion in mice with excessive erythrocytosis is due to impaired arteriogenesis of the uterine arcade.
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: Familial Erythrocytosis 5 (ECYT5, EPO) · 2026-10-15T17:22:43Z · View source

De novo curation of MONDO:0033483 (erythrocytosis, familial, 5; ECYT5), autosomal dominant erythrocytosis caused by germline EPO variants. The first draft was built from PubMed E-utilities searches; an openscientist deep-research report (research/Erythrocytosis_Familial_5-deep-research-openscientist.md, template_sha 1e7ea4ee817acfe1dda5f77fafe6f2e8b5927666) landed afterwards and was then screened and partly integrated, as recorded below. Ten references are cited. The first six, all fetched with just fetch-reference and read from references_cache before quoting, are: PMID:29514032 (Zmajkovic 2018 NEJM, the sentinel EPO c.32delG family; abstract only in cache), PMID:40305710 (Martin 2025 NEJM, six families with noncoding EPO variants and hepatic-like EPO; abstract only), PMID:41574959 (Lanikova 2026 Am J Hematol, EPO c.-136G>A promoter variant, five-generation kindred, CRISPR Hep3B functional work; full text), PMID:41713879 (Martin 2026 Drug Test Anal, erythropoietin isoelectric focusing profiles and the clinical and treatment details of four noncoding-variant patients; full text), PMID:31350093 (review, source for the ECYT5 designation, the signal-peptide frameshift, the intron 1 P2 promoter transcript and the c.19delC allele), PMID:41123216 (JAK2 unmutated erythrocytosis 2026 update, source for management and for the field-level summary of the EPO-variant mechanism). Pathophysiology is a nine-node chain with two initiating lesions that converge: the exon 2 frameshift deletion reaches excess bioactive erythropoietin through reading-frame rescue of the normally noncoding intron 1 P2 transcript, while the noncoding promoter and intron 1 variants reach it through increased transcription from hypoxia-responsive cis-regulatory elements, with a parallel branch through hepatic-type glycosylation of the secreted hormone. Both converge on increased erythropoietin receptor signalling in erythroid progenitors, increased erythroid output and increased red cell mass, which is wired to all three phenotype nodes. Patient versus cell-line attribution was kept explicit. The transcriptional gain of function, the P2 translation result, the 2.7-fold secretion increase and the receptor-proliferation results are graded IN_VITRO; segregation, hematocrit and hemoglobin values, the erythropoietin concentrations, the isoelectric focusing profiles and the phlebotomy treatment are graded HUMAN_CLINICAL. quote_role BACKGROUND is used where a sentence in PMID:41713879 restates the earlier genetic report or the textbook physiology of erythropoietin, and REVIEW_SYNTHESIS for the review-sourced items. One REFUTE item is recorded on the promoter-transcription node for the negative chromatin immunoprecipitation result. The Excess Bioactive Circulating Erythropoietin node carries the EPO gene descriptor and a molecular_functions binding, GO:0005179 hormone activity with modifier INCREASED, so the causal gene lands on a node that names what the protein does and not only on nodes naming what the cell does. The binding sits on the excess-hormone node rather than on either lesion node because that is where the hormone's activity is the claim: in the noncoding families the protein sequence is unchanged and erythropoietin purified from patient plasma signals more strongly through its receptor than wild-type hormone, which is a quantitative increase in a normal activity, so INCREASED rather than GAIN_OF_FUNCTION. Putting it on the exon 2 lesion node would have been wrong in the opposite direction: there the canonical transcript stops producing hormone altogether. The grounding evidence is a shortened extent of a snippet already quoted on the glycosylation edge, kept at the same IN_VITRO grading. check_gene_activity_grounding.py reports no newly ungrounded genes with no exemption added to tests/gene_activity_grounding_baseline.txt. Deep-research screening. just preflight-dr against MONDO:0033483 returned PASS: canonical gene EPO mentioned 134 times against EPOR 20, JAK2 20, EPAS1 6, and the report's OMIM 617907 matches MONDO's. The report's own frontmatter recorded 16 of 16 references resolved with a 0.0 confabulation rate but only 6 judged on topic and 0 off topic, so the remaining 10 were read before any were used. Term validation was flagged needs_review and its flags were acted on rather than trusted: GO:0005615 is obsolete and was never bound; HP:0200071 was reported as erythromelalgia and is in fact Peripheral vitreoretinal degeneration, so it was not bound; HP:0002315 Headache and HP:0000989 Pruritus are real terms but were traced to their sources before any decision. What the report added. Four references, all previously absent, all on the tg6 transgenic mouse that overexpresses human EPO hypoxia-independently: PMID:16690772 (the line, hematocrit to 0.89, multi-organ degeneration and reduced lifespan), PMID:18256329 (plasma erythropoietin elevated twelve-fold; midgestation abortion unless hematocrit is lowered), PMID:16254128 (reduced brain vessel density with endothelial activation), PMID:21859826 (endothelial glycocalyx nearly abolished at a hematocrit of about 0.85). These fill the animal_models gap the first draft recorded as empty. The entry now carries one animal model with two ModelMechanismLinks, to Excess Bioactive Circulating Erythropoietin and to Increased Red Cell Mass, each RECAPITULATES at MODERATE fidelity with model_scale ORGANISM (both ALIGNED, no scale extrapolation), each with a readout and typed divergences: CAUSE_UNREPRESENTED because erythropoietin excess is imposed by a transgene and no EPO allele is encoded, SPECIES_MISMATCH, and OTHER for the supraphysiological degree (hematocrit 0.85 to 0.89 against roughly 0.50 to 0.63 in patients). OTHER is used deliberately: the taxonomy has no value for a correctly modelled quantity held at a supraphysiological level, which CLAUDE.md anticipates as a likely future SUPRAPHYSIOLOGICAL_EXPRESSION value. A fourth discussion was added, kind HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP, because the model evidence here is good and consistent across four studies while its transfer to patients is the open question: the damage is attributed by the model's own authors to the degree of erythrocytosis, and the degree is the one variable that does not match. The two stale sentences claiming no animal model existed were corrected, in the tissue-of-origin gap and in notes. What the report offered and was rejected. Nine of its sixteen references were not used and their caches were pruned. Headache (HP:0002315), pruritus (HP:0000989), erythromelalgia, visual disturbance and thrombosis were declined as phenotypes: the report sources them to PMID:42557631, whose quoted sentence describes polycythemia vera, and to the general reviews PMID:41347984 and PMID:36966432, none of which observes an EPO-variant carrier. Importing them would have attributed another disease's symptom list to this one, which is the named-entity risk the preflight exists for. PMID:21511372 and PMID:33456185 concern high-oxygen-affinity hemoglobin and Hb San Diego, PMID:28699191 hydroxyurea in polycythemia vera, all different diseases; PMID:23291219 (HIF regulation of erythropoiesis) and PMID:9664155 (EPOR physiology) are background already covered by primary sources in the entry; PMID:17365666 is a further tg6 capillary-oxygen-delivery study not needed for either link; PMID:42557631 and PMID:41347984 duplicate management content already sourced from PMID:41123216. The report's own frequency column (Obligate, Characteristic, Variable, Occasional) carries no denominator in any cited source and was not used, so no frequency value was added. Its HP:0020059 for increased circulating erythropoietin was not used either: the term is real but means Increased red blood cell count, which the report's own validator surfaced in its worth-a-second-look tier rather than in the frontmatter mislabelled list. The entry keeps the erythropoietin finding in diagnosis, where the inappropriately-normal reading can be stated, and does not add a fourth overlapping lab phenotype for red cell count. One grading correction was made during validation. check-snippet-grading treats overlapping quotes of one reference as the same sentence, and the four PMID:29514032 citations quoted nested extents of a single abstract sentence under two different evidence_source values. All four are now HUMAN_CLINICAL, that publication being a family study; the in vitro demonstration of the P2 mechanism is carried separately by the PMID:31350093 transfection quotes, which stay IN_VITRO. Two review-sourced sentences that contain no clinical observation, the ECYT5 nomenclature statement and the sequence-level account of the frameshift, are graded OTHER rather than HUMAN_CLINICAL; the repository carries both conventions and that gate deliberately does not decide between them. Three deliberate omissions. No frequency values on any phenotype, because no source reports a denominator. No prevalence block, for the same reason. No thrombotic or hyperviscosity phenotype, because the sources mention vascular consequences only in passing and no cohort reports event rates; this is recorded in notes. gene_disease_validity is omitted because no cached ClinGen CGGV record exists for EPO with this disease. No animal_models section: none has been reported, and the absence is named in the tissue-of-origin knowledge gap. Three KNOWLEDGE_GAP discussions: the erythropoietin-producing tissue is inferred from hormone glycosylation and never identified directly; whether the exon 2 and noncoding routes are one disease entity, which is the lump and split question for this entry; and which transcription factor mediates the c.-136G>A promoter effect given that chromatin immunoprecipitation did not confirm HIF binding. No GeneReviews chapter exists. just check-genereviews --online over the entry's name, disease term and six synonyms returns NO_CHAPTER for both GeneReviews and StatPearls. The nearest chapter, Primary Familial and Congenital Erythrocytosis, is about EPOR and scopes itself to erythrocytosis without a secondary cause, so it is not this disease's baseline; it is named in notes but deliberately not cited, and the reason is recorded there. Validation after integration: just validate passed (schema, terms, references; 56 snippets checked, 0 issues, 66 titles checked). just validate-terms passed. just count-verified-snippets reported 56/56. just model-scale-audit reports 2 of 2 model links scale-determined and ALIGNED. check_gene_activity_grounding.py against origin/main reports no newly ungrounded genes. check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms and check-block-scalar-comments all clean for this file. The whole-KB gates check-coarse-phenotypes, check-snippet-length, check-title-snippets, check-snippet-grading, check-retired-support-prose, check-environmental-evidence, check-enum-values and check-reference-titles all report no new findings. just validate-disorders on this file passed end to end (48 snippets, 0 issues). just list-gene-term-mismatches examined all three gene bindings and found the entry names the gene it binds in each. just list-disconnected-phenotypes reports all three phenotype nodes causally connected. Cache additions are GO:0042446 and MONDO:0033483 and their enum-membership rows, all four used by this entry; just normalize-cache left the files otherwise unchanged.

