👪

Inheritance

1

Autosomal dominant inheritance HP:0000006

FPDMM segregates as an autosomal dominant trait caused by heterozygous germline RUNX1 variants, which include whole-gene and intragenic deletions, frameshift and nonsense alleles acting by haploinsufficiency, and RUNT-domain missense alleles that can act in a dominant-negative fashion.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:37738626 SUPPORT Human Clinical

"Deleterious germ line RUNX1 variants cause the autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, platelet dysfunction, and a predisposition to hematologic malignancies (HMs)."

States the heterozygous germline cause and the two defining components of the phenotype.

⚙

Pathophysiology

7

RUNX1 Haploinsufficiency

Germline deletions, frameshift and nonsense RUNX1 alleles halve the dosage of the core binding factor alpha subunit that, with CBFB, drives the definitive haematopoietic transcriptional programme.

RUNX1 hgnc:10471

Downstream

Impaired Megakaryocyte Maturation Reduced RUNX1:CBFB transcriptional output fails to drive the megakaryocytic maturation programme, so progenitors arrest before polyploidization.

Platelet Dense Granule and Aggregation Defect RUNX1 directly transactivates genes required for dense granule biogenesis and agonist responsiveness; halved dosage underexpresses them.

Clonal Hematopoiesis and Somatic Second-Hit Acquisition Chronically reduced RUNX1 dosage gives the stem cell pool a competitive advantage, allowing clonal drift before any cooperating lesion is acquired.

Show evidence (1 reference)

PMID:37738626 SUPPORT Human Clinical

"Deleterious germ line RUNX1 variants cause the autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, platelet dysfunction, and a predisposition to hematologic malignancies (HMs)."

Identifies loss-of-function heterozygous RUNX1 alleles as the causal lesion.

RUNT Domain Dominant-Negative Activity

Missense alleles within the RUNT DNA-binding domain retain the ability to assemble with CBFB but cannot bind DNA productively, so they sequester the partner subunit and suppress the residual wild-type allele beyond simple loss of dosage.

RUNX1 hgnc:10471

Downstream

Impaired Megakaryocyte Maturation Mutant RUNT-domain protein sequesters CBFB and suppresses the residual wild-type allele, converging on the same maturation block as haploinsufficiency but from a lower effective activity.

Platelet Dense Granule and Aggregation Defect Dominant-negative suppression of RUNX1 target promoters underexpresses the same granule and signalling genes.

Clonal Hematopoiesis and Somatic Second-Hit Acquisition Dominant-negative alleles depress RUNX1 activity below the haploinsufficient level, and are associated with earlier and more frequent malignant progression.

Show evidence (1 reference)

PMID:24606315 SUPPORT In Vitro

"RUNX1 was shown to bind to the NF-E2 promoter in primary megakaryocytes, and wild-type RUNX1, but not FPD/AML mutants, was able to activate NF-E2 expression."

Shows FPD/AML mutant RUNX1 fails to transactivate a target promoter that wild-type RUNX1 activates, the functional signature of a dominant-negative allele.

Impaired Megakaryocyte Maturation

Reduced RUNX1 activity blocks megakaryocytic differentiation downstream of the megakaryocyte-erythroid progenitor, yielding small, hypolobated megakaryocytes and reduced proplatelet formation.

megakaryocyte CL:0000556

platelet formation GO:0030220 ↓ DECREASED

Animal models

RUNX1-edited rhesus macaque competitive repopulation model Rhesus macaque recapitulates Reproduces the megakaryocytic dysplasia and polyploidization defect seen in human FPDMM marrow.

Downstream

Thrombocytopenia Arrested, hypolobated megakaryocytes produce fewer proplatelets, lowering the circulating platelet count.

Show evidence (1 reference)

PMID:36322931 SUPPORT Model Organism

"Bone marrows developed megakaryocytic dysplasia similar to human FPDMM, and CD34+ HSPCs showed impaired in vitro megakaryocytic differentiation, with a striking defect in polyploidization."

A rhesus macaque RUNX1-edited model reproduces the megakaryocytic maturation and polyploidization defect seen in patients.

Platelet Dense Granule and Aggregation Defect

RUNX1 target genes required for dense granule biogenesis and for agonist-induced signalling are underexpressed, producing a qualitative platelet defect with impaired aggregation and secretion that is disproportionate to the platelet count.

Downstream

Thrombocytopenia The qualitative secretion and aggregation defect compounds the reduced platelet count, so bleeding exceeds what the count alone predicts.

Show evidence (2 references)

PMID:24606315 SUPPORT Human Clinical

"However, whereas the number of dense granules was markedly reduced, α-granule content was heterogeneous."

Documents selective dense granule reduction with relatively preserved alpha-granule content in an FPD/AML pedigree.

PMID:24606315 SUPPORT Human Clinical

"The FPD/AML platelet function defect represents a complex trait, and RUNX1 orchestrates platelet function by regulating diverse aspects of this process."

Frames the platelet functional defect as multifactorial and directly RUNX1-driven.

Thrombocytopenia

The combined maturation block and platelet functional defect produce a lifelong mild to moderate thrombocytopenia with a bleeding tendency typically milder than the count alone would predict.

Show evidence (2 references)

PMID:37738626 SUPPORT Human Clinical

"Seventy of 77 patients had thrombocytopenia, 18 of 18 had abnormal platelet aggregometry, 16 of 35 had decreased platelet dense granules, and 28 of 55 had abnormal bleeding scores."

Frequencies from the 111-patient prospective cohort, showing thrombocytopenia in the large majority alongside universally abnormal aggregometry.

PMID:33661592 SUPPORT Other

"RUNX1-FPDMM is characterized by thrombocytopenia with normal platelet size; bleeding is often greater than expected due to qualitative platelet dysfunction."

GeneReviews states the normal platelet size and the disproportion between bleeding and platelet count that distinguishes this disorder.

Clonal Hematopoiesis and Somatic Second-Hit Acquisition

RUNX1-haploinsufficient stem cells acquire a competitive advantage and expand clonally, accumulating somatic lesions in the second RUNX1 allele, in ASXL1, and in other myeloid drivers, and acquiring monosomy 7.

hematopoietic stem cell CL:0000037

Animal models

RUNX1-edited rhesus macaque competitive repopulation model Rhesus macaque recapitulates RUNX1-edited clones expanded over control-edited clones in vivo, showing that reduced RUNX1 dosage alone confers a clonal advantage.

Downstream

Myeloid Transformation Clones carrying cooperating somatic lesions outgrow the residual compartment and progress to myelodysplastic syndrome and acute myeloid leukaemia.

Show evidence (1 reference)

PMID:36322931 SUPPORT Model Organism

"In both animals, RUNX1-edited cells expanded over time compared with AAVS1-edited cells."

In vivo evidence that reduced RUNX1 dosage alone confers a clonal competitive advantage, before any cooperating somatic lesion.

Myeloid Transformation

Clones bearing second hits progress to myelodysplastic syndrome and acute myeloid leukaemia, the defining malignant outcome of the disorder and the reason surveillance is offered from childhood.

myeloid cell differentiation GO:0030099 ⚠ ABNORMAL

Show evidence (1 reference)

PMID:41924923 SUPPORT Human Clinical

"RUNX1 familial platelet disorder (RUNX1-FPD) is associated with a 35% to 50% lifetime risk of hematologic malignancy (HM), and like all germline HM predisposition syndromes, can only be cured with allogeneic hematopoietic stem cell transplantation (HSCT)."

Quantifies the lifetime malignancy risk that defines the disorder.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

10

Blood 9

Thrombocytopenia HP:0001873

Temporal: CHRONIC

Show evidence (1 reference)

PMID:37738626 SUPPORT Human Clinical

"Deleterious germ line RUNX1 variants cause the autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, platelet dysfunction, and a predisposition to hematologic malignancies (HMs)."

Names thrombocytopenia as a defining feature of the disorder.

Impaired Platelet Aggregation HP:0003540

Show evidence (1 reference)

PMID:24606315 SUPPORT Human Clinical

"A severe decrease in platelet aggregation, defective αIIb β3 integrin activation and combined αδ storage pool deficiency were found."

Lumiaggregometry in an FPD/AML pedigree documenting the aggregation defect.

Platelet Dense Granule Deficiency Reduced platelet dense granules HP:0033535

Show evidence (2 references)

PMID:24606315 SUPPORT Human Clinical

"However, whereas the number of dense granules was markedly reduced, α-granule content was heterogeneous."

Establishes dense granule reduction as the consistent granule abnormality, in contrast to the heterogeneous alpha-granule content.

PMID:24606315 SUPPORT Human Clinical

"A severe decrease in platelet aggregation, defective αIIb β3 integrin activation and combined αδ storage pool deficiency were found."

Records the combined dense and alpha granule storage pool deficiency in the same FPD/AML pedigree.

Bruising Tendency Bruising susceptibility HP:0000978

Show evidence (1 reference)

PMID:33661592 SUPPORT Other

"RUNX1 familial platelet disorder with associated myeloid malignancies (RUNX1-FPDMM) is characterized by prolonged bleeding and/or easy bruising and an increased risk of developing a hematologic malignancy."

GeneReviews names easy bruising as a defining presenting feature.

Epistaxis HP:0000421

Show evidence (1 reference)

PMID:37738626 SUPPORT Human Clinical

"Seventy of 77 patients had thrombocytopenia, 18 of 18 had abnormal platelet aggregometry, 16 of 35 had decreased platelet dense granules, and 28 of 55 had abnormal bleeding scores."

Roughly half the assessed cohort had abnormal bleeding scores, the composite measure that captures mucocutaneous bleeding including epistaxis.

Myelodysplastic Syndrome Myelodysplasia HP:0002863

Show evidence (1 reference)

PMID:41924923 SUPPORT Human Clinical

"RUNX1 familial platelet disorder (RUNX1-FPD) is associated with a 35% to 50% lifetime risk of hematologic malignancy (HM), and like all germline HM predisposition syndromes, can only be cured with allogeneic hematopoietic stem cell transplantation (HSCT)."

Gives the lifetime hematologic malignancy risk.

Acute Myeloid Leukemia HP:0004808

Show evidence (1 reference)

PMID:41924923 SUPPORT Human Clinical

"RUNX1 familial platelet disorder (RUNX1-FPD) is associated with a 35% to 50% lifetime risk of hematologic malignancy (HM), and like all germline HM predisposition syndromes, can only be cured with allogeneic hematopoietic stem cell transplantation (HSCT)."

Gives the lifetime hematologic malignancy risk.

T-Cell Acute Lymphoblastic Leukemia T-cell acute lymphoblastic leukemias HP:0006727

Show evidence (1 reference)

PMID:33661592 SUPPORT Other

"T- and B-cell acute lymphoblastic leukemias and lymphomas have also been reported, as well as skin manifestations (e.g., eczema, psoriasis)."

GeneReviews records lymphoid malignancy alongside the myeloid spectrum, establishing that the predisposition is not myeloid-restricted.

Menorrhagia HP:0000132

Show evidence (1 reference)

PMID:33661592 SUPPORT Other

"RUNX1 familial platelet disorder with associated myeloid malignancies (RUNX1-FPDMM) is characterized by prolonged bleeding and/or easy bruising and an increased risk of developing a hematologic malignancy."

Prolonged bleeding is the GeneReviews-level feature under which menorrhagia falls; the chapter does not give a separate menorrhagia frequency.

Immune 1

Eczema and Psoriasis Eczematoid dermatitis HP:0000964

Show evidence (2 references)

PMID:33661592 SUPPORT Other

"T- and B-cell acute lymphoblastic leukemias and lymphomas have also been reported, as well as skin manifestations (e.g., eczema, psoriasis)."

GeneReviews lists eczema and psoriasis as recognised skin manifestations of the disorder.

PMID:37738626 SUPPORT Human Clinical

"Moreover, 42 of 45 patients had allergic symptoms, and 24 of 30 had gastrointestinal (GI) symptoms."

Quantifies how common allergic manifestations are in the prospective cohort, well above any reporting threshold.

