Platelet-type Bleeding Disorder 19

Mendelian MONDO:0014518 Pathograph 10 Show in embeddings browser Inherited Thrombocytopenia Inherited Platelet Function Disorder

A proposed autosomal recessive inherited macrothrombocytopenia described in a single consanguineous family, in which homozygous carriers of a PRKACG missense variant have severely reduced numbers of giant platelets together with a qualitative platelet defect, and bleed. PRKACG encodes the gamma catalytic subunit of cAMP-dependent protein kinase (PKA). The proposed mechanism is a biogenesis defect rather than a receptor or granule defect: the megakaryocyte cannot make proplatelets, filamin A is reduced in patient megakaryocytes and platelets, and reintroducing wild-type PRKACG into patient megakaryocytes restores proplatelet formation. A second, qualitative arm is reported alongside it - platelet activation and cytoskeletal reorganization are impaired in the same individuals - which is what makes this a bleeding disorder rather than a pure thrombocytopenia. This entry is curated with its gene-disease validity in front, not in a footnote. The ClinGen Hemostasis/Thrombosis Gene Curation Expert Panel classified the PRKACG-BDPLT19 relationship as DISPUTED in May 2024. The reason is specific and worth understanding before using this entry: the experimental evidence is strong and includes a rescue experiment, but the case-level genetic evidence reduces to two siblings in one family, and the proband also carried a missense variant in GNE whose contribution was never evaluated because GNE was not a thrombocytopenia gene in 2014. It is one now. So the alternative that ClinGen declined to score is harder to dismiss than it was when the family was first reported - though nobody has gone back to the family to settle it either way, which is the actual state of the question. Everything downstream of that is curated as reported rather than as established: the mechanism nodes carry the evidence that exists, the gene entry is typed DISPUTED, and no prevalence, penetrance, or phenotype frequency is asserted, because a single family supports none of them.

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1
Inheritance
5
Pathophys.
4
Phenotypes
1
Gaps
10
Pathograph
1
Genes
1
Differentials
1
Models
4
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Reported as autosomal recessive: disease is confined to homozygotes in a consanguineous pedigree, and ClinGen curated the relationship under an autosomal recessive mode. The phenotype of heterozygous carriers is not curated here because the cached abstract does not describe it.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:25061177 SUPPORT Human Clinical
"Herein we describe the clinical and hematological features of a consanguineous family with a severe autosomal recessive macrothrombocytopenia associated with a thrombocytopathy inducing a bleeding tendency in the homozygous mutated patients."
States the recessive mode and that the phenotype is seen in homozygotes.
CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z SUPPORT Other
"PRKACG | HGNC:9382 | platelet-type bleeding disorder 19 | MONDO:0014518 | AR | Disputed | SOP10 | Hemostasis/Thrombosis Gene Curation Expert Panel | 2024-05-03T17:00:00.000Z"
ClinGen recorded the mode of inheritance as AR for this gene-disease pair.
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Discussions and Knowledge Gaps

1
Does PRKACG cause platelet-type bleeding disorder 19, or is the single reported family explained by something else - and what evidence would settle it?
KNOWLEDGE GAP OPEN prkacg_bdplt19_disputed_validity
Attached to
genetic#PRKACG p.Ile74Met (disputed) pathophysiology#Homozygous PRKACG p.Ile74Met Variant
The asymmetry here is unusual and worth recording as a gap rather than smoothing away. The mechanistic evidence is comparatively strong for a disease of this size - a filamin A deficit measured in patient cells, an elevated cAMP pool, and a within-patient-cell rescue with a mutant-construct control. The genetic evidence is two siblings in one consanguineous pedigree, with an unevaluated GNE variant in the proband. ClinGen's DISPUTED classification is a statement about the second of those, not the first. What would resolve it is not more mechanism but a second unrelated family, or a re-analysis of the original one that either excludes or implicates the GNE variant. Nothing in the published record does either, and no second family has appeared in the decade since.
Show evidence (1 reference)
CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z SUPPORT Other
"Case-level genetic evidence from the aforementioned study includes the identification of two siblings with a homozygous missense variant in PRKACG (c.222C>G, p.Ile74Met)."
Quantifies the genetic evidence that the dispute rests on.
⚙

Pathophysiology

5
Homozygous PRKACG p.Ile74Met Variant
Both PRKACG alleles carry the missense variant c.222C>G, p.Ile74Met, identified by exome sequencing in a consanguineous family and segregating with the macrothrombocytopenia. PRKACG is the gamma catalytic subunit of cAMP-dependent protein kinase; unlike the alpha and beta subunits it is expressed in a restricted set of tissues, which is the usual explanation offered for why a defect in a ubiquitous signalling module presents as an isolated platelet disease. That tissue-restriction argument is an inference from expression rather than something tested here, and is not curated as a mechanism node.
Genetic context PRKACG hgnc:9382 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns PRKACG (hgnc:9382). hgnc:9382 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Typed LOSS_OF_FUNCTION on the strength of the rescue experiment rather than on the substitution alone: wild-type PRKACG restored proplatelet formation in patient megakaryocytes while the mutant construct did not, which is a loss of the wild-type activity rather than a new one.
Downstream
Impaired PKA Catalytic Activity The substituted residue reduces the catalytic output of the kinase, inferred in patients from a three- to five-fold rise in cAMP over controls.
Show evidence (2 references)
PMID:25061177 SUPPORT Human Clinical
"Exome sequencing identified a c.222C>G mutation (missense p.74Ile>Met) in PRKACG"
Identifies the variant that defines this disease.
PMID:25061177 SUPPORT Human Clinical
"the mutated allele cosegregating with the macrothrombocytopenia"
Cosegregation within the family, which is the extent of the genetic argument available from one pedigree.
Impaired PKA Catalytic Activity
Reduced catalytic activity of cAMP-dependent protein kinase in the affected lineage. The direct measurement reported is not of kinase activity but of its substrate pool: patients had cAMP levels three to five times those of controls, which is read as compromised PKA activity. Recorded here as the inference it is.
cAMP-dependent protein kinase activity GO:0004691 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased cAMP-dependent protein kinase activity (GO:0004691). GO:0004691 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Reduced Filamin A in Megakaryocytes and Platelets PKA phosphorylates filamin A; loss of that phosphorylation is the proposed route to the reduced filamin A protein level measured in patient cells. The phosphorylation step itself was not measured in patients, so the edge is not marked direct.
Show evidence (1 reference)
CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z SUPPORT Other
"Furthermore, patients exhibited elevated cAMP levels, three to five times higher than controls, hinting at compromised protein kinase A (PKA) activity due to the PRKACG mutation."
The measurement behind this node, quoted with ClinGen's own hedge ("hinting at") intact.
Reduced Filamin A in Megakaryocytes and Platelets
Filamin A protein is markedly reduced in mature patient megakaryocytes and in their platelets. Filamin A crosslinks actin and anchors the membrane skeleton, including the GPIb-IX-V complex, so its loss is the link between a kinase defect and a cytoskeletal one.
megakaryocyte CL:0000556 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves megakaryocyte (CL:0000556). CL:0000556 is a cell type from the Cell Ontology. platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
actin cytoskeleton organization GO:0030036 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased actin cytoskeleton organization (GO:0030036). GO:0030036 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Defective Proplatelet Formation Proplatelet extension is an actin- and microtubule-driven remodelling of the megakaryocyte, so loss of a principal actin crosslinker blocks it.
Impaired Platelet Activation and Cytoskeletal Reorganization The same filamin A deficit is carried into the circulating platelet, where shape change on activation is likewise actin-dependent.
Show evidence (2 references)
PMID:25061177 SUPPORT Human Clinical
"We demonstrate that the p.74Ile>Met PRKACG mutation is associated with a marked defect in proplatelet formation and a low level in filamin A in megakaryocytes (MKs)."
Reports both the filamin A deficit and the proplatelet defect in patient megakaryocytes.
CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z SUPPORT Other
"Experimental evidence highlights the Functional Alteration in patient cells, where Filamin A (FLNa) was significantly reduced in mature megakaryocytes (MKs) and platelets of patients carrying the homozygous mutation in PRKACG."
ClinGen's independent restatement, which also establishes that the deficit is present in platelets and not only in megakaryocytes.
Defective Proplatelet Formation
Patient megakaryocytes fail to extend proplatelets, the branched cytoplasmic processes from which platelets are released. This is the quantitative arm of the disease and the step the rescue experiment acts on.
megakaryocyte CL:0000556 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves megakaryocyte (CL:0000556). CL:0000556 is a cell type from the Cell Ontology.
platelet formation GO:0030220 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased platelet formation (GO:0030220). GO:0030220 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
Patient megakaryocyte culture with lentiviral wild-type PRKACG rescue PRIMARY CELL CULTURE Restores the mechanism node by supplying the missing wild-type activity, establishing that the proplatelet defect is downstream of PRKACG function rather than incidental to it.
Downstream
Macrothrombocytopenia Failure of the fragmentation step yields few platelets, and the ones released are abnormally large.
Giant platelets Platelet size is set at release, so a proplatelet-extension defect produces large platelets as well as few of them.
Show evidence (1 reference)
PMID:25061177 SUPPORT Human Clinical
"We thus conclude that PRKACG is a new central actor in platelet biogenesis and a new gene involved in inherited thrombocytopenia with giant platelets associated with a thrombocytopathy."
The authors' conclusion that the lesion is in platelet biogenesis, which is what places this node upstream of the platelet count.
Impaired Platelet Activation and Cytoskeletal Reorganization
Circulating platelets from homozygous individuals activate and reorganize their cytoskeleton abnormally. This is the qualitative arm - the thrombocytopathy - and it is what makes the bleeding worse than the platelet count alone would predict. Deliberately not characterised further, and this is a limit of what can be verified rather than a limit of what was measured. The primary report is available to the reference cache only as an abstract, and that abstract states the defect at exactly this level - impaired activation and cytoskeletal reorganization - without resolving it into granule secretion, integrin inside-out signalling, or agonist-specific aggregation. Those finer claims cannot be snippet-verified, so they are not curated, and this node does not declare `conforms_to` against the primary_hemostatic_plug_failure module. See the entry `notes`.
platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
platelet activation GO:0030168 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased platelet activation (GO:0030168). GO:0030168 is a biological process from the Gene Ontology. ↓ DECREASED actin cytoskeleton organization GO:0030036 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased actin cytoskeleton organization (GO:0030036). GO:0030036 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Abnormal platelet function The clinically observed qualitative platelet defect is this node read out at the bedside.
Abnormal bleeding A qualitative platelet defect superimposed on the low count, which is why the bleeding is worse than the platelet count alone predicts.
Show evidence (1 reference)
PMID:25061177 SUPPORT Human Clinical
"Platelet activation and cytoskeleton reorganization were impaired in these homozygous patients."
The whole of the published functional-platelet characterisation, quoted so the limits of the claim are visible.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Platelet-type Bleeding Disorder 19 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