OpenScientist ▸
Familial Erythrocytosis 5 (ECYT5): Comprehensive Disease Characteristics Report
openscientist-autonomous 16 citations 2026-10-15T19:00:31.529471

Familial Erythrocytosis 5 (ECYT5): Comprehensive Disease Characteristics Report

Disease: Familial Erythrocytosis 5 (ECYT5) MONDO ID: MONDO:0033483 · OMIM: #617907 · Causal gene: EPO (HGNC:3415), chromosome 7q22.1 Category: Mendelian (autosomal dominant) Evidence base: Individual-family case reports + functional studies; disease-level resources (OMIM/Orphanet) and broader erythrocytosis reviews.

Summary

Familial Erythrocytosis 5 (ECYT5) is an ultra-rare, autosomal dominant form of secondary (EPO-driven) erythrocytosis caused by germline gain-of-function variants in the erythropoietin structural gene (EPO) itself. It is biologically distinctive among the hereditary erythrocytoses because, whereas the other familial forms disrupt the EPO receptor (ECYT1/EPOR), the oxygen-sensing pathway (ECYT2/VHL, ECYT3/EGLN1, ECYT4/EPAS1), or hemoglobin oxygen affinity, ECYT5 is the only one in which the gene encoding erythropoietin is the site of the lesion. The result is constitutive or ectopic overproduction of erythropoietin uncoupled from the normal hypoxia-sensing feedback loop, driving excessive red-cell production through an otherwise-normal signaling cascade.