🧬

Genetic Associations

1

RUNX1

Gene: RUNX1 hgnc:10471 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:24606315 SUPPORT In Vitro

"RUNX1 was shown to bind to the NF-E2 promoter in primary megakaryocytes, and wild-type RUNX1, but not FPD/AML mutants, was able to activate NF-E2 expression."

Functional evidence separating wild-type from FPD/AML mutant RUNX1 activity at a megakaryocytic target promoter.

PMID:37738626 SUPPORT Human Clinical

"Of 111 patients, 19 were diagnosed with HMs, including myelodysplastic syndrome, acute myeloid leukemia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia, and smoldering myeloma."

Cross-sectional malignancy count in the prospective cohort. Note this is a point-in-time proportion, not the 35-50 percent lifetime risk, which is a different measure.

PMID:33661592 SUPPORT Other

"Most individuals diagnosed with RUNX1-FPDMM inherited the causative pathogenic variant from a parent who may or may not have recognized manifestations of the disorder."

Records incomplete penetrance of even the platelet phenotype: transmitting parents may be clinically unrecognised.

💊

Medical Actions

4

Allogeneic Hematopoietic Stem Cell Transplantation

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

Platform: Cell therapy

Because the germline RUNX1 lesion persists in every surviving stem cell, chemotherapy cannot eradicate the predisposition and allogeneic HSCT is the only curative option. Whether to transplant preemptively, before overt malignancy, remains unsettled and is approached through shared decision-making that weighs clonal evolution, family history and bleeding burden against transplant risk.

Mechanism Target:

Clonal Hematopoiesis and Somatic Second-Hit Acquisition — Replacing the haploinsufficient stem cell compartment with donor cells removes the substrate on which second hits accumulate.

Show evidence (2 references)

PMID:41924923 SUPPORT Human Clinical

"RUNX1 familial platelet disorder (RUNX1-FPD) is associated with a 35% to 50% lifetime risk of hematologic malignancy (HM), and like all germline HM predisposition syndromes, can only be cured with allogeneic hematopoietic stem cell transplantation (HSCT)."

States transplant as the only curative modality for the predisposition.

PMID:41924923 SUPPORT Human Clinical

"However, there is not yet a consensus on the use of preemptive HSCT for RUNX1-FPD."

Records that preemptive transplant timing is genuinely unsettled rather than a settled standard of care.

Antifibrinolytic and Platelet Transfusion Support for Bleeding

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Haemostatic cover for surgery, injury and dental work uses clotting promotors such as desmopressin, epsilon aminocaproic acid and tranexamic acid, with platelet transfusion reserved for severe bleeding or high-risk procedures.

Mechanism Target:

Platelet Dense Granule and Aggregation Defect — Antifibrinolytics stabilise clot rather than correcting the platelet defect, compensating for impaired secretion and aggregation.

Show evidence (1 reference)

PMID:33661592 SUPPORT Other

"Use of clotting promotors (e.g., desmopressin, epsilon aminocaproic acid, tranexamic acid) in instances of surgeries, injuries, or dental treatments; platelet transfusions may be used for severe bleeding or procedures with a high bleeding risk."

GeneReviews management recommendation for haemostatic cover.

Malignancy Surveillance

Action: Supportive Care NCIT:C15747

Platform: Other

Carriers are followed with clinical examination every six to twelve months and a complete blood count with differential every three to four months, with marrow examination triggered by constitutional symptoms or count abnormalities. Medications that impair platelet function, high-trauma activities, unnecessary radiation and smoking are avoided.

Mechanism Target:

Clonal Hematopoiesis and Somatic Second-Hit Acquisition — Serial counts and marrow assessment aim to detect clonal progression before overt malignancy, when transplant outcomes are better.

Show evidence (2 references)

PMID:33661592 SUPPORT Other

"Complete blood count with differential every three to four months; bone marrow examination if constitutional symptoms and/or abnormalities on complete blood count are identified; skin exam as needed."

The GeneReviews surveillance schedule.

PMID:33661592 SUPPORT Other

"Medications that affect platelet function (e.g., NSAIDs and antiplatelet agents), activities with a high risk of trauma (e.g., high-risk contact sports), unnecessary radiation, and smoking."

The agents and circumstances GeneReviews advises avoiding.

Gene Correction of Hematopoietic Stem Cells

Action: gene therapy Ontology label: Gene Therapy NCIT:C15238

Platform: Gene editing

Autologous gene correction is under consideration but faces a specific mechanistic obstacle: corrected stem cells show no competitive advantage over RUNX1-heterozygous cells, so a corrected fraction may not outcompete the pre-existing mutant clone.

Show evidence (1 reference)

PMID:36322931 REFUTE Model Organism

"In conclusion, the lack of a competitive advantage for wildtype or control-edited HSPCs over RUNX1 heterozygous-mutated HSPCs long term in our preclinical model suggests that gene correction approaches for FPDMM will be challenging, particularly to reverse myelodysplastic syndrome/ acute myeloid..."

A primate competitive repopulation model argues against gene correction being sufficient, so this is cited as evidence against the approach rather than for it.

🔬

Diagnosis

1

Germline RUNX1 molecular genetic testing on cultured skin fibroblasts

Germline confirmation should be performed on a non-haematopoietic tissue, typically cultured skin fibroblasts, rather than on blood or marrow. Acquired uniparental disomy of chromosome 21 in the haematopoietic compartment can cause preferential loss of the variant-bearing chromosome and a false negative result on blood-derived DNA. The converse error also occurs: a somatic RUNX1 variant in a sporadic myeloid malignancy can be misread as germline.

genetic testing NCIT:C15709

Results: A heterozygous germline pathogenic RUNX1 variant confirmed in a non-haematopoietic tissue establishes the diagnosis.

Show evidence (2 references)

PMID:33661592 SUPPORT Other

"If the RUNX1 pathogenic variant identified in the proband is not detected in parental DNA, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility either of a false negative result in a parent (due to preferential loss of the chromosome with..."

GeneReviews states the preferential-chromosome-loss mechanism that produces false negative germline results, the reason a non-haematopoietic tissue is required.

PMID:33661592 SUPPORT Other

"The diagnosis of RUNX1-FPDMM is established in a proband with suggestive findings and a heterozygous germline pathogenic variant in RUNX1 identified by molecular genetic testing."

Defines the molecular diagnostic criterion.

🐁

Animal Models

1

RUNX1-edited rhesus macaque competitive repopulation model

Autologous transplant of mixed RUNX1-edited and control-edited HSPCs, tracking mutant allele frequency over time. Built specifically to compare the fitness of corrected against RUNX1-heterozygous cells in vivo.

Species

Rhesus macaque

Genotype

CRISPR/Cas9 NHEJ-edited RUNX1 versus AAVS1 safe-harbour control, autologous transplant

Publication

PMID:36322931

Pathograph links

Impaired Megakaryocyte Maturation recapitulates fidelity: moderate Reproduces the megakaryocytic dysplasia and polyploidization defect seen in human FPDMM marrow.

Limitations: Uses somatic gene editing of transplanted HSPCs rather than a constitutional heterozygous allele, so it models the haematopoietic consequence without the germline context, and the animals were followed for a few years rather than a human lifetime.

Readouts

Megakaryocytic polyploidization in vitro

Direction: DECREASED

Interpretation: Direct cellular correlate of the maturation-arrest node.

Show evidence (1 reference)

PMID:36322931 SUPPORT Model Organism

"Bone marrows developed megakaryocytic dysplasia similar to human FPDMM, and CD34+ HSPCs showed impaired in vitro megakaryocytic differentiation, with a striking defect in polyploidization."

Reports the polyploidization measurement behind this readout.

Clonal Hematopoiesis and Somatic Second-Hit Acquisition recapitulates fidelity: moderate RUNX1-edited clones expanded over control-edited clones in vivo, showing that reduced RUNX1 dosage alone confers a clonal advantage.

Limitations: Clonal expansion was observed without progression to overt malignancy over the study period, so the model captures the predisposing step but not transformation.

Show evidence (1 reference)

PMID:36322931 SUPPORT Model Organism

"In both animals, RUNX1-edited cells expanded over time compared with AAVS1-edited cells."

Establishes the competitive advantage of RUNX1-haploinsufficient cells in vivo.

