GFI1B-related platelet-type bleeding disorder

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Inheritance

2

Autosomal dominant HP:0000006

The originally described and most common form. Heterozygous variants disrupting the zinc-finger DNA-binding region produce a mutant protein that inhibits wild-type GFI1B, so a single allele suffices.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:24325358 SUPPORT Human Clinical

"We detected a nonsense mutation in the gene encoding the transcription factor GFI1B (growth factor independent 1B) that causes autosomal dominant gray platelet syndrome."

Establishes autosomal dominant transmission for the founding variant.

Autosomal recessive HP:0000007

A separate recessive form was reported in a consanguineous kindred whose affected members carry a homozygous insertion creating a premature stop codon in the full-length p37 isoform only; heterozygous carriers, including both parents, are clinically unaffected. This is a different molecular lesion from the dominant-negative alleles, not a dosage variant of them.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:28550182 SUPPORT Human Clinical

"In contrast, the index patient's husband (II.4), her parents (I.1 and I.2) and the children of the deceased brother (III.1, III.2, III.3) were clinically unaffected."

Unaffected heterozygous carriers including both parents establish recessive transmission in this kindred.

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Discussions and Knowledge Gaps

1

Homozygous Gfi1b deletion in mice is embryonically lethal through failure to produce mature enucleated erythrocytes, yet human GFI1B disease presents as a platelet disorder with largely preserved erythropoiesis. How far does the mouse null actually model the human erythroid requirement for GFI1B?

HUMAN MODEL MISMATCH mismatch_gfi1b_erythroid_requirement_mouse_vs_human

Attached to

pathophysiology#Isoform-Selective Loss of Full-Length GFI1B-p37 pathophysiology#Impaired GFI1B-Dependent Megakaryocyte Maturation

The mouse knockout is the main evidence that GFI1B is required for erythroid development, and it is unambiguous: the animals die in utero from failed erythrocyte maturation. Human patients do not reproduce that. The isoform-selective kindred explains its own case cleanly, since the erythroid isoform p32 is retained there, but it does not explain why the dominant negative alleles, which disrupt both isoforms, also present as macrothrombocytopenia rather than as anaemia. Either the human erythroid lineage tolerates partial GFI1B disruption in a way the mouse null cannot test, or a human-specific compensatory factor operates downstream of the megakaryocyte-erythroid progenitor. Until this is settled, the mouse null should not be cited as evidence for a human erythroid phenotype in this disorder, and this entry does not curate one.

Proposed experiments

Isoform-selective depletion in human MEP-stage progenitors

exp_gfi1b_isoform_selective_lineage_output

Selectively deplete p37 versus p32 versus both in human CD34-positive progenitors and compare erythroid differentiation, enucleation efficiency and megakaryocyte maturation, testing directly whether the lineage split inferred from one kindred is a general property of the human megakaryocyte-erythroid progenitor.

Decision criterion

A clean split, with p37 depletion giving a megakaryocyte defect and p32 depletion an erythroid one, would establish isoform-specific lineage commitment in humans and retire the mouse null as the reference model for the erythroid arm. A shared defect would instead mean the kindred's preserved erythropoiesis needs a different explanation.

Red-cell phenotyping across dominant-negative and isoform-selective alleles

exp_gfi1b_erythroid_indices_across_allele_classes

Compare red cell indices, reticulocyte counts and marrow erythroid morphology between patients carrying dominant-negative zinc-finger alleles, which affect both isoforms, and those carrying the isoform-selective p37 lesion, controlling for iron status, splenic function and any thrombopoietin receptor agonist exposure.

Decision criterion

A subclinical erythroid phenotype confined to the dominant-negative group would make the human requirement real but milder than the mouse predicts. Normal indices in both groups would place the species difference itself, not allele dosage, as the thing needing explanation.

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Pathophysiology

6

Dominant-Negative GFI1B Zinc-Finger Variants

Heterozygous variants disrupting the essential DNA-binding zinc-finger region yield a protein that cannot bind its consensus site, cannot repress transcription, and actively interferes with the wild-type allele's activity. The dominant-negative behaviour has been shown for three independent patient-derived alleles.

GFI1B hgnc:4238

Genetic context functional_impact_category: DOMINANT_NEGATIVE

DNA-binding transcription repressor activity, RNA polymerase II-specific GO:0001227 ⇓ LOSS OF FUNCTION

Downstream

Impaired GFI1B-Dependent Megakaryocyte Maturation Loss of GFI1B repressor activity in megakaryocytes derails the transcriptional programme those cells depend on.

Show evidence (2 references)

PMID:24325358 SUPPORT In Vitro

"The GFI1B mutant protein inhibited nonmutant GFI1B transcriptional activity in a dominant-negative manner."

Direct functional demonstration of the dominant-negative effect on wild-type GFI1B.

PMID:27122003 SUPPORT In Vitro

"Consistent with the previous studies, the three patient-derived mutants were unable to repress the expression of the reporter gene and had a dominant-negative effect over wild-type GFI1B. In addition, the three mutations abolished recognition of a consensus-binding site in gel shift assays."

Replicates the dominant-negative effect across three alleles and adds the loss of DNA binding that explains it.

Isoform-Selective Loss of Full-Length GFI1B-p37

Alternative splicing of exon 9 produces two GFI1B isoforms: the full-length p37 protein with all six zinc fingers, and a shorter p32 isoform lacking the first two zinc fingers, which is the one necessary for human erythropoiesis. In a consanguineous kindred with severe recessive bleeding, a homozygous insertion creates a premature stop codon that affects only the longer p37 transcript, leaving p32 intact. GFI1B protein was undetectable in the index patient's megakaryocytes. Because the retained p32 covers the erythroid requirement, these patients have a platelet disease with essentially unaffected erythropoiesis, which is what makes this family evidence for isoform-specific lineage commitment at the megakaryocyte-erythroid progenitor stage rather than simply a milder GFI1B deficiency.

GFI1B hgnc:4238

Downstream

Impaired GFI1B-Dependent Megakaryocyte Maturation Loss of the p37 isoform removes GFI1B function from the megakaryocyte lineage while sparing the erythroid lineage that p32 serves.