Two mechanistically distinct causal variants are documented. The founding kindred (PMID: 29514032) carried a single-nucleotide frameshift deletion (EPO c.32delG) that paradoxically silences translation of the main EPO mRNA while rerouting ribosomes to a normally non-coding transcript initiated from an alternative promoter in intron 1 — thereby producing excess erythropoietin from a frameshifted allele. A second kindred (PMID: 41574959) carried a promoter variant (EPO c.-136 G>A) that creates a new hypoxia-response element (HRE) on the reverse strand, driving increased, oxygen-independent EPO transcription confirmed in CRISPR-edited Hep3B cells and luciferase reporter assays. Both lesions sit upstream of the erythropoietin receptor (EPOR)–JAK2–STAT5 axis and over-drive a normal pathway rather than altering the receptor or its downstream effectors.

Clinically, ECYT5 manifests as lifelong, isolated erythrocytosis (elevated hemoglobin and hematocrit) with inappropriately normal-to-elevated serum EPO and a positive family history, but without the leukocytosis, thrombocytosis, or splenomegaly of polycythemia vera (PV). The principal risks arise from hyperviscosity and thrombosis. Management is extrapolated from PV and the broader category of JAK2-unmutated erythrocytosis: hematocrit-lowering phlebotomy for symptom control, low-dose aspirin, and cardiovascular risk optimization, while cytoreductive therapy is explicitly avoided because the disorder is non-clonal. Disease biology and the consequences of sustained high hematocrit are illuminated by EPO-overexpressing transgenic tg6 mice and by CRISPR-edited human hepatoma cell models.

Key Findings

Finding 1 — ECYT5 is an autosomal dominant erythrocytosis caused by a gain-of-function EPO mutation

The founding description (Zmajkovic et al., A Gain-of-Function Mutation in EPO in Familial Erythrocytosis, NEJM 2018) identified an EPO mutation that cosegregated with autosomal dominant erythrocytosis in a single large family with a logarithm-of-the-odds (LOD) score of 3.3 — statistically significant genetic linkage. The verified quote establishes the core genetics: "We identified a mutation in EPO that cosegregated with disease with a logarithm of the odds (LOD) score of 3.3 in a family with autosomal dominant erythrocytosis. This mutation, a single-nucleotide deletion (c.32delG), introduces a frameshift in exon 2" (PMID: 29514032). This defines the gene (EPO, HGNC:3415, chromosome 7q22.1), the inheritance pattern (autosomal dominant), and the identifiers (OMIM #617907; MONDO:0033483).

Finding 2 — A paradoxical gain-of-function: the frameshift silences the main transcript but activates a normally non-coding intron-1 transcript

The most counterintuitive feature of c.32delG is that a frameshift — usually a loss-of-function lesion — produces a gain of EPO. Per Zmajkovic et al., the deletion "introduces a frameshift in exon 2 that interrupts translation of the main EPO messenger RNA (mRNA) transcript but initiates excess production of erythropoietin from what is normally a noncoding EPO mRNA transcribed from an alternative promoter located in intron 1" (PMID: 29514032). The frameshift unmasks an alternative, intron-1–driven transcript whose translation yields functional erythropoietin in excess — explaining how a single-base coding deletion produces a secondary (high-EPO) rather than primary erythrocytosis.

Finding 3 — A second, promoter-based mechanism: EPO c.-136 G>A creates a new hypoxia-response element

A five-generation kindred with autosomal dominant erythrocytosis carried a germline EPO promoter variant, c.-136 G>A (Lanikova et al., 2026). The variant creates a new HRE consensus sequence on the reverse strand, and this gain of function was confirmed functionally: "This mutation creates a new hypoxia response element (HRE) consensus sequence on the reverse strand suggesting a gain of function mutation. CRISPR/Cas9-edited Hep3B cells harboring the c.-136 G>A variant had increased EPO mRNA and protein expression under both normoxic and hypoxic conditions compared to wild-type cells" (PMID: 41574959). Luciferase assays confirmed increased mutant-promoter transcription, and urine/plasma isoelectric focusing showed a more basic EPO isoform pattern consistent with decreased renal and increased non-renal (ectopic) EPO production. This establishes a second, independent route to ECYT5 — a cis-regulatory promoter variant — broadening the mutational spectrum.

Finding 4 — EPO-overexpressing tg6 transgenic mice model the disease and reveal multi-organ/vascular consequences

The tg6 mouse constitutively overexpresses human EPO in a hypoxia-independent manner — directly paralleling the oxygen-uncoupled EPO excess of ECYT5 — reaching hematocrit up to 0.89: "transgenic mouse line (tg6) that constitutively overexpresses erythropoietin (Epo) in a hypoxia-independent manner, thereby reaching hematocrit levels of up to 0.89" (PMID: 16690772). Chronic excessive erythrocytosis caused hepatic, renal, neuronal, and muscular degeneration and reduced lifespan (PMID: 16690772); endothelial activation and damage with reduced brain-vessel density (PMID: 16254128); near-abolition of the endothelial glycocalyx (wild-type 0.52 µm vs tg6 0.13 µm; P < 0.001) (PMID: 21859826); and pregnancy loss from impaired uterine arteriogenesis rescued by lowering hematocrit: "pregnant human erythropoietin-overexpressing (plasma levels elevated 12-fold) mice (termed tg6 mice) suffering from excessive erythrocytosis generally abort at midgestation unless their hematocrit of 0.85 is drastically lowered" (PMID: 18256329). These data causally link the degree of erythrocytosis (hematocrit) — not EPO per se — to vascular/end-organ harm, supporting hematocrit-lowering as the central therapeutic lever.

Finding 5 — Diagnostic framework and management for EPO-driven erythrocytosis

The diagnostic approach begins by excluding PV: "Foremost in the evaluation of erythrocytosis is the exclusion of PV through JAK2 (inclusive of exons 12-15) mutation screening" (Gangat/Szuber/Tefferi, 2023; PMID: 36966432). Thereafter, serum EPO and germline mutation screening are used: subnormal EPO points to EPOR (ECYT1), whereas oxygen-sensing/EPO defects such as ECYT5 show normal/elevated EPO with a normal P50. High-oxygen-affinity hemoglobins (left-shifted P50) are a key differential (PMID: 21511372; PMID: 33456185). Management targets are borrowed from PV data — maintain hematocrit <45% via phlebotomy: "received only phlebotomy (PHL) or HU to maintain the hematocrit level < 45%" (PMID: 28699191).