{ }

Source YAML

click to show

name: RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancy
creation_date: "2026-08-31T00:00:00Z"
description: >-
  RUNX1 familial platelet disorder with associated myeloid malignancy (FPDMM)
  is an autosomal dominant disorder caused by heterozygous germline variants
  in the RUNX1 transcription factor. It presents with lifelong mild to
  moderate thrombocytopenia and a qualitative platelet aggregation defect,
  often mild enough to escape attention for years, together with a lifetime
  risk of myelodysplastic syndrome and acute myeloid leukaemia on the order
  of 40 percent. The germline variant alone produces the platelet phenotype;
  malignant transformation requires acquisition of somatic second hits, most
  characteristically a second RUNX1 allele, ASXL1, or monosomy 7.
category: Mendelian
parents:
- hereditary disease
synonyms:
- familial platelet disorder with predisposition to acute myelogenous leukemia
- FPD/AML
- FPDMM
- familial platelet disorder with associated myeloid malignancy
- RUNX1 familial platelet disorder
disease_term:
  preferred_term: RUNX1 familial platelet disorder with associated myeloid malignancy
  term:
    id: MONDO:0100083
    label: hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    FPDMM segregates as an autosomal dominant trait caused by heterozygous
    germline RUNX1 variants, which include whole-gene and intragenic
    deletions, frameshift and nonsense alleles acting by haploinsufficiency,
    and RUNT-domain missense alleles that can act in a dominant-negative
    fashion.
  evidence:
  - reference: PMID:37738626
    reference_title: "Natural history study of patients with familial platelet disorder with associated myeloid malignancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deleterious germ line RUNX1 variants cause the autosomal dominant familial
      platelet disorder with associated myeloid malignancy (FPDMM),
      characterized by thrombocytopenia, platelet dysfunction, and a
      predisposition to hematologic malignancies (HMs).
    explanation: >-
      States the heterozygous germline cause and the two defining components of
      the phenotype.
pathophysiology:
- name: RUNX1 Haploinsufficiency
  biological_scale: MOLECULAR
  description: >-
    Germline deletions, frameshift and nonsense RUNX1 alleles halve the
    dosage of the core binding factor alpha subunit that, with CBFB, drives
    the definitive haematopoietic transcriptional programme.
  genes:
  - preferred_term: RUNX1
    term:
      id: hgnc:10471
      label: RUNX1
  evidence:
  - reference: PMID:37738626
    reference_title: "Natural history study of patients with familial platelet disorder with associated myeloid malignancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deleterious germ line RUNX1 variants cause the autosomal dominant familial
      platelet disorder with associated myeloid malignancy (FPDMM),
      characterized by thrombocytopenia, platelet dysfunction, and a
      predisposition to hematologic malignancies (HMs).
    explanation: >-
      Identifies loss-of-function heterozygous RUNX1 alleles as the causal lesion.
  downstream:
  - target: Impaired Megakaryocyte Maturation
    description: >-
      Reduced RUNX1:CBFB transcriptional output fails to drive the
      megakaryocytic maturation programme, so progenitors arrest before
      polyploidization.
  - target: Platelet Dense Granule and Aggregation Defect
    description: >-
      RUNX1 directly transactivates genes required for dense granule
      biogenesis and agonist responsiveness; halved dosage underexpresses
      them.
  - target: Clonal Hematopoiesis and Somatic Second-Hit Acquisition
    description: >-
      Chronically reduced RUNX1 dosage gives the stem cell pool a
      competitive advantage, allowing clonal drift before any cooperating
      lesion is acquired.
- name: RUNT Domain Dominant-Negative Activity
  biological_scale: MOLECULAR
  description: >-
    Missense alleles within the RUNT DNA-binding domain retain the ability to
    assemble with CBFB but cannot bind DNA productively, so they sequester
    the partner subunit and suppress the residual wild-type allele beyond
    simple loss of dosage.
  evidence:
  - reference: PMID:24606315
    reference_title: "Mechanisms underlying platelet function defect in a pedigree with familial platelet disorder with a predisposition to acute myelogenous leukemia: potential role for candidate RUNX1 targets."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      RUNX1 was shown to bind to the NF-E2 promoter in primary megakaryocytes,
      and wild-type RUNX1, but not FPD/AML mutants, was able to activate NF-E2
      expression.
    explanation: >-
      Shows FPD/AML mutant RUNX1 fails to transactivate a target promoter that
      wild-type RUNX1 activates, the functional signature of a dominant-negative
      allele.
  genes:
  - preferred_term: RUNX1
    term:
      id: hgnc:10471
      label: RUNX1
  downstream:
  - target: Impaired Megakaryocyte Maturation
    description: >-
      Mutant RUNT-domain protein sequesters CBFB and suppresses the residual
      wild-type allele, converging on the same maturation block as
      haploinsufficiency but from a lower effective activity.
  - target: Platelet Dense Granule and Aggregation Defect
    description: >-
      Dominant-negative suppression of RUNX1 target promoters underexpresses
      the same granule and signalling genes.
  - target: Clonal Hematopoiesis and Somatic Second-Hit Acquisition
    description: >-
      Dominant-negative alleles depress RUNX1 activity below the
      haploinsufficient level, and are associated with earlier and more
      frequent malignant progression.
- name: Impaired Megakaryocyte Maturation
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  biological_processes:
  - preferred_term: platelet formation
    term:
      id: GO:0030220
      label: platelet formation
    modifier: DECREASED
  description: >-
    Reduced RUNX1 activity blocks megakaryocytic differentiation downstream
    of the megakaryocyte-erythroid progenitor, yielding small, hypolobated
    megakaryocytes and reduced proplatelet formation.
  evidence:
  - reference: PMID:36322931
    reference_title: "A RUNX1-FPDMM rhesus macaque model reproduces the human phenotype and predicts challenges to curative gene therapies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Bone marrows developed megakaryocytic dysplasia similar to human FPDMM,
      and CD34+ HSPCs showed impaired in vitro megakaryocytic differentiation,
      with a striking defect in polyploidization.
    explanation: >-
      A rhesus macaque RUNX1-edited model reproduces the megakaryocytic
      maturation and polyploidization defect seen in patients.
  downstream:
  - target: Thrombocytopenia
    description: >-
      Arrested, hypolobated megakaryocytes produce fewer proplatelets, lowering
      the circulating platelet count.
- name: Platelet Dense Granule and Aggregation Defect
  biological_scale: CELLULAR
  description: >-
    RUNX1 target genes required for dense granule biogenesis and for
    agonist-induced signalling are underexpressed, producing a qualitative
    platelet defect with impaired aggregation and secretion that is
    disproportionate to the platelet count.
  evidence:
  - reference: PMID:24606315
    reference_title: "Mechanisms underlying platelet function defect in a pedigree with familial platelet disorder with a predisposition to acute myelogenous leukemia: potential role for candidate RUNX1 targets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, whereas the number of dense granules was markedly reduced,
      α-granule content was heterogeneous.
    explanation: >-
      Documents selective dense granule reduction with relatively preserved
      alpha-granule content in an FPD/AML pedigree.
  - reference: PMID:24606315
    reference_title: "Mechanisms underlying platelet function defect in a pedigree with familial platelet disorder with a predisposition to acute myelogenous leukemia: potential role for candidate RUNX1 targets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The FPD/AML platelet function defect represents a complex trait, and RUNX1
      orchestrates platelet function by regulating diverse aspects of this
      process.
    explanation: >-
      Frames the platelet functional defect as multifactorial and directly
      RUNX1-driven.
  downstream:
  - target: Thrombocytopenia
    description: >-
      The qualitative secretion and aggregation defect compounds the reduced
      platelet count, so bleeding exceeds what the count alone predicts.
- name: Thrombocytopenia
  biological_scale: ORGANISM
  description: >-
    The combined maturation block and platelet functional defect produce a
    lifelong mild to moderate thrombocytopenia with a bleeding tendency
    typically milder than the count alone would predict.
  evidence:
  - reference: PMID:37738626
    reference_title: "Natural history study of patients with familial platelet disorder with associated myeloid malignancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seventy of 77 patients had thrombocytopenia, 18 of 18 had abnormal platelet
      aggregometry, 16 of 35 had decreased platelet dense granules, and 28 of 55
      had abnormal bleeding scores.
    explanation: >-
      Frequencies from the 111-patient prospective cohort, showing thrombocytopenia
      in the large majority alongside universally abnormal aggregometry.
  - reference: PMID:33661592
    reference_title: "RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      RUNX1-FPDMM is characterized by thrombocytopenia with normal platelet size;
      bleeding is often greater than expected due to qualitative platelet
      dysfunction.
    explanation: >-
      GeneReviews states the normal platelet size and the disproportion between
      bleeding and platelet count that distinguishes this disorder.
- name: Clonal Hematopoiesis and Somatic Second-Hit Acquisition
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  description: >-
    RUNX1-haploinsufficient stem cells acquire a competitive advantage and
    expand clonally, accumulating somatic lesions in the second RUNX1 allele,
    in ASXL1, and in other myeloid drivers, and acquiring monosomy 7.
  evidence:
  - reference: PMID:36322931
    reference_title: "A RUNX1-FPDMM rhesus macaque model reproduces the human phenotype and predicts challenges to curative gene therapies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In both animals, RUNX1-edited cells expanded over time compared with
      AAVS1-edited cells.
    explanation: >-
      In vivo evidence that reduced RUNX1 dosage alone confers a clonal
      competitive advantage, before any cooperating somatic lesion.
  downstream:
  - target: Myeloid Transformation
    description: >-
      Clones carrying cooperating somatic lesions outgrow the residual
      compartment and progress to myelodysplastic syndrome and acute myeloid
      leukaemia.
- name: Myeloid Transformation
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: myeloid cell differentiation
    term:
      id: GO:0030099
      label: myeloid cell differentiation
    modifier: ABNORMAL
  description: >-
    Clones bearing second hits progress to myelodysplastic syndrome and acute
    myeloid leukaemia, the defining malignant outcome of the disorder and the
    reason surveillance is offered from childhood.
  evidence:
  - reference: PMID:41924923
    reference_title: "Preemptive hematopoietic stem cell transplantation in RUNX1 familial platelet disorder: a shared decision-making framework."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RUNX1 familial platelet disorder (RUNX1-FPD) is associated with a 35% to
      50% lifetime risk of hematologic malignancy (HM), and like all germline HM
      predisposition syndromes, can only be cured with allogeneic hematopoietic
      stem cell transplantation (HSCT).
    explanation: >-
      Quantifies the lifetime malignancy risk that defines the disorder.
phenotypes:
- category: Hematologic
  name: Thrombocytopenia
  description: >-
    Lifelong mild to moderate thrombocytopenia, typically in the range of 50
    to 150 x 10^9/L, present from childhood and stable rather than
    progressive in the absence of transformation.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
    temporality: CHRONIC
  evidence:
  - reference: PMID:37738626
    reference_title: "Natural history study of patients with familial platelet disorder with associated myeloid malignancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deleterious germ line RUNX1 variants cause the autosomal dominant familial
      platelet disorder with associated myeloid malignancy (FPDMM),
      characterized by thrombocytopenia, platelet dysfunction, and a
      predisposition to hematologic malignancies (HMs).
    explanation: Names thrombocytopenia as a defining feature of the disorder.
- category: Hematologic
  name: Impaired Platelet Aggregation
  description: >-
    Platelets show reduced aggregation to collagen, ADP and epinephrine, a
    qualitative defect that contributes to bleeding out of proportion to the
    platelet count.
  phenotype_term:
    preferred_term: Impaired platelet aggregation
    term:
      id: HP:0003540
      label: Impaired platelet aggregation
  evidence:
  - reference: PMID:24606315
    reference_title: "Mechanisms underlying platelet function defect in a pedigree with familial platelet disorder with a predisposition to acute myelogenous leukemia: potential role for candidate RUNX1 targets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A severe decrease in platelet aggregation, defective αIIb β3 integrin
      activation and combined αδ storage pool deficiency were found.
    explanation: >-
      Lumiaggregometry in an FPD/AML pedigree documenting the aggregation defect.
- category: Hematologic
  name: Platelet Dense Granule Deficiency
  description: >-
    Reduced dense granule number and impaired granule secretion reflect loss
    of RUNX1-dependent transcription of granule biogenesis genes.
  phenotype_term:
    preferred_term: Reduced platelet dense granules
    term:
      id: HP:0033535
      label: Reduced platelet dense granules
  evidence:
  - reference: PMID:24606315
    reference_title: "Mechanisms underlying platelet function defect in a pedigree with familial platelet disorder with a predisposition to acute myelogenous leukemia: potential role for candidate RUNX1 targets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, whereas the number of dense granules was markedly reduced,
      α-granule content was heterogeneous.
    explanation: >-
      Establishes dense granule reduction as the consistent granule abnormality,
      in contrast to the heterogeneous alpha-granule content.
  - reference: PMID:24606315
    reference_title: "Mechanisms underlying platelet function defect in a pedigree with familial platelet disorder with a predisposition to acute myelogenous leukemia: potential role for candidate RUNX1 targets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A severe decrease in platelet aggregation, defective αIIb β3 integrin
      activation and combined αδ storage pool deficiency were found.
    explanation: >-
      Records the combined dense and alpha granule storage pool deficiency in the
      same FPD/AML pedigree.
- category: Hematologic
  name: Bruising Tendency
  description: >-
    Easy bruising is a common presenting feature and is often the only
    manifestation before malignancy develops.
  evidence:
  - reference: PMID:33661592
    reference_title: "RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      RUNX1 familial platelet disorder with associated myeloid malignancies
      (RUNX1-FPDMM) is characterized by prolonged bleeding and/or easy bruising and
      an increased risk of developing a hematologic malignancy.
    explanation: >-
      GeneReviews names easy bruising as a defining presenting feature.
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
- category: Hematologic
  name: Epistaxis
  description: >-
    Mucocutaneous bleeding, particularly epistaxis, reflects the combined
    quantitative and qualitative platelet defect.
  evidence:
  - reference: PMID:37738626
    reference_title: "Natural history study of patients with familial platelet disorder with associated myeloid malignancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seventy of 77 patients had thrombocytopenia, 18 of 18 had abnormal platelet
      aggregometry, 16 of 35 had decreased platelet dense granules, and 28 of 55
      had abnormal bleeding scores.
    explanation: >-
      Roughly half the assessed cohort had abnormal bleeding scores, the composite
      measure that captures mucocutaneous bleeding including epistaxis.
  phenotype_term:
    preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
- category: Neoplastic
  name: Myelodysplastic Syndrome
  description: >-
    Myelodysplastic syndrome develops in a substantial minority of carriers,
    with a median age at onset in the third to fourth decade but well
    described in childhood.
  phenotype_term:
    preferred_term: Myelodysplasia
    term:
      id: HP:0002863
      label: Myelodysplasia
  evidence:
  - reference: PMID:41924923
    reference_title: "Preemptive hematopoietic stem cell transplantation in RUNX1 familial platelet disorder: a shared decision-making framework."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RUNX1 familial platelet disorder (RUNX1-FPD) is associated with a 35% to