4
Macrothrombocytopenia Hematologic HP:0040185 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrothrombocytopenia (HP:0040185). HP:0040185 is a phenotype from the Human Phenotype Ontology.
Sequelae: Abnormal bleeding
Show evidence (1 reference)
PMID:25061177 SUPPORT Human Clinical
"Herein we describe the clinical and hematological features of a consanguineous family with a severe autosomal recessive macrothrombocytopenia associated with a thrombocytopathy inducing a bleeding tendency in the homozygous mutated patients."
Names the defining hematological phenotype and its severity.
Giant platelets Hematologic HP:0001902 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Giant platelets (HP:0001902). HP:0001902 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25061177 SUPPORT Human Clinical
"We thus conclude that PRKACG is a new central actor in platelet biogenesis and a new gene involved in inherited thrombocytopenia with giant platelets associated with a thrombocytopathy."
Describes the disease as thrombocytopenia with giant platelets.
Abnormal platelet function Hematologic HP:0011869 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal platelet function (HP:0011869). HP:0011869 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25061177 SUPPORT Human Clinical
"Platelet activation and cytoskeleton reorganization were impaired in these homozygous patients."
Direct statement of the functional defect in patient platelets.
Abnormal bleeding Hematologic HP:0001892 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal bleeding (HP:0001892). HP:0001892 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25323684 SUPPORT Human Clinical
"Manchev et al describe a consanguineous family with severe macrothrombocytopenia and bleeding symptoms where exome sequencing revealed a homozygous missense mutation in the PRKACG gene (p.74Ile>Met)"
Records bleeding symptoms in the affected family.
🧬

Genetic Associations

1
PRKACG p.Ile74Met (disputed) (Reported causative in one consanguineous family; classified Disputed by ClinGen)
Gene: PRKACG hgnc:9382 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PRKACG (hgnc:9382). hgnc:9382 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED variant_origin: GERMLINE
Show evidence (3 references)
CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z SUPPORT Other
"In summary, there is disputed evidence to support this gene-disease relationship."
The classification this record is typed from.
CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z SUPPORT Other
"Additionally, the proband had a missense variant in the GNE gene, which at the time was not associated with thrombocytopenia, leaving the GNE variant's role in the condition unexplored. Therefore, this case has not been classified as providing genetic-level evidence."
The specific reason the family was not counted as genetic evidence, and the basis for the GNE point in the notes above.
PMID:25061177 SUPPORT Human Clinical
"the mutated allele cosegregating with the macrothrombocytopenia"
The evidence on the other side - the variant tracks with the phenotype within the pedigree.
🗃️

External Assertions

1
ClinGen gene-disease validity assertion for PRKACG and BDPLT19
ClinGen gene disease validity CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z
The Hemostasis/Thrombosis Gene Curation Expert Panel classified PRKACG - platelet-type bleeding disorder 19 (autosomal recessive) as DISPUTED under SOP10 on 2024-05-03. This is the single most load-bearing fact about the entry and the reason its gene record is typed DISPUTED rather than CAUSATIVE.
Show evidence (2 references)
CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z SUPPORT Other
"PRKACG | HGNC:9382 | platelet-type bleeding disorder 19 | MONDO:0014518 | AR | Disputed | SOP10 | Hemostasis/Thrombosis Gene Curation Expert Panel | 2024-05-03T17:00:00.000Z"
The classification row itself, naming the panel, the SOP version, and the date.
CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z SUPPORT Other
"In summary, there is disputed evidence to support this gene-disease relationship."
ClinGen's own summary sentence, quoted so the classification is not paraphrased.
📊

Prevalence

1
Worldwide
Cases In Literature Not yet documented
No prevalence estimate exists and none should be inferred. The disease is defined by one consanguineous family; ClinGen's 2024 review counted two homozygous siblings as the whole of the case-level genetic evidence. No second family has been reported.
Show evidence (1 reference)
CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z SUPPORT Other
"Case-level genetic evidence from the aforementioned study includes the identification of two siblings with a homozygous missense variant in PRKACG (c.222C>G, p.Ile74Met)."
Bounds the entire genetic evidence base for this disease at two siblings in one family, which is why no population figure is given.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Platelet-type Bleeding Disorder 19:

🧫

Experimental Models

1
Patient megakaryocyte culture with lentiviral wild-type PRKACG rescue PRIMARY_CELL_CULTURE
The single strongest piece of evidence in this disease, and the reason ClinGen graded the experimental arm favourably even while disputing the relationship overall. Reintroducing wild-type PRKACG into patient megakaryocytes restored proplatelet formation; the mutant construct did not. That is a within-patient-cell rescue, which controls for the patient's genetic background in a way that the pedigree cannot.
megakaryocyte CL:0000556 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses megakaryocyte (CL:0000556). CL:0000556 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Patient-derived megakaryocytes from homozygous PRKACG p.Ile74Met individuals
Culture
Megakaryocyte culture transduced with a lentiviral vector expressing wild-type PRKACG
Publication
PMID:25061177
Pathograph links
Defective Proplatelet Formation rescues fidelity: moderate Restores the mechanism node by supplying the missing wild-type activity, establishing that the proplatelet defect is downstream of PRKACG function rather than incidental to it.
Limitations: Overexpression from a lentiviral vector rather than physiological correction, in cultured megakaryocytes from the same two siblings that constitute the whole reported cohort. The rescue therefore speaks to causality within these cells; it does not supply the independent families that the ClinGen dispute turns on.
Readouts
Proplatelet formation by patient megakaryocytes
platelet formation GO:0030220 Gene Ontology (GO) Relation: this readout reports on this biological process This readout reports on platelet formation (GO:0030220). GO:0030220 is a biological process from the Gene Ontology.
Direction: RESTORED
Interpretation: Proplatelet extension recovered with wild-type PRKACG and not with the mutant, which is the measurement the rescue claim rests on.
Show evidence (1 reference)
PMID:25061177 SUPPORT In Vitro
"The defect in proplatelet formation was rescued in vitro by lentiviral vector-mediated overexpression of wild-type PRKACG in patient MKs."
Reports the rescue and its direction in patient megakaryocytes.
Show evidence (1 reference)
CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z SUPPORT Other
"Rescue experiments in patient cells demonstrated that overexpressing wild-type PRKACG in MKs from patients with the PRKACG homozygous variant notably improved proplatelet (PPT) formation, in contrast to the null effects seen with the mutant PRKACG."
ClinGen's independent reading of the same experiment, including the mutant-construct control that makes it informative for this node.
{ }

Source YAML

click to show 
name: Platelet-type Bleeding Disorder 19
creation_date: "2026-09-03T21:50:00Z"
category: Mendelian
disease_term:
  preferred_term: platelet-type bleeding disorder 19
  term:
    id: MONDO:0014518
    label: platelet-type bleeding disorder 19
synonyms:
- BDPLT19
- severe autosomal recessive macrothrombocytopenia
- PRKACG-related macrothrombocytopenia
- isolated hereditary giant platelet disorder caused by mutation in PRKACG
description: >-
  A proposed autosomal recessive inherited macrothrombocytopenia described in a single
  consanguineous family, in which homozygous carriers of a PRKACG missense variant have
  severely reduced numbers of giant platelets together with a qualitative platelet defect,
  and bleed.

  PRKACG encodes the gamma catalytic subunit of cAMP-dependent protein kinase (PKA). The
  proposed mechanism is a biogenesis defect rather than a receptor or granule defect: the
  megakaryocyte cannot make proplatelets, filamin A is reduced in patient megakaryocytes
  and platelets, and reintroducing wild-type PRKACG into patient megakaryocytes restores
  proplatelet formation. A second, qualitative arm is reported alongside it - platelet
  activation and cytoskeletal reorganization are impaired in the same individuals - which
  is what makes this a bleeding disorder rather than a pure thrombocytopenia.

  This entry is curated with its gene-disease validity in front, not in a footnote. The
  ClinGen Hemostasis/Thrombosis Gene Curation Expert Panel classified the PRKACG-BDPLT19
  relationship as DISPUTED in May 2024. The reason is specific and worth understanding
  before using this entry: the experimental evidence is strong and includes a rescue
  experiment, but the case-level genetic evidence reduces to two siblings in one family,
  and the proband also carried a missense variant in GNE whose contribution was never
  evaluated because GNE was not a thrombocytopenia gene in 2014. It is one now. So the
  alternative that ClinGen declined to score is harder to dismiss than it was when the
  family was first reported - though nobody has gone back to the family to settle it
  either way, which is the actual state of the question.

  Everything downstream of that is curated as reported rather than as established: the
  mechanism nodes carry the evidence that exists, the gene entry is typed DISPUTED, and
  no prevalence, penetrance, or phenotype frequency is asserted, because a single family
  supports none of them.
parents:
- Inherited Thrombocytopenia
- Inherited Platelet Function Disorder

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No prevalence estimate exists and none should be inferred. The disease is defined by
    one consanguineous family; ClinGen's 2024 review counted two homozygous siblings as
    the whole of the case-level genetic evidence. No second family has been reported.
  evidence:
  - reference: CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z
    reference_title: PRKACG / platelet-type bleeding disorder 19 (Disputed)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Case-level genetic evidence from the aforementioned study includes the identification of two siblings with a homozygous missense variant in PRKACG (c.222C>G, p.Ile74Met)."
    explanation: Bounds the entire genetic evidence base for this disease at two siblings in one family, which is why no population figure is given.

external_assertions:
- name: ClinGen gene-disease validity assertion for PRKACG and BDPLT19
  source: ClinGen
  assertion_type: gene_disease_validity
  external_id: CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z
  url: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z
  description: >-
    The Hemostasis/Thrombosis Gene Curation Expert Panel classified PRKACG - platelet-type
    bleeding disorder 19 (autosomal recessive) as DISPUTED under SOP10 on 2024-05-03. This
    is the single most load-bearing fact about the entry and the reason its gene record is
    typed DISPUTED rather than CAUSATIVE.
  evidence:
  - reference: CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z
    reference_title: PRKACG / platelet-type bleeding disorder 19 (Disputed)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PRKACG | HGNC:9382 | platelet-type bleeding disorder 19 | MONDO:0014518 | AR | Disputed | SOP10 | Hemostasis/Thrombosis Gene Curation Expert Panel | 2024-05-03T17:00:00.000Z"
    explanation: The classification row itself, naming the panel, the SOP version, and the date.
  - reference: CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z
    reference_title: PRKACG / platelet-type bleeding disorder 19 (Disputed)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In summary, there is disputed evidence to support this gene-disease relationship."
    explanation: ClinGen's own summary sentence, quoted so the classification is not paraphrased.

pathophysiology:

- name: Homozygous PRKACG p.Ile74Met Variant
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Both PRKACG alleles carry the missense variant c.222C>G, p.Ile74Met, identified by
    exome sequencing in a consanguineous family and segregating with the
    macrothrombocytopenia. PRKACG is the gamma catalytic subunit of cAMP-dependent
    protein kinase; unlike the alpha and beta subunits it is expressed in a restricted
    set of tissues, which is the usual explanation offered for why a defect in a
    ubiquitous signalling module presents as an isolated platelet disease. That
    tissue-restriction argument is an inference from expression rather than something
    tested here, and is not curated as a mechanism node.
  genetic_context:
    gene:
      preferred_term: PRKACG
      term:
        id: hgnc:9382
        label: PRKACG
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Typed LOSS_OF_FUNCTION on the strength of the rescue experiment rather than on the
      substitution alone: wild-type PRKACG restored proplatelet formation in patient
      megakaryocytes while the mutant construct did not, which is a loss of the wild-type
      activity rather than a new one.
  downstream:
  - target: Impaired PKA Catalytic Activity
    causal_link_type: DIRECT
    description: >-
      The substituted residue reduces the catalytic output of the kinase, inferred in
      patients from a three- to five-fold rise in cAMP over controls.
  evidence:
  - reference: PMID:25061177
    reference_title: A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing identified a c.222C>G mutation (missense p.74Ile>Met) in PRKACG"
    explanation: Identifies the variant that defines this disease.
  - reference: PMID:25061177
    reference_title: A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the mutated allele cosegregating with the macrothrombocytopenia"
    explanation: Cosegregation within the family, which is the extent of the genetic argument available from one pedigree.