Finding 6 — Clinical phenotype: isolated erythrocytosis with hyperviscosity symptoms and thrombotic risk

ECYT5 presents as lifelong, isolated erythrocytosis with inappropriately normal or elevated serum EPO and a positive family history, without the leukocytosis, thrombocytosis, or splenomegaly of PV: "Hereditary erythrocytosis (HE) is lifelong and typically associated with a positive family history. Subnormal serum erythropoietin (EPO) suggests an EPO receptor mutation" (PMID: 41347984) — with ECYT5 falling into the normal/high EPO category. Hyperviscosity manifestations shared by erythrocytosis states include headache, visual disturbances, pruritus, and erythromelalgia; splenomegaly is PV-specific: "Polycythemia vera is characterized by headache, visual disturbances, pruritus, erythromelalgia and splenomegaly" (PMID: 42557631). In the original kindred, c.32delG cosegregated with the phenotype (LOD 3.3; PMID: 29514032).

Finding 7 — Epidemiology and a management caveat: ultra-rare, and cytoreduction should be avoided

JAK2-unmutated erythrocytosis has a reported incidence of 0.13%–4.1% ("Incidence has been reported to be between 0.13% and 4.1%"; PMID: 41347984), but ECYT5 specifically is vanishingly rare — a handful of families worldwide (PMID: 29514032; PMID: 41574959). The 2026 management update is explicit for non-clonal (hereditary/idiopathic) erythrocytosis: "Cytoreductive therapy should be avoided. Phlebotomy should be considered for symptom control. Cardiovascular risk optimization and low-dose aspirin are advised" (PMID: 41123216).

Finding 8 — The EPO signaling causal chain

Physiologically, HIF-2 regulates EPO synthesis in response to hypoxia: "HIF-2 has emerged as the transcription factor that regulates EPO synthesis in the kidney and liver" (Haase, 2013; PMID: 23291219). EPO then binds EPOR on erythroid progenitors, activating JAK2 and downstream STAT5, PI3K/AKT, and MAPK, which inhibit apoptosis and promote erythroid proliferation/differentiation: "EPO activates the JAK2-STAT5 pathway, and two tyrosine residues (Y343, Y401) in the cytoplasmic domain of EPOR are important for STAT5 activation" (PMID: 9664155). In ECYT5 the lesion is upstream of this axis: a gain-of-function EPO variant causes constitutive/ectopic EPO overproduction uncoupled from hypoxia, over-driving the otherwise-normal cascade.

Report by Research Section

1. Disease Information

ECYT5 is a hereditary, EPO-driven (secondary-type) erythrocytosis: a lifelong increase in red-cell mass (elevated hemoglobin/hematocrit) caused by germline gain-of-function variants in the erythropoietin gene (EPO) itself. It is the fifth-defined familial erythrocytosis locus and the only one in which the EPO structural gene is mutated, as opposed to its upstream oxygen-sensing regulators (VHL/ECYT2, EGLN1/ECYT3, EPAS1/ECYT4) or its receptor (EPOR/ECYT1) (PMID: 29514032).

Key identifiers: MONDO:0033483; OMIM #617907 (ERYTHROCYTOSIS, FAMILIAL, 5); gene EPO, HGNC:3415, NCBI Gene 2056, chromosome 7q22.1; Orphanet within "Familial erythrocytosis" group (no separate well-populated ECYT5 code); ICD-10 D75.1 (Secondary polycythaemia) / ICD-11 3A51; MeSH closest "Polycythemia" (D011087).

Synonyms: ECYT5; Familial erythrocytosis type 5; EPO-related familial erythrocytosis; autosomal dominant erythrocytosis due to EPO mutation.

Information source: Aggregated disease-level resources (OMIM, Orphanet) plus individual-family reports (two kindreds) and in-vitro functional assays. Not EHR-derived.

2. Etiology

Primary cause — genetic. ECYT5 is monogenic: a heterozygous gain-of-function germline EPO variant causes inappropriate EPO overproduction uncoupled from oxygen-sensing feedback. Two causal variants are documented: (1) c.32delG (exon-2 frameshift), cosegregating with disease at LOD 3.3 (PMID: 29514032); (2) c.-136 G>A (promoter variant creating a novel HRE) (PMID: 41574959).

  • Genetic risk factors: The causal EPO allele itself; a single mutant allele confers the phenotype (dominant). No susceptibility loci or modifier genes established.
  • Environmental risk factors: None causal. Exogenous drivers of red-cell mass (altitude/chronic hypoxia, smoking/CO, androgens, SGLT2 inhibitors, ESAs) could additively worsen hematocrit (inferred; PMID: 42557631, PMID: 41123216).
  • Protective factors: None specific; lowering hematocrit (phlebotomy) and avoiding additive erythropoietic exposures are mitigating.
  • Gene–environment interactions: Plausible additive effect of hypoxia/erythropoietic drugs on the genetically elevated baseline (inferred, not formally studied in ECYT5).

3. Phenotypes

ECYT5 is fundamentally a laboratory-defined phenotype; clinical symptoms, when present, arise from hyperviscosity and attendant thrombotic risk.

Phenotype Type HPO term Onset / course Frequency
Erythrocytosis/polycythemia (↑RBC mass) Lab abnormality HP:0001901 (Polycythemia) Lifelong, early, stable Obligate (defining)
Elevated hemoglobin/hematocrit Lab abnormality HP:0001899 (Increased hematocrit) / HP:0001900 Lifelong Obligate
Increased serum EPO (inappropriately normal/high) Lab abnormality HP:0020059 (Increased circulating EPO) Lifelong Characteristic
Headache Symptom HP:0002315 Episodic, with high Hct Variable
Pruritus Symptom HP:0000989 Variable Occasional
Erythromelalgia Clinical sign HP:0200071 Episodic Occasional
Plethora / facial redness Physical sign HP:0001050 (Plethora) Chronic Variable
Visual disturbance / dizziness Symptom HP:0000504 / HP:0002321 Episodic Variable
Thrombosis (arterial/venous) Clinical complication HP:0001907 (Thromboembolism) Event-driven, adult Risk; undefined for ECYT5

Symptom source: hyperviscosity complex shared across erythrocytosis (PMID: 42557631); unlike PV, ECYT5 shows no splenomegaly, leukocytosis, or thrombocytosis (PMID: 41347984). Severity/progression: generally mild–moderate, chronic, non-progressive; variable between individuals. Quality-of-life impact: not formally measured (no EQ-5D/SF-36 data for ECYT5); driven mainly by thrombotic events and recurrent phlebotomy.