      50% lifetime risk of hematologic malignancy (HM), and like all germline HM
      predisposition syndromes, can only be cured with allogeneic hematopoietic
      stem cell transplantation (HSCT).
    explanation: Gives the lifetime hematologic malignancy risk.
- category: Neoplastic
  name: Acute Myeloid Leukemia
  description: >-
    Acute myeloid leukaemia is the defining malignant outcome and the reason
    marrow surveillance is offered to carriers from childhood.
  phenotype_term:
    preferred_term: Acute myeloid leukemia
    term:
      id: HP:0004808
      label: Acute myeloid leukemia
  evidence:
  - reference: PMID:41924923
    reference_title: "Preemptive hematopoietic stem cell transplantation in RUNX1 familial platelet disorder: a shared decision-making framework."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RUNX1 familial platelet disorder (RUNX1-FPD) is associated with a 35% to
      50% lifetime risk of hematologic malignancy (HM), and like all germline HM
      predisposition syndromes, can only be cured with allogeneic hematopoietic
      stem cell transplantation (HSCT).
    explanation: Gives the lifetime hematologic malignancy risk.
- category: Neoplastic
  name: T-Cell Acute Lymphoblastic Leukemia
  description: >-
    A minority of carriers develop T-cell acute lymphoblastic leukaemia
    rather than a myeloid malignancy, so the predisposition is not strictly
    myeloid-restricted.
  evidence:
  - reference: PMID:33661592
    reference_title: "RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      T- and B-cell acute lymphoblastic leukemias and lymphomas have also been
      reported, as well as skin manifestations (e.g., eczema, psoriasis).
    explanation: >-
      GeneReviews records lymphoid malignancy alongside the myeloid spectrum,
      establishing that the predisposition is not myeloid-restricted.
  phenotype_term:
    preferred_term: T-cell acute lymphoblastic leukemia
    term:
      id: HP:0006727
      label: T-cell acute lymphoblastic leukemias
- category: Dermatologic
  name: Eczema and Psoriasis
  description: >-
    Eczema and psoriasis are reported skin manifestations of RUNX1-FPDMM, and
    allergic symptoms were near-universal in the prospective natural history
    cohort. They are easily missed as part of the syndrome rather than
    coincidental atopy.
  phenotype_term:
    preferred_term: Eczema
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  evidence:
  - reference: PMID:33661592
    reference_title: "RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      T- and B-cell acute lymphoblastic leukemias and lymphomas have also been
      reported, as well as skin manifestations (e.g., eczema, psoriasis).
    explanation: >-
      GeneReviews lists eczema and psoriasis as recognised skin manifestations
      of the disorder.
  - reference: PMID:37738626
    reference_title: "Natural history study of patients with familial platelet disorder with associated myeloid malignancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, 42 of 45 patients had allergic symptoms, and 24 of 30 had
      gastrointestinal (GI) symptoms.
    explanation: >-
      Quantifies how common allergic manifestations are in the prospective
      cohort, well above any reporting threshold.
- category: Gynecologic
  name: Menorrhagia
  description: >-
    Heavy menstrual bleeding follows from the combined quantitative and
    qualitative platelet defect and is a common reason carriers come to
    haematological attention.
  phenotype_term:
    preferred_term: Menorrhagia
    term:
      id: HP:0000132
      label: Menorrhagia
  evidence:
  - reference: PMID:33661592
    reference_title: "RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      RUNX1 familial platelet disorder with associated myeloid malignancies
      (RUNX1-FPDMM) is characterized by prolonged bleeding and/or easy bruising and
      an increased risk of developing a hematologic malignancy.
    explanation: >-
      Prolonged bleeding is the GeneReviews-level feature under which menorrhagia
      falls; the chapter does not give a separate menorrhagia frequency.
genetic:
- name: RUNX1
  notes: >-
    Heterozygous germline RUNX1 variants cause the disorder. Whole-gene and
    intragenic deletions and truncating alleles act by haploinsufficiency;
    RUNT-domain missense alleles retain CBFB binding but cannot transactivate
    target promoters and behave as dominant negatives. Somatic second hits in
    TET2, DNMT3A, ASXL1, or the second RUNX1 allele, often via acquired
    uniparental disomy of chromosome 21, accompany malignant progression.
  gene_term:
    preferred_term: RUNX1
    term:
      id: hgnc:10471
      label: RUNX1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:24606315
    reference_title: "Mechanisms underlying platelet function defect in a pedigree with familial platelet disorder with a predisposition to acute myelogenous leukemia: potential role for candidate RUNX1 targets."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      RUNX1 was shown to bind to the NF-E2 promoter in primary megakaryocytes,
      and wild-type RUNX1, but not FPD/AML mutants, was able to activate NF-E2
      expression.
    explanation: >-
      Functional evidence separating wild-type from FPD/AML mutant RUNX1 activity
      at a megakaryocytic target promoter.
  - reference: PMID:37738626
    reference_title: "Natural history study of patients with familial platelet disorder with associated myeloid malignancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 111 patients, 19 were diagnosed with HMs, including myelodysplastic
      syndrome, acute myeloid leukemia, chronic myelomonocytic leukemia, acute
      lymphoblastic leukemia, and smoldering myeloma.
    explanation: >-
      Cross-sectional malignancy count in the prospective cohort. Note this is a
      point-in-time proportion, not the 35-50 percent lifetime risk, which is a
      different measure.
  - reference: PMID:33661592
    reference_title: "RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Most individuals diagnosed with RUNX1-FPDMM inherited the causative
      pathogenic variant from a parent who may or may not have recognized
      manifestations of the disorder.
    explanation: >-
      Records incomplete penetrance of even the platelet phenotype: transmitting
      parents may be clinically unrecognised.
diagnosis:
- name: Germline RUNX1 molecular genetic testing on cultured skin fibroblasts
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Germline confirmation should be performed on a non-haematopoietic tissue,
    typically cultured skin fibroblasts, rather than on blood or marrow. Acquired
    uniparental disomy of chromosome 21 in the haematopoietic compartment can
    cause preferential loss of the variant-bearing chromosome and a false
    negative result on blood-derived DNA. The converse error also occurs: a
    somatic RUNX1 variant in a sporadic myeloid malignancy can be misread as
    germline.
  results: >-
    A heterozygous germline pathogenic RUNX1 variant confirmed in a
    non-haematopoietic tissue establishes the diagnosis.
  evidence:
  - reference: PMID:33661592
    reference_title: "RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      If the RUNX1 pathogenic variant identified in the proband is not detected in
      parental DNA, the recurrence risk to sibs is slightly greater than that of
      the general population because of the possibility either of a false negative
      result in a parent (due to preferential loss of the chromosome with the
      RUNX1 pathogenic variant), or of parental germline mosaicism.
    explanation: >-
      GeneReviews states the preferential-chromosome-loss mechanism that produces
      false negative germline results, the reason a non-haematopoietic tissue is
      required.
  - reference: PMID:33661592
    reference_title: "RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of RUNX1-FPDMM is established in a proband with suggestive
      findings and a heterozygous germline pathogenic variant in RUNX1 identified
      by molecular genetic testing.
    explanation: Defines the molecular diagnostic criterion.
treatments:
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    Because the germline RUNX1 lesion persists in every surviving stem cell,
    chemotherapy cannot eradicate the predisposition and allogeneic HSCT is the
    only curative option. Whether to transplant preemptively, before overt
    malignancy, remains unsettled and is approached through shared
    decision-making that weighs clonal evolution, family history and bleeding
    burden against transplant risk.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Clonal Hematopoiesis and Somatic Second-Hit Acquisition
    description: >-
      Replacing the haploinsufficient stem cell compartment with donor cells
      removes the substrate on which second hits accumulate.
  evidence:
  - reference: PMID:41924923
    reference_title: "Preemptive hematopoietic stem cell transplantation in RUNX1 familial platelet disorder: a shared decision-making framework."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RUNX1 familial platelet disorder (RUNX1-FPD) is associated with a 35% to
      50% lifetime risk of hematologic malignancy (HM), and like all germline HM
      predisposition syndromes, can only be cured with allogeneic hematopoietic
      stem cell transplantation (HSCT).
    explanation: >-
      States transplant as the only curative modality for the predisposition.
  - reference: PMID:41924923
    reference_title: "Preemptive hematopoietic stem cell transplantation in RUNX1 familial platelet disorder: a shared decision-making framework."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, there is not yet a consensus on the use of preemptive HSCT for
      RUNX1-FPD.
    explanation: >-
      Records that preemptive transplant timing is genuinely unsettled rather
      than a settled standard of care.
- name: Antifibrinolytic and Platelet Transfusion Support for Bleeding
  description: >-
    Haemostatic cover for surgery, injury and dental work uses clotting
    promotors such as desmopressin, epsilon aminocaproic acid and tranexamic
    acid, with platelet transfusion reserved for severe bleeding or high-risk
    procedures.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Platelet Dense Granule and Aggregation Defect
    description: >-
      Antifibrinolytics stabilise clot rather than correcting the platelet
      defect, compensating for impaired secretion and aggregation.
  evidence:
  - reference: PMID:33661592
    reference_title: "RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Use of clotting promotors (e.g., desmopressin, epsilon aminocaproic acid,
      tranexamic acid) in instances of surgeries, injuries, or dental treatments;
      platelet transfusions may be used for severe bleeding or procedures with a
      high bleeding risk.
    explanation: GeneReviews management recommendation for haemostatic cover.
- name: Malignancy Surveillance
  description: >-
    Carriers are followed with clinical examination every six to twelve months
    and a complete blood count with differential every three to four months,
    with marrow examination triggered by constitutional symptoms or count
    abnormalities. Medications that impair platelet function, high-trauma
    activities, unnecessary radiation and smoking are avoided.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Clonal Hematopoiesis and Somatic Second-Hit Acquisition
    description: >-
      Serial counts and marrow assessment aim to detect clonal progression
      before overt malignancy, when transplant outcomes are better.
  evidence:
  - reference: PMID:33661592
    reference_title: "RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Complete blood count with differential every three to four months; bone
      marrow examination if constitutional symptoms and/or abnormalities on
      complete blood count are identified; skin exam as needed.
    explanation: The GeneReviews surveillance schedule.
  - reference: PMID:33661592
    reference_title: "RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Medications that affect platelet function (e.g., NSAIDs and antiplatelet
      agents), activities with a high risk of trauma (e.g., high-risk contact
      sports), unnecessary radiation, and smoking.
    explanation: The agents and circumstances GeneReviews advises avoiding.
- name: Gene Correction of Hematopoietic Stem Cells
  description: >-
    Autologous gene correction is under consideration but faces a specific
    mechanistic obstacle: corrected stem cells show no competitive advantage
    over RUNX1-heterozygous cells, so a corrected fraction may not outcompete
    the pre-existing mutant clone.
  therapeutic_modality: GENE_EDITING
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  evidence:
  - reference: PMID:36322931
    reference_title: "A RUNX1-FPDMM rhesus macaque model reproduces the human phenotype and predicts challenges to curative gene therapies."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In conclusion, the lack of a competitive advantage for wildtype or
      control-edited HSPCs over RUNX1 heterozygous-mutated HSPCs long term in our
      preclinical model suggests that gene correction approaches for FPDMM will
      be challenging, particularly to reverse myelodysplastic syndrome/ acute
      myeloid leukemia predisposition and thrombopoietic defects.
    explanation: >-
      A primate competitive repopulation model argues against gene correction
      being sufficient, so this is cited as evidence against the approach rather
      than for it.
animal_models:
- name: RUNX1-edited rhesus macaque competitive repopulation model
  species: Rhesus macaque
  genotype: CRISPR/Cas9 NHEJ-edited RUNX1 versus AAVS1 safe-harbour control, autologous transplant
  publication: PMID:36322931
  description: >-
    Autologous transplant of mixed RUNX1-edited and control-edited HSPCs,
    tracking mutant allele frequency over time. Built specifically to compare
    the fitness of corrected against RUNX1-heterozygous cells in vivo.
  modeled_mechanisms:
  - target: Impaired Megakaryocyte Maturation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the megakaryocytic dysplasia and polyploidization defect seen in
      human FPDMM marrow.
    limitations: >-
      Uses somatic gene editing of transplanted HSPCs rather than a constitutional
      heterozygous allele, so it models the haematopoietic consequence without the
      germline context, and the animals were followed for a few years rather than
      a human lifetime.
    readouts:
    - name: Megakaryocytic polyploidization in vitro
      target: Impaired Megakaryocyte Maturation
      direction: DECREASED
      interpretation: >-
        Direct cellular correlate of the maturation-arrest node.
      evidence:
      - reference: PMID:36322931
        reference_title: "A RUNX1-FPDMM rhesus macaque model reproduces the human phenotype and predicts challenges to curative gene therapies."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Bone marrows developed megakaryocytic dysplasia similar to human FPDMM,
          and CD34+ HSPCs showed impaired in vitro megakaryocytic differentiation,
          with a striking defect in polyploidization.
        explanation: Reports the polyploidization measurement behind this readout.
  - target: Clonal Hematopoiesis and Somatic Second-Hit Acquisition
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      RUNX1-edited clones expanded over control-edited clones in vivo, showing
      that reduced RUNX1 dosage alone confers a clonal advantage.
    limitations: >-
      Clonal expansion was observed without progression to overt malignancy over
      the study period, so the model captures the predisposing step but not
      transformation.
    evidence:
    - reference: PMID:36322931
      reference_title: "A RUNX1-FPDMM rhesus macaque model reproduces the human phenotype and predicts challenges to curative gene therapies."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In both animals, RUNX1-edited cells expanded over time compared with
        AAVS1-edited cells.
      explanation: >-
        Establishes the competitive advantage of RUNX1-haploinsufficient cells
        in vivo.
datasets: []
references:
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK568319/
  title: "RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies - GeneReviews - NCBI Bookshelf"
  tags:
  - GeneReviews
  findings:
  - statement: >-
      GeneReviews provides the clinical baseline for RUNX1-FPDMM, covering
      clinical characteristics, molecular diagnosis, management of bleeding,
      malignancy surveillance, agents to avoid, and genetic counseling including
      the false-negative germline testing pitfall.
notes: >-
  Curated against MONDO:0100083, the RUNX1-specific term, rather than the
  gene-agnostic parent MONDO:0011071. That parent has exactly two descendants:
  this entity and MONDO:0014536 (thrombocytopenia 5, which is ETV6-related).
  ANKRD26-related thrombocytopenia 2 is MONDO:0008555 and sits elsewhere in
  MONDO, so it is not covered by that parent. Because ETV6-THC5 is not yet
  curated, a grouping under MONDO:0011071 would have one real member and one
  placeholder, so that stub is deliberately left in the curation queue. The
  broader germline myeloid malignancy predisposition grouping spanning RUNX1,
  GATA2, ETV6, ANKRD26, CEBPA and DDX41 is the more useful union and is worth
  building once more members exist.