Show evidence (3 references)

PMID:28550182 SUPPORT Human Clinical

"In humans, alternative splicing of exon 9 leads to the formation of a shorter isoform of GFI1B (p32; NP_001128503). This isoform lacks the first two zinc fingers as compared to the p37 full length protein (NP_004179) and is implicated in erythropoiesis."

Defines the two isoforms and assigns the erythroid role to the shorter p32, which is the isoform retained in these patients.

PMID:28550182 SUPPORT Human Clinical

"the insertion variant identified in this family results in a premature stop codon (p.Ser185Leufs*3) that only affects the longer p37 isoform"

Establishes that the lesion is isoform-selective, removing p37 while leaving p32 expressed.

PMID:28550182 SUPPORT Human Clinical

"GFI1B was present in most HC megakaryocytes (left column), but absent in the index patient's megakaryocytes"

Demonstrates absence of GFI1B protein in the patient's megakaryocytes, distinguishing this from the dominant-negative mechanism.

Impaired GFI1B-Dependent Megakaryocyte Maturation

GFI1B is a SNAG-domain transcriptional repressor that recruits histone deacetylases and histone methyltransferases, and mouse knockouts establish that it is required for both megakaryocytic and erythroid development. When its repressor function is lost, megakaryocytes become dysplastic, are abnormally distributed in the marrow, retain the progenitor marker CD34 that maturing megakaryocytes normally lose, and produce enlarged proplatelet tips in reduced numbers.

megakaryocyte CL:0000556

megakaryocyte differentiation GO:0030219 ⚠ ABNORMAL platelet formation GO:0030220 ⚠ ABNORMAL

Downstream

Large Granule-Deficient Dysfunctional Platelets Abnormal proplatelet formation yields a reduced number of enlarged platelets lacking normal granule content.

Show evidence (2 references)

PMID:28401061 SUPPORT Model Organism

"However, knockout mice have demonstrated that Gfi1b is required for development of both erythroid and megakaryocytic lineages."

Establishes the lineage requirement for GFI1B in a model system, underlying the human phenotype.

PMID:27122003 SUPPORT In Vitro

"Mutant-transduced megakaryocytes produced enlarged proplatelet tips which were reduced in number."

Links the transcriptional defect to the cell-biological step that produces few, large platelets.

Large Granule-Deficient Dysfunctional Platelets

Circulating platelets are reduced in number, enlarged, and stain poorly with May-Grunwald-Giemsa. Alpha-granule markers von Willebrand factor and P-selectin are reduced, and a delta-granule defect is often present as well, giving a combined alpha-delta storage pool deficiency. Aggregation and activation responses to ADP, collagen, TRAP-6 and arachidonic acid are impaired, so the bleeding tendency reflects both a low count and defective function.

platelet CL:0000233

platelet alpha granule GO:0031091

Downstream

Failure of Primary Hemostatic Plug Formation Reduced numbers of functionally defective platelets cannot assemble a competent haemostatic plug at the site of vessel injury.

Show evidence (2 references)

PMID:28550182 SUPPORT Human Clinical

"decreased immunofluorescence staining for alpha-granule markers von Willebrand factor and P-selectin, suggesting an alpha storage pool deficiency"

Documents the alpha-granule deficiency directly.

PMID:28550182 SUPPORT Human Clinical

"Platelet function testing by flow cytometry and aggregometry revealed reduced responses to ADP, collagen, TRAP-6 and arachidonic acid"

Establishes the functional defect independent of the reduced platelet count.

Failure of Primary Hemostatic Plug Formation

The shared destination of the inherited platelet function disorders, reached here by a combined route: too few platelets, and those that circulate cannot amplify haemostasis by secretion because their granules are depleted. This node is the point at which a disorder whose proximal lesion is transcriptional converges with the receptor, signalling and procoagulant disorders of the same family.

platelet CL:0000233

primary hemostasis GO:0007599 ↓ DECREASED

Downstream

Bleeding Diathesis Failure of platelet-dependent primary hemostasis declares itself as the clinical bleeding tendency.

Show evidence (2 references)

PMID:21781244 SUPPORT Human Clinical

"Genetic defects of platelet function give rise to mucocutaneous bleeding of varying severity because platelets fail to fulfil their haemostatic role after vessel injury."

Supports the convergence this node represents - a genetic platelet-function defect producing failure of the platelet's haemostatic role, and thence mucocutaneous bleeding.

PMID:28401061 SUPPORT Human Clinical

"Consistent with this, human mutations of GFI1B produce bleeding disorders with low platelet count and abnormal function."

Ties the convergence specifically to GFI1B, naming the two platelet deficits that reach this node.

Bleeding Diathesis

Clinical severity ranges widely. In the reported recessive kindred it was life-threatening: the index patient had petechiae and haematoma from childhood and repeated emergency surgery for intra-abdominal bleeding, and her brother died at 33 of spontaneous cerebral haemorrhage. Milder presentations with cutaneous bleeding and epistaxis are also described. The disorder is misdiagnosable as immune thrombocytopenia, and the index patient had been splenectomised and treated with a thrombopoietin receptor agonist without improvement before the genetic diagnosis was made.

Show evidence (1 reference)

PMID:28550182 SUPPORT Human Clinical

"The index patient's brother (II.2) had also suffered from a severe bleeding diathesis with thrombocytopenia, and had died at age 33 due to a spontaneous cerebral hemorrhage."

Documents the fatal end of the severity range in a genetically confirmed family.

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Pathograph

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

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Phenotypes

8

Blood 4

Thrombocytopenia VERY_FREQUENT HP:0001873

Show evidence (1 reference)

PMID:28401061 SUPPORT Human Clinical

"human mutations of GFI1B produce bleeding disorders with low platelet count and abnormal function"

Establishes thrombocytopenia as a defining feature of the disorder.

Abnormal Bleeding VERY_FREQUENT HP:0001892

Show evidence (1 reference)

PMID:28550182 SUPPORT Human Clinical

"We describe a Chechen family from eastern Georgia whose affected members presented with a severe, life-threatening bleeding diathesis."

Documents the bleeding phenotype in the reported kindred.

Petechiae HP:0000967

Show evidence (1 reference)

PMID:28550182 SUPPORT Human Clinical

"had suffered from multiple petechiae and hematoma since childhood"

Documents petechiae from childhood in the index patient.