4. Genetic / Molecular Information

Causal gene: EPO (HGNC:3415; OMIM *133170; chr 7q22.1; UniProt P01588).

Pathogenic variants (germline, heterozygous, AD): - c.32delG — exon-2 frameshift; paradoxical gain of function in EPO output via an intron-1 alternative transcript (PMID: 29514032). - c.-136 G>A — promoter/regulatory variant; gain of function via novel HRE (PMID: 41574959). - Note: the pathogenic lesions lie in exon-2 frameshift context, the promoter, and intron 1 — standard exon-focused panels can miss them.

Variant classification (ACMG/AMP): Pathogenic/likely pathogenic based on cosegregation (LOD 3.3), functional confirmation (CRISPR-edited Hep3B, luciferase, isoelectric focusing), and absence in population controls. Allele frequency: essentially absent from gnomAD (private family variants). Origin: germline. Functional consequence: gain of function (increased EPO production) — a translational/transcriptional rerouting that augments EPO output rather than an activating protein change.

Modifier genes: none established. Epigenetic information: no disease-specific methylation/histone data; c.-136 G>A acts via a cis-regulatory (HRE) element, not epigenetic modification. Chromosomal abnormalities: none — ECYT5 is a point/indel disorder.

5. Environmental Information

  • Environmental factors: None causal; hypoxic exposures (altitude, cardiopulmonary disease, CO) can compound the erythrocytosis (inferred).
  • Lifestyle factors: Smoking, androgen/anabolic-steroid use, testosterone therapy, SGLT2 inhibitors, and ESAs independently raise hematocrit and would aggravate ECYT5 (PMID: 41123216, PMID: 42557631).
  • Infectious agents: Not applicable.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

  1. A germline gain-of-function EPO variant (c.32delG frameshift or c.-136 G>A promoter HRE) is present in EPO-producing cells. (demonstrated: linkage + functional assays)
  2. Frameshift branch (c.32delG): translation of the main EPO mRNA is interrupted, but excess erythropoietin is produced from a normally non-coding alternative EPO transcript driven by an intron-1 promoter → leads to EPO overproduction (demonstrated). Promoter branch (c.-136 G>A): a new reverse-strand HRE results in increased EPO transcription under normoxia and hypoxia, with a shift toward non-renal/ectopic EPO → leads to EPO overproduction (demonstrated in Hep3B + luciferase).
  3. Both branches result in constitutive/ectopic EPO overproduction uncoupled from oxygen sensing (inappropriately normal-to-high serum EPO despite normal oxygenation). (demonstrated clinically)
  4. Circulating EPO binds EPOR on erythroid progenitors, activating JAK2 → STAT5 (and PI3K/AKT, MAPK). (inferred from canonical EPO biology; PMID: 9664155)
  5. This inhibits erythroid-progenitor apoptosis and promotes proliferation/differentiation. (demonstrated in EPO biology)
  6. Expanded red-cell mass raises hematocrit → increases whole-blood viscosity. (demonstrated)
  7. Hyperviscosity leads to impaired microcirculation, endothelial activation, and increased thrombotic risk plus hyperviscosity symptoms; at extreme Hct it causes endothelial/glycocalyx damage and multi-organ degeneration (tg6 mice; PMID: 16690772, PMID: 16254128, PMID: 21859826). (model-organism evidence + clinical inference)

Detail by category. Molecular pathways: EPO–EPOR–JAK2–STAT5 (primary), PI3K/AKT and RAS–MAPK (secondary) (PMID: 9664155); the upstream physiologic regulator normally dysregulated is HIF-2/EPAS1, controlling renal/hepatic EPO synthesis (PMID: 23291219). Cellular processes: anti-apoptosis and proliferation of erythroid progenitors; erythron expansion. Protein dysfunction: not altered EPO structure — the defect is excess production of functional EPO (gain of function in dosage/expression); isoelectric focusing shows a more basic, non-renal-type EPO isoform in the promoter-variant family (PMID: 41574959). Metabolic/biochemical: secondary to erythrocytosis (↑iron utilization, possible phlebotomy-induced iron deficiency; altered 2,3-BPG/oxygen delivery in models, PMID: 17365666). Immune: none primary; chronic hyperviscosity-associated endothelial inflammation is a downstream model finding. Tissue-damage: hyperviscosity, endothelial activation, reduced glycocalyx, impaired arteriogenesis (model organism; PMID: 18256329, PMID: 21859826). Ontology suggestions: GO:0038162 (erythropoietin-mediated signaling pathway), GO:0030218 (erythrocyte differentiation), GO:0043066 (negative regulation of apoptotic process); CL:0000038 (erythroid progenitor cell), CL:0000765 (erythroblast), CL:0000115 (endothelial cell, downstream); UBERON:0002113 (kidney), UBERON:0002107 (liver), UBERON:0002371 (bone marrow).

7. Anatomical Structures Affected

  • Organ level — primary: Bone marrow (UBERON:0002371, erythroid expansion); EPO-producing kidney (UBERON:0002113) and liver (UBERON:0002107) as the site of the lesion's expression; blood/vasculature (UBERON:0000178) as effector compartment.
  • Secondary/complication organs: Cerebral and coronary vasculature, splanchnic/portal veins (thrombosis sites); in models, liver, kidney, brain, peripheral nerve, and skeletal muscle degenerate under extreme Hct (PMID: 16690772).
  • Body systems: Hematologic, cardiovascular (thrombosis/hyperviscosity); nervous (headache; neuropathy in models).
  • Tissue/cell level: Erythroid lineage (CL:0000764), erythroid progenitors (CL:0000038); vascular endothelial cells (CL:0000115) as downstream targets.
  • Subcellular (GO CC): EPO secreted (GO:0005615 extracellular space); signaling at plasma membrane/receptor complex (GO:0005886).
  • Localization/laterality: Systemic/bilateral (blood-borne); thrombotic events are focal and variable.