📚

References & Deep Research

References

1

url:https://www.ncbi.nlm.nih.gov/books/NBK568319/

RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies - GeneReviews - NCBI Bookshelf

1 finding

GeneReviews provides the clinical baseline for RUNX1-FPDMM, covering clinical characteristics, molecular diagnosis, management of bleeding, malignancy surveillance, agents to avoid, and genetic counseling including the false-negative germline testing pitfall.

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: RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancy · 2026-08-31T20:13:18Z · View source

Created kb/disorders/RUNX1_Familial_Platelet_Disorder.yaml against MONDO:0100083, the RUNX1-specific entity. The claim issue was keyed on the gene-agnostic parent MONDO:0011071, whose stub also covers the ANKRD26 and ETV6 forms; that stub is deliberately left in place because a grouping for the three genes is out of scope here and was flagged to the user as an open decision. Seven pathophysiology nodes separate haploinsufficiency from RUNT-domain dominant-negative activity, then run through megakaryocyte maturation arrest, the dense granule and aggregation defect, thrombocytopenia, clonal hematopoiesis with second-hit acquisition, and myeloid transformation. Eight phenotypes, a genetic block, and two treatments. The gene therapy treatment carries a REFUTE evidence item: the rhesus macaque competitive repopulation model found no fitness advantage for corrected over mutant HSPCs, which argues against the approach, so it is recorded as evidence against rather than for. Deep research: falcon returned HTTP 403 for an invalid EDISON_API_KEY and the run fell back to claude_code via --fallback-provider, recorded in the report frontmatter. Report references resolved 17 of 17, confabulation_rate 0.0; its term section proposed the obsolete GO:0043433, which was not used. All HP and HGNC bindings were resolved independently from the committed caches and exact-match OLS queries. One duplicate evidence key arose during editing and was fixed by merging both blocks rather than dropping either, per the duplicate-key guidance. One snippet initially transliterated Greek letters and was corrected to the exact source text. Validated with just validate, 18 of 18 snippets verified exactly, plus check-duplicate-keys, check-entity-refs and validate-terms.

Claude Code ▸

RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancy (RUNX1‑FPDMM): Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 36 citations 2026-08-31T19:59:47.702973

RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancy (RUNX1‑FPDMM): Comprehensive Research Report

1. Disease Information

Overview. RUNX1‑FPDMM (also called FPD/AML, familial platelet disorder with propensity to myeloid malignancy, or "hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1") is an autosomal dominant condition caused by heterozygous germline pathogenic variants in RUNX1. It is defined by (1) quantitative and qualitative platelet defects causing a bleeding diathesis and (2) a markedly elevated, lifelong risk of myeloid malignancy — principally myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), with T‑ and B‑cell acute lymphoblastic leukemia also reported (GeneReviews, updated 2024–2025). It was first delineated as a Mendelian entity by Song et al. in 1999 and is now formally recognized by the WHO 5th‑edition and ICC classifications as a prototypic "myeloid neoplasm with germline predisposition and pre-existing platelet disorder."

Key identifiers: - OMIM disease: #601399 — Platelet Disorder, Familial, with Associated Myeloid Malignancy (FPDMM) (OMIM) - OMIM gene (RUNX1): *151385, chromosome 21q22.12 (OMIM) - HGNC: gene ID 10471 - Orphanet: ORPHA:71290 — Familial platelet disorder with associated myeloid malignancy (Orphanet) - MONDO: MONDO:0100083 - ClinVar condition record example: NM_001754.5(RUNX1):c.602G>A (p.Arg201Gln) AND "Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1" (ClinVar) - NCI PDQ summary exists as a dedicated cancer genetics resource: "RUNX1‑Familial Platelet Disorder (PDQ®)" (NCBI Bookshelf NBK598339)

Synonyms: FPD/AML; familial platelet disorder with propensity to AML; thrombocytopenia 2 (historic); familial platelet syndrome with predisposition to acute myelogenous leukemia (Orphanet synonym).

Evidence basis: This entry is derived almost entirely from aggregated disease-level resources — GeneReviews, OMIM, Orphanet, WHO/ICC classification, ClinGen curation, and case-series/cohort literature (~200 families and >130 individuals reported cumulatively) — rather than from a single large EHR population, reflecting genuine rarity.

2. Etiology

Primary cause: Heterozygous germline loss-of-function or dominant-negative pathogenic variants in RUNX1 (encoding RUNX1/AML1/CBFA2, a core-binding transcription factor that heterodimerizes with CBFβ). This is a purely monogenic, highly penetrant-for-phenotype/variably-penetrant-for-malignancy Mendelian disorder — there is no known environmental or infectious primary cause of the germline predisposition itself.

Genetic risk factors: - Causal variants: ~80% are detected by sequence analysis — missense, nonsense, splice-site variants, and small indels, concentrated in the Runt homology domain (RHD), which mediates both DNA binding and CBFβ heterodimerization; variants also occur in the transactivation domain (TAD) and at splice sites. ~20% are gross deletions/duplications (including whole-gene deletion) detected by dosage analysis (GeneReviews). - Mechanistic classes: frameshift and large deletions → haploinsufficiency (loss-of-function); some missense/nonsense variants in the RHD act as dominant-negative alleles that impair DNA binding/transactivation of the wild-type allele product, generally associated with a more severe phenotype than simple haploinsufficiency (Simon et al., Leukemia 2020, functional classification of RUNX1 variants). - Second-hit/somatic modifier variants driving progression to malignancy: somatic pathogenic variants in ASXL1, CBL, CDC25C, FLT3, PHF6, SRSF2, and WT1, plus loss of the remaining wild-type RUNX1 allele (often via acquired uniparental disomy of chromosome 21, or biallelic RUNX1 inactivation). Age-related clonal hematopoiesis genes — TET2 and DNMT3A — are the most frequently observed secondary somatic variants in surveillance cohorts and are thought to mark early clonal evolution rather than transformation itself (PMC9320507, "Beyond Pathogenic RUNX1 Germline Variants"). - Genotype–severity correlation: functional class (null/haploinsufficient vs. dominant-negative) and possibly variant location within RHD vs. TAD influence leukemogenic risk, though penetrance remains incompletely predictable from genotype alone.

Environmental/lifestyle risk factors: Not disease-causing, but GeneReviews management guidance flags obesity and chemical/genotoxic exposure (e.g., unnecessary ionizing radiation, tobacco smoke) as plausible modifiers that may increase malignancy risk in carriers, and recommends avoidance as a precaution rather than as an evidence-graded finding.

Protective factors: No validated genetic or environmental protective factors are established in the literature; this remains an evidence gap.

Gene–environment interaction: No specific GxE interaction has been characterized; the dominant model is a two-(or multi-)hit somatic evolution model layered on a haploinsufficient/dominant-negative germline background, analogous to but mechanistically distinct from classical tumor-suppressor two-hit kinetics (biallelic inactivation is one but not the only path to leukemic transformation here — cooperating epigenetic-regulator mutations are more common).

3. Phenotypes

Bleeding/platelet phenotype (present in ~90% of affected individuals): - Thrombocytopenia: typically mild-to-moderate (platelet counts 50–150 × 10⁹/L); a subset have normal counts (>150 × 10⁹/L) despite qualitative dysfunction. - Qualitative platelet dysfunction exceeding what platelet count alone predicts: abnormal aggregation (blunted response to arachidonic acid, collagen, ADP, epinephrine), abnormal secretion, and platelet dense-granule and/or alpha-granule storage pool deficiency on electron microscopy in roughly half of tested patients. - Clinical bleeding: easy bruising without trauma, mucocutaneous bleeding, gum bleeding, menorrhagia, peri-/post-partum hemorrhage, excess surgical/dental bleeding; 20–25% require platelet transfusion or antifibrinolytics for hemostatic challenges (GeneReviews). - Suggested HPO terms: HP:0001873 (Thrombocytopenia), HP:0011869 (Abnormal platelet function), HP:0000978 (Bruising susceptibility), HP:0000979 (Purpura), HP:0000032 (Dysmenorrhea/Menorrhagia — HP:0000132 Menorrhagia), HP:0011024 (Abnormality of the digestive system — for GI bleeding as needed).

Hematologic malignancy phenotype: - Lifetime risk of hematologic malignancy: ~35–50% (frequently cited as ~44% by age 50) (HemaSphere 2025, Ernst et al.; natural history study, Blood 2023, PMID 37738626). - Median age of malignancy onset: 33 years, though pediatric- and later adult-onset cases both occur. - Predominant malignancies: AML and MDS are the most common initial presentations (AML in ~26.9%, MDS in ~13.4% of malignancy presentations in cohort data); T‑ and B‑cell ALL and lymphomas occur in a minority of families (~25% of families report a lymphoid malignancy at some point). - HPO terms: HP:0004808 (Myelodysplasia), HP:0004808-adjacent HP:0002488 (Acute myeloid leukemia would map via MONDO/HP disease terms rather than phenotype terms — flag for curation), HP:0005506 (Leukemia, general).

Skin manifestations: eczema and/or psoriasis reported in ~50% of families, typically childhood-onset and mild, managed topically (HP:0000964 Eczema; HP:0003765 Psoriasiform dermatitis / HP:0003765).

Bone marrow histopathology: hypocellular-to-normocellular marrow; atypical, non-dysplastic megakaryocytes — small, hypolobated, scant cytoplasm — a described feature distinguishing pre-leukemic RUNX1-FPDMM marrow from classic MDS dysplasia (Haematologica, bone marrow pathology in FPDMM).

Quality of life: No dedicated EQ-5D/SF-36 disease-specific data were identified in the literature; qualitative burden is described via chronic bleeding-diathesis management, psychosocial impact of unexplained bruising (including risk of misattributed child-abuse concern, explicitly flagged in GeneReviews management guidance), and the substantial anxiety burden of lifelong malignancy surveillance — this is a genuine evidence gap rather than an omission.

4. Genetic/Molecular Information

Causal gene: RUNX1 (RUNX Family Transcription Factor 1; previously AML1/CBFA2), HGNC:10471, chromosome 21q22.12, 12 exons.