Epistaxis HP:0000421

Show evidence (1 reference)

PMID:28550182 SUPPORT Human Clinical

"exhibited severe thrombocytopenia (platelet counts: 23–44×10/L) and similar cutaneous bleeding patterns as the index patient (II.3), recurring epistaxis and caries"

Documents recurrent epistaxis in the two affected children.

Other 4

Macrothrombocytopenia VERY_FREQUENT HP:0040185

Show evidence (1 reference)

PMID:28550182 SUPPORT Human Clinical

"Standard blood smears show large platelets with reduced, grayish staining in the index patient"

Documents both the enlargement and the characteristic grey staining.

Abnormal Platelet Function HP:0011869

Show evidence (1 reference)

PMID:28550182 SUPPORT Human Clinical

"Platelet function testing by flow cytometry and aggregometry revealed reduced responses to ADP, collagen, TRAP-6 and arachidonic acid"

Documents the multi-agonist functional defect.

Reduced Platelet Alpha Granules HP:0033536

Show evidence (2 references)

PMID:28550182 SUPPORT Human Clinical

"decreased immunofluorescence staining for alpha-granule markers von Willebrand factor and P-selectin, suggesting an alpha storage pool deficiency"

Documents the reduced alpha-granule content directly.

PMID:24325358 SUPPORT Human Clinical

"The gray platelet syndrome is a hereditary, usually autosomal recessive bleeding disorder caused by a deficiency of alpha granules in platelets."

Establishes alpha-granule deficiency as the feature defining the grey-platelet phenotype this disorder shares.

Ectopic Platelet CD34 Expression

Left deliberately unbound. HP:0011875 (Abnormal platelet morphology) was tried and rejected: this is an antigen-expression abnormality, not a morphological one, and the platelets here are already covered by a separate macrothrombocytopenia entry. HP:0011878 (Abnormal platelet membrane protein expression) is the closest resolvable candidate but its textual definition reads "Presence of reduced amount of a membrane protein", whereas CD34 here is ectopically INCREASED - the opposite direction. No HPO term currently expresses gain of a progenitor marker on mature platelets, so this is recorded as a new-term request rather than bound to an approximate parent.

Show evidence (1 reference)

PMID:27122003 SUPPORT Human Clinical

"An immunofluorescence analysis revealed decreased thrombospondin-1 and increased CD34 expression in platelets from our patient."

Documents the ectopic CD34 expression together with reduced alpha-granule cargo.

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Genetic Associations

1

GFI1B (Heterozygous dominant-negative zinc-finger variants, or recessive isoform-selective loss of GFI1B-p37)

Gene: GFI1B hgnc:4238 relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:27122003 SUPPORT Human Clinical

"p.G272fsX274 and the previous two mutations all predicted disruption of an essential DNA-binding domain in GFI1B."

Establishes that the reported dominant alleles converge on the same functional domain.

PMID:28401061 SUPPORT Human Clinical

"Both GFI1 and GFI1B have six C-terminal C2H2 zinc fingers and an N-terminal SNAG (SNAIL/GFI1) transcriptional repression domain."

Describes the protein architecture the pathogenic variants disrupt.

PMID:28550182 SUPPORT Human Clinical

"that possibly disrupts a splice enhancer-binding site in exon 9 with a minor allele frequency of 0.009"

Supplies the only allele-frequency figure available for a GFI1B variant in any reference cached for this entry.

+ 1 more reference

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Medical Actions

1

Avoidance of Immune-Thrombocytopenia-Directed Therapy

Action: Supportive Care NCIT:C15747

The single most consequential management point in this disorder is a negative one. GFI1B-related thrombocytopenia is regularly mistaken for immune thrombocytopenia, and ITP-directed therapy does not work: the reported index patient had been splenectomised and was on eltrombopag under a working diagnosis of hepatitis C-associated ITP, with no improvement in her bleeding phenotype. Recognising the inherited cause spares a patient a splenectomy that cannot help.

Show evidence (1 reference)

PMID:28550182 SUPPORT Human Clinical

"she was splenectomized and being treated with eltrombopag (according to a working diagnosis of hepatitis C-associated immune thrombocytopenia), but the bleeding phenotype had not improved"

A documented failure of both splenectomy and a thrombopoietin receptor agonist in a genetically confirmed patient.

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Diagnosis

3

Platelet CD34 Immunofluorescence

Immunofluorescence for platelet CD34 has been proposed as a screening test: the marker is ectopically present in this disorder and absent from normal mature platelets. It is a screening aid rather than a confirmatory test, and the diagnosis rests on sequencing.

Diagnostic Procedure NCIT:C18020

Show evidence (1 reference)

PMID:27122003 SUPPORT Human Clinical

"An immunofluorescence analysis of the platelet CD34 expression can be useful as a screening test."

The authors' own proposal of CD34 as a screening test.

Blood Smear and Platelet Function Testing

Large, grey-staining platelets on a standard smear raise the diagnosis, and aggregometry plus flow cytometry establish the functional defect and the combined alpha-delta storage pool deficiency.

Diagnostic Procedure NCIT:C18020

Show evidence (1 reference)

PMID:28550182 SUPPORT Human Clinical

"Standard blood smears show large platelets with reduced, grayish staining in the index patient"

Establishes the smear appearance that prompts further testing.

Distinction from Immune Thrombocytopenia

An inherited macrothrombocytopenia is readily mistaken for immune thrombocytopenia, with real consequences: the reported index patient had been splenectomised and started on a thrombopoietin receptor agonist under a working diagnosis of hepatitis C-associated ITP, without improvement in the bleeding phenotype.

Diagnostic Procedure NCIT:C18020

Show evidence (1 reference)

PMID:28550182 SUPPORT Human Clinical

"she was splenectomized and being treated with eltrombopag (according to a working diagnosis of hepatitis C-associated immune thrombocytopenia), but the bleeding phenotype had not improved"

A documented case of the misdiagnosis and of the ineffective treatment that followed from it.