8. Temporal Development

  • Onset: Congenital/early-life predisposition; lifelong erythrocytosis typically detected in childhood–adulthood (PMID: 41347984); chronic/insidious pattern.
  • Progression: Stable, non-progressive erythrocytosis with no transformation to malignancy — a key contrast with PV (non-clonal).
  • Course: Lifelong/chronic; "remission" only via treatment-induced hematocrit lowering (phlebotomy); no spontaneous remission; no anticipation (point/indel mutation).
  • Critical periods: Pregnancy (hyperviscosity risk; model shows hematocrit-dependent pregnancy loss, PMID: 18256329) and perioperative/immobilization windows for thrombosis.

9. Inheritance and Population

  • Inheritance: Autosomal dominant (single heterozygous EPO gain-of-function allele; cosegregation LOD 3.3; PMID: 29514032).
  • Penetrance/expressivity: High penetrance for the erythrocytosis trait within kindreds; variable clinical expressivity (symptomatic burden differs).
  • Anticipation / germline mosaicism / consanguinity: Not expected/not relevant (dominant). Founder effects: none — private family variants.
  • Carrier frequency: Not applicable (dominant); variants essentially absent from gnomAD.
  • Epidemiology: Ultra-rare — a handful of families worldwide; within JAK2-unmutated erythrocytosis (incidence 0.13%–4.1%, PMID: 41347984), but a vanishingly small subset. No ECYT5-specific prevalence/incidence figures exist.
  • Demographics: Both sexes affected (autosomal; thresholds sex-specific); no ethnic predilection; variants are family-private.

10. Diagnostics

Diagnostic algorithm (PMID: 41347984, PMID: 41123216, PMID: 36966432): 1. Confirm true erythrocytosis (↑Hgb/Hct vs age/sex thresholds; exclude relative/apparent polycythemia). LOINC: hemoglobin 718-7; hematocrit 4544-3; erythropoietin 14743-9. 2. Exclude PV — screen JAK2 (exons 12–15); ECYT5 is JAK2-wild-type with normal WBC/platelets and no splenomegaly. 3. Serum EPO: inappropriately normal or elevated in ECYT5 (contrast: subnormal → EPOR mutation/PV). 4. P50: normal in ECYT5 (contrast: low/left-shifted → high-oxygen-affinity hemoglobin; PMID: 21511372, PMID: 33456185). 5. Genetic testing: sequence EPO including exon 2, the promoter (5′), and intron 1 — exon-only panels can miss ECYT5 variants. Hereditary-erythrocytosis gene panels (EPOR, VHL, EGLN1, EPAS1, EPO, HBA/HBB, BPGM, PIEZO1) via NGS; WES/WGS when panel-negative (noting promoter variants may be missed by exome-only approaches).

Clinical tests/biomarkers: CBC, serum EPO, P50, JAK2; the genetic variant is the definitive biomarker. Isoelectric focusing of urine/plasma EPO can reveal a non-renal isoform pattern (PMID: 41574959). Bone marrow biopsy not required (no clonal myeloproliferation). Differential diagnosis: PV (JAK2+); EPOR-mutant PFCP (low EPO); oxygen-sensing erythrocytoses (VHL/Chuvash, EGLN1, EPAS1); high-oxygen-affinity hemoglobinopathies (low P50); acquired secondary causes. Screening: cascade genetic testing of at-risk first-degree relatives in known kindreds.

11. Outcome / Prognosis

  • Survival/life expectancy: Generally favorable; ECYT5 does not transform to leukemia/myelofibrosis (unlike PV). No ECYT5-specific survival statistics.
  • Mortality/morbidity: Driven by thrombosis (arterial/venous) from hyperviscosity; event rates undefined for ECYT5. Models under extreme Hct show reduced lifespan and multi-organ damage (PMID: 16690772).
  • Complications: Thromboembolism (stroke, MI, venous/splanchnic thrombosis), hyperviscosity symptoms, pregnancy complications (inferred/model).
  • Prognostic factors: Degree of hematocrit elevation, prior thrombosis, conventional cardiovascular risk factors (extrapolated from PV cohorts where CV risk factors and prior thrombosis predict events).
  • Recovery: Hematocrit control is effective at reducing hyperviscosity; the genetic driver is lifelong.

12. Treatment

No ECYT5-specific trials exist; management is extrapolated from hereditary/secondary erythrocytosis and PV data.

  • Therapeutic phlebotomy / venesection — mainstay to lower hematocrit and control symptoms (NCIT: Therapeutic Phlebotomy). Target historically <45% (from PV; PMID: 28699191), individualized for secondary erythrocytosis (PMID: 41123216).
  • Low-dose aspirin — antiplatelet thromboprophylaxis: "Cardiovascular risk optimization and low-dose aspirin are advised" (PMID: 41123216) (NCIT: Aspirin, C287).
  • Cardiovascular risk-factor optimization — blood pressure, smoking cessation, avoid additive erythropoietic agents (androgens, SGLT2i, ESAs).
  • Cytoreduction (hydroxyurea) — generally AVOIDED in non-clonal hereditary erythrocytosis: "Cytoreductive therapy should be avoided" (PMID: 41123216) (NCIT: Hydroxyurea, C546).
  • Experimental/targeted: Role of HIF-2α inhibitors remains unclear for hereditary erythrocytosis (PMID: 41123216); no gene/cell/RNA therapy exists. Pharmacogenomics: none established.
  • Supportive: Hydration, standard anticoagulation for thrombotic events, iron monitoring given repeated phlebotomy.