Protein domains: - Runt homology domain (RHD), exons 2–4, ~128 amino acids: mediates sequence-specific DNA binding (5′-PyGPyGGTPy-3′ consensus) and heterodimerization with CBFβ, which stabilizes RHD–DNA contacts. Most pathogenic missense/nonsense variants cluster here (ScienceDirect structural review; GeneCards). - Transactivation domain (TAD), C-terminal/exon 6 region: required for transcriptional activation and contains a nuclear matrix-targeting signal essential for in vivo function.

Variant spectrum and classification (ACMG/AMP-graded): - Missense, nonsense, frameshift, splice-site variants, and small indels (~80% of pathogenic findings by sequence analysis) plus gross deletions/duplications, including whole-gene deletion (~20%, detected by CNV/dosage analysis). - ClinVar carries numerous graded examples, e.g., NM_001754.5(RUNX1):c.602G>A (p.Arg201Gln) and c.1283dup (p.Leu429fs) associated with "Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1." - Functional classification (Simon et al., Leukemia 2021) stratifies variants by transcriptional activity into loss-of-function/haploinsufficient vs. dominant-negative classes, which correlates with clinical severity (Nature/Leukemia). - gnomAD/population databases: pathogenic RUNX1-FPDMM variants are essentially absent or present only as extreme rarities in the general population given the phenotype's severity and rarity (~200 families reported worldwide); this is consistent with dominant, disease-causing rarity rather than a common-variant susceptibility architecture.

Somatic vs. germline distinction (critical for testing): - Somatic RUNX1 mutations are common in sporadic AML/MDS and in breast cancer, unrelated to germline predisposition; variant allele fraction <40% in tumor tissue is a practical (not absolute) heuristic suggesting a somatic rather than constitutional origin (GeneReviews). - Critical technical pitfall: acquired loss of heterozygosity via uniparental disomy of chromosome 21 can occur in hematopoietic tissue of carriers, causing false-negative germline testing results from blood/marrow DNA. GeneReviews explicitly recommends cultured skin fibroblasts (buccal samples as a fallback, with risk of blood contamination) for definitive germline testing, and states testing during active malignancy is unreliable because ~10% of sporadic hematologic malignancy cases carry (typically somatic) RUNX1 variants incidentally.

Somatic "second hits" driving leukemic transformation: most frequently affect epigenetic regulators TET2 and DNMT3A (age-related clonal hematopoiesis genes, seen on longitudinal surveillance), plus cooperating driver mutations in ASXL1, CBL, CDC25C, FLT3, PHF6, SRSF2, WT1, and biallelic RUNX1 loss (PMC9320507; Blood Advances 2024, genomic landscape). A 2025 focused study (PMC11919008) further characterizes germline RUNX1 variant frequency and function specifically within diagnosed myeloid neoplasm cohorts.

Modifier genes: No validated independent modifier locus beyond the acquired somatic events above; functional variant class (haploinsufficient vs. dominant-negative) is currently the best-supported intrinsic modifier of risk.

Epigenetics: RUNX1 haploinsufficiency itself alters chromatin/transcriptional output at hematopoietic target loci (see Mechanism, below); no disease-specific DNA methylation biomarker panel is yet clinically validated, though clonal TET2/DNMT3A mutations (epigenetic regulators) are mechanistically linked to progression.

Chromosomal abnormalities: Whole-gene or partial-gene deletions of RUNX1 (21q22.12) are a recognized causal mechanism (~20% of pathogenic findings), detectable by chromosomal microarray/MLPA; distinguish from constitutional trisomy 21 (Down syndrome), which independently confers its own myeloid leukemia predisposition through a different (GATA1-related, transient abnormal myelopoiesis) mechanism — a differential that should not be conflated with RUNX1-FPDMM.

5. Environmental Information

RUNX1‑FPDMM is a purely monogenic predisposition; environmental factors modulate the timing/likelihood of second-hit malignant transformation rather than causing the underlying platelet/predisposition phenotype.

Chemical/toxin exposure: GeneReviews management guidance advises avoidance of unnecessary genotoxic exposures (radiation, tobacco smoke, occupational chemical exposures) as a precautionary measure to reduce mutagenic pressure on the already-haploinsufficient hematopoietic compartment, though this is expert consensus rather than a quantified epidemiologic effect size.
Lifestyle factors: Obesity is flagged as a possible malignancy-risk modifier; NSAIDs, antiplatelet agents, and statins are specifically listed as agents to avoid because they can unmask or worsen the underlying qualitative platelet defect (bleeding risk, not malignancy risk).
Infectious agents: No infectious trigger has been identified or is biologically plausible as a primary driver; this is not an infection-associated disease.

6. Mechanism / Pathophysiology

Causal chain (numbered, from germline lesion to clinical manifestations)

A heterozygous germline pathogenic variant in RUNX1 reduces functional RUNX1 dosage in hematopoietic stem/progenitor cells — either by simple loss-of-function/haploinsufficiency (frameshift, nonsense, deletion) or by a dominant-negative mechanism in which a mutant RHD protein still binds CBFβ/DNA but fails to transactivate target genes, poisoning the wild-type allele's output (Simon et al. 2021).
Reduced RUNX1:CBFβ transcriptional activity impairs megakaryocyte maturation and polyploidization, demonstrated directly in a rhesus macaque RUNX1-FPDMM model in which CD34+ HSPCs showed "impaired in vitro megakaryocytic differentiation, with a striking defect in polyploidization" and marrow "megakaryocytic dysplasia similar to human FPDMM" (Blood 2023, DOI 10.1182/blood.2022018193, PMID 36322931).
This leads to quantitative thrombocytopenia (reduced platelet output from dysplastic megakaryocytes) — the clinical bleeding phenotype's first component.
In parallel, RUNX1 haploinsufficiency directly downregulates specific platelet-granule biogenesis genes, most notably PLDN (pallidin), a subunit of the BLOC-1 complex required for dense-granule biogenesis: "PLDN is a direct transcriptional target of RUNX1, and its decreased expression constitutes a mechanism for the platelet dense granule deficiency in patients with RUNX1 haplodeficiency" (ASH abstract, PLDN mechanism). Additional dysregulated RUNX1 targets include RAB27B, MYL9, ALOX12, PF4, PRKCQ (PKC‑θ), RAB1B, TREML1, ITGA2, MPL, NFE2, NOTCH4, and A4GALT.
Loss of these targets produces qualitative platelet dysfunction: decreased aggregation, decreased secretion (dense- and alpha-granule storage pool deficiency, plus a broader defect in acid-hydrolase/lysosomal secretion independent of granule content — Haemophilia 2017, Rao et al.), reduced myosin light chain/pleckstrin phosphorylation, reduced 12-HETE production, and impaired αIIbβ3 activation (J Thromb Haemost 2014, Glembotsky et al., PMID 24606315). This qualitative defect explains why bleeding severity exceeds what platelet count alone predicts.
Independently, chronically reduced RUNX1 dosage in hematopoietic stem cells creates a pre-leukemic clonal state: the residual (haploinsufficient or dominant-negative-poisoned) HSC/progenitor pool is intrinsically primed for clonal drift. In the rhesus macaque model, RUNX1-edited HSPC clones progressively expanded relative to control-edited clones over time even without additional mutations — direct in vivo evidence that reduced RUNX1 dosage alone confers a clonal competitive advantage.
Over years, this primed clone acquires cooperating somatic ("second-hit") mutations — most commonly in the epigenetic regulators TET2 and DNMT3A (age-related clonal hematopoiesis genes), and less commonly in ASXL1, CBL, CDC25C, FLT3, PHF6, SRSF2, WT1, or biallelic RUNX1 inactivation (frequently via acquired uniparental disomy of chromosome 21) (Genomic Landscape studies; Blood Advances 2024).
Clonal outgrowth with these cooperating lesions leads to myelodysplastic syndrome — marrow dysplasia and cytopenias — which in a substantial fraction of patients progresses to overt acute myeloid leukemia (or, less commonly, T-/B-lymphoblastic leukemia/lymphoma via a still less well-characterized branch of the same predisposed hematopoietic compartment).
Because malignant transformation depends on this multi-hit somatic evolution layered on a chronically haploinsufficient stem cell compartment, RUNX1‑FPDMM-associated leukemia is not curable with chemotherapy alone — the germline lesion persists in every surviving HSC — and allogeneic hematopoietic stem cell transplantation is the only curative modality, a direct mechanistic consequence of step 1 rather than merely a treatment-guideline statement.

Branch point (step 9, inferred/translationally important): the rhesus macaque data specifically predict that autologous gene-correction/gene-therapy approaches will be mechanistically challenged, because corrected (wild-type-restored) HSPCs did not show a competitive advantage over RUNX1-heterozygous mutant HSPCs long-term in the primate model — i.e., simply correcting a fraction of stem cells may not be sufficient to outcompete the pre-existing mutant clone, an inference explicitly flagged by the study authors as a challenge for curative gene therapy design (PMID 36322931).

Molecular pathways, cellular processes, and profiling

Pathway: RUNX1:CBFβ core-binding-factor transcriptional network governing megakaryopoiesis and myeloid/lymphoid differentiation (KEGG/Reactome: "Transcriptional regulation by RUNX1," Reactome R-HSA-8878171).
Cellular processes: megakaryocyte differentiation and polyploidization (defective); platelet granule biogenesis and secretion (defective); HSC self-renewal/clonal fitness (dysregulated, pro-clonal).
Suggested GO terms: GO:0030220 (platelet formation), GO:0007596 (blood coagulation), GO:0045055 (regulated exocytosis — granule secretion), GO:0030220-adjacent GO:0061564-type differentiation terms, GO:0004725-unrelated (not applicable here — RUNX1 is a transcription factor, not a phosphatase); more precisely GO:0043433 (negative regulation of DNA-binding transcription factor activity, for dominant-negative variant mechanism), GO:0030099 (myeloid cell differentiation).
Suggested CL terms: CL:0000556 (megakaryocyte), CL:0000767 (basophil — not primary), CL:0000037 (hematopoietic stem cell), CL:0000234 (phagocyte — not primary); most central: CL:0000556 megakaryocyte and CL:0000037 HSC.
Molecular profiling: No large-scale disease-dedicated transcriptomic/proteomic/metabolomic public dataset was identified beyond targeted RUNX1-target-gene expression studies (PLDN, RAB27B, MYL9, etc.) and the genomic-landscape (targeted/whole-exome) sequencing cohorts cited above; single-cell and spatial transcriptomic characterization of RUNX1‑FPDMM marrow specifically is an evidence gap relative to sporadic AML/MDS single-cell atlases.
Functional genomics screens: CRISPR-based functional variant classification (Simon et al. 2021) is the primary functional-genomics dataset directly informing pathogenicity/severity stratification for this disease.

7. Anatomical Structures Affected

Primary organ/system: Bone marrow (hematopoietic system) — megakaryocyte lineage primarily, with secondary myeloid (and occasionally lymphoid) lineage involvement upon transformation.
Secondary involvement: Skin (eczema/psoriasis in ~50% of families); systemic bleeding manifestations (mucosal surfaces — gingiva, uterus/reproductive tract — menorrhagia, peripartum hemorrhage; GI tract in severe bleeding).
Tissue/cell level: Megakaryocytes (CL:0000556) — small, hypolobated, scant-cytoplasm, non-dysplastic-appearing but functionally abnormal; hematopoietic stem/progenitor cells (CL:0000037); platelets (anucleate cell fragments) with dense-granule (lysosome-related organelle) and alpha-granule defects.
Subcellular level: Platelet dense granules and alpha granules (GO Cellular Component: GO:0042582 azurophil granule-adjacent; specifically GO:0031091 platelet alpha granule, and the platelet dense granule / delta granule compartment linked to BLOC-1 complex dysfunction via PLDN loss); nucleus (RUNX1 is a nuclear transcription factor, GO:0005634).
Localization/laterality: Systemic/hematologic — not applicable to lateralization; marrow involvement is diffuse/multifocal rather than localized.
UBERON suggestions: UBERON:0002371 (bone marrow), UBERON:0001977 (platelet — note: UBERON models platelet as a cell type via CL, not strictly organ), UBERON:0002097 (skin of body) for the dermatologic manifestations.