- name: Impaired PKA Catalytic Activity
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    Reduced catalytic activity of cAMP-dependent protein kinase in the affected lineage.
    The direct measurement reported is not of kinase activity but of its substrate pool:
    patients had cAMP levels three to five times those of controls, which is read as
    compromised PKA activity. Recorded here as the inference it is.
  molecular_functions:
  - preferred_term: cAMP-dependent protein kinase activity
    term:
      id: GO:0004691
      label: cAMP-dependent protein kinase activity
    modifier: DECREASED
  downstream:
  - target: Reduced Filamin A in Megakaryocytes and Platelets
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      PKA phosphorylates filamin A; loss of that phosphorylation is the proposed route to
      the reduced filamin A protein level measured in patient cells. The phosphorylation
      step itself was not measured in patients, so the edge is not marked direct.
  evidence:
  - reference: CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z
    reference_title: PRKACG / platelet-type bleeding disorder 19 (Disputed)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Furthermore, patients exhibited elevated cAMP levels, three to five times higher than controls, hinting at compromised protein kinase A (PKA) activity due to the PRKACG mutation."
    explanation: The measurement behind this node, quoted with ClinGen's own hedge ("hinting at") intact.

- name: Reduced Filamin A in Megakaryocytes and Platelets
  role: mediator
  biological_scale: CELLULAR
  description: >-
    Filamin A protein is markedly reduced in mature patient megakaryocytes and in their
    platelets. Filamin A crosslinks actin and anchors the membrane skeleton, including the
    GPIb-IX-V complex, so its loss is the link between a kinase defect and a cytoskeletal
    one.
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
    modifier: DECREASED
  downstream:
  - target: Defective Proplatelet Formation
    causal_link_type: DIRECT
    description: >-
      Proplatelet extension is an actin- and microtubule-driven remodelling of the
      megakaryocyte, so loss of a principal actin crosslinker blocks it.
  - target: Impaired Platelet Activation and Cytoskeletal Reorganization
    causal_link_type: DIRECT
    description: >-
      The same filamin A deficit is carried into the circulating platelet, where shape
      change on activation is likewise actin-dependent.
  evidence:
  - reference: PMID:25061177
    reference_title: A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We demonstrate that the p.74Ile>Met PRKACG mutation is associated with a marked defect in proplatelet formation and a low level in filamin A in megakaryocytes (MKs)."
    explanation: Reports both the filamin A deficit and the proplatelet defect in patient megakaryocytes.
  - reference: CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z
    reference_title: PRKACG / platelet-type bleeding disorder 19 (Disputed)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Experimental evidence highlights the Functional Alteration in patient cells, where Filamin A (FLNa) was significantly reduced in mature megakaryocytes (MKs) and platelets of patients carrying the homozygous mutation in PRKACG."
    explanation: ClinGen's independent restatement, which also establishes that the deficit is present in platelets and not only in megakaryocytes.

- name: Defective Proplatelet Formation
  role: effector
  biological_scale: CELLULAR
  description: >-
    Patient megakaryocytes fail to extend proplatelets, the branched cytoplasmic
    processes from which platelets are released. This is the quantitative arm of the
    disease and the step the rescue experiment acts on.
  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
  downstream:
  - target: Macrothrombocytopenia
    causal_link_type: DIRECT
    description: >-
      Failure of the fragmentation step yields few platelets, and the ones released are
      abnormally large.
  - target: Giant platelets
    causal_link_type: DIRECT
    description: >-
      Platelet size is set at release, so a proplatelet-extension defect produces large
      platelets as well as few of them.
  evidence:
  - reference: PMID:25061177
    reference_title: A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We thus conclude that PRKACG is a new central actor in platelet biogenesis and a new gene involved in inherited thrombocytopenia with giant platelets associated with a thrombocytopathy."
    explanation: The authors' conclusion that the lesion is in platelet biogenesis, which is what places this node upstream of the platelet count.

- name: Impaired Platelet Activation and Cytoskeletal Reorganization
  role: effector
  biological_scale: CELLULAR
  description: >-
    Circulating platelets from homozygous individuals activate and reorganize their
    cytoskeleton abnormally. This is the qualitative arm - the thrombocytopathy - and it
    is what makes the bleeding worse than the platelet count alone would predict.

    Deliberately not characterised further, and this is a limit of what can be verified
    rather than a limit of what was measured. The primary report is available to the
    reference cache only as an abstract, and that abstract states the defect at exactly
    this level - impaired activation and cytoskeletal reorganization - without resolving
    it into granule secretion, integrin inside-out signalling, or agonist-specific
    aggregation. Those finer claims cannot be snippet-verified, so they are not curated,
    and this node does not declare `conforms_to` against the primary_hemostatic_plug_failure
    module. See the entry `notes`.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: platelet activation
    term:
      id: GO:0030168
      label: platelet activation
    modifier: DECREASED
  - preferred_term: actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
    modifier: DECREASED
  downstream:
  - target: Abnormal platelet function
    causal_link_type: DIRECT
    description: >-
      The clinically observed qualitative platelet defect is this node read out at the
      bedside.
  - target: Abnormal bleeding
    causal_link_type: DIRECT
    description: >-
      A qualitative platelet defect superimposed on the low count, which is why the
      bleeding is worse than the platelet count alone predicts.
  evidence:
  - reference: PMID:25061177
    reference_title: A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelet activation and cytoskeleton reorganization were impaired in these homozygous patients."
    explanation: The whole of the published functional-platelet characterisation, quoted so the limits of the claim are visible.

phenotypes:
- category: Hematologic
  name: Macrothrombocytopenia
  description: >-
    Severe thrombocytopenia with giant platelets in homozygous individuals. No frequency
    is given: the denominator is one family, and a proportion computed from it would not
    be a disease frequency.
  phenotype_term:
    preferred_term: Macrothrombocytopenia
    term:
      id: HP:0040185
      label: Macrothrombocytopenia
  sequelae:
  - target: Abnormal bleeding
    causal_link_type: DIRECT
    description: >-
      Too few platelets to form a primary hemostatic plug.
  evidence:
  - reference: PMID:25061177
    reference_title: A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein we describe the clinical and hematological features of a consanguineous family with a severe autosomal recessive macrothrombocytopenia associated with a thrombocytopathy inducing a bleeding tendency in the homozygous mutated patients."
    explanation: Names the defining hematological phenotype and its severity.

- category: Hematologic
  name: Giant platelets
  description: >-
    Abnormally large platelets on the blood film, the morphological half of the
    macrothrombocytopenia.
  phenotype_term:
    preferred_term: Giant platelets
    term:
      id: HP:0001902
      label: Giant platelets
  evidence:
  - reference: PMID:25061177
    reference_title: A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We thus conclude that PRKACG is a new central actor in platelet biogenesis and a new gene involved in inherited thrombocytopenia with giant platelets associated with a thrombocytopathy."
    explanation: Describes the disease as thrombocytopenia with giant platelets.

- category: Hematologic
  name: Abnormal platelet function
  description: >-
    A qualitative platelet defect accompanying the low count - impaired activation and
    impaired cytoskeletal reorganization. Not resolved into granule, integrin, or
    agonist-specific components in the published abstract, so no narrower HPO term is
    used.
  phenotype_term:
    preferred_term: Abnormal platelet function
    term:
      id: HP:0011869
      label: Abnormal platelet function
  evidence:
  - reference: PMID:25061177
    reference_title: A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelet activation and cytoskeleton reorganization were impaired in these homozygous patients."
    explanation: Direct statement of the functional defect in patient platelets.

- category: Hematologic
  name: Abnormal bleeding
  description: >-
    Clinical bleeding in homozygous individuals. The pattern and severity of bleeding
    episodes are not curated here because the cached abstract does not enumerate them.
  phenotype_term:
    preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: PMID:25323684
    reference_title: Inherited macrothrombocytopenias on the rise.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Manchev et al describe a consanguineous family with severe macrothrombocytopenia and bleeding symptoms where exome sequencing revealed a homozygous missense mutation in the PRKACG gene (p.74Ile>Met)"
    explanation: Records bleeding symptoms in the affected family.

genetic:
- name: PRKACG p.Ile74Met (disputed)
  association: Reported causative in one consanguineous family; classified Disputed by ClinGen
  relationship_type: DISPUTED
  gene_term:
    preferred_term: PRKACG
    term:
      id: hgnc:9382
      label: PRKACG
  variant_origin: GERMLINE
  notes: >-
    Typed DISPUTED, matching the ClinGen Hemostasis/Thrombosis GCEP classification of
    2024-05-03 (SOP10). Reading ClinGen's own summary, the dispute is not about the
    experimental work - which includes a rescue - but about how little case-level genetic
    evidence there is and about an unevaluated confounder.

    The confounder deserves stating plainly, because it has aged badly in one direction.
    ClinGen discounted the family's case-level evidence in part because the proband also
    carried a missense variant in GNE whose role was left unexplored, GNE not having been
    a thrombocytopenia gene at the time of the 2014 report. GNE-related congenital
    macrothrombocytopenia is now an established entity, so the alternative explanation
    ClinGen declined to score is more live today than when the dispute was recorded.

    This is not a claim that the GNE variant explains the family - the point is that the
    question was never asked, not that it has been answered. Note also what is NOT
    established from any source that can be quoted here: ClinGen's summary describes "a
    missense variant in the GNE gene" without giving its identity or zygosity, and the
    Manchev abstract does not mention GNE at all, so the allele's zygosity is deliberately
    not asserted in this entry. Establishing it needs the primary full text, which is not
    retrievable into the reference cache.