13. Prevention

  • Primary prevention: Not possible (germline). Focus on genetic counseling and avoidance of additive erythrocytosis triggers.
  • Secondary prevention: Cascade genetic screening of first-degree relatives; early hematocrit monitoring; prompt phlebotomy.
  • Tertiary prevention: Thromboprophylaxis (aspirin), hematocrit control, cardiovascular risk management.
  • Genetic counseling: Autosomal dominant → 50% transmission risk; prenatal/preimplantation testing technically feasible for a known family variant but rarely pursued given the generally manageable course.
  • Immunization / public-health / environmental: Not applicable.

14. Other Species / Natural Disease

  • Taxonomy / orthologs: EPO is conserved across mammals. Mouse Epo (NCBI Gene 13856), rat Epo (NCBI Gene 24335). NCBI Taxon: Mus musculus 10090, Rattus norvegicus 10116, Homo sapiens 9606.
  • Natural disease: No naturally occurring EPO gain-of-function erythrocytosis catalogued in companion/wild animals (OMIA: not established). No breed-associated EPO variants (no VBO entry).
  • Comparative biology: The EPO–EPOR–JAK2–STAT5 axis and HIF-mediated EPO regulation are highly evolutionarily conserved (PMID: 23291219), underpinning rodent-model validity.
  • Transmission/zoonosis: Not applicable (non-infectious genetic disease).

15. Model Organisms

  • Primary model — tg6 transgenic mouse (Mus musculus, 10090): constitutively overexpresses human EPO hypoxia-independently, reaching Hct up to 0.89 (PMID: 16690772), mimicking the ECYT5 principle (oxygen-uncoupled EPO excess → erythrocytosis).
  • Phenotype recapitulation: Strong for the consequences of EPO-driven erythrocytosis — hyperviscosity, endothelial activation and glycocalyx loss (PMID: 21859826), reduced brain-vessel density/BBB changes (PMID: 16254128), multi-organ (hepatic/renal/neuronal/muscular) degeneration and reduced lifespan (PMID: 16690772), and hematocrit-dependent pregnancy loss reversible by lowering Hct (PMID: 18256329).
  • Limitations: Models EPO overexpression generically (human EPO transgene), not the specific ECYT5 alleles; extreme Hct (0.85–0.89) exceeds typical human ECYT5 levels, exaggerating organ pathology.
  • Cellular/in-vitro models: CRISPR/Cas9-edited Hep3B hepatoma cells carrying EPO c.-136 G>A (increased EPO mRNA/protein under normoxia and hypoxia) and luciferase promoter-reporter assays confirming transcriptional gain of function (PMID: 41574959); the frameshift-driven alternative-transcript mechanism was demonstrated in cellular expression systems (PMID: 29514032).
  • Applications: Study of EPO regulation, hyperviscosity vascular pathology, and testing of hematocrit-lowering/anti-thrombotic strategies. Resources: MGI (Epo), Alliance of Genome Resources.

Mechanistic Model / Interpretation

    ┌────────────────────────────────────────────────────────────┐
    │  Germline gain-of-function EPO variant (7q22.1, AD)         │
    └───────────────┬───────────────────────────┬─────────────────┘
            │                           │
  Branch A: c.32delG (exon-2 frameshift)   Branch B: c.-136 G>A (promoter)
  silences main EPO mRNA; activates        creates new reverse-strand HRE;
  non-coding intron-1 transcript →          ↑EPO transcription (normoxia &
  EXCESS EPO protein                         hypoxia); shift to non-renal EPO
            │                           │
            └─────────────┬─────────────┘
                          ▼
 Oxygen-UNCOUPLED erythropoietin overproduction
     (bypasses normal HIF-2 feedback loop)
                          ▼
 EPO binds EPOR on erythroid progenitors (bone marrow)
                          ▼
 JAK2 activation → STAT5 (+ PI3K/AKT, MAPK)
                          ▼
 ↓ apoptosis, ↑ proliferation/differentiation of erythroid cells
                          ▼
 ↑ Red-cell mass  →  ↑ Hematocrit / Hemoglobin
                          ▼
 ↑ Blood viscosity → hyperviscosity symptoms + THROMBOSIS risk
 (+ endothelial/glycocalyx damage at extreme Hct — tg6 evidence)

ECYT5 vs other familial erythrocytoses (differential-diagnostic context):

Type Gene Mechanism Serum EPO P50
ECYT5 EPO GoF EPO overproduction (ligand excess) Normal/high Normal
ECYT1 EPOR GoF truncated receptor (EPO hypersensitivity) Low/subnormal Normal
ECYT2 VHL LoF → HIF stabilization → ↑EPO Normal/high Normal
ECYT3 EGLN1/PHD2 LoF → HIF stabilization → ↑EPO Normal/high Normal
ECYT4 EPAS1/HIF2A GoF → ↑EPO Normal/high Normal
High-affinity Hb globin genes ↑O₂ affinity → tissue hypoxia → ↑EPO Normal/high Low (left-shift)

Unifying interpretation: ECYT5 is a "ligand-excess" secondary erythrocytosis in which the EPO gene itself is the driver. The signaling machinery (EPOR–JAK2–STAT5) is intact and normal; it is simply over-stimulated. This explains the clinical picture (isolated erythrocytosis with normal/high EPO, no cytopenias, no splenomegaly, no clonal transformation) and dictates management (hematocrit control, not cytoreduction).