{ }

Source YAML

click to show

name: GFI1B-related platelet-type bleeding disorder
creation_date: "2026-08-24T22:35:00Z"
category: Mendelian
description: >-
  Platelet-type bleeding disorder 17 (BDPLT17) is an inherited
  macrothrombocytopenia with a grey-platelet-like phenotype, caused by variants
  in GFI1B, the zinc-finger transcriptional repressor required for megakaryocyte
  and erythrocyte development. Platelets are large, deficient in alpha granules
  (often with a delta-granule defect as well), stain poorly on
  May-Grunwald-Giemsa, function abnormally, and ectopically express the
  progenitor marker CD34 — a marker that is normally lost as megakaryocytes
  mature and that has been proposed as a screening test. Bleeding ranges from
  cutaneous petechiae and epistaxis to fatal cerebral haemorrhage. Two genetically
  distinct routes are documented and are not interchangeable: heterozygous
  zinc-finger variants act as dominant negatives over wild-type GFI1B, while a
  recessive form arises from isoform-selective loss of the full-length p37
  protein with the shorter p32 isoform retained. The disorder
  is distinct from classic NBEAL2 grey platelet syndrome despite the shared
  platelet appearance.
disease_term:
  preferred_term: platelet-type bleeding disorder 17
  term:
    id: MONDO:0008553
    label: platelet-type bleeding disorder 17
parents:
- inherited bleeding disorder, platelet-type
synonyms:
- platelet-type bleeding disorder 17
- BDPLT17
- GFI1B-related thrombocytopenia
- autosomal dominant gray platelet syndrome
- GFI1B-related macrothrombocytopenia
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    The originally described and most common form. Heterozygous variants
    disrupting the zinc-finger DNA-binding region produce a mutant protein that
    inhibits wild-type GFI1B, so a single allele suffices.
  evidence:
  - reference: PMID:24325358
    reference_title: "A dominant-negative GFI1B mutation in the gray platelet syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We detected a nonsense mutation in the gene encoding the transcription
      factor GFI1B (growth factor independent 1B) that causes autosomal dominant
      gray platelet syndrome.
    explanation: Establishes autosomal dominant transmission for the founding variant.
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    A separate recessive form was reported in a consanguineous kindred whose
    affected members carry a homozygous insertion creating a premature stop codon
    in the full-length p37 isoform only; heterozygous carriers, including both
    parents, are clinically unaffected. This is a different molecular lesion from
    the dominant-negative alleles, not a dosage variant of them.
  evidence:
  - reference: PMID:28550182
    reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, the index patient's husband (II.4), her parents (I.1 and I.2)
      and the children of the deceased brother (III.1, III.2, III.3) were
      clinically unaffected.
    explanation: >-
      Unaffected heterozygous carriers including both parents establish recessive
      transmission in this kindred.
notes: >-
  **The two inheritance patterns here are two different molecular lesions, and
  the entry keeps them apart.** This is not the same situation as a contested
  mode of inheritance. The dominant alleles are zinc-finger variants whose
  product actively inhibits wild-type GFI1B — demonstrated in reporter assays,
  and accompanied by abolished consensus-site binding in gel shift. The
  recessive family instead carries an isoform-selective stop codon that removes
  only the full-length p37 protein, leaving the shorter p32 isoform expressed,
  with heterozygous carriers unaffected. Collapsing these into one "GFI1B
  loss-of-function" claim would erase the dominant-negative mechanism, which is
  the reason a single allele is sufficient in most reported patients. The
  pathophysiology therefore carries two trigger nodes, and the `genetic` entry
  uses `functional_impact_category: DOMINANT_NEGATIVE` for the dominant arm.

  **Ectopic platelet CD34 is curated as a phenotype, not as a mechanism.** It is
  reproducible across independent reports and has been proposed as a screening
  test, but no source cited here shows that CD34 expression itself contributes
  to the bleeding. It is curated as a laboratory phenotype of arrested
  megakaryocyte maturation.

  **Two cached records carry no abstract.** `PMID:28096094` and `PMID:28580815`
  are both directly relevant by title, but the cached PubMed records hold
  metadata only, so there is no quotable text and nothing is cited from them.
  Per the evidence SOP a title is not a finding, so they are omitted entirely
  rather than cited on their titles.

  **Naming.** MONDO's OMIM xref for this entity is 187900, while PMID:28550182
  writes "BDPLT17 (MIM 604383)" — 604383 is the GFI1B *gene* MIM number. The
  entry makes no OMIM claim to avoid propagating that conflation.

  Research input: `research/Platelet-type_Bleeding_Disorder_17-deep-research-perplexity.md`,
  NEC preflight PASS against MONDO:0008553 (GFI1B mentioned 178 times). It
  returned no PMIDs in its body; all references were located independently in
  PubMed.
pathophysiology:
- name: Dominant-Negative GFI1B Zinc-Finger Variants
  biological_scale: MOLECULAR
  conforms_to: "primary_hemostatic_plug_failure#Loss of a Platelet Primary-Hemostatic Component"
  description: >-
    Heterozygous variants disrupting the essential DNA-binding zinc-finger region
    yield a protein that cannot bind its consensus site, cannot repress
    transcription, and actively interferes with the wild-type allele's activity.
    The dominant-negative behaviour has been shown for three independent
    patient-derived alleles.
  genes:
  - preferred_term: GFI1B
    term:
      id: hgnc:4238
      label: GFI1B
  molecular_functions:
  - preferred_term: "DNA-binding transcription repressor activity, RNA polymerase II-specific"
    term:
      id: GO:0001227
      label: "DNA-binding transcription repressor activity, RNA polymerase II-specific"
    modifier: LOSS_OF_FUNCTION
  genetic_context:
    functional_impact_category: DOMINANT_NEGATIVE
  evidence:
  - reference: PMID:24325358
    reference_title: "A dominant-negative GFI1B mutation in the gray platelet syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The GFI1B mutant protein inhibited nonmutant GFI1B transcriptional activity
      in a dominant-negative manner.
    explanation: >-
      Direct functional demonstration of the dominant-negative effect on wild-type
      GFI1B.
  - reference: PMID:27122003
    reference_title: "Functional characterization of a novel GFI1B mutation causing congenital macrothrombocytopenia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consistent with the previous studies, the three patient-derived mutants were
      unable to repress the expression of the reporter gene and had a
      dominant-negative effect over wild-type GFI1B. In addition, the three
      mutations abolished recognition of a consensus-binding site in gel shift
      assays.
    explanation: >-
      Replicates the dominant-negative effect across three alleles and adds the
      loss of DNA binding that explains it.
  downstream:
  - target: Impaired GFI1B-Dependent Megakaryocyte Maturation
    description: >-
      Loss of GFI1B repressor activity in megakaryocytes derails the
      transcriptional programme those cells depend on.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24325358
      reference_title: "A dominant-negative GFI1B mutation in the gray platelet syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In addition, the megakaryocytes had dysplastic features, and they were
        abnormally distributed in the bone marrow.
      explanation: >-
        Documents the megakaryocyte abnormality in patients carrying the
        dominant-negative allele.
- name: Isoform-Selective Loss of Full-Length GFI1B-p37
  biological_scale: MOLECULAR
  conforms_to: "primary_hemostatic_plug_failure#Loss of a Platelet Primary-Hemostatic Component"
  description: >-
    Alternative splicing of exon 9 produces two GFI1B isoforms: the full-length
    p37 protein with all six zinc fingers, and a shorter p32 isoform lacking the
    first two zinc fingers, which is the one necessary for human erythropoiesis.
    In a consanguineous kindred with severe recessive bleeding, a homozygous
    insertion creates a premature stop codon that affects only the longer p37
    transcript, leaving p32 intact. GFI1B protein was undetectable in the index
    patient's megakaryocytes. Because the retained p32 covers the erythroid
    requirement, these patients have a platelet disease with essentially
    unaffected erythropoiesis, which is what makes this family evidence for
    isoform-specific lineage commitment at the megakaryocyte-erythroid
    progenitor stage rather than simply a milder GFI1B deficiency.
  genes:
  - preferred_term: GFI1B
    term:
      id: hgnc:4238
      label: GFI1B
  evidence:
  - reference: PMID:28550182
    reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In humans, alternative splicing of exon 9 leads to the formation of a
      shorter isoform of GFI1B (p32; NP_001128503). This isoform lacks the first
      two zinc fingers as compared to the p37 full length protein (NP_004179) and
      is implicated in erythropoiesis.
    explanation: >-
      Defines the two isoforms and assigns the erythroid role to the shorter p32,
      which is the isoform retained in these patients.
  - reference: PMID:28550182
    reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the insertion variant identified in this family results in a premature stop
      codon (p.Ser185Leufs*3) that only affects the longer p37 isoform
    explanation: >-
      Establishes that the lesion is isoform-selective, removing p37 while leaving
      p32 expressed.
  - reference: PMID:28550182
    reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GFI1B was present in most HC megakaryocytes (left column), but absent in the
      index patient's megakaryocytes
    explanation: >-
      Demonstrates absence of GFI1B protein in the patient's megakaryocytes,
      distinguishing this from the dominant-negative mechanism.
  downstream:
  - target: Impaired GFI1B-Dependent Megakaryocyte Maturation
    description: >-
      Loss of the p37 isoform removes GFI1B function from the megakaryocyte
      lineage while sparing the erythroid lineage that p32 serves.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28550182
      reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        abrogating the complete GFI1B-p37 isoform results in autosomal-recessive
        macrothrombocytopenia with diminished platelet function as seen in the
        presented trait
      explanation: >-
        States the causal consequence of losing p37 specifically.
- name: Impaired GFI1B-Dependent Megakaryocyte Maturation
  biological_scale: CELLULAR
  description: >-
    GFI1B is a SNAG-domain transcriptional repressor that recruits histone
    deacetylases and histone methyltransferases, and mouse knockouts establish
    that it is required for both megakaryocytic and erythroid development. When
    its repressor function is lost, megakaryocytes become dysplastic, are
    abnormally distributed in the marrow, retain the progenitor marker CD34 that
    maturing megakaryocytes normally lose, and produce enlarged proplatelet tips
    in reduced numbers.
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  biological_processes:
  - preferred_term: megakaryocyte differentiation
    term:
      id: GO:0030219
      label: megakaryocyte differentiation
    modifier: ABNORMAL
  - preferred_term: platelet formation
    term:
      id: GO:0030220
      label: platelet formation
    modifier: ABNORMAL
  evidence:
  - reference: PMID:28401061
    reference_title: "Transcription Factor GFI1B in Health and Disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      However, knockout mice have demonstrated that Gfi1b is required for
      development of both erythroid and megakaryocytic lineages.
    explanation: >-
      Establishes the lineage requirement for GFI1B in a model system, underlying
      the human phenotype.
  - reference: PMID:27122003
    reference_title: "Functional characterization of a novel GFI1B mutation causing congenital macrothrombocytopenia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mutant-transduced megakaryocytes produced enlarged proplatelet tips which
      were reduced in number.
    explanation: >-
      Links the transcriptional defect to the cell-biological step that produces
      few, large platelets.
  downstream:
  - target: Large Granule-Deficient Dysfunctional Platelets
    description: >-
      Abnormal proplatelet formation yields a reduced number of enlarged platelets
      lacking normal granule content.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24325358
      reference_title: "A dominant-negative GFI1B mutation in the gray platelet syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both gray platelets and megakaryocytes had abnormal marker expression.
      explanation: >-
        Connects the megakaryocyte defect to the abnormal platelets it produces.
- name: Large Granule-Deficient Dysfunctional Platelets
  biological_scale: CELLULAR
  conforms_to: "primary_hemostatic_plug_failure#Impaired Platelet Activation, Granule Secretion, and Integrin Inside-Out Signalling"
  description: >-
    Circulating platelets are reduced in number, enlarged, and stain poorly with
    May-Grunwald-Giemsa. Alpha-granule markers von Willebrand factor and
    P-selectin are reduced, and a delta-granule defect is often present as well,
    giving a combined alpha-delta storage pool deficiency. Aggregation and
    activation responses to ADP, collagen, TRAP-6 and arachidonic acid are
    impaired, so the bleeding tendency reflects both a low count and defective
    function.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  cellular_components:
  - preferred_term: platelet alpha granule
    term:
      id: GO:0031091
      label: platelet alpha granule
    modifier: DECREASED
  evidence:
  - reference: PMID:28550182
    reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      decreased immunofluorescence staining for alpha-granule markers von
      Willebrand factor and P-selectin, suggesting an alpha storage pool
      deficiency
    explanation: Documents the alpha-granule deficiency directly.
  - reference: PMID:28550182
    reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Platelet function testing by flow cytometry and aggregometry revealed
      reduced responses to ADP, collagen, TRAP-6 and arachidonic acid
    explanation: >-
      Establishes the functional defect independent of the reduced platelet count.
  downstream:
  - target: Failure of Primary Hemostatic Plug Formation
    description: >-
      Reduced numbers of functionally defective platelets cannot assemble a
      competent haemostatic plug at the site of vessel injury.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28401061
      reference_title: "Transcription Factor GFI1B in Health and Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Consistent with this, human mutations of GFI1B produce bleeding disorders
        with low platelet count and abnormal function.
      explanation: >-
        States both components of the platelet defect - a low count and abnormal
        function - that together underlie the failure of plug formation.
- name: Failure of Primary Hemostatic Plug Formation
  biological_scale: TISSUE
  conforms_to: "primary_hemostatic_plug_failure#Failure of Primary Hemostatic Plug Formation"
  description: >-
    The shared destination of the inherited platelet function disorders, reached
    here by a combined route: too few platelets, and those that circulate cannot
    amplify haemostasis by secretion because their granules are depleted. This
    node is the point at which a disorder whose proximal lesion is
    transcriptional converges with the receptor, signalling and procoagulant
    disorders of the same family.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: primary hemostasis
    term:
      id: GO:0007599
      label: hemostasis
    modifier: DECREASED
  evidence:
  - reference: PMID:21781244
    reference_title: Advances in our understanding of the molecular basis of disorders of platelet function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic defects of platelet function give rise to mucocutaneous bleeding of varying severity because platelets fail to fulfil their haemostatic role after vessel injury."
    explanation: >-
      Supports the convergence this node represents - a genetic platelet-function
      defect producing failure of the platelet's haemostatic role, and thence
      mucocutaneous bleeding.
  - reference: PMID:28401061
    reference_title: "Transcription Factor GFI1B in Health and Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Consistent with this, human mutations of GFI1B produce bleeding disorders
      with low platelet count and abnormal function.
    explanation: >-
      Ties the convergence specifically to GFI1B, naming the two platelet
      deficits that reach this node.
  downstream:
  - target: Bleeding Diathesis
    description: >-
      Failure of platelet-dependent primary hemostasis declares itself as the
      clinical bleeding tendency.
    causal_link_type: DIRECT
- name: Bleeding Diathesis
  biological_scale: ORGANISM
  conforms_to: "primary_hemostatic_plug_failure#Mucocutaneous Bleeding Diathesis"
  description: >-
    Clinical severity ranges widely. In the reported recessive kindred it was
    life-threatening: the index patient had petechiae and haematoma from
    childhood and repeated emergency surgery for intra-abdominal bleeding, and
    her brother died at 33 of spontaneous cerebral haemorrhage. Milder
    presentations with cutaneous bleeding and epistaxis are also described. The
    disorder is misdiagnosable as immune thrombocytopenia, and the index patient
    had been splenectomised and treated with a thrombopoietin receptor agonist
    without improvement before the genetic diagnosis was made.
  evidence:
  - reference: PMID:28550182
    reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The index patient's brother (II.2) had also suffered from a severe bleeding
      diathesis with thrombocytopenia, and had died at age 33 due to a spontaneous
      cerebral hemorrhage.
    explanation: >-
      Documents the fatal end of the severity range in a genetically confirmed
      family.
phenotypes:
- name: Thrombocytopenia
  category: Hematological
  description: >-
    Reduced platelet count is a constant feature. Counts in the low twenties to
    forties per nanolitre were recorded in the affected children of the recessive
    kindred.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:28401061
    reference_title: "Transcription Factor GFI1B in Health and Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      human mutations of GFI1B produce bleeding disorders with low platelet count
      and abnormal function
    explanation: Establishes thrombocytopenia as a defining feature of the disorder.
- name: Macrothrombocytopenia
  category: Hematological
  description: >-
    Platelets are enlarged and reduced in number, and stain poorly and greyish on
    standard blood smears, the appearance that gives the grey-platelet-like
    designation.
  phenotype_term:
    preferred_term: Macrothrombocytopenia
    term:
      id: HP:0040185
      label: Macrothrombocytopenia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:28550182
    reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Standard blood smears show large platelets with reduced, grayish staining in
      the index patient
    explanation: Documents both the enlargement and the characteristic grey staining.
- name: Abnormal Platelet Function
  category: Hematological
  description: >-
    Aggregation and activation responses are impaired across multiple agonists,
    independent of the platelet count.
  phenotype_term:
    preferred_term: Abnormal platelet function
    term:
      id: HP:0011869
      label: Abnormal platelet function
  evidence:
  - reference: PMID:28550182
    reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Platelet function testing by flow cytometry and aggregometry revealed
      reduced responses to ADP, collagen, TRAP-6 and arachidonic acid
    explanation: Documents the multi-agonist functional defect.
- name: Reduced Platelet Alpha Granules
  category: Hematological
  description: >-
    Alpha-granule content is reduced, shown by decreased immunofluorescence for
    von Willebrand factor and P-selectin. A delta-granule defect is often present
    as well, giving a combined alpha-delta storage pool deficiency. This is the
    defining grey-platelet feature.
  phenotype_term:
    preferred_term: Reduced platelet alpha granules
    term:
      id: HP:0033536
      label: Reduced platelet alpha granules
  evidence:
  - reference: PMID:28550182
    reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      decreased immunofluorescence staining for alpha-granule markers von
      Willebrand factor and P-selectin, suggesting an alpha storage pool
      deficiency
    explanation: Documents the reduced alpha-granule content directly.
  - reference: PMID:24325358
    reference_title: "A dominant-negative GFI1B mutation in the gray platelet syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The gray platelet syndrome is a hereditary, usually autosomal recessive
      bleeding disorder caused by a deficiency of alpha granules in platelets.
    explanation: >-
      Establishes alpha-granule deficiency as the feature defining the
      grey-platelet phenotype this disorder shares.
- name: Abnormal Bleeding
  category: Hematological
  phenotype_term:
    preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:28550182
    reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a Chechen family from eastern Georgia whose affected members
      presented with a severe, life-threatening bleeding diathesis.
    explanation: Documents the bleeding phenotype in the reported kindred.
- name: Petechiae
  category: Hematological
  phenotype_term:
    preferred_term: Petechiae
    term:
      id: HP:0000967
      label: Petechiae
  evidence:
  - reference: PMID:28550182
    reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      had suffered from multiple petechiae and hematoma since childhood
    explanation: Documents petechiae from childhood in the index patient.
- name: Epistaxis
  category: Hematological
  phenotype_term:
    preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
  evidence:
  - reference: PMID:28550182
    reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      exhibited severe thrombocytopenia (platelet counts: 23–44×10/L) and similar
      cutaneous bleeding patterns as the index patient (II.3), recurring epistaxis
      and caries
    explanation: Documents recurrent epistaxis in the two affected children.
- name: Ectopic Platelet CD34 Expression
  category: Laboratory
  description: >-
    Platelets and megakaryocytes ectopically express CD34, a progenitor marker
    normally lost during megakaryocyte maturation. It is reproducible across
    independent reports and has been proposed as an immunofluorescence screening
    test. Curated as a marker of arrested maturation, not as a step in the
    bleeding mechanism.
  phenotype_term:
    preferred_term: Ectopic CD34 expression on platelets and megakaryocytes
  notes: >-
    Left deliberately unbound. HP:0011875 (Abnormal platelet morphology) was
    tried and rejected: this is an antigen-expression abnormality, not a
    morphological one, and the platelets here are already covered by a separate
    macrothrombocytopenia entry. HP:0011878 (Abnormal platelet membrane protein
    expression) is the closest resolvable candidate but its textual definition
    reads "Presence of reduced amount of a membrane protein", whereas CD34 here
    is ectopically INCREASED - the opposite direction. No HPO term currently
    expresses gain of a progenitor marker on mature platelets, so this is
    recorded as a new-term request rather than bound to an approximate parent.
  evidence:
  - reference: PMID:27122003
    reference_title: "Functional characterization of a novel GFI1B mutation causing congenital macrothrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An immunofluorescence analysis revealed decreased thrombospondin-1 and
      increased CD34 expression in platelets from our patient.
    explanation: >-
      Documents the ectopic CD34 expression together with reduced alpha-granule
      cargo.
genetic:
- name: GFI1B
  gene_term:
    preferred_term: GFI1B
    term:
      id: hgnc:4238
      label: GFI1B
  association: Heterozygous dominant-negative zinc-finger variants, or recessive isoform-selective loss of GFI1B-p37
  relationship_type: CAUSATIVE
  features: >-
    GFI1B encodes a six-zinc-finger transcriptional repressor with an N-terminal
    SNAG repression domain, paralogous to GFI1 and mapping to 9q34.13. The
    dominant alleles reported so far (including a nonsense variant and the
    frameshift p.Gly272fsX274) all disrupt the essential DNA-binding domain,
    abolish consensus-site recognition, fail to repress a reporter gene, and act
    dominant-negatively over wild-type protein. A mechanistically separate
    recessive form arises from a homozygous insertion (p.Ser185Leufs*3) that
    truncates only the full-length p37 isoform, sparing the shorter p32 variant
    produced by alternative splicing of exon 9. The reported variant classes
    therefore span nonsense, frameshift and in-frame changes in the zinc-finger
    region, an isoform-selective insertion, and at least one hypomorphic
    recessive missense allele in zinc finger 6 (p.Leu308Pro). A separate,
    GWAS-detected splice-affecting polymorphism is also known: rs150813342
    (minor allele frequency 0.009), reported as possibly disrupting a splice
    enhancer-binding site in exon 9 and associated with a mild phenotype that
    the source attributes, again only possibly, to residual p37 expression. Both
    hedges are the source's own and are retained here; if the attribution holds
    it is consistent with the isoform logic of the recessive kindred, where p37
    is lost entirely.
  evidence:
  - reference: PMID:27122003
    reference_title: "Functional characterization of a novel GFI1B mutation causing congenital macrothrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      p.G272fsX274 and the previous two mutations all predicted disruption of an
      essential DNA-binding domain in GFI1B.
    explanation: >-
      Establishes that the reported dominant alleles converge on the same
      functional domain.
  - reference: PMID:28401061
    reference_title: "Transcription Factor GFI1B in Health and Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both GFI1 and GFI1B have six C-terminal C2H2 zinc fingers and an N-terminal
      SNAG (SNAIL/GFI1) transcriptional repression domain.
    explanation: Describes the protein architecture the pathogenic variants disrupt.
  - reference: PMID:28550182
    reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      that possibly disrupts a splice enhancer-binding site in exon 9 with a minor
      allele frequency of 0.009
    explanation: >-
      Supplies the only allele-frequency figure available for a GFI1B variant in
      any reference cached for this entry.
  - reference: PMID:28550182
    reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, this was associated with a mild phenotype, possibly due to the
      residual expression of the p37 isoform.
    explanation: >-
      Ties phenotype severity to residual p37, supporting the isoform-dosage
      reading this entry curates.
diagnosis:
- name: Platelet CD34 Immunofluorescence
  description: >-
    Immunofluorescence for platelet CD34 has been proposed as a screening test:
    the marker is ectopically present in this disorder and absent from normal
    mature platelets. It is a screening aid rather than a confirmatory test, and
    the diagnosis rests on sequencing.
  diagnosis_term:
    preferred_term: Diagnostic Procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:27122003
    reference_title: "Functional characterization of a novel GFI1B mutation causing congenital macrothrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An immunofluorescence analysis of the platelet CD34 expression can be useful