8. Temporal Development

Onset of platelet/bleeding phenotype: Often present from birth/early childhood (congenital thrombocytopenia recognized incidentally or via bleeding symptoms), though it may go unrecognized for years given mild severity.
Onset of malignancy: Highly variable — pediatric AML/MDS cases occur, but median age of malignancy onset is 33 years, spanning a wide range into later adulthood; this is a lifelong, not time-limited, risk window.
Progression pattern: Not a single linear staged disease — better modeled as (a) a stable baseline phenotype (thrombocytopenia/bleeding, present from an early age and generally non-progressive in isolation) with (b) a superimposed, stochastic clonal-evolution risk that can manifest at any point in life as MDS (often insidious, detected via cytopenia surveillance) which may then progress to overt AML. Some patients transform directly to AML without a preceding clinically apparent MDS phase.
Remission/course: MDS/AML in this context is generally not self-limited and, per GeneReviews, "not thought to be curable with chemotherapy alone" because the germline lesion persists in the entire stem cell compartment — allogeneic HSCT is required for cure.
Critical periods/intervention windows: The literature explicitly frames the open clinical question as when (if ever) to intervene preemptively with HSCT versus continued surveillance — a 2025 paper proposes a formal "shared decision-making framework" for exactly this question, underscoring that no consensus critical intervention window yet exists (PMID 41924923, preemptive HSCT decision framework).

9. Inheritance and Population

Inheritance pattern: Autosomal dominant. Most probands inherit the variant from an affected (sometimes subclinically affected/unrecognized) parent; de novo occurrence is reported but its proportion is not firmly established in the literature.
Penetrance: Incomplete and variable. GeneReviews states penetrance is formally "unknown"; commonly cited figures are a 35–50% lifetime risk of hematologic malignancy (frequently summarized as ~44% by age 50), while "a minority of individuals have no clinical or laboratory features" despite carrying a pathogenic variant — i.e., even the bleeding/platelet phenotype is not fully penetrant. RUNX1 is explicitly grouped with ANKRD26, DDX41, and ETV6 as a "variable malignant penetrance" germline predisposition syndrome, distinct from high-penetrance syndromes (Seminars in Hematology 2024 review).
Expressivity: Highly variable, both between and within families — spectrum from asymptomatic carriage to severe transfusion-dependent bleeding and/or early leukemic transformation.
Anticipation, mosaicism, founder effects: No genetic anticipation phenomenon (not a repeat-expansion disorder). Germline mosaicism and somatic (hematopoietic-tissue-restricted) loss of heterozygosity via uniparental disomy 21 are both specifically discussed as causes of apparent non-transmission or false-negative parental testing — this is a distinctive, clinically important feature of RUNX1-FPDMM genetic counseling (mandates non-hematopoietic tissue, e.g., cultured fibroblasts, for definitive parental/germline testing). No specific founder variant/population is described; the ~200 reported families span diverse ancestries without a dominant founder mutation.
Consanguinity: Not a relevant risk factor for this autosomal dominant disorder.
Epidemiology: Rare disease — approximately 200 families described worldwide in the literature to date, likely an underestimate due to underdiagnosis (mild bleeding phenotypes are easily missed, and molecular testing requires awareness of the false-negative blood-DNA pitfall). No formal population-based prevalence/incidence rate (cases per 100,000) has been established; Orphanet does not list a numeric prevalence class for ORPHA:71290 in the material reviewed. A 2023 U.S./international natural history study enrolled 214 participants including 111 patients with 39 different RUNX1 variants from 45 unrelated families — the largest prospective cohort to date (Blood 2023, PMID 37738626).
Sex ratio / geographic distribution: No sex predilection or endemic geographic clustering has been reported; cases are described across North America, Europe, and Asia (e.g., a French pediatric cohort, PMC9928638, and a French inherited-platelet-disorder network study of nine families, PMC4845427).

10. Diagnostics

Laboratory/clinical tests: - CBC with differential (thrombocytopenia, often mild); peripheral smear (normal platelet size, distinguishing from macrothrombocytopenia syndromes like MYH9-related disease). - Platelet aggregometry: decreased response to arachidonic acid, collagen; decreased ADP/epinephrine-induced secretion. - Platelet electron microscopy: dense-granule/alpha-granule storage pool deficiency (in ~50%). - Bone marrow aspirate/biopsy: performed when constitutional symptoms or evolving cytopenias arise, looking for the atypical (non-dysplastic) small hypolobated megakaryocyte pattern versus frank MDS dysplasia.

Genetic testing (definitive diagnosis): - Gene-targeted sequence analysis of RUNX1: detects ~80% of pathogenic variants (missense/nonsense/splice/small indel). - Gene-targeted deletion/duplication (dosage) analysis: detects the remaining ~20% (exon-level or whole-gene deletions/duplications). - Multigene inherited-platelet-disorder/bone-marrow-failure panels (including RUNX1, ANKRD26, ETV6, CEBPA, DDX41, GATA2, TP53) are recommended as an efficient first-line strategy given phenotypic overlap; comprehensive exome/genome sequencing is reserved for atypical presentations. - Critical pitfall: test cultured skin fibroblasts (preferred) or buccal cells (acceptable, risk of blood contamination) rather than peripheral blood/marrow DNA for germline confirmation, because somatically acquired uniparental disomy of chromosome 21 in hematopoietic tissue can mask (false-negative) or, conversely, an incidental somatic RUNX1 variant found during active leukemia workup (~10% of unrelated hematologic malignancies) can be misinterpreted as germline without orthogonal tissue confirmation (GeneReviews). - Variant allele fraction <40% in tumor/marrow tissue is a practical (non-definitive) flag suggesting somatic rather than germline origin, pending confirmatory fibroblast testing.

Differential diagnosis (per GeneReviews): ANKRD26-related thrombocytopenia, CEBPA-associated familial AML, DDX41-associated familial MDS/AML, ETV6-related thrombocytopenia, GATA2 deficiency, Li-Fraumeni syndrome (TP53); acquired mimics include immune thrombocytopenia and drug-induced thrombocytopenia (NSAIDs, antiplatelet agents, statins). A direct 2023 Blood comparative study specifically distinguishes RUNX1, ETV6, and ANKRD26 hereditary platelet disorders, noting that although they "may initially present as similarly mild-moderate thrombocytopenia, each ... [has] distinct penetrance of HM and a different range of somatic alterations associated with malignancy development" (PMID 36626254).

Screening/surveillance for known carriers (no formal published consensus guideline exists on frequency, per literature review, though GeneReviews offers expert-consensus recommendations): - Clinical exam for constitutional symptoms (fatigue, fever, weight loss, dyspnea) every 6–12 months. - CBC with differential every 3–4 months. - Bone marrow examination triggered by new symptoms or CBC abnormalities (not routinely scheduled in the absence of a trigger). - Skin exam as needed. - A 2025 publication formally proposes a shared decision-making framework to fill the gap in consensus surveillance/timing guidance, explicitly noting "guidelines on the type of testing or frequency of surveillance have not been published" (PMID 41924923).

Prenatal/preimplantation testing: Feasible once a familial variant is identified; uptake and professional guidance vary by family/center.

11. Outcome/Prognosis

Malignancy risk: 35–50% lifetime risk (often summarized ~44%), median onset age 33 years; AML and MDS are the dominant malignancy types (AML ~26.9%, MDS ~13.4% as initial presentation in cohort data).
Curability: MDS/AML arising in this context is generally not curable by chemotherapy alone; allogeneic HSCT is the only curative approach, consistent with the mechanistic persistence of the germline lesion in every hematopoietic stem cell.
Transplant outcomes: Case reports and small series describe successful allogeneic HSCT for RUNX1‑FPDMM-associated MDS/AML, including a detailed case report/literature review (PMC9800216); a dedicated 2025 HemaSphere study specifically examined AML outcomes in germline RUNX1 deficiency, characterizing disease features and transplant/treatment outcomes in this population (Ernst et al. 2025, DOI 10.1002/hem3.70057) — a key resource for prognostic detail beyond what could be fully retrieved here (site access was restricted during this research pass; recommend direct follow-up retrieval for exact survival statistics).
Related-donor transplant caveat: because RUNX1-FPDMM is autosomal dominant with variable expressivity, potential related HSCT donors must be genetically tested and excluded as variant carriers before use as a stem cell source — a critical, disease-specific transplant-planning consideration flagged throughout the clinical literature.
Morbidity outside of malignancy: primarily bleeding-related (transfusion dependence in a minority, procedural bleeding risk requiring premedication), and dermatologic (eczema/psoriasis, generally mild).
Quality of life / disability data: No RUNX1-FPDMM-specific EQ-5D/SF-36/PROMIS dataset was identified; this is a notable evidence gap.
Prognostic factors under active study: variant functional class (dominant-negative vs. haploinsufficient), clonal hematopoiesis mutation burden (TET2/DNMT3A) and its trajectory on serial sequencing, and specific cooperating driver mutations (ASXL1, CBL, FLT3, PHF6, SRSF2, WT1) at time of transformation.

12. Treatment

Pharmacotherapy for bleeding manifestations: - Desmopressin (DDAVP) — NCIT term for pharmacotherapy: NCIT:C15986 (Pharmacotherapy); specific agent term for desmopressin should be bound via CHEBI/NCIT lookup. - Antifibrinolytics: epsilon-aminocaproic acid, tranexamic acid — for surgical/dental/menstrual bleeding management. - Platelet transfusion (NCIT: transfusion-related procedure term) reserved for severe bleeding episodes or high-risk procedures.

Topical therapy for skin manifestations: emollients and topical corticosteroids for eczema/psoriasis (NCIT:C15986-adjacent topical pharmacotherapy terms).

Definitive/curative therapy for malignancy: - Allogeneic hematopoietic stem cell transplantation (NCIT:C15431, Hematopoietic Cell Transplantation) — the only curative approach for MDS/AML in this syndrome; timing (preemptive vs. at overt malignancy) remains actively debated and is the subject of a 2025 shared decision-making framework publication. - Standard AML/MDS induction chemotherapy and hypomethylating agents (e.g., azacitidine) plus venetoclax are used as in sporadic disease for bridging/cytoreduction, though not curative as monotherapy in this germline-predisposed context. Notably, RUNX1-mutated AML/MDS (germline or somatic) shows meaningful response rates to venetoclax-based regimens in broader AML/MDS cohorts (e.g., RUNX1-mutated subgroup ORR 54% in one venetoclax/azacitidine study), though these studies were not RUNX1-FPDMM-specific. - A dedicated early-phase trial specifically targets RUNX1-mutant relapsed/refractory AML/MDS with omacetaxine and venetoclax (NCT04874194) — while enrollment criteria include somatic RUNX1-mutant disease broadly rather than being exclusive to germline FPDMM, it is directly relevant to this molecular subgroup (ClinicalTrials.gov protocol; PMC12447878).

Experimental/gene-therapy landscape: - Autologous gene-correction approaches are under early preclinical investigation, but the rhesus macaque RUNX1-FPDMM model (PMID 36322931) demonstrated that corrected/control-edited HSPCs did not outcompete RUNX1-heterozygous mutant HSPCs long-term — a specific, mechanistically grounded caution that curative gene therapy for this disorder faces a nontrivial clonal-competition barrier not present in simpler monogenic HSC disorders. - A 2025 review, "Targeting RUNX1 Germline Variants: Agents Under Investigation" (Current Hematologic Malignancy Reports), catalogs emerging pharmacologic strategies aimed at clonal hematopoiesis interception in this population (Springer).

Supportive care: genetic counseling (NCIT:C15240), medical alert documentation to prevent misattributed-bleeding (child abuse) concerns, avoidance counseling for antiplatelet/NSAID medications and contact sports.

Treatment algorithm summary: (1) manage bleeding symptomatically/prophylactically; (2) structured surveillance (CBC q3–4 months, exam q6–12 months, marrow exam if triggered); (3) upon MDS/AML diagnosis, pursue allogeneic HSCT (related donors must be RUNX1-variant-tested and excluded) as the only curative modality, with cytoreductive chemotherapy/hypomethylating-agent bridging as needed; (4) no validated pharmacologic clonal-hematopoiesis-interception therapy yet exists outside clinical trials.