Evidence Base

PMID Role How it supports/challenges findings
29514032 Founding ECYT5 description EPO c.32delG, AD inheritance, LOD 3.3, paradoxical intron-1 transcript mechanism (F1, F2)
41574959 Second causal mechanism EPO c.-136 G>A promoter HRE; functional confirmation in Hep3B + luciferase (F3)
16690772 Model organism tg6 mouse, hypoxia-independent EPO overexpression, Hct up to 0.89, multi-organ degeneration (F4)
18256329 Model organism Hematocrit-dependent pregnancy loss reversible by lowering Hct (F4; management rationale)
16254128 Model organism Endothelial activation/damage, reduced brain-vessel density (F4)
21859826 Model organism Glycocalyx near-abolished (0.52→0.13 µm, P<0.001) at high Hct (F4)
36966432 Diagnostic framework JAK2 exclusion as first step; EPO-based workup (F5)
28699191 Management target Hematocrit <45% via phlebotomy/HU (F5)
41347984 Phenotype & epidemiology Lifelong familial HE; EPO level distinguishes EPOR; incidence 0.13–4.1% (F6, F7)
42557631 Phenotype Hyperviscosity symptom complex; splenomegaly PV-specific (F6)
41123216 Management (2026) Avoid cytoreduction; phlebotomy + aspirin + CV risk optimization (F7)
23291219 Normal physiology HIF-2 regulates kidney/liver EPO synthesis — the circuit ECYT5 bypasses (F8)
9664155 Downstream signaling EPO→JAK2-STAT5; EPOR Y343/Y401 (F8)
21511372, 33456185 Differential diagnosis High-O₂-affinity Hb, left-shifted P50 (Section 10)

Evidence source types: human clinical/genetic (29514032, 41574959, 36966432, 41347984, 41123216, 42557631, 28699191, 21511372, 33456185); model organism (16690772, 18256329, 16254128, 21859826); molecular/in-vitro + review (9664155, 23291219, plus the Hep3B/luciferase work within 41574959).

Supported vs. Refuted Hypotheses

Supported: - ECYT5 is an autosomal dominant erythrocytosis caused by gain-of-function EPO variants (PMID: 29514032). - The c.32delG mechanism is a paradoxical gain of function via an intron-1 alternative transcript (PMID: 29514032). - A promoter variant (c.-136 G>A) creating a new HRE is a second causal mechanism (PMID: 41574959). - Pathology downstream of EPO excess is hyperviscosity/endothelial, demonstrated in tg6 mice (PMID: 16690772, PMID: 16254128, PMID: 21859826, PMID: 18256329).

Refuted / excluded: - ECYT5 is not a JAK2-mutated myeloproliferative neoplasm (no clonal transformation). - It is not caused by altered EPO protein structure or by oxygen-sensing-pathway genes (those define ECYT2–4). - It is not associated with low serum EPO (that pattern indicates EPOR mutations/PV).

Limitations and Knowledge Gaps

  • Extreme rarity: ECYT5 rests on essentially two reported kindreds (c.32delG and c.-136 G>A). No cohort-level data exist on penetrance, expressivity, long-term thrombotic rates, survival, or quality of life specific to ECYT5; prognosis and management are extrapolated from PV and the broader JAK2-unmutated category.
  • Extrapolated management: The hematocrit <45% target and aspirin recommendation derive from PV/erythrocytosis data, not ECYT5-specific trials. No randomized evidence exists for this ultra-rare entity.
  • Model fidelity: The tg6 mouse reaches more extreme hematocrit (0.85–0.89) than typical human ECYT5 and overexpresses EPO via a transgene rather than the specific human regulatory lesions, potentially overstating human risk. The Hep3B model addresses transcription but not systemic physiology.
  • Variant ascertainment: The promoter variant (c.-136 G>A) lies outside coding exons and could be missed by exome-only panels — a diagnostic gap.
  • Mechanistic inference: Steps linking EPO excess to the EPOR–JAK2–STAT5 cascade in ECYT5 patients are inferred from general EPO biology rather than demonstrated in ECYT5 tissue.
  • No data on epigenetics, modifier genes, single-cell/spatial profiling, or non-human natural disease specific to ECYT5.

Proposed Follow-up Experiments / Actions

  1. International kindred registry / variant catalog: Aggregate all reported ECYT5 families (and newly ascertained ones via GeneMatcher) to estimate penetrance, thrombotic incidence, and natural history.
  2. Promoter-aware sequencing: Recommend that hereditary-erythrocytosis panels explicitly cover the EPO promoter/5′UTR and intron 1 to capture c.-136 G>A–type and intron-1 transcript–activating variants that exome panels miss.
  3. Patient-derived models: Generate iPSC-derived erythroid cultures or CRISPR knock-in cell lines for both c.32delG and c.-136 G>A to directly quantify EPO output and confirm EPOR–JAK2–STAT5 over-activation in a human ECYT5 context.
  4. Transcript-level validation: Use targeted long-read RNA-seq in c.32delG carriers to confirm and quantify the intron-1–driven EPO transcript and its translation product in vivo.
  5. Thrombosis-risk and management study: Prospectively monitor hematocrit, thrombotic events, and outcomes under phlebotomy ± low-dose aspirin in known carriers to generate ECYT5-specific (rather than PV-extrapolated) management evidence.
  6. Pregnancy-management guidance: Given the tg6 reproductive data, develop hematocrit-control protocols for pregnant ECYT5 patients and document uteroplacental outcomes.
  7. Knock-in mouse model: Create a mouse carrying the exact human EPO alleles to improve mechanistic fidelity over the generic tg6 overexpression model.

Report compiled from 8 confirmed findings and 38 reviewed papers over 5 investigation iterations. All mechanistic and clinical claims are anchored to the cited PMIDs with verified abstract quotes.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 16
Resolved 16
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 16
On topic 6
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 26
Resolved 24
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 1
Terms whose name was checked 17
Terms named correctly 11
Terms named as a different term 3
Terms whose name is worth a second look 3

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:

  • HP:0002315 (1 mention) - the report calls it "Symptom"; HP calls it Headache
  • HP:0000989 (1 mention) - the report calls it "Symptom"; HP calls it Pruritus
  • HP:0200071 (1 mention) - the report calls it "Clinical sign"; HP calls it Peripheral vitreoretinal degeneration

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0005615 (obsolete extracellular space) (1 mention) - replaced by GO:0005576

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:0020059 (1 mention) - the report calls it "Increased circulating EPO"; HP calls it Increased red blood cell count, and lists "Increased RBC count" among its other names
  • CL:0000115 (2 mentions) - the report calls it "endothelial cell, downstream"; CL calls it endothelial cell
  • CL:0000764 (1 mention) - the report calls it "Tissue/cell level: Erythroid lineage"; CL calls it erythroid lineage cell**