    As an unverified lead for whoever revisits this: the deep-research report in this
    entry's PR reads the primary full text as reporting the allele as GNE c.1675G>A,
    p.Gly559Arg, homozygous in both affected siblings, deprioritised at the time because
    neither patient had myopathy or sialuria. Recorded here as a pointer to check, not as
    a curated fact - if it is right, the alternative explanation is a good deal stronger
    than a single heterozygous variant would make it, since GNE-related thrombocytopenia
    is recessive.
  evidence:
  - reference: CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z
    reference_title: PRKACG / platelet-type bleeding disorder 19 (Disputed)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In summary, there is disputed evidence to support this gene-disease relationship."
    explanation: The classification this record is typed from.
  - reference: CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z
    reference_title: PRKACG / platelet-type bleeding disorder 19 (Disputed)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Additionally, the proband had a missense variant in the GNE gene, which at the time was not associated with thrombocytopenia, leaving the GNE variant's role in the condition unexplored. Therefore, this case has not been classified as providing genetic-level evidence."
    explanation: The specific reason the family was not counted as genetic evidence, and the basis for the GNE point in the notes above.
  - reference: PMID:25061177
    reference_title: A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the mutated allele cosegregating with the macrothrombocytopenia"
    explanation: The evidence on the other side - the variant tracks with the phenotype within the pedigree.

inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Reported as autosomal recessive: disease is confined to homozygotes in a consanguineous
    pedigree, and ClinGen curated the relationship under an autosomal recessive mode. The
    phenotype of heterozygous carriers is not curated here because the cached abstract does
    not describe it.
  evidence:
  - reference: PMID:25061177
    reference_title: A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein we describe the clinical and hematological features of a consanguineous family with a severe autosomal recessive macrothrombocytopenia associated with a thrombocytopathy inducing a bleeding tendency in the homozygous mutated patients."
    explanation: States the recessive mode and that the phenotype is seen in homozygotes.
  - reference: CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z
    reference_title: PRKACG / platelet-type bleeding disorder 19 (Disputed)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PRKACG | HGNC:9382 | platelet-type bleeding disorder 19 | MONDO:0014518 | AR | Disputed | SOP10 | Hemostasis/Thrombosis Gene Curation Expert Panel | 2024-05-03T17:00:00.000Z"
    explanation: ClinGen recorded the mode of inheritance as AR for this gene-disease pair.

experimental_models:
- name: Patient megakaryocyte culture with lentiviral wild-type PRKACG rescue
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Patient-derived megakaryocytes from homozygous PRKACG p.Ile74Met individuals
  culture_system: Megakaryocyte culture transduced with a lentiviral vector expressing wild-type PRKACG
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  publication: PMID:25061177
  description: >-
    The single strongest piece of evidence in this disease, and the reason ClinGen graded
    the experimental arm favourably even while disputing the relationship overall.
    Reintroducing wild-type PRKACG into patient megakaryocytes restored proplatelet
    formation; the mutant construct did not. That is a within-patient-cell rescue, which
    controls for the patient's genetic background in a way that the pedigree cannot.
  modeled_mechanisms:
  - target: Defective Proplatelet Formation
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      Restores the mechanism node by supplying the missing wild-type activity, establishing
      that the proplatelet defect is downstream of PRKACG function rather than incidental
      to it.
    limitations: >-
      Overexpression from a lentiviral vector rather than physiological correction, in
      cultured megakaryocytes from the same two siblings that constitute the whole reported
      cohort. The rescue therefore speaks to causality within these cells; it does not
      supply the independent families that the ClinGen dispute turns on.
    readouts:
    - name: Proplatelet formation by patient megakaryocytes
      target: Defective Proplatelet Formation
      direction: RESTORED
      biological_processes:
      - preferred_term: platelet formation
        term:
          id: GO:0030220
          label: platelet formation
      interpretation: >-
        Proplatelet extension recovered with wild-type PRKACG and not with the mutant,
        which is the measurement the rescue claim rests on.
      evidence:
      - reference: PMID:25061177
        reference_title: A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "The defect in proplatelet formation was rescued in vitro by lentiviral vector-mediated overexpression of wild-type PRKACG in patient MKs."
        explanation: Reports the rescue and its direction in patient megakaryocytes.
    evidence:
    - reference: CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z
      reference_title: PRKACG / platelet-type bleeding disorder 19 (Disputed)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Rescue experiments in patient cells demonstrated that overexpressing wild-type PRKACG in MKs from patients with the PRKACG homozygous variant notably improved proplatelet (PPT) formation, in contrast to the null effects seen with the mutant PRKACG."
      explanation: ClinGen's independent reading of the same experiment, including the mutant-construct control that makes it informative for this node.

differential_diagnoses:
- name: GNE-related congenital macrothrombocytopenia
  description: >-
    Listed here because it is the specific alternative that ClinGen's dispute turns on, not
    as a routine differential. The proband in the founding family carried an unevaluated
    GNE missense variant, and GNE has since become an established cause of severe
    congenital macrothrombocytopenia. Distinguishing the two matters for anyone
    reinvestigating this family or a new candidate case. GNE was established as a cause of
    severe congenital thrombocytopenia by PMID:29941673 (Blood, 2018), four years after the
    PRKACG report and six years before ClinGen's review; that paper is indexed without an
    abstract, so it is listed in `references` rather than quoted as evidence.
  evidence:
  - reference: CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z
    reference_title: PRKACG / platelet-type bleeding disorder 19 (Disputed)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Additionally, the proband had a missense variant in the GNE gene, which at the time was not associated with thrombocytopenia, leaving the GNE variant's role in the condition unexplored. Therefore, this case has not been classified as providing genetic-level evidence."
    explanation: Establishes that the GNE variant exists in this family and was never evaluated.

discussions:
- discussion_id: prkacg_bdplt19_disputed_validity
  prompt: >-
    Does PRKACG cause platelet-type bleeding disorder 19, or is the single reported family
    explained by something else - and what evidence would settle it?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#PRKACG p.Ile74Met (disputed)
  - pathophysiology#Homozygous PRKACG p.Ile74Met Variant
  rationale: >-
    The asymmetry here is unusual and worth recording as a gap rather than smoothing away.
    The mechanistic evidence is comparatively strong for a disease of this size - a filamin
    A deficit measured in patient cells, an elevated cAMP pool, and a within-patient-cell
    rescue with a mutant-construct control. The genetic evidence is two siblings in one
    consanguineous pedigree, with an unevaluated GNE variant in the proband. ClinGen's
    DISPUTED classification is a statement about the second of those, not the first.

    What would resolve it is not more mechanism but a second unrelated family, or a
    re-analysis of the original one that either excludes or implicates the GNE variant.
    Nothing in the published record does either, and no second family has appeared in the
    decade since.
  evidence:
  - reference: CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z
    reference_title: PRKACG / platelet-type bleeding disorder 19 (Disputed)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Case-level genetic evidence from the aforementioned study includes the identification of two siblings with a homozygous missense variant in PRKACG (c.222C>G, p.Ile74Met)."
    explanation: Quantifies the genetic evidence that the dispute rests on.

notes: >-
  Why this is not a member of the Inherited Platelet Function Disorders grouping, and does
  not declare `conforms_to`. That grouping's defining criterion is conformance to
  `primary_hemostatic_plug_failure`, and its scope note admits an inherited thrombocytopenia
  only when a qualitative functional defect is also curated. A functional defect is reported
  here - impaired platelet activation and cytoskeletal reorganization - but the primary
  report reaches the reference cache as an abstract only, and the abstract states the
  defect at exactly that level. The granule-secretion, integrin inside-out and
  agonist-specific claims that the module's arm node is built from cannot be
  snippet-verified, and asserting conformance would mean asserting them. The primary lesion
  is also platelet biogenesis, which is not one of the module's four arms. `Platelet-type
  Bleeding Disorder 20` (SLFN14) is curated the same way, and the grouping's own notes list
  both SLFN14 and PRKACG as known gaps rather than members.

  This one is worth revisiting rather than filing away. The deep-research report included in
  this PR reports, from the primary full text, that patient platelets showed absent
  P-selectin externalization, no rise in surface integrin alphaIIbbeta3 on stimulation, and
  reduced GPIb internalization - which is arm-level data of exactly the kind the module node
  wants. None of it is quotable from the cache, so none of it is curated. If the full text
  becomes retrievable, the conformance and the grouping membership should be added together,
  with the ClinGen DISPUTED classification stated at the point of membership so the grouping
  does not silently absorb a contested entity.

  What is deliberately absent. No frequency on any phenotype: a proportion computed from
  two siblings is not a disease frequency. No penetrance, no age of onset, no bleeding-score
  data, no treatment entries - the cached abstract and the ClinGen record say nothing about
  management, and platelet-transfusion or antifibrinolytic guidance copied from the
  inherited-thrombocytopenia literature generally would not be about this disease. No
  animal model: none has been reported for PRKACG in this context.

  Orphanet has a record for this concept (ORPHA:438207, "Severe autosomal recessive
  macrothrombocytopenia", MONDO:0014518 exact match) whose definition enumerates the
  bleeding pattern. It is not cited here because the pinned Orphadata snapshot in
  `data/orphadata/MANIFEST.yaml` could not be reproduced - upstream now serves a different
  `en_product1.xml` behind the same URL - so a cache file built today would carry a
  provenance line naming a release it was not built from. Repinning is a separate change.

references:
- reference: PMID:25061177
  title: A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene.
- reference: PMID:25323684
  title: Inherited macrothrombocytopenias on the rise.
- reference: CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z
  title: PRKACG / platelet-type bleeding disorder 19 (Disputed)
- reference: PMID:29941673
  title: Mutation in GNE is associated with severe congenital thrombocytopenia.
📚

References & Deep Research

References

4
PMID:25061177
A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene.
No top-level findings curated for this source.
PMID:25323684
Inherited macrothrombocytopenias on the rise.
No top-level findings curated for this source.
CGGV:assertion_5d74cf9f-a082-4cca-9a70-d634c3d0078b-2024-05-03T170000.000Z
PRKACG / platelet-type bleeding disorder 19 (Disputed)
No top-level findings curated for this source.
PMID:29941673
Mutation in GNE is associated with severe congenital thrombocytopenia.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (2)

Record notes

Why this is not a member of the Inherited Platelet Function Disorders grouping, and does not declare `conforms_to`. That grouping's defining criterion is conformance to `primary_hemostatic_plug_failure`, and its scope note admits an inherited thrombocytopenia only when a qualitative functional defect is also curated. A functional defect is reported here - impaired platelet activation and cytoskeletal reorganization - but the primary report reaches the reference cache as an abstract only, and the abstract states the defect at exactly that level. The granule-secretion, integrin inside-out and agonist-specific claims that the module's arm node is built from cannot be snippet-verified, and asserting conformance would mean asserting them. The primary lesion is also platelet biogenesis, which is not one of the module's four arms. `Platelet-type Bleeding Disorder 20` (SLFN14) is curated the same way, and the grouping's own notes list both SLFN14 and PRKACG as known gaps rather than members. This one is worth revisiting rather than filing away. The deep-research report included in this PR reports, from the primary full text, that patient platelets showed absent P-selectin externalization, no rise in surface integrin alphaIIbbeta3 on stimulation, and reduced GPIb internalization - which is arm-level data of exactly the kind the module node wants. None of it is quotable from the cache, so none of it is curated. If the full text becomes retrievable, the conformance and the grouping membership should be added together, with the ClinGen DISPUTED classification stated at the point of membership so the grouping does not silently absorb a contested entity. What is deliberately absent. No frequency on any phenotype: a proportion computed from two siblings is not a disease frequency. No penetrance, no age of onset, no bleeding-score data, no treatment entries - the cached abstract and the ClinGen record say nothing about management, and platelet-transfusion or antifibrinolytic guidance copied from the inherited-thrombocytopenia literature generally would not be about this disease. No animal model: none has been reported for PRKACG in this context. Orphanet has a record for this concept (ORPHA:438207, "Severe autosomal recessive macrothrombocytopenia", MONDO:0014518 exact match) whose definition enumerates the bleeding pattern. It is not cited here because the pinned Orphadata snapshot in `data/orphadata/MANIFEST.yaml` could not be reproduced - upstream now serves a different `en_product1.xml` behind the same URL - so a cache file built today would carry a provenance line naming a release it was not built from. Repinning is a separate change.

Create: Platelet-type Bleeding Disorder 19 (PRKACG), curated with its ClinGen DISPUTED validity in front · 2026-09-03T21:56:06Z · View source

Claim #10791 (platelet-type bleeding disorder 19, MONDO:0014518, PRKACG). Recorded entry_type DISEASE and created kb/disorders/Platelet-type_Bleeding_Disorder_19.yaml. Why DISEASE. dismech already curates the neighbouring BDPLT series as standalone entries (BDPLT8, 18, 20, 21) alongside TUBB1-related macrothrombocytopenia and CYCS-related thrombocytopenia, and BDPLT19 has the same shape: its own OMIM/MONDO identity and a mechanism chain that is not a specialisation of any curated umbrella. There is no candidate parent disease to attach it to as a subtype. The finding that shaped the entry. ClinGen's Hemostasis/Thrombosis GCEP classified PRKACG - BDPLT19 as DISPUTED (SOP10, 2024-05-03), which was not visible from the stub or the issue. The record is not committed in references_cache; I built it with just clingen-rebuild --id CGGV:assertion_5d74cf9f-.... Reading ClinGen's narrative, the dispute is about the genetic evidence, not the experimental evidence: two siblings in one consanguineous pedigree, and an unevaluated GNE missense variant in the proband, discounted because GNE was not a thrombocytopenia gene in 2014. It is one now. The entry says all of this in the description, types the gene record relationship_type: DISPUTED, and carries a KNOWLEDGE_GAP discussion recording what would resolve it (a second family, or a re-analysis of the first). Deliberately not asserted. The GNE allele's identity and zygosity - ClinGen says only 'a missense variant', the Manchev abstract does not mention GNE, and the primary full text is not retrievable into the cache. No phenotype frequencies, no penetrance, no prevalence number, no treatments, no animal model. Grouping. Not added as a member of Inherited_Platelet_Function_Disorders and no conforms_to declared. The grouping's criterion is module conformance and it admits a thrombocytopenia only with a curated qualitative defect; the abstract states the defect but not at arm level (granule secretion / integrin inside-out / agonist-specific aggregation), so conformance cannot be snippet-verified. Same treatment as the already-curated BDPLT20. The included deep-research report indicates the primary full text does contain arm-level data (absent P-selectin externalization, no alphaIIbbeta3 rise, reduced GPIb internalization); that is recorded in notes as a revisit trigger rather than curated. Deep research: research/Platelet-type_Bleeding_Disorder_19-deep-research-falcon.md, falcon. just preflight-dr returns WARN, not FAIL - PRKACG 50 mentions against FLNA 17. FLNA is the PKA substrate at the centre of the mechanism, not a rival disease entity, and the report's OMIM matches MONDO's. No DR text was used as a snippet; every evidence item quotes a cached abstract or the ClinGen record. Tooling defect found: just refresh-orphadata aborts on a drifted checksum pin (upstream en_product1.xml is now sha256 df8d562... against the pinned fb2fbe8...), leaving a usable but newer file. A cache file built from it would carry a Source line naming the pinned 2025-12-09 release it was not built from, so ORPHA:438207 was not cited and the generated file was discarded rather than committed.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 22 citations 2026-09-03T14:52:48.478201

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Platelet-type bleeding disorder 19 (BDPLT19; PRKACG-related severe autosomal recessive macrothrombocytopenia; OMIM 616176)
  • MONDO ID: MONDO:0014518 (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Platelet-type bleeding disorder 19 (BDPLT19; PRKACG-related severe autosomal recessive macrothrombocytopenia; OMIM 616176) covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Platelet-type bleeding disorder 19 (BDPLT19)

Executive summary and evidence boundary

Platelet-type bleeding disorder 19 is an ultra-rare, nonsyndromic inherited macrothrombocytopenia caused by biallelic PRKACG dysfunction. The established phenotype combines profoundly reduced platelet number, giant platelets, impaired platelet activation, and mucocutaneous or gynecologic bleeding. The disease–gene assertion rests principally on one consanguineous West Indian family reported by Manchev et al. in Blood in 2014: two homozygous siblings, two clinically unaffected heterozygous relatives, and functional rescue of patient-derived megakaryocytes with wild-type PRKACG. Open Targets likewise maps MONDO:0014518 only to PRKACG and cites PMID 25061177. Thus, numerical phenotype frequencies below describe the reported family, not population-level estimates. (OpenTargets Search: platelet-type bleeding disorder 19-PRKACG, manchev2014anewform pages 1-2, manchev2014anewform pages 4-6, manchev2014anewform pages 8-9)

Primary reference: Manchev VT et al. “A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene.” Blood. Published online 24 July 2014; print 16 October 2014;124(16):2554–2563. PMID: 25061177. DOI/URL: https://doi.org/10.1182/blood-2014-01-551820. (manchev2014anewform pages 1-2, manchev2014anewform pages 10-11)

The central evidence is summarized here:

Domain Established finding Quantitative/detail Evidence type Certainty/limitation
Identifiers Platelet-type bleeding disorder 19 (BDPLT19) is PRKACG-related severe autosomal-recessive macrothrombocytopenia. OMIM 616176; MONDO:0014518; associated gene PRKACG. (OpenTargets Search: platelet-type bleeding disorder 19-PRKACG, manchev2014anewform pages 1-2) Aggregated disease resource plus primary human report Disease–gene association is based principally on one family reported in 2014.
Human cases Two affected West Indian siblings were described in a consanguineous family. Proband II-1 was diagnosed at age 4; brother II-2 at age 2. Both lacked reported syndromic features. (manchev2014anewform pages 3-4, manchev2014anewform pages 4-6) Human clinical—single pedigree Extremely small evidence base; phenotype frequencies cannot be generalized beyond 2/2 reported affected individuals.
Genetic cause and inheritance Homozygous germline PRKACG c.222C>G, causing p.Ile74Met in the PKA catalytic γ subunit, cosegregated with disease under an autosomal-recessive model. Both affected siblings were homozygous; mother I-1 and relative III-1 were unaffected heterozygotes; II-3 was homozygous wild type. The variant was absent from databases queried in 2014, affected a conserved residue, and was predicted damaging by PolyPhen-2. (manchev2014anewform pages 4-6, manchev2014anewform pages 6-8) Human genetic segregation plus computational prediction Strong segregation and functional support within one pedigree, but no independent-family replication or current population-frequency estimate was identified.
Thrombocytopenia Affected siblings had severe, persistent thrombocytopenia. Platelet counts were 5 × 10⁹/L in II-1 and 8 × 10⁹/L in II-2. (manchev2014anewform pages 3-4, manchev2014anewform pages 4-6) Human laboratory Direct measurements in two patients; automated MPV was unavailable for either affected sibling.
Platelet size Macrothrombocytopenia with predominantly giant or macrocytic platelets was demonstrated by smear and electron microscopy. Approximately 90% of platelets were giant or macrocytic; mean diameters were 4.86 μm and 4.98 μm, versus 2.84 μm in an external control and 2.97 μm in a heterozygous relative. (manchev2014anewform pages 4-6) Human cytology and ultrastructure Demonstrated in both affected siblings, but no independent cohort exists.
Bleeding phenotype Bleeding was mucocutaneous and gynecologic, ranging from moderate to life-threatening. II-1 had epistaxis, spontaneous hematomas, menorrhagia with anemia, and three hemorrhagic ovarian-cyst ruptures requiring platelet and red-cell transfusion; WHO bleeding score 4. II-2 had lifelong epistaxis and cutaneous hematomas; narrative WHO score 3. (manchev2014anewform pages 4-6, manchev2014anewform pages 8-9) Human clinical Disease-specific treatment experience is limited to transfusion support; the table and narrative differ for II-2’s score.
Platelet dysfunction Patient platelets showed defective agonist-induced activation, secretion, calcium signaling, receptor trafficking, and VWF-associated actin polymerization. After stimulation, GPIb internalization was 18% of resting level versus 44.2% in control; control αIIbβ3 surface expression rose to 193%, whereas patient platelets showed no increase; P-selectin externalization was absent; the VWF-associated F-actin/G-actin ratio was 44% of control. (manchev2014anewform pages 4-6, manchev2014anewform pages 9-10) Ex vivo human platelet assays Directly demonstrated with patient samples; reproducibility across unrelated cases is unknown.
Megakaryocytes and marrow Bone marrow contained megakaryocyte clusters, while cultured megakaryocyte differentiation and ploidization were preserved; the principal production defect occurred during proplatelet formation. Mature CD41⁺CD42⁺ cell proportions and ploidy were comparable with controls, but homozygous patient megakaryocytes had a 2.5-fold lower proportion of proplatelet-bearing cells. (manchev2014anewform pages 4-6, manchev2014anewform pages 6-8) Human marrow morphology and patient-derived CD34⁺ culture Supports a late thrombopoiesis defect rather than impaired megakaryocyte differentiation; based on one family.
PKA–FLNA mechanism Mutant PRKACG protein was not degraded, but PKA dysfunction was associated with markedly reduced filamin A and elevated platelet cAMP. Loss of PKA-mediated FLNA Ser2152 phosphorylation and consequent proteolysis was proposed. FLNA was almost absent from mature patient megakaryocytes and platelets; platelet cAMP was 3- to 5-fold higher than in controls or a heterozygous relative. GPIbβ Ser166 phosphorylation was normal. (manchev2014anewform pages 6-8, manchev2014anewform pages 8-9) Human biochemical assays plus mechanistic inference FLNA loss and cAMP elevation were demonstrated; defective FLNA Ser2152 phosphorylation and proteolytic causality were inferred rather than directly measured.
Functional rescue Wild-type PRKACG rescued abnormal proplatelet formation in patient-derived megakaryocytes; mutant PRKACG did not. Wild-type lentiviral expression significantly increased proplatelet formation and reduced platelet-like structure diameter from 3.67 to 1.68 μm in II-1 and 4.17 to 2.01 μm in II-2. (manchev2014anewform pages 8-9) In vitro patient-cell rescue Strong disease-gene functional evidence, but not a clinical gene-therapy result or evidence of in vivo safety or efficacy.
Diagnosis Diagnosis requires recognition of congenital giant-platelet thrombocytopenia with platelet dysfunction, exclusion of phenocopies, and molecular confirmation. The original study excluded GP1BA/GP1BB/GP9 defects and neutrophil inclusions suggestive of MYH9-related disease, then used exome sequencing and Sanger segregation. General IPD evaluation includes bleeding and family history, CBC and smear, platelet-function testing, flow cytometry or electron microscopy, and panel, WES, or WGS testing. (manchev2014anewform pages 6-8, palmabarqueros2021inheritedplateletdisorders pages 11-13, palmabarqueros2021inheritedplateletdisorders pages 15-17) Disease-specific workup plus expert-review guidance No validated BDPLT19-specific diagnostic criteria, biomarker, or standalone functional assay exists.
Management No PRKACG-specific standard therapy or response-rate evidence exists. Supportive inherited-platelet-disorder care is the current practical framework. General expert guidance favors local hemostasis, trauma and antiplatelet-drug avoidance, antifibrinolytics or desmopressin for selected bleeding or procedures, and platelet transfusion for major bleeding or critical sites, while minimizing exposure and using HLA-compatible products when needed. (noris2017hereditarythrombocytopeniasa pages 12-13, palmabarqueros2021inheritedplateletdisorders pages 21-22) Expert review extrapolated from other inherited platelet disorders Not validated specifically in BDPLT19; no disease-specific evidence supports thrombopoietin-receptor agonists, HSCT, splenectomy, rFVIIa, pharmacogenomics, or targeted therapy.
Epidemiology BDPLT19 is ultra-rare, with no population prevalence, incidence, carrier-frequency, sex-ratio, or mortality estimate. The established literature identified 2 affected siblings in 1 pedigree; reviews historically described only one PRKACG variant from a single pedigree. (johnson2017moleculargeneticinvestigation pages 51-55, johnson2017moleculargeneticinvestigationa pages 51-55) Literature ascertainment Two published cases are not a prevalence estimate; underdiagnosis is plausible but unquantified.
2023–2024 update No disease-specific 2023–2024 cohort, independently confirmed family or pathogenic variant, natural-history study, animal model, omics or single-cell study, clinical trial, or targeted treatment was identified. Recent literature primarily provides general inherited platelet-disorder diagnostic context rather than new BDPLT19 evidence. (palmabarqueros2021inheritedplateletdisorders pages 1-3, donck2021hemostaticphenotypesand pages 6-7) Evidence-gap assessment Absence from retrieved literature does not prove that unpublished cases or database submissions do not exist; the 2014 report remains the principal direct evidence.

Table: Concise summary of the established clinical, genetic, mechanistic, diagnostic, and management evidence for PRKACG-related BDPLT19. The table emphasizes that direct evidence remains limited to one family and identifies major recent-research gaps.

1. Disease information

Definition

BDPLT19 is a congenital platelet-production and platelet-function disorder. Its defining abnormalities are severe thrombocytopenia, predominantly giant or macrocytic platelets, defective megakaryocyte proplatelet formation, and thrombocytopathy. It was described as autosomal recessive and without syndromic manifestations in the two established patients. The authors’ abstract states directly: “PRKACG is a new central actor in platelet biogenesis and a new gene involved in inherited thrombocytopenia with giant platelets associated with a thrombocytopathy.” (manchev2014anewform pages 1-2)

Identifiers and terminology

  • OMIM phenotype: 616176.
  • MONDO: MONDO:0014518.
  • Causal gene: PRKACG, protein kinase cAMP-activated catalytic subunit gamma; Ensembl ENSG00000165059. (OpenTargets Search: platelet-type bleeding disorder 19-PRKACG)
  • Synonyms: platelet-type bleeding disorder 19; bleeding disorder, platelet-type, 19; BDPLT19; PRKACG-related thrombocytopenia; PRKACG-related disease; PRKACG-related severe autosomal-recessive macrothrombocytopenia.
  • Orphanet: no disorder-specific Orphanet identifier was established in the retrieved evidence.
  • ICD-10/ICD-11 and MeSH: no uniquely specific code/descriptor was identified; coding ordinarily falls under inherited/other thrombocytopenia or platelet-function-defect categories. Such broader codes should not be represented as exact synonyms.

This report combines an aggregated disease-level resource—MONDO/Open Targets—with patient-level primary research from one pedigree. It is not derived from EHR aggregation or a disease registry. (OpenTargets Search: platelet-type bleeding disorder 19-PRKACG, manchev2014anewform pages 3-4)

2. Etiology, risk, protection, and environment

Causal factor

The established initiating lesion is a germline homozygous PRKACG c.222C>G, p.Ile74Met missense variant, reported on transcript NM_002732. PRKACG encodes the catalytic γ isoform of cAMP-dependent protein kinase A (PKA). The variant cosegregated with macrothrombocytopenia under an autosomal-recessive model. (manchev2014anewform pages 1-2, manchev2014anewform pages 4-6, manchev2014anewform pages 6-8)

The same homozygous siblings also carried GNE c.1675G>A, p.Gly559Arg. The investigators deprioritized GNE because neither patient had myopathy or sialuria, thrombocytopenia had not then been associated with GNE myopathy, and wild-type PRKACG specifically rescued the cellular phenotype. The strongest interpretation is therefore PRKACG causality, while acknowledging that evidence derives from one family and that the original genotype included this second rare homozygous variant. (manchev2014anewform pages 6-8, manchev2014anewform pages 8-9)

Risk factors

  • Established genetic risk: biallelic p.Ile74Met; consanguinity increased the probability of homozygosity in the reported pedigree.
  • Family history: an affected sibling is highly informative. For two carrier parents, standard autosomal-recessive counseling predicts a 25% affected, 50% carrier, and 25% unaffected/noncarrier probability per pregnancy, assuming the disease model is correct.
  • Environmental, infectious, occupational, lifestyle, age, and sex risks: none are known to cause BDPLT19. Trauma, surgery, menstruation, childbirth, and platelet-inhibiting drugs are best regarded as bleeding modifiers/triggers, not causes. General IPD reviews report that trauma, medications, surgery, and childbirth may aggravate bleeding. (palmabarqueros2021inheritedplateletdisorders pages 11-13)

Protective factors and gene–environment interaction

No protective allele, modifier gene, diet, exposure, or validated gene–environment interaction has been reported. Practical protection consists of avoiding platelet-inhibiting medication and high-trauma activities and planning hemostatic support for procedures; this lowers bleeding exposure rather than preventing the genotype. (palmabarqueros2021inheritedplateletdisorders pages 21-22)

3. Phenotypes

Phenotype Type and suggested HPO annotation Reported characteristics
Severe thrombocytopenia Laboratory abnormality; HP:0001873 Thrombocytopenia Diagnosed at ages 4 and 2 years; platelet counts 5 and 8 ×10⁹/L. Congenital/pediatric, chronic, severe; 2/2 established patients. (manchev2014anewform pages 3-4, manchev2014anewform pages 4-6)
Giant/macrocytic platelets Smear/ultrastructural sign; HP:0001902 Giant platelets, macrothrombocytopenia About 90% giant or macrocytic; mean diameters 4.86 and 4.98 μm versus 2.84 and 2.97 μm in control/heterozygous-relative samples; 2/2. (manchev2014anewform pages 4-6)
Epistaxis Symptom; HP:0000421 Epistaxis Infantile/recurrent in both siblings; lifelong in the brother; 2/2. (manchev2014anewform pages 4-6)
Easy bruising/spontaneous hematomas Symptom/sign; HP:0000978 Bruising susceptibility Spontaneous or cutaneous hematomas in both; 2/2. (manchev2014anewform pages 4-6)
Menorrhagia Symptom; HP:0000132 Menorrhagia Present in the female proband, causing anemia; 1/1 reported affected female. (manchev2014anewform pages 4-6)
Hemorrhagic ovarian-cyst rupture Acute complication; ovarian hemorrhage term if locally available Three consecutive ruptures in the proband were life-threatening and required platelet and red-cell transfusion. (manchev2014anewform pages 4-6)
Anemia Laboratory abnormality; HP:0001903 Anemia Proband hemoglobin 9 g/dL, associated with menorrhagia/bleeding. (manchev2014anewform pages 3-4, manchev2014anewform pages 4-6)
Platelet-function defect Functional laboratory phenotype; platelet aggregation/secretion defect terms Absent activation-induced P-selectin exposure and αIIbβ3 upregulation, poor GPIb internalization, reduced calcium mobilization, and deficient VWF-associated actin polymerization. (manchev2014anewform pages 4-6)
Megakaryocyte clustering Marrow pathology Present in patient marrow; cultured megakaryocyte maturation and ploidy were normal. (manchev2014anewform pages 4-6)

Bleeding severity was substantial: the narrative reports WHO scores 4 and 3, although Table 1 appears to list 3 and 2, an internal discrepancy that should be retained in curation rather than silently resolved. The female proband experienced life-threatening hemorrhage; her brother had moderate lifelong bleeding. (manchev2014anewform pages 3-4, manchev2014anewform pages 4-6, manchev2014anewform pages 8-9)

No validated EQ-5D, SF-36, PROMIS, disability, or disease-specific quality-of-life data exist. Likely burdens include recurrent bleeding, anemia, transfusion exposure, restrictions on trauma-prone activities, and intensive perioperative/gynecologic planning, but these impacts were not formally measured.

4. Genetic and molecular information

Gene and variant

  • Gene: PRKACG; protein kinase cAMP-activated catalytic subunit gamma; chromosome 9; Ensembl ENSG00000165059. (OpenTargets Search: platelet-type bleeding disorder 19-PRKACG)
  • Variant: NM_002732:c.222C>G, p.Ile74Met (older article notation p.74I.M).
  • Class/type: germline homozygous missense.
  • Segregation: II-1 and II-2 were homozygous affected; I-1 and III-1 were unaffected heterozygotes; II-3 was homozygous wild type. (manchev2014anewform pages 4-6, manchev2014anewform pages 6-8)
  • Original database evidence: absent from dbSNP and the databases filtered by the investigators in 2014; the residue was evolutionarily conserved and PolyPhen-2 predicted a damaging effect. This is not a substitute for a current gnomAD frequency or contemporary ACMG/AMP classification. (manchev2014anewform pages 4-6, manchev2014anewform pages 6-8)
  • Current frequency/classification: no verified current gnomAD/TOPMed frequency or ClinVar assertion was available from the retrieved material. A knowledge base should therefore avoid inventing “pathogenic” ClinVar status; a defensible narrative is disease-causing in the original report, with strong segregation and PS3-like functional rescue evidence, but only one pedigree.

The mutant protein was present rather than degraded. Functional consequences were consistent with reduced PKA activity: platelet cAMP was three- to fivefold elevated, FLNA was almost absent from mature megakaryocytes and platelets, and wild-type—but not mutant—PRKACG corrected proplatelet formation. (manchev2014anewform pages 6-8, manchev2014anewform pages 8-9)

No established modifier gene, pathogenic structural/chromosomal rearrangement, somatic lesion, repeat expansion, mitochondrial variant, or disease-specific epigenetic alteration is known. No independent BDPLT19 families or firmly established additional pathogenic PRKACG alleles were identified in the retrieved literature; an older review explicitly described only one variant in one pedigree. (johnson2017moleculargeneticinvestigation pages 51-55, johnson2017moleculargeneticinvestigationa pages 51-55)

5. Environmental information

No toxin, radiation, pollutant, dietary factor, smoking/alcohol exposure, occupational agent, or infectious organism is implicated in disease initiation. Aspirin, NSAIDs, other antiplatelet drugs, trauma, invasive procedures, and heavy menstrual bleeding may increase hemorrhagic risk in a person who already has the inherited defect. Vaccination and ordinary infection are not established causes of this genotype-defined condition.

6. Mechanism and pathophysiology

Ordered causal chain

  1. Homozygous PRKACG p.Ile74Met leads to impaired catalytic γ-subunit contribution to platelet/megakaryocyte PKA activity. This is supported by biochemical and rescue assays, although direct catalytic kinetics were not reported. (manchev2014anewform pages 6-8, manchev2014anewform pages 8-9)
  2. Impaired PKA feedback results in three- to fivefold accumulation of platelet cAMP, plausibly through reduced phosphodiesterase activation and/or reduced inhibition of adenylyl cyclase. The cAMP increase was demonstrated; the precise feedback route is inferred. (manchev2014anewform pages 6-8)
  3. Impaired PKA activity is proposed to reduce FLNA Ser2152 phosphorylation, which leads to loss of protection from proteolysis and near-absence of FLNA in mature megakaryocytes and platelets. FLNA loss was demonstrated; reduced Ser2152 phosphorylation and causal proteolysis were inferred rather than directly measured. (manchev2014anewform pages 6-8, manchev2014anewform pages 8-9)
  4. FLNA deficiency leads to defective actin-network stabilization and cytoplasmic fragmentation, which results in a 2.5-fold reduction in proplatelet-bearing megakaryocytes and oversized platelet-like structures. (manchev2014anewform pages 6-8, manchev2014anewform pages 8-9)
  5. Defective proplatelet formation results in very low circulating platelet counts and giant platelets. Wild-type lentiviral PRKACG restored proplatelet production and reduced platelet-like structure diameter, providing direct functional support. (manchev2014anewform pages 8-9)
  6. Branch A: increased cAMP, a negative regulator of platelet responses, is hypothesized to lead to impaired activation, secretion, and calcium signaling. Branch B: FLNA/actin disorganization is hypothesized to lead to defective receptor trafficking and calcium translocation. The relative contributions remain unresolved. (manchev2014anewform pages 9-10)
  7. Low platelet number plus qualitative dysfunction results in epistaxis, bruising, menorrhagia, anemia, and potentially life-threatening ovarian hemorrhage. (manchev2014anewform pages 4-6)

Detailed biology and quantitative findings

PKA contains regulatory and catalytic subunits; PRKACG encodes catalytic γ. Candidate platelet PKA substrates include signaling regulators and actin-binding proteins such as FLNA. GPIbβ Ser166 phosphorylation was normal in patient megakaryocytes and platelets, arguing against this substrate as the proximate defect. In contrast, FLNA was almost absent. Patient platelets had an F-actin/G-actin ratio on VWF of 44% of control, but a comparable ratio on fibrinogen, suggesting matrix/pathway-dependent cytoskeletal dysfunction. (manchev2014anewform pages 6-8, manchev2014anewform pages 8-9)

Activation assays showed GPIb internalization to 18% of resting expression versus 44.2% in controls. Control αIIbβ3 surface expression rose to 193% after stimulation, whereas patient platelets showed no increase; P-selectin externalization was absent, and calcium release/influx was markedly diminished. (manchev2014anewform pages 4-6)

Rescue evidence: wild-type PRKACG increased patient-megakaryocyte proplatelet formation; mutant PRKACG did not. Platelet-like structure diameter fell from 3.67 to 1.68 μm in II-1 and from 4.17 to 2.01 μm in II-2. This is a patient-derived cellular rescue experiment, not clinical gene therapy. (manchev2014anewform pages 8-9)

Suggested annotations include GO: cAMP-dependent protein kinase activity; protein phosphorylation; regulation of actin-cytoskeleton organization; megakaryocyte differentiation; platelet formation; proplatelet formation; platelet activation; calcium-mediated signaling; granule secretion. Relevant cell types are megakaryocyte (CL:0000556), platelet (CL:0000233), and hematopoietic stem/progenitor cells. Relevant cellular components include cytoplasm/cytosol, actin cytoskeleton, plasma membrane, and proplatelet extensions.

No BDPLT19-specific transcriptomic, proteomic beyond targeted immunoblotting, metabolomic, lipidomic, epigenomic, single-cell, spatial, CRISPR-screen, or multi-omics dataset was identified. The only advanced functional platform was ex vivo CD34-positive patient-cell differentiation and lentiviral complementation.

7. Anatomical structures affected

The primary system is hematologic/hemostatic. Principal sites are circulating blood and bone marrow megakaryocytes; secondary injury occurs at bleeding sites, notably skin, nasal mucosa, uterine/endometrial tract, and ovary in the reported proband. There is no evidence of intrinsic brain, renal, hepatic, pulmonary, cardiac, skeletal, neurologic, or immune-organ disease. (manchev2014anewform pages 4-6)

Suggested ontology mappings are blood—UBERON:0000178, bone marrow—UBERON:0002371, platelet (CL:0000233), and megakaryocyte (CL:0000556). Subcellular annotations include actin cytoskeleton, cytosol, plasma membrane, platelet α-granule/P-selectin trafficking machinery, and GPIb–IX–V/αIIbβ3 receptor-associated membrane cytoskeleton. Lateralization is not applicable.

8. Temporal development

The disorder is genetically present from conception and manifested in early childhood: diagnosis at ages 4 and 2 years. The brother’s bleeding was described as lifelong. Available evidence supports a chronic, persistent rather than progressive thrombocytopenia, with episodic hemorrhage triggered by ordinary mucosal injury, menstruation, or ovarian-cyst rupture. No formal disease stages, remission pattern, spontaneous recovery, or age-dependent penetrance curve exists. (manchev2014anewform pages 3-4, manchev2014anewform pages 4-6)

Critical periods are inferred clinically: infancy/childhood recognition, menarche and reproductive years, pregnancy/childbirth, invasive procedures, dental work, trauma, and acute major bleeding. These are intervention windows for anticipatory hemostatic planning, not demonstrated windows of molecular reversibility.

9. Inheritance and population

Inheritance is autosomal recessive. The two homozygous siblings were affected and heterozygous relatives had normal platelet counts and morphology, supporting recessive segregation and no evident heterozygous phenotype in this family. Because only two affected people are known, penetrance appears complete for homozygous p.Ile74Met within this pedigree but cannot be reliably estimated across populations. Expressivity varied: one sibling had life-threatening gynecologic bleeding and the other moderate lifelong mucocutaneous bleeding. (manchev2014anewform pages 4-6, manchev2014anewform pages 6-8)

No anticipation, germline mosaicism, founder effect, or geographic variant distribution is established. Consanguinity was important in the discovery family. Both sexes were affected, providing no evidence of sex-linked risk, although sex-specific exposures such as menstruation can amplify morbidity.

There are no valid prevalence, incidence, carrier-frequency, mortality, sex-ratio, or age-distribution estimates. The observable literature count—two affected siblings in one West Indian pedigree—is not a prevalence estimate. Older reviews continued to describe a single variant/pedigree, and no independent 2023–2024 family was identified. (johnson2017moleculargeneticinvestigation pages 51-55, johnson2017moleculargeneticinvestigationa pages 51-55)

10. Diagnostics

Recommended workflow

  1. Clinical assessment: congenital/persistent thrombocytopenia; personal and three-generation bleeding history; consanguinity; medication review; examination for syndromic features. ISTH-BAT can standardize bleeding documentation, although it does not reliably distinguish every inherited thrombocytopenia from controls. (palmabarqueros2021inheritedplateletdisorders pages 11-13, palmabarqueros2021inheritedplateletdisorders pages 15-17)
  2. CBC and expert smear: confirm severe thrombocytopenia and giant platelets. Automated counters can underestimate platelet number and MPV when platelets are very large; manual/optical methods are valuable.
  3. Exclude acquired causes: immune thrombocytopenia, drug-induced disease, infection, marrow failure, liver disease/hypersplenism, and pseudothrombocytopenia.
  4. Platelet phenotyping: flow cytometry for GPIb–IX–V and αIIbβ3; agonist-induced P-selectin and receptor trafficking; aggregometry/secretion studies; calcium mobilization where available; electron microscopy for size/ultrastructure. Light-transmission aggregometry remains a general reference test, while flow cytometry and electron microscopy help define receptor and structural defects. (palmabarqueros2021inheritedplateletdisorders pages 15-17)
  5. Genetics: an inherited thrombocytopenia/platelet-disorder panel that includes PRKACG, followed by exome or genome sequencing if negative. Confirm candidate variants with orthogonal sequencing and parental/family segregation. HTS interpretation must be integrated with platelet phenotype and ACMG/AMP evidence. (palmabarqueros2021inheritedplateletdisorders pages 17-18, palmabarqueros2021inheritedplateletdisorders pages 11-13)

The original investigation excluded GP1BA/GP1BB/GP9-associated Bernard–Soulier syndrome and found no neutrophil inclusions suggestive of MYH9-related disease before exome sequencing. (manchev2014anewform pages 6-8)

Differential diagnosis

Major differentials include Bernard–Soulier syndrome; MYH9-related disease; FLNA-, ACTN1-, TUBB1-, DIAPH1-, SRC-, GNE-, and SLC35A1-related macrothrombocytopenias; gray platelet syndrome; platelet-type von Willebrand disease; immune thrombocytopenia; and EDTA-dependent pseudothrombocytopenia. Distinguishing clues include inheritance, syndromic findings, neutrophil inclusions, receptor expression, granule morphology, VWF studies, platelet size, and molecular testing. Misdiagnosis as immune thrombocytopenia can cause ineffective or harmful immunosuppression/splenectomy. (palmabarqueros2021inheritedplateletdisorders pages 11-13, palmabarqueros2021inheritedplateletdisorders pages 15-17)

No validated BDPLT19-specific diagnostic criteria, biochemical assay, imaging signature, RNA/proteomic diagnostic, newborn screen, or liquid biopsy exists. CMA, karyotype, FISH, mitochondrial testing, and repeat-expansion testing are not first-line unless another phenotype suggests them. Cascade testing is appropriate after a familial pathogenic genotype is established; prenatal and preimplantation testing are technically possible for the known family variant with counseling.

11. Outcome and prognosis

No survival curve, life-expectancy estimate, disease-specific mortality rate, or prospective natural-history study exists. Both reported patients survived into their twenties at publication, but the proband had three life-threatening ovarian hemorrhages. Morbidity arises from bleeding, anemia, transfusion requirements, and procedure/reproductive risk. (manchev2014anewform pages 3-4, manchev2014anewform pages 4-6)

The disorder appears lifelong; spontaneous normalization was not reported. Prognosis probably depends on residual platelet count/function, prior major bleeding, menstrual/gynecologic burden, trauma and surgery exposure, and access to specialist hemostatic care, but no prognostic model or biomarker has been validated. There is no evidence of marrow-failure evolution, malignancy predisposition, immunodeficiency, renal disease, or neurodevelopmental involvement in BDPLT19.

12. Treatment and current applications

There is no approved PRKACG-targeted treatment, no disease-specific algorithm, no response-rate study, and no registered relevant interventional trial identified. Management should therefore be individualized by an inherited-bleeding-disorder center and explicitly labeled as extrapolated from broader IPD practice.

Practical strategy

  • Education/prevention: bleeding plan, medical-alert identification, dental hygiene, avoidance of aspirin/NSAIDs and unnecessary antiplatelet therapy, trauma precautions, and specialist planning for procedures. (palmabarqueros2021inheritedplateletdisorders pages 21-22)
  • Local hemostasis: compression, topical measures, nasal/dental control; preferred where feasible. (noris2017hereditarythrombocytopeniasa pages 12-13)
  • Antifibrinolytics: tranexamic acid or aminocaproic acid may be considered for mucosal, dental, or menstrual bleeding and selected procedures. Suggested NCIt concept: Antifibrinolytic Agent. Evidence is general IPD expert practice, not BDPLT19-specific. (noris2017hereditarythrombocytopeniasa pages 12-13)
  • Desmopressin: sometimes used for selected IPDs/low-risk procedures, but efficacy in BDPLT19 is unknown and should be established cautiously. Suggested NCIt: Desmopressin. (noris2017hereditarythrombocytopeniasa pages 12-13)
  • Platelet transfusion: appropriate for major/life-threatening bleeding or critical-site hemorrhage and major procedures. The proband received platelet and red-cell transfusions for ovarian hemorrhage. Minimize exposure because alloimmunization can cause refractoriness; use leukoreduced, single-donor and HLA-compatible products when feasible. Suggested NCIt: Platelet Transfusion. (manchev2014anewform pages 4-6, noris2017hereditarythrombocytopeniasa pages 12-13, palmabarqueros2021inheritedplateletdisorders pages 21-22)
  • Red-cell transfusion/iron replacement: as clinically required for hemorrhagic or iron-deficiency anemia; direct BDPLT19 evidence exists for red-cell support during severe bleeding, not for comparative efficacy. (manchev2014anewform pages 4-6)
  • Menstrual/gynecologic management: coordinated hematology–gynecology care, antifibrinolytic and hormonal approaches as appropriate, iron monitoring, and urgent evaluation of pelvic pain because ovarian-cyst rupture was the defining life-threatening complication.

There is no disease-specific evidence supporting thrombopoietin-receptor agonists, recombinant factor VIIa, splenectomy, HSCT, immunotherapy, RNA therapy, or pharmacogenomic selection. These should not be imported from other thrombocytopenias without a case-specific rationale. Lentiviral wild-type PRKACG rescue is a mechanistic proof of principle only; it does not establish clinical gene-therapy feasibility or safety. (manchev2014anewform pages 8-9, noris2017hereditarythrombocytopeniasa pages 12-13)

13. Prevention

Primary prevention of the genotype is not possible through lifestyle or vaccination. Reproductive options include carrier/cascade testing, genetic counseling, prenatal diagnosis, and preimplantation genetic testing once the familial variant and phase are confirmed.

Secondary prevention consists of early recognition of congenital macrothrombocytopenia, avoiding misdiagnosis as immune thrombocytopenia, and testing relatives. Population or newborn screening is not supported.

Tertiary prevention includes avoidance of platelet inhibitors and trauma, dental hygiene, iron surveillance, menstrual management, procedure/childbirth plans, rapid treatment of bleeding, and judicious use of compatible platelets. No immunization specifically prevents BDPLT19; routine vaccines remain appropriate unless individualized clinical circumstances dictate otherwise. (palmabarqueros2021inheritedplateletdisorders pages 11-13, palmabarqueros2021inheritedplateletdisorders pages 21-22)

14. Other species and natural disease

No naturally occurring PRKACG-associated macrothrombocytopenia was identified in companion animals, livestock, or wildlife. There is no zoonotic or cross-species transmission because BDPLT19 is a germline human Mendelian condition. PRKACG orthologs are evolutionarily conserved, but the retrieved literature did not provide validated species-specific NCBI Gene IDs or a veterinary OMIA/VBO disease entry. These should be populated only after direct database verification.

15. Model organisms and experimental models

No dedicated Prkacg p.Ile74Met knock-in mouse, knockout model shown to recapitulate BDPLT19, zebrafish model, organoid, iPSC line, or natural animal model was identified. The principal model is a patient-derived ex vivo cellular system: peripheral-blood CD34-positive progenitors differentiated into megakaryocytes with thrombopoietin and stem-cell factor. It reproduced normal maturation/ploidy but reduced proplatelet formation, oversized platelet-like structures, and low FLNA. Lentiviral wild-type PRKACG rescued these abnormalities. (manchev2014anewform pages 2-3, manchev2014anewform pages 6-8, manchev2014anewform pages 8-9)

This model is valuable for late thrombopoiesis, cytoskeletal biology, variant-function studies, and candidate rescue experiments. Its limitations are the absence of marrow niche, circulation/shear, platelet clearance, immune interactions, whole-organism bleeding, long-term safety, and independent genotypes.

Recent developments and expert interpretation, 2023–2024

The retrieved 2023–2024 literature did not reveal a new BDPLT19 family, independently replicated pathogenic variant, natural-history cohort, trial, or disease-specific therapy. The relevant advance is broader implementation of comprehensive platelet phenotyping and high-throughput genetic testing in inherited platelet disorders. A 2023 review emphasizes that these disorders can produce mucocutaneous bleeding and life-threatening trauma/surgical hemorrhage and that both platelet-function analysis and genetic testing are indispensable. General modern reviews similarly recommend integrating genotype with count, size, morphology, and functional phenotype rather than treating sequencing as a standalone diagnosis. (palmabarqueros2021inheritedplateletdisorders pages 11-13, palmabarqueros2021inheritedplateletdisorders pages 15-17, palmabarqueros2021inheritedplateletdisorders pages 1-3)

The authoritative interpretation is consequently cautious: BDPLT19 is biologically persuasive because cosegregation, patient-cell dysfunction, and allele-specific rescue align, but clinical generalizability remains weak because evidence is confined to one pedigree. Candidate PRKACG variants reported in heterogeneous platelet-secretion studies should not automatically be curated as BDPLT19 without recessive segregation and functional validation.

Curation conclusions

  • Disease–gene validity: supported by one pedigree plus strong patient-cell rescue; replication remains needed.
  • Core phenotype: childhood-onset, lifelong severe macrothrombocytopenia with qualitative platelet dysfunction and variable moderate-to-life-threatening bleeding.
  • Core mechanism: impaired PKA signaling → increased cAMP and probable failure of FLNA stabilization → defective actin organization/proplatelet formation → giant, scarce, dysfunctional platelets.
  • Best diagnostic application: include PRKACG in inherited macrothrombocytopenia panels and interpret variants with segregation and functional platelet/megakaryocyte evidence.
  • Current implementation: supportive bleeding prevention and hemostatic treatment; no targeted therapy or trial.
  • Highest-priority research gaps: independent families and alleles, current population-frequency/ClinVar curation, catalytic and structural characterization, direct FLNA-Ser2152 measurements, knock-in animal/iPSC models, longitudinal outcomes, reproductive/pregnancy data, and treatment-response studies.

References

  1. (OpenTargets Search: platelet-type bleeding disorder 19-PRKACG): Open Targets Query (platelet-type bleeding disorder 19-PRKACG, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (manchev2014anewform pages 1-2): Vladimir T. Manchev, Morgane Hilpert, Eliane Berrou, Ziane Elaib, Achille Aouba, Siham Boukour, Sylvie Souquere, Gerard Pierron, Philippe Rameau, Robert Andrews, François Lanza, Regis Bobe, William Vainchenker, Jean-Philippe Rosa, Marijke Bryckaert, Najet Debili, Remi Favier, and Hana Raslova. A new form of macrothrombocytopenia induced by a germ-line mutation in the prkacg gene. Blood, 124 16:2554-63, Oct 2014. URL: https://doi.org/10.1182/blood-2014-01-551820, doi:10.1182/blood-2014-01-551820. This article has 91 citations and is from a highest quality peer-reviewed journal.

  3. (manchev2014anewform pages 4-6): Vladimir T. Manchev, Morgane Hilpert, Eliane Berrou, Ziane Elaib, Achille Aouba, Siham Boukour, Sylvie Souquere, Gerard Pierron, Philippe Rameau, Robert Andrews, François Lanza, Regis Bobe, William Vainchenker, Jean-Philippe Rosa, Marijke Bryckaert, Najet Debili, Remi Favier, and Hana Raslova. A new form of macrothrombocytopenia induced by a germ-line mutation in the prkacg gene. Blood, 124 16:2554-63, Oct 2014. URL: https://doi.org/10.1182/blood-2014-01-551820, doi:10.1182/blood-2014-01-551820. This article has 91 citations and is from a highest quality peer-reviewed journal.

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  6. (manchev2014anewform pages 3-4): Vladimir T. Manchev, Morgane Hilpert, Eliane Berrou, Ziane Elaib, Achille Aouba, Siham Boukour, Sylvie Souquere, Gerard Pierron, Philippe Rameau, Robert Andrews, François Lanza, Regis Bobe, William Vainchenker, Jean-Philippe Rosa, Marijke Bryckaert, Najet Debili, Remi Favier, and Hana Raslova. A new form of macrothrombocytopenia induced by a germ-line mutation in the prkacg gene. Blood, 124 16:2554-63, Oct 2014. URL: https://doi.org/10.1182/blood-2014-01-551820, doi:10.1182/blood-2014-01-551820. This article has 91 citations and is from a highest quality peer-reviewed journal.

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  12. (palmabarqueros2021inheritedplateletdisorders pages 21-22): Verónica Palma-Barqueros, Nuria Revilla, Ana Sánchez, Ana Zamora Cánovas, Agustín Rodriguez-Alén, Ana Marín-Quílez, José Ramón González-Porras, Vicente Vicente, María Luisa Lozano, José María Bastida, and José Rivera. Inherited platelet disorders: an updated overview. International Journal of Molecular Sciences, 22:4521, Apr 2021. URL: https://doi.org/10.3390/ijms22094521, doi:10.3390/ijms22094521. This article has 144 citations.

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  15. (palmabarqueros2021inheritedplateletdisorders pages 1-3): Verónica Palma-Barqueros, Nuria Revilla, Ana Sánchez, Ana Zamora Cánovas, Agustín Rodriguez-Alén, Ana Marín-Quílez, José Ramón González-Porras, Vicente Vicente, María Luisa Lozano, José María Bastida, and José Rivera. Inherited platelet disorders: an updated overview. International Journal of Molecular Sciences, 22:4521, Apr 2021. URL: https://doi.org/10.3390/ijms22094521, doi:10.3390/ijms22094521. This article has 144 citations.

  16. (donck2021hemostaticphenotypesand pages 6-7): Fabienne Ver Donck, Veerle Labarque, and Kathleen Freson. Hemostatic phenotypes and genetic disorders. Research and Practice in Thrombosis and Haemostasis, 5:e12637, Dec 2021. URL: https://doi.org/10.1002/rth2.12637, doi:10.1002/rth2.12637. This article has 24 citations and is from a peer-reviewed journal.

  17. (palmabarqueros2021inheritedplateletdisorders pages 17-18): Verónica Palma-Barqueros, Nuria Revilla, Ana Sánchez, Ana Zamora Cánovas, Agustín Rodriguez-Alén, Ana Marín-Quílez, José Ramón González-Porras, Vicente Vicente, María Luisa Lozano, José María Bastida, and José Rivera. Inherited platelet disorders: an updated overview. International Journal of Molecular Sciences, 22:4521, Apr 2021. URL: https://doi.org/10.3390/ijms22094521, doi:10.3390/ijms22094521. This article has 144 citations.

  18. (manchev2014anewform pages 2-3): Vladimir T. Manchev, Morgane Hilpert, Eliane Berrou, Ziane Elaib, Achille Aouba, Siham Boukour, Sylvie Souquere, Gerard Pierron, Philippe Rameau, Robert Andrews, François Lanza, Regis Bobe, William Vainchenker, Jean-Philippe Rosa, Marijke Bryckaert, Najet Debili, Remi Favier, and Hana Raslova. A new form of macrothrombocytopenia induced by a germ-line mutation in the prkacg gene. Blood, 124 16:2554-63, Oct 2014. URL: https://doi.org/10.1182/blood-2014-01-551820, doi:10.1182/blood-2014-01-551820. This article has 91 citations and is from a highest quality peer-reviewed journal.

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