      as a screening test.
    explanation: The authors' own proposal of CD34 as a screening test.
- name: Blood Smear and Platelet Function Testing
  description: >-
    Large, grey-staining platelets on a standard smear raise the diagnosis, and
    aggregometry plus flow cytometry establish the functional defect and the
    combined alpha-delta storage pool deficiency.
  diagnosis_term:
    preferred_term: Diagnostic Procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:28550182
    reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Standard blood smears show large platelets with reduced, grayish staining in
      the index patient
    explanation: Establishes the smear appearance that prompts further testing.
- name: Distinction from Immune Thrombocytopenia
  description: >-
    An inherited macrothrombocytopenia is readily mistaken for immune
    thrombocytopenia, with real consequences: the reported index patient had been
    splenectomised and started on a thrombopoietin receptor agonist under a
    working diagnosis of hepatitis C-associated ITP, without improvement in the
    bleeding phenotype.
  diagnosis_term:
    preferred_term: Diagnostic Procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:28550182
    reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      she was splenectomized and being treated with eltrombopag (according to a
      working diagnosis of hepatitis C-associated immune thrombocytopenia), but
      the bleeding phenotype had not improved
    explanation: >-
      A documented case of the misdiagnosis and of the ineffective treatment that
      followed from it.
treatments:
- name: Avoidance of Immune-Thrombocytopenia-Directed Therapy
  description: >-
    The single most consequential management point in this disorder is a
    negative one. GFI1B-related thrombocytopenia is regularly mistaken for immune
    thrombocytopenia, and ITP-directed therapy does not work: the reported index
    patient had been splenectomised and was on eltrombopag under a working
    diagnosis of hepatitis C-associated ITP, with no improvement in her bleeding
    phenotype. Recognising the inherited cause spares a patient a splenectomy
    that cannot help.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:28550182
    reference_title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      she was splenectomized and being treated with eltrombopag (according to a
      working diagnosis of hepatitis C-associated immune thrombocytopenia), but
      the bleeding phenotype had not improved
    explanation: >-
      A documented failure of both splenectomy and a thrombopoietin receptor
      agonist in a genetically confirmed patient.
  notes: >-
    This is the only treatment entry the available evidence supports, and the
    omission of the rest is deliberate rather than an oversight. Platelet
    transfusion, antifibrinolytics such as tranexamic acid, hormonal control of
    menorrhagia and iron supplementation are all standard supportive management
    for inherited platelet disorders and are described in this entry's
    deep-research report, but that report carries no PMIDs and none of the
    references cached for this entry contains quotable text for any of them.
    Curating them would mean either an evidence-free treatment block or a snippet
    manufactured to fit, and the evidence SOP rules out both. They should be
    added when a citable management source is fetched.
discussions:
- discussion_id: mismatch_gfi1b_erythroid_requirement_mouse_vs_human
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Isoform-Selective Loss of Full-Length GFI1B-p37
  - pathophysiology#Impaired GFI1B-Dependent Megakaryocyte Maturation
  prompt: >-
    Homozygous Gfi1b deletion in mice is embryonically lethal through failure to
    produce mature enucleated erythrocytes, yet human GFI1B disease presents as a
    platelet disorder with largely preserved erythropoiesis. How far does the
    mouse null actually model the human erythroid requirement for GFI1B?
  rationale: >-
    The mouse knockout is the main evidence that GFI1B is required for erythroid
    development, and it is unambiguous: the animals die in utero from failed
    erythrocyte maturation. Human patients do not reproduce that. The
    isoform-selective kindred explains its own case cleanly, since the erythroid
    isoform p32 is retained there, but it does not explain why the dominant
    negative alleles, which disrupt both isoforms, also present as
    macrothrombocytopenia rather than as anaemia. Either the human erythroid
    lineage tolerates partial GFI1B disruption in a way the mouse null cannot
    test, or a human-specific compensatory factor operates downstream of the
    megakaryocyte-erythroid progenitor. Until this is settled, the mouse null
    should not be cited as evidence for a human erythroid phenotype in this
    disorder, and this entry does not curate one.
  proposed_experiments:
  - experiment_id: exp_gfi1b_isoform_selective_lineage_output
    name: Isoform-selective depletion in human MEP-stage progenitors
    description: >-
      Selectively deplete p37 versus p32 versus both in human CD34-positive
      progenitors and compare erythroid differentiation, enucleation efficiency
      and megakaryocyte maturation, testing directly whether the lineage split
      inferred from one kindred is a general property of the human
      megakaryocyte-erythroid progenitor.
    decision_criterion: >-
      A clean split, with p37 depletion giving a megakaryocyte defect and p32
      depletion an erythroid one, would establish isoform-specific lineage
      commitment in humans and retire the mouse null as the reference model for
      the erythroid arm. A shared defect would instead mean the kindred's
      preserved erythropoiesis needs a different explanation.
  - experiment_id: exp_gfi1b_erythroid_indices_across_allele_classes
    name: Red-cell phenotyping across dominant-negative and isoform-selective alleles
    description: >-
      Compare red cell indices, reticulocyte counts and marrow erythroid
      morphology between patients carrying dominant-negative zinc-finger alleles,
      which affect both isoforms, and those carrying the isoform-selective p37
      lesion, controlling for iron status, splenic function and any
      thrombopoietin receptor agonist exposure.
    decision_criterion: >-
      A subclinical erythroid phenotype confined to the dominant-negative group
      would make the human requirement real but milder than the mouse predicts.
      Normal indices in both groups would place the species difference itself, not
      allele dosage, as the thing needing explanation.
references:
- reference: PMID:24325358
  title: "A dominant-negative GFI1B mutation in the gray platelet syndrome."
- reference: PMID:27122003
  title: "Functional characterization of a novel GFI1B mutation causing congenital macrothrombocytopenia."
- reference: PMID:28401061
  title: "Transcription Factor GFI1B in Health and Disease."
- reference: PMID:28550182
  title: "Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37."

📚

References & Deep Research

References

4

PMID:24325358

A dominant-negative GFI1B mutation in the gray platelet syndrome.

No top-level findings curated for this source.

PMID:27122003

Functional characterization of a novel GFI1B mutation causing congenital macrothrombocytopenia.

No top-level findings curated for this source.

PMID:28401061

Transcription Factor GFI1B in Health and Disease.

No top-level findings curated for this source.

PMID:28550182

Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37.

No top-level findings curated for this source.

GFI1B-related platelet-type bleeding disorder

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Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Source YAML

References & Deep Research

References