13. Prevention

Primary prevention: Not applicable in the classic sense (germline variant cannot be prevented once inherited); avoidance of genotoxic exposures (radiation, smoking, occupational chemical exposure) and platelet-function-impairing medications (NSAIDs, antiplatelet agents, statins) is recommended as a precautionary risk-reduction measure for both bleeding and, speculatively, malignancy risk.
Secondary prevention (early detection): Structured hematologic surveillance in known carriers (as above) to catch MDS/pre-AML changes at the earliest, most treatable stage; this is the closest analog to a "screening program" for this disorder, though it is expert-consensus rather than a formally validated USPSTF/CDC-style program.
Genetic screening: Cascade testing of at-risk relatives once a familial variant is identified is explicitly recommended (using non-hematopoietic tissue for definitive results) to identify asymptomatic carriers who need surveillance; prenatal and preimplantation genetic testing are technically available once the familial variant is known, with uptake being a family-preference-driven decision.
Genetic counseling: Central to management — communicating the 50% transmission risk to offspring, the variable/incomplete penetrance (a minority of carriers are entirely asymptomatic), the germline-mosaicism/loss-of-heterozygosity testing pitfalls, and reproductive options.
Tertiary prevention: Once malignancy develops, allogeneic HSCT is pursued specifically to prevent relapse/progression, given the ineffectiveness of chemotherapy alone at achieving durable remission in this predisposed stem cell compartment.
Immunization/prophylaxis/public health measures: Not applicable — this is not an infectious or environmentally-driven condition amenable to vaccination or public-health-level intervention.

14. Other Species / Natural Disease

Taxonomy of model use: Macaca mulatta (rhesus macaque, NCBITaxon:9544), Danio rerio (zebrafish, NCBITaxon:7955), Mus musculus (mouse, NCBITaxon:10090) are the principal non-human systems used — this is a research-model landscape rather than a naturally occurring veterinary disease.
Naturally occurring veterinary disease: No OMIA entry or naturally occurring companion-animal/livestock phenocopy of RUNX1-FPDMM specific to a germline RUNX1 variant was identified in this search; this is an evidence gap (worth a targeted OMIA search if precise veterinary comparanda are needed) rather than a confirmed absence.
Orthologous gene: Runx1 is highly conserved across vertebrates (mouse, zebrafish orthologs confirmed functionally essential for definitive hematopoiesis; NCBI Gene mouse Runx1 and zebrafish runx1 entries exist), underlying the strong translational relevance of the animal models below despite no known spontaneous animal phenocopy.
Comparative pathology: Complete constitutional Runx1 knockout is embryonic lethal in mouse (loss of all definitive hematopoiesis, death ~E12.5–13); this establishes RUNX1 as absolutely essential for HSC emergence from hemogenic endothelium, and by extension explains why FPDMM arises from partial (heterozygous) rather than complete loss of function — complete biallelic loss is not compatible with a viable postnatal disease state, reinforcing the haploinsufficiency/dominant-negative disease model in humans.
Zoonotic potential: None; not applicable.

15. Model Organisms

Mouse models: Multiple germline loss-of-function Runx1-FPD mouse models exist. One key model demonstrated "hematopoietic cell autonomous disruption of hematopoiesis in a germline loss-of-function mouse model of RUNX1-FPD" (PMID 36741355). Compound-mutant mice (RUNX1-FPD background plus a cooperating secondary mutation) developed MDS/AML with ~30% penetrance, directly modeling the two-hit progression described in the human mechanism section (2023 ASH/EHA presentation, ScienceDirect abstract). These models are explicitly being used and shared with the field to test candidate drugs for delaying/preventing/reversing clonal HSC expansion.
Complete Runx1 knockout mice are embryonic lethal (E13), confirming RUNX1's essential, non-redundant role in definitive HSC emergence — relevant context for why FPDMM models use partial/heterozygous or hematopoietic-cell-conditional alleles rather than full knockouts.
Zebrafish models: Zebrafish runx1 knockout embryos are transiently "bloodless" during embryonic definitive hematopoiesis but, unexpectedly, recover and develop multi-lineage hematopoiesis as adults, revealing a RUNX1-independent, developmental-stage-specific compensatory hematopoietic program not present in mammals — an important species-translation caveat (a candidate HUMAN_MODEL_MISMATCH-type consideration for curation: complete loss is tolerated long-term in zebrafish but embryonic-lethal in mouse and pathogenic-but-viable as heterozygous loss in humans) (Blood, "Development of RUNX1-Independent Hematopoiesis in Three Zebrafish runx1-KO Models"). CBFβ and RUNX1 were also shown to be required at two distinct steps of zebrafish HSC development, refining the developmental-timing model of RUNX1 dependency (Blood 2014, PMID-linked study).
Non-human primate model (highest translational fidelity): The rhesus macaque RUNX1-FPDMM competitive-repopulation model (CRISPR/Cas9 NHEJ editing of autologous HSPCs, transplanted as a mixed RUNX1-edited/AAVS1-control-edited population) is the most human-relevant model to date. It recapitulates megakaryocytic dysplasia and the polyploidization defect seen in human marrow, and demonstrates in vivo clonal expansion of RUNX1-mutant HSPCs relative to controls — directly supporting the pre-leukemic clonal-priming mechanism proposed for human disease, and yielding the specific translational caution about gene-therapy feasibility described above (Blood 2023, PMID 36322931, DOI 10.1182/blood.2022018193).
Model limitations: No model fully recapitulates the human bleeding-diathesis/dense-granule-deficiency phenotype with clinical-grade fidelity alongside the full malignancy-progression timeline in a single system; the mouse compound-mutant models best capture leukemic progression kinetics (30% penetrance), while the macaque model best captures the megakaryocyte/HSC-fitness phenotype, and zebrafish models are primarily informative for developmental RUNX1 dependency rather than adult disease modeling.
Resources: Models described in the cited primary literature are stated to be shared with investigators (mouse model, per RUNX1 Research Program communications); no dedicated public repository (JAX/IMSR/ZFIN stock number) was confirmed in this search pass and should be verified directly with the originating labs (RUNX1 Research Program, runx1-fpd.org) before citing a specific stock/strain identifier.

Summary of Notable Evidence Gaps (flagged rather than smoothed over)

No consensus surveillance or preemptive-HSCT timing guideline exists in the literature to date; a 2025 shared decision-making framework is the closest current answer (PMID 41924923).
No formal population-based prevalence/incidence rate (cases per 100,000) is established — only "≈200 families reported."
No disease-specific QoL instrument data (EQ-5D/SF-36/PROMIS) were located.
De novo variant proportion is not precisely quantified in current GeneReviews text.
No confirmed naturally occurring veterinary/OMIA phenocopy was found — absence is reported as unconfirmed rather than definitively ruled out.
The HemaSphere 2025 AML-outcomes paper (Ernst et al.) could not be fully retrieved (403 error) in this session; its precise survival/outcome statistics should be verified by direct PMID/DOI lookup (DOI: 10.1002/hem3.70057) before being cited with specific numbers in a curated entry.

Full Source List

GeneReviews: RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies (updated Jan 2024/2025)
OMIM #601399 FPDMM; OMIM *151385 RUNX1
Orphanet ORPHA:71290
NCI PDQ: RUNX1-Familial Platelet Disorder
NORD: FPDMM
Ernst et al. 2025, HemaSphere, "Disease characteristics and outcomes of AML in germline RUNX1 deficiency" — DOI 10.1002/hem3.70057
Natural history study, Blood 2023 — PMID 37738626, DOI 10.1182/blood.2023019746 — link
Rhesus macaque model, Blood 2023 — PMID 36322931, DOI 10.1182/blood.2022018193 — link
Simon et al., functional classification of RUNX1 variants, Leukemia 2021 — link
"Beyond Pathogenic RUNX1 Germline Variants" — PMC9320507
Genomic landscape, Blood Advances 2024 — link
Hereditary platelet disorders (RUNX1/ETV6/ANKRD26), Blood 2023 — PMID 36626254 — link
Glembotsky et al., platelet function mechanism, J Thromb Haemost 2014 — PMID 24606315
PLDN/pallidin mechanism, ASH abstract — link
Bone marrow histopathology, Haematologica — link
Preemptive HSCT shared decision-making framework — PMID 41924923
Zebrafish runx1-KO models, Blood — link
CBFβ/RUNX1 zebrafish HSC steps, Blood 2014 — link
Hematopoietic-cell-autonomous mouse model — PMID 36741355
Germline predisposition to myeloid neoplasms review, Seminars in Hematology 2024 — link
Omacetaxine + venetoclax RUNX1-mutant AML/MDS trial (NCT04874194) — protocol; PMC12447878
"Targeting RUNX1 Germline Variants: Agents Under Investigation," Curr Hematol Malig Rep 2025 — link

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	17
Resolved	17
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	6
Quoted claims found in source	4
Quoted claims not found in source	2
References weighed for topical relevance	17
On topic	15
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMID:41924923 (abstract only): "guidelines on the type of testing or frequency of surveillance have not been published"
closest text in source: "We introduce a shared decision-making framework designed to support individuals with RUNX1-FPD, their families, and their multidisciplinary clinical teams in evaluating whether and when to pursue preemptive HSCT versus continued surveillance"
DOI:10.1002/hem3.70057 (abstract only): "Disease characteristics and outcomes of AML in germline RUNX1 deficiency"
closest text in source: "AbstractFamilial Platelet Disorder with associated Myeloid Malignancy (FPDMM, FPD/AML, RUNX1‐FPD), caused by monoallelic deleterious germline RUNX1 variants, is characterized by bleeding diathesis and predisposition for hematologic malignancies, particularly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)"

Term Validation

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

Outcome	Count
Terms checked	38
Resolved	35
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	2
Terms whose name was checked	21
Terms named correctly	11
Terms named as a different term	3
Terms whose name is worth a second look	7

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:0002488 (1 mention) - the report calls it "Acute myeloid leukemia would map via MONDO/HP disease terms rather than phenotype terms — flag for curation"; HP calls it Acute leukemia
HP:0005506 (1 mention) - the report calls it "Leukemia, general"; HP calls it Chronic myelogenous leukemia
UBERON:0001977 (1 mention) - the report calls it "platelet — note: UBERON models platelet as a cell type via CL, not strictly organ"; UBERON calls it blood serum

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:0043433 (obsolete negative regulation of DNA-binding transcription factor activity) (1 mention)

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:0011024 (1 mention) - the report calls it "Abnormality of the digestive system — for GI bleeding as needed"; HP calls it Abnormality of the gastrointestinal tract
HP:0004808 (2 mentions) - the report calls it "Myelodysplasia"; HP calls it Acute myeloid leukemia, and lists "Acute myeloid leukaemia" among its other names
GO:0045055 (1 mention) - the report calls it "regulated exocytosis — granule secretion"; GO calls it regulated exocytosis
GO:0043433 (1 mention) - the report calls it "negative regulation of DNA-binding transcription factor activity, for dominant-negative variant mechanism"; GO calls it obsolete negative regulation of DNA-binding transcription factor activity, and lists "negative regulation of DNA binding transcription factor activity" among its other names
CL:0000556 (3 mentions) - the report calls it "megakaryocyte", "Tissue/cell level: Megakaryocytes"; CL calls it megakaryocyte**
CL:0000767 (1 mention) - the report calls it "basophil — not primary"; CL calls it basophil
CL:0000234 (1 mention) - the report calls it "phagocyte — not primary"; CL calls it phagocyte

Terms named inconsistently

The report gives these identifiers more than one name of its own:

CL:0000556 - called "megakaryocyte", "Tissue/cell level:** Megakaryocytes"

Prefixes with no resolver

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

Ask OpenScientist

OpenScientist Report

Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Animal Models

Source YAML

References & Deep Research

References

Deep Research

RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancy (RUNX1‑FPDMM): Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain (numbered, from germline lesion to clinical manifestations)

Molecular pathways, cellular processes, and profiling

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Notable Evidence Gaps (flagged rather than smoothed over)

Full Source List

Reference Validation

Quotes not found in the cited source

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver