Platelet-type Bleeding Disorder 20

Mendelian MONDO:0014830 Pathograph 12 Show in embeddings browser Inherited Thrombocytopenia Inherited Platelet Function Disorder

An autosomal dominant inherited thrombocytopenia caused by heterozygous variants in SLFN14, which encodes a ribosome-associated endoribonuclease. Patients have moderate thrombocytopenia with enlarged platelets, reduced dense granules and impaired ATP secretion, and a lifelong mucocutaneous bleeding tendency that is more troublesome than the modest laboratory abnormalities predict. The entry is organised around one fact that makes this disease unusual: the defect is in RNA turnover, not in any platelet receptor, granule protein or cytoskeletal component. SLFN14 sits on the ribosome and cleaves RNA. Megakaryocytes and erythroid precursors are where it is expressed, and a megakaryocyte in the act of shedding platelets is unusually dependent on getting ribosome and transcript turnover right - so a general defect in RNA handling lands on this one lineage and produces a bleeding disorder. Two things are curated here as unresolved rather than smoothed over. The first is the molecular mechanism, which has two incompatible accounts in the literature and no adjudicating experiment. On the older account the AAA-domain variants misfold, are degraded, and drag down the wild-type protein with them - a dominant negative that works by loss of SLFN14 activity. On the newer account the variants do not simply lose activity but redirect it, shifting the enzyme's preference from ribosomal RNA towards type II tRNAs and stalling translation. These predict opposite things about what a therapy should do, so the entry curates both as competing hypotheses and tags the causal edges accordingly. The second is that the obvious mouse model does not work. A knockin carrying the mouse equivalent of the commonest patient variant is not a bleeding model at all - it is an erythroid one. A later conditional knockout restricted to the megakaryocyte lineage does reproduce the bleeding phenotype. Both are curated, with the failure recorded as a failure.

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1
Inheritance
8
Pathophys.
8
Phenotypes
2
Hypotheses
2
Gaps
12
Pathograph
1
Genes
3
Medical Actions
2
Models
6
References
1
Deep Research
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Inheritance

1
Autosomal dominant HP:0000006
A single variant allele is sufficient, with dominant segregation in all three founding families. The mechanism of dominance is exactly what the two competing hypotheses disagree about: interference with the wild-type product on one account, an acquired activity on the other.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:42213791 SUPPORT Human Clinical
"Heterozygous missense mutations in SLFN14 cause an autosomal dominant form of IT, characterized by defective platelet function and excessive bleeding"
States the inheritance pattern and the phenotype it transmits.
◈

Mechanistic Hypotheses

2
Dominant-negative loss of SLFN14 through misfolding and degradation
dominant_negative_degradation CANONICAL
Evidence balance 1 support
The variants destabilise the protein, which is degraded post-translationally; because SLFN14 oligomerises, mutant subunits also reduce the wild-type pool, giving dominance from what is fundamentally a loss of enzyme. This is the older account and the one the measured reduction of SLFN14 in patient platelets most directly supports.
Pathograph links
Heterozygous SLFN14 Variant -> Reduced SLFN14 Protein Abundance DIRECT On the dominant-negative account, the substituted residues destabilise the fold and the protein is degraded post-translationally.
Reduced SLFN14 Protein Abundance -> Dysregulated Ribosomal RNA Turnover DIRECT Less enzyme on the ribosome means less of the rRNA degradation it normally performs.
Show evidence (1 reference)
PMID:29678925 SUPPORT In Vitro
"Compared to SLFN14 WT, expression of mutants is dramatically reduced as a result of post-translational degradation due to partial misfolding of the protein."
The degradation mechanism this hypothesis rests on.
Redirected endoribonuclease specificity towards type II tRNAs
redirected_substrate_specificity EMERGING
Evidence balance 1 support
The variants do not merely reduce activity but change which RNAs are cleaved, driving type II tRNA depletion, ribosome stalling and translational arrest. On this account the disease is caused by an activity the mutant enzyme has, not by one it lacks - which inverts the therapeutic goal.
Pathograph links
Heterozygous SLFN14 Variant -> Redirected Endoribonuclease Substrate Specificity DIRECT On the altered-specificity account, the same substitutions sit in the RNA-binding cleft and change which RNAs the enzyme prefers rather than abolishing activity.
Redirected Endoribonuclease Substrate Specificity -> Dysregulated Ribosomal RNA Turnover DIRECT Reduced rRNA cleavage is part of the same substrate shift, so this account reaches the shared downstream node too - by a different route and with the opposite sign on the tRNA arm.
Show evidence (1 reference)
PMID:42213791 SUPPORT In Vitro
"IT-linked mutations alter SLFN14 RNA substrate specificity, enhancing depletion of type II tRNAs while reducing rRNA cleavage."
The substrate shift that defines this hypothesis.
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Discussions and Knowledge Gaps

2
Do SLFN14 variants cause disease by removing enzyme activity, or by redirecting it onto the wrong substrates?
CONTROVERSY OPEN controversy_lof_versus_neomorph
Attached to
pathophysiology#Reduced SLFN14 Protein Abundance pathophysiology#Redirected Endoribonuclease Substrate Specificity mechanistic_hypotheses#dominant_negative_degradation mechanistic_hypotheses#redirected_substrate_specificity
Both accounts are supported by real data and they are not compatible. The loss account has the more direct clinical observation behind it: SLFN14 protein is markedly reduced in patient platelets, the reduction is explained by misfolding and post-translational degradation, and oligomerisation gives a route to dominance. Most disease-associated RNase-domain mutations reduce cleavage activity in vitro. The redirection account explains something the loss account does not. If the lesion were simply less enzyme, a heterozygote with roughly half-normal activity should be mildly affected in proportion; instead these variants shift which RNAs are cleaved, deplete type II tRNAs, stall ribosomes and trigger cell death - an active injury rather than a shortfall. The distinction is not academic. If the disease is loss of SLFN14, a therapy should restore or stabilise the protein. If it is redirected activity, restoring the protein delivers more of the harmful activity and inhibition is the rational goal. A therapeutic programme cannot be designed until this is settled. Neither body of work has been done in megakaryocytes. The degradation studies used transfected cell lines; the substrate-specificity study used HEK293T overexpression. The lineage where the disease actually happens has not been used to test either.
Proposed experiments
Substrate profiling and rescue in patient-genotype megakaryocytes
slfn14_mechanism_discrimination_in_mk
In megakaryocytic lines carrying a patient variant at the endogenous locus, measure SLFN14 protein level and profile tRNA and rRNA cleavage in the same cells, then test two interventions against proplatelet formation: raising wild-type SLFN14, and inhibiting SLFN14 catalytic activity.
Would support
mechanistic_hypotheses#redirected_substrate_specificity
Would refute
mechanistic_hypotheses#dominant_negative_degradation
Supporting outcome
  • Type II tRNAs are selectively depleted in patient-genotype megakaryocytes and catalytic inhibition rescues proplatelet formation while adding wild-type protein does not, which would establish redirected activity as the operative mechanism.
Refuting outcome
  • Adding wild-type SLFN14 rescues proplatelet formation and no selective tRNA depletion is detectable, which would support simple dominant-negative loss and retire the redirection account for this lineage.
Why does a knockin of the mouse equivalent of the commonest patient variant produce an erythroid disease in mice and a platelet disease in humans?
HUMAN MODEL MISMATCH OPEN mismatch_mouse_lineage
Attached to
animal_models#Global Slfn14 K208N knockin mouse pathophysiology#Impaired Megakaryocyte Maturation and Proplatelet Formation
This is a mismatch rather than a gap: the model exists, the result is clear, and it disagrees with the patients. Homozygous K208N mice have microcytic erythrocytosis and die in utero; heterozygotes have anaemia and splenomegaly. Neither shows the bleeding or platelet defect that defines the human disease. SLFN14 is expressed in both megakaryocyte and erythroid precursors, so a shift in which of the two is rate-limiting between species is a plausible explanation - and it is only that. It has not been tested. It matters for how the rest of the model evidence is read. The conditional knockout that does reproduce bleeding was made by deleting the gene in the megakaryocyte lineage, which guarantees a megakaryocyte phenotype by construction. It shows what losing SLFN14 in megakaryocytes does; it does not show that the patient variants do that.
Proposed experiments
Comparative lineage dependence on SLFN14 in mouse and human progenitors
slfn14_lineage_dependence_cross_species
Quantify SLFN14 expression and the consequences of its loss in matched megakaryocyte and erythroid progenitors from mouse and human, and test whether the mouse erythroid phenotype converts to a platelet phenotype when the human expression ratio is imposed.
Would support
pathophysiology#Impaired Megakaryocyte Maturation and Proplatelet Formation
Supporting outcome
  • Mouse erythroid progenitors depend on SLFN14 more than their human counterparts while the megakaryocyte dependence is reversed, which would make the mismatch a species artefact and leave the human megakaryocyte mechanism transferable.
Refuting outcome
  • Lineage dependence is comparable across species, which would point instead to the variant acting differently on the mouse protein and would undercut using any mouse model to reason about the human variants.
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Pathophysiology

8
Heterozygous SLFN14 Variant
A single SLFN14 allele carries a missense variant. The reported variants cluster tightly: K218E, K219N and V220D lie in three consecutive residues of the AAA domain, and R223W sits four residues further along, so the recurrent lesion is a small patch of the RNA-binding cleft rather than a scatter across the protein. Later reports have added variants in the C-terminal helicase domain, which is a different part of the protein and appears to act differently; those are noted on the gene entry rather than folded into this node.
Dominant-negative loss of SLFN14 through misfolding and degradation Redirected endoribonuclease specificity towards type II tRNAs
Genetic context SLFN14 hgnc:32689 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns SLFN14 (hgnc:32689). hgnc:32689 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS
Heterozygous missense variants segregating dominantly. Deliberately carries no `functional_impact_category`: the two competing mechanistic accounts below disagree on whether these alleles are loss-of-function or neomorphic, and choosing a value here would silently settle a question the literature has not.
Downstream
Reduced SLFN14 Protein Abundance On the dominant-negative account, the substituted residues destabilise the fold and the protein is degraded post-translationally. Dominant-negative loss of SLFN14 through misfolding and degradation
Redirected Endoribonuclease Substrate Specificity On the altered-specificity account, the same substitutions sit in the RNA-binding cleft and change which RNAs the enzyme prefers rather than abolishing activity. Redirected endoribonuclease specificity towards type II tRNAs
Show evidence (2 references)
PMID:26280575 SUPPORT Human Clinical
"Three heterozygous missense mutations were identified in affected family members and predicted to encode substitutions (K218E, K219N, and V220D) within an ATPase-AAA-4, GTP/ATP-binding region of SLFN14."
The founding variants and the domain they fall in.
PMID:42213791 SUPPORT In Vitro
"most IT-associated SLFN14 mutations, including K218E, K219N/E, V220D, and R223W, cluster within the RNA-binding cleft of the RNase domain"
Locates the recurrent variants structurally, which is the observation both mechanistic accounts start from.
Reduced SLFN14 Protein Abundance
SLFN14 protein is markedly reduced in patient platelets and in cells transfected with the mutant construct. The reduction is post-translational: the variants partially misfold and are degraded, and because the mutant protein also oligomerises, the wild-type product made from the normal allele is dragged down with it. That is the proposed basis of dominance. Curated as ESTABLISHED because the measurement itself - less protein in patient platelets - is reproduced across reports. What is contested is whether losing protein is the whole story, which is the point of the competing node below.
Dominant-negative loss of SLFN14 through misfolding and degradation
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.
Downstream
Dysregulated Ribosomal RNA Turnover Less enzyme on the ribosome means less of the rRNA degradation it normally performs. Dominant-negative loss of SLFN14 through misfolding and degradation
Show evidence (3 references)
PMID:26280575 SUPPORT Human Clinical
"Endogenous SLFN14 expression was reduced in platelets from all patients, and mutant SLFN14 expression was markedly decreased compared with that of WT SLFN14 when overexpressed in transfected cells."
The reduction measured in patients and reproduced in transfected cells.
PMID:29678925 SUPPORT In Vitro
"Compared to SLFN14 WT, expression of mutants is dramatically reduced as a result of post-translational degradation due to partial misfolding of the protein."
Identifies the mechanism of the reduction as misfolding and degradation rather than reduced transcription.
PMID:29678925 SUPPORT In Vitro
"These findings could explain the dominant negative effect of heterozygous mutation on SLFN14 expression in patients' platelets."
PARTIAL because the source frames the dominant-negative reading as an explanation its data could support rather than one it demonstrates.
Redirected Endoribonuclease Substrate Specificity
The competing account. Rather than simply having less enzyme, patient variants have an enzyme that prefers different substrates: depletion of type II tRNAs is enhanced while cleavage of ribosomal RNA is reduced. That is a change in what the enzyme does, not only in how much of it there is. The distinction matters because the two accounts point opposite ways therapeutically. If the lesion is loss of SLFN14, restoring or stabilising the protein is the goal. If the lesion is redirected activity, restoring the protein would deliver more of the wrong enzymatic activity, and inhibiting it would be closer to right. PROVISIONAL: the work is in an overexpression cell system rather than in megakaryocytes or patient cells, and no experiment has yet distinguished the two accounts in the lineage that actually fails.
Redirected endoribonuclease specificity towards type II tRNAs
RNA endonuclease activity GO:0004521 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal RNA endonuclease activity (GO:0004521). GO:0004521 is a molecular function from the Gene Ontology. ⚠ ABNORMAL
Downstream
Dysregulated Ribosomal RNA Turnover Reduced rRNA cleavage is part of the same substrate shift, so this account reaches the shared downstream node too - by a different route and with the opposite sign on the tRNA arm. Redirected endoribonuclease specificity towards type II tRNAs
Show evidence (2 references)
PMID:42213791 SUPPORT In Vitro
"IT-linked mutations alter SLFN14 RNA substrate specificity, enhancing depletion of type II tRNAs while reducing rRNA cleavage."
The substrate shift itself, which is the whole of this node's claim.
PMID:42213791 SUPPORT In Vitro
"Most IT-associated mutations in the RNase domain reduce RNA cleavage activity in vitro"
PARTIAL and cited deliberately against this node: the same paper records the prior in-vitro consensus that these mutations reduce activity, which is what the dominant-negative account rests on.
Dysregulated Ribosomal RNA Turnover
Whichever route reaches it, the shared consequence is that RNA turnover on the ribosome is no longer normal in this lineage. Patient platelets and mature megakaryocytes show signs of ribosomal RNA degradation, and the observation is lineage- and stage-restricted - it is absent from undifferentiated megakaryocytic cells and from granulocytes, which is the clearest evidence that the defect only bites where SLFN14 normally works hardest.
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.
rRNA catabolic process GO:0016075 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal rRNA catabolic process (GO:0016075). GO:0016075 is a biological process from the Gene Ontology. ⚠ ABNORMAL tRNA decay GO:0016078 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal tRNA decay (GO:0016078). GO:0016078 is a biological process from the Gene Ontology. ⚠ ABNORMAL
ribosome GO:0005840 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves ribosome (GO:0005840). GO:0005840 is a cellular component from the Gene Ontology.
Downstream
Impaired Megakaryocyte Maturation and Proplatelet Formation Typed with unknown intermediates deliberately. That disordered ribosomal RNA turnover precedes the megakaryocyte defect is established by the staging of the observations, but which transcripts fail to be made, and why proplatelet formation specifically is the step that breaks, has not been shown.
Show evidence (3 references)
PMID:36790527 SUPPORT In Vitro
"SLFN14-defective platelets and mature MK showed signs of rRNA degradation; however, this was absent in undifferentiated imMKCL cells and granulocytes."
Both halves matter: the rRNA abnormality, and its restriction to mature cells of this lineage, which is what makes it a plausible explanation for a lineage-specific disease.
PMID:29678925 SUPPORT In Vitro
"Here, we show that all SLFN14 variants colocalize with ribosomes and mediate rRNA endonucleolytic degradation."
Places the enzyme and its variants on the ribosome, which is the physical basis for this node.
PMID:42213791 SUPPORT In Vitro
"This shift promotes ribosome stalling at codons decoded by type II tRNAs, triggering global translational arrest, stress signaling, and cell death."
The translational consequence proposed by the altered-specificity account, which is why this node names tRNA decay alongside rRNA turnover.
Impaired Megakaryocyte Maturation and Proplatelet Formation
The cellular step at which the disease becomes a platelet disease. Megakaryocytes cultured from patients make fewer proplatelets, and the ones they make are shorter and less branched - a defect in the physical act of shedding platelets rather than in megakaryocyte number alone. Engineered megakaryocytic lines carrying the commonest patient variant reproduce it, together with disordered mitochondrial organisation.
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 megakaryocyte differentiation GO:0030219 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal megakaryocyte differentiation (GO:0030219). GO:0030219 is a biological process from the Gene Ontology. ⚠ ABNORMAL
bone marrow UBERON:0002371 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in bone marrow (UBERON:0002371). UBERON:0002371 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Megakaryocyte- and platelet-specific Slfn14 conditional knockout mouse (Slfn14 PF4-Cre) Mouse recapitulates Fewer megakaryocytes in situ in the bone marrow, consistent with the megakaryocyte defect seen in patient-derived cultures.
Downstream
Macrothrombocytopenia Fewer and abnormally formed proplatelets yield fewer, larger circulating platelets.
Platelet Dense Granule Deficiency Platelets shed from a megakaryocyte that matured abnormally carry an abnormal granule complement.
Show evidence (2 references)
PMID:36790527 SUPPORT In Vitro
"Megakaryocyte (MK) cultures from patients produce less proplatelets with shorter elongation and reduced ramification of their shafts."
The proplatelet defect measured in patient-derived megakaryocytes, in the specific terms this node claims.
PMID:36790527 SUPPORT In Vitro
"MK derived from heterozygous and homozygous SLFN14 K219N imMKCL and stem cells of blood from patients mainly presented with a defect in proplatelet formation and mitochondrial organization."
Reproduces the defect in an engineered line carrying the patient variant, which controls for patient background.
Macrothrombocytopenia
Moderately reduced platelet count with enlarged platelets. The combination is the diagnostic signature, and its moderate degree is part of why the disease is easy to under-rate: the count alone does not predict how much these patients bleed.
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.
Downstream
Mucocutaneous Bleeding Diathesis Fewer circulating platelets contribute to impaired primary haemostasis, alongside the secretion defect.
Show evidence (1 reference)
PMID:26280575 SUPPORT Human Clinical
"Patients harboring SLFN14 mutations displayed an analogous phenotype that consisted of moderate thrombocytopenia, enlarged platelets, decreased ATP secretion, and a dominant inheritance pattern."
The full phenotype as first described, including the two components of this node and the inheritance pattern.
Platelet Dense Granule Deficiency
Electron microscopy shows fewer dense granules in patient platelets, and the deficit tracks with the measured loss of ATP secretion on lumiaggregometry - so this is a storage-pool defect with a matching functional readout rather than an isolated morphological observation.
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 degranulation GO:0002576 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased platelet degranulation (GO:0002576). GO:0002576 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Mucocutaneous Bleeding Diathesis Failure of dense-granule release removes the ADP- and ATP-dependent amplification that recruits further platelets to a forming plug.
Show evidence (2 references)
PMID:26280575 SUPPORT Human Clinical
"Electron microscopy revealed a reduced number of dense granules in affected patients platelets, correlating with a decreased ATP secretion observed in lumiaggregometry studies."
The structural deficit and the functional correlate reported together, which is what this node asserts.
PMID:40794453 SUPPORT Human Clinical
"Initial functional investigation of the patients with SLFN14 mutations (V220D, K218E, and K219N) revealed mild macrothrombocytopenia; platelet function defects in response to adenosine diphosphate (ADP), collagen, and protease-activated receptor 1 (PAR1) peptide; and decreased adenosine..."
The agonist-specific aggregation defects alongside the secretion defect, restating the patient phenotype from a later review of the same families.
Mucocutaneous Bleeding Diathesis
The clinical endpoint: bruising, epistaxis, gum bleeding, heavy menstrual bleeding and excessive bleeding after trauma, dental work or delivery. Its most striking feature is disproportion. Every patient in the founding families had an obvious bleeding tendency while the laboratory abnormalities - platelet count, aggregation, secretion - were only mildly deranged. A normal-looking platelet panel does not exclude this diagnosis.
Animal models
Megakaryocyte- and platelet-specific Slfn14 conditional knockout mouse (Slfn14 PF4-Cre) Mouse recapitulates Reproduces the bleeding phenotype with impaired platelet responses and delayed thrombus formation in vivo.
Global Slfn14 K208N knockin mouse Mouse fails to recapitulate The genotype-matched model produces an erythroid disease rather than a bleeding disease.
Show evidence (1 reference)
PMID:36790527 SUPPORT Human Clinical
"Obvious bleeding tendencies were reported in all patients whereas laboratory testing showed mild defects in platelet aggregation and adenosine triphosphate (ATP) secretion, and platelet counts that were mildly reduced."
States the disproportion between symptoms and laboratory findings directly, which is the clinically load-bearing part of this node.
⬡

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 20 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

8
Blood 3
Excessive Mucocutaneous Bleeding VERY_FREQUENT Bruising susceptibility HP:0000978 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bruising susceptibility (HP:0000978). HP:0000978 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36790527 SUPPORT Human Clinical
"Obvious bleeding tendencies were reported in all patients whereas laboratory testing showed mild defects in platelet aggregation and adenosine triphosphate (ATP) secretion, and platelet counts that were mildly reduced."
Establishes that the bleeding tendency was universal and disproportionate to the laboratory findings.
Epistaxis FREQUENT HP:0000421 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epistaxis (HP:0000421). HP:0000421 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26280575 SUPPORT Human Clinical
"a history of spontaneous epistaxis starting in childhood"
Records spontaneous childhood-onset epistaxis in an affected member of the founding cohort.
PMID:36790527 SUPPORT Human Clinical
"Mucocutaneous bleeding symptoms (epistaxis, hematomas)"
The clinical characteristics table lists epistaxis among the mucocutaneous symptoms in two affected family members.
Menorrhagia OCCASIONAL HP:0000132 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Menorrhagia (HP:0000132). HP:0000132 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26280575 SUPPORT Human Clinical
"menorrhagia, postpartum hemorrhage, and spontaneous muscle"
From the bleeding history of the family A proband. The quote stops mid-phrase because the cached text is hard-wrapped at that point; the sentence continues "hematoma".
Other 5
Macrothrombocytopenia VERY_FREQUENT 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.
Show evidence (1 reference)
PMID:26280575 SUPPORT Human Clinical
"Patients harboring SLFN14 mutations displayed an analogous phenotype that consisted of moderate thrombocytopenia, enlarged platelets, decreased ATP secretion, and a dominant inheritance pattern."
Names both components in the same sentence and states they were shared across affected members; the source for this and the two phenotypes below.
Impaired Platelet Aggregation FREQUENT HP:0003540 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired platelet aggregation (HP:0003540). HP:0003540 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40794453 SUPPORT Human Clinical
"Initial functional investigation of the patients with SLFN14 mutations (V220D, K218E, and K219N) revealed mild macrothrombocytopenia; platelet function defects in response to adenosine diphosphate (ADP), collagen, and protease-activated receptor 1 (PAR1) peptide; and decreased adenosine..."
Names the three agonists to which the response is defective.
Reduced Platelet ATP Secretion VERY_FREQUENT Abnormal platelet ATP dense granule secretion HP:0030398 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal platelet ATP dense granule secretion (HP:0030398). HP:0030398 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26280575 SUPPORT Human Clinical
"Electron microscopy revealed a reduced number of dense granules in affected patients platelets, correlating with a decreased ATP secretion observed in lumiaggregometry studies."
The secretion defect together with the granule deficit that explains it.
Prolonged Bleeding After Surgery FREQUENT HP:0004846 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prolonged bleeding after surgery (HP:0004846). HP:0004846 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36790527 SUPPORT Human Clinical
"Bleeding after surgery and tooth extraction, oral cavity bleeding"
The clinical characteristics table records post-surgical and post-extraction bleeding for an affected family member.
Reduced Platelet Dense Granules VERY_FREQUENT HP:0033535 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced platelet dense granules (HP:0033535). HP:0033535 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26280575 SUPPORT Human Clinical
"Electron microscopy revealed a reduced number of dense granules in affected patients platelets, correlating with a decreased ATP secretion observed in lumiaggregometry studies."
Reports the reduced dense-granule count directly, and ties it to the ATP-secretion defect curated as a separate phenotype.
🧬

Genetic Associations

1
SLFN14 (Heterozygous SLFN14 variants cause this disease. The gene was established by exome sequencing of a national platelet-genotyping cohort, which found variants in 12 patients across 3 unrelated families with a shared and distinctive platelet phenotype - a strong founding design, because the families were ascertained on bleeding rather than on the gene. The variant spectrum is unusually concentrated. K218E, K219N and V220D occupy three consecutive residues; R223W is four residues away. All four sit in the RNA-binding cleft of the RNase domain. Variants have since been reported in the C-terminal helicase domain, which is a different region and appears to produce its effects by a different route; whether helicase-domain disease is the same entity as AAA-domain disease is not settled, and this entry does not assume it is. SLFN14 is expressed in megakaryocyte and erythroid precursors, which is what makes a general RNA-handling enzyme into a lineage-restricted disease gene.)
Gene: SLFN14 hgnc:32689 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLFN14 (hgnc:32689). hgnc:32689 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:26280575 SUPPORT Human Clinical
"We performed platelet phenotyping and whole-exome sequencing (WES) on all patients and identified mutations in schlafen 14 (SLFN14) in 12 patients from 3 unrelated families."
The gene-disease claim and the design that supports it.
PMID:42213791 SUPPORT Other
"SLFN14 is predominantly expressed in hematopoietic lineages, especially megakaryocyte (MK) and erythroid precursors"
The expression pattern that explains why a ubiquitous biochemical function produces a platelet-restricted disease.
💊

Medical Actions

3
Antifibrinolytic Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: tranexamic acid CHEBI:48669 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tranexamic acid (CHEBI:48669). CHEBI:48669 is a therapeutic agent from Chemical Entities of Biological Interest.
Tranexamic acid for mucosal bleeding and menorrhagia, on the general principle for inherited platelet function disorders that stabilising a formed clot compensates for a platelet that cannot amplify plug formation. No SLFN14-specific outcome data exist.
Mechanism Target:
Mucocutaneous Bleeding Diathesis — Acts on the clinical endpoint by preventing clot lysis. It does nothing about the granule or megakaryocyte defects upstream.
Platelet Transfusion
Action: platelet transfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is platelet transfusion (NCIT:C15366). NCIT:C15366 is a clinical intervention from the NCI Thesaurus. Ontology label: Platelet Transfusion NCIT:C15366
Reserved for major bleeding or surgical cover, as in other inherited platelet function disorders. Repeated transfusion carries alloimmunisation risk, which is the usual reason to prefer antifibrinolytics for mucosal bleeding.
Mechanism Target:
Platelet Dense Granule Deficiency — Supplies platelets with a normal granule complement, bypassing rather than correcting the patient's own secretion defect.
Genetic Counselling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Autosomal dominant inheritance with a 50% recurrence risk per pregnancy. Two points are worth raising specifically. First, bleeding severity is not predicted by the platelet count - the cited pedigree was followed for bleeding disproportionate to the degree of thrombocytopenia. Second, an apparently de novo case does not exclude parental transmission: maternal gonosomal mosaicism has been reported in SLFN14 (PMID:36237120, listed in references). No evidence item is attached to that second point because only the title of that report is retrievable, and a title is not a finding.
Show evidence (2 references)
PMID:42213791 SUPPORT Human Clinical
"Heterozygous missense mutations in SLFN14 cause an autosomal dominant form of IT, characterized by defective platelet function and excessive bleeding"
The inheritance pattern that sets the recurrence risk counselling is based on.
PMID:36790527 SUPPORT Human Clinical
"an extensive history of bleeding symptoms, which was disproportionate to the degree of TP"
Supports the counselling point that bleeding severity is not predicted by the platelet count.
🔬

Diagnosis

2
Platelet Function Testing with Lumiaggregometry
Aggregation and ATP-release testing is what separates this disease from an isolated thrombocytopenia. The pattern is reduced aggregation to ADP, collagen and PAR1 peptide together with reduced ATP secretion; electron microscopy showing a reduced dense-granule count supports it. The abnormalities are mild, so a normal-looking screen in a patient who bleeds should not close the question.
Show evidence (1 reference)
PMID:26280575 SUPPORT Human Clinical
"Electron microscopy revealed a reduced number of dense granules in affected patients platelets, correlating with a decreased ATP secretion observed in lumiaggregometry studies."
The two tests and the fact that their results correspond, which is what makes the pair diagnostically useful.
Exome or Platelet-Disorder Panel Sequencing
The disease was found by exome sequencing of a bleeding cohort and is diagnosed the same way. SLFN14 belongs on inherited-thrombocytopenia panels; the phenotype is not distinctive enough at the bedside to prompt single-gene testing.
Show evidence (1 reference)
PMID:26280575 SUPPORT Human Clinical
"We performed platelet phenotyping and whole-exome sequencing (WES) on all patients and identified mutations in schlafen 14 (SLFN14) in 12 patients from 3 unrelated families."
The diagnostic route that established the disease and remains the one that finds it.
📊

Prevalence

1
Worldwide
Cases In Literature Not yet documented
No prevalence estimate exists. The founding report identified 12 patients from 3 unrelated families within a 36-patient thrombocytopenia cohort recruited to a national platelet-genotyping study; subsequent reports have added single families. The disease is defined from case series rather than from any population sample.
Show evidence (1 reference)
PMID:26280575 SUPPORT Human Clinical
"We performed platelet phenotyping and whole-exome sequencing (WES) on all patients and identified mutations in schlafen 14 (SLFN14) in 12 patients from 3 unrelated families."
The size of the founding cohort and how it was ascertained, which is what bounds any statement about how common this disease is.
🐁

Animal Models

2
Megakaryocyte- and platelet-specific Slfn14 conditional knockout mouse (Slfn14 PF4-Cre)
A conditional knockout restricting Slfn14 deletion to the megakaryocyte and platelet lineage. It was built after the global knockin failed to model the human disease, and it succeeds where that model did not: these mice bleed.
Species
Mouse
Genotype
Slfn14 exons 2-3 deleted under PF4-Cre (megakaryocyte/platelet lineage)
Publication
PMID:40794453
Pathograph links
Mucocutaneous Bleeding Diathesis recapitulates fidelity: moderate Reproduces the bleeding phenotype with impaired platelet responses and delayed thrombus formation in vivo.
Limitations: A lineage-restricted complete knockout, whereas patients are heterozygous for missense alleles in every cell. It therefore models the consequence of losing SLFN14 in megakaryocytes, which is the dominant-negative account's prediction, and cannot speak to the altered-specificity account at all - a mutant enzyme with redirected activity is not the same thing as no enzyme.
Readouts
Bleeding tendency and thrombus formation by intravital imaging
Direction: INCREASED
Interpretation: Increased bleeding and delayed thrombus formation relative to Cre-negative littermates.
Show evidence (1 reference)
PMID:40794453 SUPPORT Model Organism
"Slfn14 PF4-Cre+ platelets displayed reduced platelet signaling to thrombin, reduced thrombin formation, increased bleeding tendency, and delayed thrombus formation as assessed by intravital imaging."
The in vivo bleeding and thrombus measurements behind this readout.
Show evidence (1 reference)
PMID:40794453 SUPPORT Model Organism
"Slfn14 PF4-Cre+ platelets displayed reduced platelet signaling to thrombin, reduced thrombin formation, increased bleeding tendency, and delayed thrombus formation as assessed by intravital imaging."
Supports treating this mouse as informative for the human bleeding phenotype.
Impaired Megakaryocyte Maturation and Proplatelet Formation recapitulates fidelity: moderate Fewer megakaryocytes in situ in the bone marrow, consistent with the megakaryocyte defect seen in patient-derived cultures.
Limitations: The mouse readout is megakaryocyte number in marrow; the human readout is proplatelet morphology in culture. They point the same way but are not the same measurement.
Readouts
Bone marrow megakaryocyte number in situ
Direction: DECREASED
Interpretation: Fewer megakaryocytes present in situ compared with control marrow.
Show evidence (1 reference)
PMID:40794453 SUPPORT Model Organism
"Moreover, fewer in situ bone marrow MKs were present compared with controls."
The marrow measurement behind this readout.
Show evidence (1 reference)
PMID:40794453 SUPPORT Model Organism
"Moreover, fewer in situ bone marrow MKs were present compared with controls."
Supports the model as informative for the megakaryocyte node.
Global Slfn14 K208N knockin mouse
The obvious model - a knockin of the mouse equivalent of the commonest patient variant, in every cell, matching the human genotype in kind. It does not model the human disease. Homozygotes have an erythroid phenotype with microcytic erythrocytosis and die in utero; heterozygotes have anaemia and splenomegaly. The platelet and bleeding phenotype that defines the human condition is absent. Curated because a negative result of this size constrains how the rest of the model evidence should be read, and because it is the reason the conditional knockout above exists.
Species
Mouse
Genotype
Slfn14 K208N knockin (mouse homologue of human K219N), global
Publication
PMID:40794453
Pathograph links
Mucocutaneous Bleeding Diathesis fails to recapitulate fidelity: low The genotype-matched model produces an erythroid disease rather than a bleeding disease.
Limitations: The divergence is attributed to species differences in which lineage depends most on SLFN14, but that explanation has not been tested. Until it is, the mouse cannot be used to argue either for or against a mechanism of the human bleeding phenotype, and no therapeutic inference should be drawn from it.
Show evidence (2 references)
PMID:40794453 REFUTE Model Organism
"Unlike the human SLFN14 K219N mutation, mice did not present with a major bleeding or platelet defect"
REFUTE against the proposition that this model reproduces the human phenotype, which is what FAILS_TO_RECAPITULATE asserts.
+ 1 more reference
{ }

Source YAML

click to show 
name: Platelet-type Bleeding Disorder 20
creation_date: "2026-08-26T16:00:00Z"
category: Mendelian
disease_term:
  preferred_term: platelet-type bleeding disorder 20
  term:
    id: MONDO:0014830
    label: platelet-type bleeding disorder 20
synonyms:
- BDPLT20
- SLFN14-related thrombocytopenia
- SLFN14-related macrothrombocytopenia
description: >-
  An autosomal dominant inherited thrombocytopenia caused by heterozygous variants in
  SLFN14, which encodes a ribosome-associated endoribonuclease. Patients have moderate
  thrombocytopenia with enlarged platelets, reduced dense granules and impaired ATP
  secretion, and a lifelong mucocutaneous bleeding tendency that is more troublesome than
  the modest laboratory abnormalities predict.

  The entry is organised around one fact that makes this disease unusual: the defect is in
  RNA turnover, not in any platelet receptor, granule protein or cytoskeletal component.
  SLFN14 sits on the ribosome and cleaves RNA. Megakaryocytes and erythroid precursors are
  where it is expressed, and a megakaryocyte in the act of shedding platelets is unusually
  dependent on getting ribosome and transcript turnover right - so a general defect in RNA
  handling lands on this one lineage and produces a bleeding disorder.

  Two things are curated here as unresolved rather than smoothed over.

  The first is the molecular mechanism, which has two incompatible accounts in the
  literature and no adjudicating experiment. On the older account the AAA-domain variants
  misfold, are degraded, and drag down the wild-type protein with them - a dominant
  negative that works by loss of SLFN14 activity. On the newer account the variants do not
  simply lose activity but redirect it, shifting the enzyme's preference from ribosomal RNA
  towards type II tRNAs and stalling translation. These predict opposite things about what
  a therapy should do, so the entry curates both as competing hypotheses and tags the
  causal edges accordingly.

  The second is that the obvious mouse model does not work. A knockin carrying the mouse
  equivalent of the commonest patient variant is not a bleeding model at all - it is an
  erythroid one. A later conditional knockout restricted to the megakaryocyte lineage does
  reproduce the bleeding phenotype. Both are curated, with the failure recorded as a
  failure.

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. The founding report identified 12 patients from 3
    unrelated families within a 36-patient thrombocytopenia cohort recruited to a national
    platelet-genotyping study; subsequent reports have added single families. The disease
    is defined from case series rather than from any population sample.
  evidence:
  - reference: PMID:26280575
    reference_title: "SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed platelet phenotyping and whole-exome sequencing (WES) on all patients
      and identified mutations in schlafen 14 (SLFN14) in 12 patients from 3 unrelated
      families.
    explanation: >-
      The size of the founding cohort and how it was ascertained, which is what bounds any
      statement about how common this disease is.

pathophysiology:

- name: Heterozygous SLFN14 Variant
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    A single SLFN14 allele carries a missense variant. The reported variants cluster
    tightly: K218E, K219N and V220D lie in three consecutive residues of the AAA domain,
    and R223W sits four residues further along, so the recurrent lesion is a small patch of
    the RNA-binding cleft rather than a scatter across the protein.

    Later reports have added variants in the C-terminal helicase domain, which is a
    different part of the protein and appears to act differently; those are noted on the
    gene entry rather than folded into this node.
  genetic_context:
    gene:
      preferred_term: SLFN14
      term:
        id: hgnc:32689
        label: SLFN14
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    description: >-
      Heterozygous missense variants segregating dominantly. Deliberately carries no
      `functional_impact_category`: the two competing mechanistic accounts below disagree
      on whether these alleles are loss-of-function or neomorphic, and choosing a value
      here would silently settle a question the literature has not.
  downstream:
  - target: Reduced SLFN14 Protein Abundance
    causal_link_type: DIRECT
    hypothesis_groups:
    - dominant_negative_degradation
    description: >-
      On the dominant-negative account, the substituted residues destabilise the fold and
      the protein is degraded post-translationally.
  - target: Redirected Endoribonuclease Substrate Specificity
    causal_link_type: DIRECT
    hypothesis_groups:
    - redirected_substrate_specificity
    description: >-
      On the altered-specificity account, the same substitutions sit in the RNA-binding
      cleft and change which RNAs the enzyme prefers rather than abolishing activity.
  evidence:
  - reference: PMID:26280575
    reference_title: "SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three heterozygous missense mutations were identified in affected family members and
      predicted to encode substitutions (K218E, K219N, and V220D) within an ATPase-AAA-4,
      GTP/ATP-binding region of SLFN14.
    explanation: >-
      The founding variants and the domain they fall in.
  - reference: PMID:42213791
    reference_title: "Type II tRNA cleavage by SLFN14 endoribonuclease variants linked to inherited thrombocytopenia drives global translational repression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      most IT-associated SLFN14 mutations, including K218E, K219N/E, V220D, and R223W,
      cluster within the RNA-binding cleft of the RNase domain
    explanation: >-
      Locates the recurrent variants structurally, which is the observation both
      mechanistic accounts start from.

- name: Reduced SLFN14 Protein Abundance
  role: mechanism
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    SLFN14 protein is markedly reduced in patient platelets and in cells transfected with
    the mutant construct. The reduction is post-translational: the variants partially
    misfold and are degraded, and because the mutant protein also oligomerises, the
    wild-type product made from the normal allele is dragged down with it. That is the
    proposed basis of dominance.

    Curated as ESTABLISHED because the measurement itself - less protein in patient
    platelets - is reproduced across reports. What is contested is whether losing protein
    is the whole story, which is the point of the competing node below.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  downstream:
  - target: Dysregulated Ribosomal RNA Turnover
    causal_link_type: DIRECT
    hypothesis_groups:
    - dominant_negative_degradation
    description: >-
      Less enzyme on the ribosome means less of the rRNA degradation it normally performs.
  evidence:
  - reference: PMID:26280575
    reference_title: "SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Endogenous SLFN14 expression was reduced in platelets from all patients, and mutant
      SLFN14 expression was markedly decreased compared with that of WT SLFN14 when
      overexpressed in transfected cells.
    explanation: >-
      The reduction measured in patients and reproduced in transfected cells.
  - reference: PMID:29678925
    reference_title: "Role of the novel endoribonuclease SLFN14 and its disease-causing mutations in ribosomal degradation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Compared to SLFN14 WT, expression of mutants is dramatically reduced as a result of
      post-translational degradation due to partial misfolding of the protein.
    explanation: >-
      Identifies the mechanism of the reduction as misfolding and degradation rather than
      reduced transcription.
  - reference: PMID:29678925
    reference_title: "Role of the novel endoribonuclease SLFN14 and its disease-causing mutations in ribosomal degradation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These findings could explain the dominant negative effect of heterozygous mutation on
      SLFN14 expression in patients' platelets.
    explanation: >-
      PARTIAL because the source frames the dominant-negative reading as an explanation its
      data could support rather than one it demonstrates.

- name: Redirected Endoribonuclease Substrate Specificity
  role: mechanism
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    The competing account. Rather than simply having less enzyme, patient variants have an
    enzyme that prefers different substrates: depletion of type II tRNAs is enhanced while
    cleavage of ribosomal RNA is reduced. That is a change in what the enzyme does, not
    only in how much of it there is.

    The distinction matters because the two accounts point opposite ways therapeutically.
    If the lesion is loss of SLFN14, restoring or stabilising the protein is the goal. If
    the lesion is redirected activity, restoring the protein would deliver more of the
    wrong enzymatic activity, and inhibiting it would be closer to right.

    PROVISIONAL: the work is in an overexpression cell system rather than in
    megakaryocytes or patient cells, and no experiment has yet distinguished the two
    accounts in the lineage that actually fails.
  molecular_functions:
  - preferred_term: RNA endonuclease activity
    term:
      id: GO:0004521
      label: RNA endonuclease activity
    modifier: ABNORMAL
  downstream:
  - target: Dysregulated Ribosomal RNA Turnover
    causal_link_type: DIRECT
    hypothesis_groups:
    - redirected_substrate_specificity
    description: >-
      Reduced rRNA cleavage is part of the same substrate shift, so this account reaches
      the shared downstream node too - by a different route and with the opposite sign on
      the tRNA arm.
  evidence:
  - reference: PMID:42213791
    reference_title: "Type II tRNA cleavage by SLFN14 endoribonuclease variants linked to inherited thrombocytopenia drives global translational repression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      IT-linked mutations alter SLFN14 RNA substrate specificity, enhancing depletion of
      type II tRNAs while reducing rRNA cleavage.
    explanation: >-
      The substrate shift itself, which is the whole of this node's claim.
  - reference: PMID:42213791
    reference_title: "Type II tRNA cleavage by SLFN14 endoribonuclease variants linked to inherited thrombocytopenia drives global translational repression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Most IT-associated mutations in the RNase domain reduce RNA cleavage activity in
      vitro
    explanation: >-
      PARTIAL and cited deliberately against this node: the same paper records the prior
      in-vitro consensus that these mutations reduce activity, which is what the
      dominant-negative account rests on.

- name: Dysregulated Ribosomal RNA Turnover
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    Whichever route reaches it, the shared consequence is that RNA turnover on the ribosome
    is no longer normal in this lineage. Patient platelets and mature megakaryocytes show
    signs of ribosomal RNA degradation, and the observation is lineage- and
    stage-restricted - it is absent from undifferentiated megakaryocytic cells and from
    granulocytes, which is the clearest evidence that the defect only bites where SLFN14
    normally works hardest.
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  cellular_components:
  - preferred_term: ribosome
    term:
      id: GO:0005840
      label: ribosome
  biological_processes:
  - preferred_term: rRNA catabolic process
    term:
      id: GO:0016075
      label: rRNA catabolic process
    modifier: ABNORMAL
  - preferred_term: tRNA decay
    term:
      id: GO:0016078
      label: tRNA decay
    modifier: ABNORMAL
  downstream:
  - target: Impaired Megakaryocyte Maturation and Proplatelet Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Typed with unknown intermediates deliberately. That disordered ribosomal RNA turnover
      precedes the megakaryocyte defect is established by the staging of the observations,
      but which transcripts fail to be made, and why proplatelet formation specifically is
      the step that breaks, has not been shown.
  evidence:
  - reference: PMID:36790527
    reference_title: "Ribosome dysfunction underlies SLFN14-related thrombocytopenia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      SLFN14-defective platelets and mature MK showed signs of rRNA degradation; however,
      this was absent in undifferentiated imMKCL cells and granulocytes.
    explanation: >-
      Both halves matter: the rRNA abnormality, and its restriction to mature cells of this
      lineage, which is what makes it a plausible explanation for a lineage-specific disease.
  - reference: PMID:29678925
    reference_title: "Role of the novel endoribonuclease SLFN14 and its disease-causing mutations in ribosomal degradation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we show that all SLFN14 variants colocalize with ribosomes and mediate rRNA
      endonucleolytic degradation.
    explanation: >-
      Places the enzyme and its variants on the ribosome, which is the physical basis for
      this node.
  - reference: PMID:42213791
    reference_title: "Type II tRNA cleavage by SLFN14 endoribonuclease variants linked to inherited thrombocytopenia drives global translational repression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This shift promotes ribosome stalling at codons decoded by type II tRNAs, triggering
      global translational arrest, stress signaling, and cell death.
    explanation: >-
      The translational consequence proposed by the altered-specificity account, which is
      why this node names tRNA decay alongside rRNA turnover.

- name: Impaired Megakaryocyte Maturation and Proplatelet Formation
  role: effector
  biological_scale: CELLULAR
  description: >-
    The cellular step at which the disease becomes a platelet disease. Megakaryocytes
    cultured from patients make fewer proplatelets, and the ones they make are shorter and
    less branched - a defect in the physical act of shedding platelets rather than in
    megakaryocyte number alone. Engineered megakaryocytic lines carrying the commonest
    patient variant reproduce it, together with disordered mitochondrial organisation.
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  biological_processes:
  - preferred_term: platelet formation
    term:
      id: GO:0030220
      label: platelet formation
    modifier: DECREASED
  - preferred_term: megakaryocyte differentiation
    term:
      id: GO:0030219
      label: megakaryocyte differentiation
    modifier: ABNORMAL
  downstream:
  - target: Macrothrombocytopenia
    causal_link_type: DIRECT
    description: >-
      Fewer and abnormally formed proplatelets yield fewer, larger circulating platelets.
  - target: Platelet Dense Granule Deficiency
    causal_link_type: DIRECT
    description: >-
      Platelets shed from a megakaryocyte that matured abnormally carry an abnormal granule
      complement.
  evidence:
  - reference: PMID:36790527
    reference_title: "Ribosome dysfunction underlies SLFN14-related thrombocytopenia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Megakaryocyte (MK) cultures from patients produce less proplatelets with shorter
      elongation and reduced ramification of their shafts.
    explanation: >-
      The proplatelet defect measured in patient-derived megakaryocytes, in the specific
      terms this node claims.
  - reference: PMID:36790527
    reference_title: "Ribosome dysfunction underlies SLFN14-related thrombocytopenia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      MK derived from heterozygous and homozygous SLFN14 K219N imMKCL and stem cells of
      blood from patients mainly presented with a defect in proplatelet formation and
      mitochondrial organization.
    explanation: >-
      Reproduces the defect in an engineered line carrying the patient variant, which
      controls for patient background.

- name: Macrothrombocytopenia
  role: outcome
  biological_scale: ORGANISM
  description: >-
    Moderately reduced platelet count with enlarged platelets. The combination is the
    diagnostic signature, and its moderate degree is part of why the disease is easy to
    under-rate: the count alone does not predict how much these patients bleed.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  downstream:
  - target: Mucocutaneous Bleeding Diathesis
    causal_link_type: DIRECT
    description: >-
      Fewer circulating platelets contribute to impaired primary haemostasis, alongside the
      secretion defect.
  evidence:
  - reference: PMID:26280575
    reference_title: "SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients harboring SLFN14 mutations displayed an analogous phenotype that consisted
      of moderate thrombocytopenia, enlarged platelets, decreased ATP secretion, and a
      dominant inheritance pattern.
    explanation: >-
      The full phenotype as first described, including the two components of this node and
      the inheritance pattern.

- name: Platelet Dense Granule Deficiency
  role: effector
  biological_scale: CELLULAR
  description: >-
    Electron microscopy shows fewer dense granules in patient platelets, and the deficit
    tracks with the measured loss of ATP secretion on lumiaggregometry - so this is a
    storage-pool defect with a matching functional readout rather than an isolated
    morphological observation.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: platelet degranulation
    term:
      id: GO:0002576
      label: platelet degranulation
    modifier: DECREASED
  downstream:
  - target: Mucocutaneous Bleeding Diathesis
    causal_link_type: DIRECT
    description: >-
      Failure of dense-granule release removes the ADP- and ATP-dependent amplification
      that recruits further platelets to a forming plug.
  evidence:
  - reference: PMID:26280575
    reference_title: "SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electron microscopy revealed a reduced number of dense granules in affected patients
      platelets, correlating with a decreased ATP secretion observed in lumiaggregometry
      studies.
    explanation: >-
      The structural deficit and the functional correlate reported together, which is what
      this node asserts.
  - reference: PMID:40794453
    reference_title: "Platelet-specific SLFN14 deletion causes macrothrombocytopenia and platelet dysfunction through dysregulated megakaryocyte and platelet gene expression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Initial functional investigation of the patients with SLFN14 mutations (V220D, K218E,
      and K219N) revealed mild macrothrombocytopenia; platelet function defects in response
      to adenosine diphosphate (ADP), collagen, and protease-activated receptor 1 (PAR1)
      peptide; and decreased adenosine triphosphate (ATP) secretion
    explanation: >-
      The agonist-specific aggregation defects alongside the secretion defect, restating the
      patient phenotype from a later review of the same families.

- name: Mucocutaneous Bleeding Diathesis
  role: outcome
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint: bruising, epistaxis, gum bleeding, heavy menstrual bleeding and
    excessive bleeding after trauma, dental work or delivery.

    Its most striking feature is disproportion. Every patient in the founding families had
    an obvious bleeding tendency while the laboratory abnormalities - platelet count,
    aggregation, secretion - were only mildly deranged. A normal-looking platelet panel
    does not exclude this diagnosis.
  evidence:
  - reference: PMID:36790527
    reference_title: "Ribosome dysfunction underlies SLFN14-related thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Obvious bleeding tendencies were reported in all patients whereas laboratory testing
      showed mild defects in platelet aggregation and adenosine triphosphate (ATP)
      secretion, and platelet counts that were mildly reduced.
    explanation: >-
      States the disproportion between symptoms and laboratory findings directly, which is
      the clinically load-bearing part of this node.

mechanistic_hypotheses:

- hypothesis_group_id: dominant_negative_degradation
  hypothesis_label: Dominant-negative loss of SLFN14 through misfolding and degradation
  status: CANONICAL
  description: >-
    The variants destabilise the protein, which is degraded post-translationally; because
    SLFN14 oligomerises, mutant subunits also reduce the wild-type pool, giving dominance
    from what is fundamentally a loss of enzyme. This is the older account and the one the
    measured reduction of SLFN14 in patient platelets most directly supports.
  evidence:
  - reference: PMID:29678925
    reference_title: "Role of the novel endoribonuclease SLFN14 and its disease-causing mutations in ribosomal degradation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Compared to SLFN14 WT, expression of mutants is dramatically reduced as a result of
      post-translational degradation due to partial misfolding of the protein.
    explanation: >-
      The degradation mechanism this hypothesis rests on.

- hypothesis_group_id: redirected_substrate_specificity
  hypothesis_label: Redirected endoribonuclease specificity towards type II tRNAs
  status: EMERGING
  description: >-
    The variants do not merely reduce activity but change which RNAs are cleaved, driving
    type II tRNA depletion, ribosome stalling and translational arrest. On this account the
    disease is caused by an activity the mutant enzyme has, not by one it lacks - which
    inverts the therapeutic goal.
  evidence:
  - reference: PMID:42213791
    reference_title: "Type II tRNA cleavage by SLFN14 endoribonuclease variants linked to inherited thrombocytopenia drives global translational repression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      IT-linked mutations alter SLFN14 RNA substrate specificity, enhancing depletion of
      type II tRNAs while reducing rRNA cleavage.
    explanation: >-
      The substrate shift that defines this hypothesis.

phenotypes:

- category: Hematologic
  name: Macrothrombocytopenia
  frequency: VERY_FREQUENT
  description: >-
    Moderately reduced platelet count with enlarged platelets, present in all affected
    members of the founding families.
  phenotype_term:
    preferred_term: Macrothrombocytopenia
    term:
      id: HP:0040185
      label: Macrothrombocytopenia
  evidence:
  - reference: PMID:26280575
    reference_title: "SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients harboring SLFN14 mutations displayed an analogous phenotype that consisted
      of moderate thrombocytopenia, enlarged platelets, decreased ATP secretion, and a
      dominant inheritance pattern.
    explanation: >-
      Names both components in the same sentence and states they were shared across
      affected members; the source for this and the two phenotypes below.

- category: Hematologic
  name: Impaired Platelet Aggregation
  frequency: FREQUENT
  description: >-
    Reduced aggregation to ADP, collagen and the PAR1 thrombin-receptor peptide. The
    defects are mild in degree, which is part of this disease's diagnostic difficulty.
  phenotype_term:
    preferred_term: Impaired platelet aggregation
    term:
      id: HP:0003540
      label: Impaired platelet aggregation
  evidence:
  - reference: PMID:40794453
    reference_title: "Platelet-specific SLFN14 deletion causes macrothrombocytopenia and platelet dysfunction through dysregulated megakaryocyte and platelet gene expression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Initial functional investigation of the patients with SLFN14 mutations (V220D, K218E,
      and K219N) revealed mild macrothrombocytopenia; platelet function defects in response
      to adenosine diphosphate (ADP), collagen, and protease-activated receptor 1 (PAR1)
      peptide; and decreased adenosine triphosphate (ATP) secretion
    explanation: >-
      Names the three agonists to which the response is defective.

- category: Hematologic
  name: Reduced Platelet ATP Secretion
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Decreased ATP release on lumiaggregometry, corresponding to the reduced dense-granule
    count on electron microscopy. This is the most discriminating laboratory finding in the
    disease.
  phenotype_term:
    preferred_term: Abnormal platelet ATP dense granule secretion
    term:
      id: HP:0030398
      label: Abnormal platelet ATP dense granule secretion
  evidence:
  - reference: PMID:26280575
    reference_title: "SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electron microscopy revealed a reduced number of dense granules in affected patients
      platelets, correlating with a decreased ATP secretion observed in lumiaggregometry
      studies.
    explanation: >-
      The secretion defect together with the granule deficit that explains it.

- category: Hematologic
  name: Excessive Mucocutaneous Bleeding
  frequency: VERY_FREQUENT
  severity: MODERATE
  description: >-
    Bruising, epistaxis, gum bleeding and heavy menstrual bleeding, with excessive bleeding
    after trauma and procedures. Present in every reported patient and out of proportion to
    the laboratory abnormalities.
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:36790527
    reference_title: "Ribosome dysfunction underlies SLFN14-related thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Obvious bleeding tendencies were reported in all patients whereas laboratory testing
      showed mild defects in platelet aggregation and adenosine triphosphate (ATP)
      secretion, and platelet counts that were mildly reduced.
    explanation: >-
      Establishes that the bleeding tendency was universal and disproportionate to the
      laboratory findings.

- category: Hematologic
  name: Epistaxis
  frequency: FREQUENT
  description: >-
    Spontaneous nosebleeds, reported from childhood in the founding cohort and recorded as a
    presenting mucocutaneous symptom in a later family.
  phenotype_term:
    preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
  evidence:
  - reference: PMID:26280575
    reference_title: "SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a history of spontaneous epistaxis starting in childhood
    explanation: >-
      Records spontaneous childhood-onset epistaxis in an affected member of the founding
      cohort.
  - reference: PMID:36790527
    reference_title: "Ribosome dysfunction underlies SLFN14-related thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mucocutaneous bleeding symptoms (epistaxis, hematomas)
    explanation: >-
      The clinical characteristics table lists epistaxis among the mucocutaneous symptoms in
      two affected family members.

- category: Hematologic
  name: Prolonged Bleeding After Surgery
  frequency: FREQUENT
  description: >-
    Excessive bleeding provoked by surgery and dental extraction. This is the manifestation
    that most often brings an otherwise mildly affected carrier to attention, since the
    resting platelet count can be only marginally reduced.
  phenotype_term:
    preferred_term: Prolonged bleeding after surgery
    term:
      id: HP:0004846
      label: Prolonged bleeding after surgery
  evidence:
  - reference: PMID:36790527
    reference_title: "Ribosome dysfunction underlies SLFN14-related thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bleeding after surgery and tooth extraction, oral cavity bleeding
    explanation: >-
      The clinical characteristics table records post-surgical and post-extraction bleeding
      for an affected family member.

- category: Hematologic
  name: Menorrhagia
  frequency: OCCASIONAL
  description: >-
    Heavy menstrual bleeding in affected women, reported in the founding cohort alongside
    postpartum haemorrhage. Curated as OCCASIONAL because it is documented for individual
    probands rather than counted across the cohort.
  phenotype_term:
    preferred_term: Menorrhagia
    term:
      id: HP:0000132
      label: Menorrhagia
  evidence:
  - reference: PMID:26280575
    reference_title: "SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      menorrhagia, postpartum hemorrhage, and spontaneous muscle
    explanation: >-
      From the bleeding history of the family A proband. The quote stops mid-phrase because
      the cached text is hard-wrapped at that point; the sentence continues "hematoma".

- category: Hematologic
  name: Reduced Platelet Dense Granules
  frequency: VERY_FREQUENT
  description: >-
    Fewer dense granules per platelet on whole-mount electron microscopy - the structural
    storage-pool defect underlying the secretion abnormality, distinct from the functional
    ATP-secretion readout curated separately above.
  phenotype_term:
    preferred_term: Reduced platelet dense granules
    term:
      id: HP:0033535
      label: Reduced platelet dense granules
  evidence:
  - reference: PMID:26280575
    reference_title: "SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electron microscopy revealed a reduced number of dense granules in affected patients
      platelets, correlating with a decreased ATP secretion observed in lumiaggregometry
      studies.
    explanation: >-
      Reports the reduced dense-granule count directly, and ties it to the ATP-secretion
      defect curated as a separate phenotype.

genetic:

- name: SLFN14
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: SLFN14
    term:
      id: hgnc:32689
      label: SLFN14
  association: >-
    Heterozygous SLFN14 variants cause this disease. The gene was established by exome
    sequencing of a national platelet-genotyping cohort, which found variants in 12
    patients across 3 unrelated families with a shared and distinctive platelet phenotype -
    a strong founding design, because the families were ascertained on bleeding rather than
    on the gene.

    The variant spectrum is unusually concentrated. K218E, K219N and V220D occupy three
    consecutive residues; R223W is four residues away. All four sit in the RNA-binding
    cleft of the RNase domain. Variants have since been reported in the C-terminal helicase
    domain, which is a different region and appears to produce its effects by a different
    route; whether helicase-domain disease is the same entity as AAA-domain disease is not
    settled, and this entry does not assume it is.

    SLFN14 is expressed in megakaryocyte and erythroid precursors, which is what makes a
    general RNA-handling enzyme into a lineage-restricted disease gene.
  evidence:
  - reference: PMID:26280575
    reference_title: "SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed platelet phenotyping and whole-exome sequencing (WES) on all patients
      and identified mutations in schlafen 14 (SLFN14) in 12 patients from 3 unrelated
      families.
    explanation: >-
      The gene-disease claim and the design that supports it.
  - reference: PMID:42213791
    reference_title: "Type II tRNA cleavage by SLFN14 endoribonuclease variants linked to inherited thrombocytopenia drives global translational repression."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SLFN14 is predominantly expressed in hematopoietic lineages, especially megakaryocyte
      (MK) and erythroid precursors
    explanation: >-
      The expression pattern that explains why a ubiquitous biochemical function produces a
      platelet-restricted disease.

inheritance:

- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    A single variant allele is sufficient, with dominant segregation in all three founding
    families. The mechanism of dominance is exactly what the two competing hypotheses
    disagree about: interference with the wild-type product on one account, an acquired
    activity on the other.
  evidence:
  - reference: PMID:42213791
    reference_title: "Type II tRNA cleavage by SLFN14 endoribonuclease variants linked to inherited thrombocytopenia drives global translational repression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous missense mutations in SLFN14 cause an autosomal dominant form of IT,
      characterized by defective platelet function and excessive bleeding
    explanation: >-
      States the inheritance pattern and the phenotype it transmits.

animal_models:

- name: Megakaryocyte- and platelet-specific Slfn14 conditional knockout mouse (Slfn14 PF4-Cre)
  species: Mouse
  genotype: Slfn14 exons 2-3 deleted under PF4-Cre (megakaryocyte/platelet lineage)
  publication: PMID:40794453
  description: >-
    A conditional knockout restricting Slfn14 deletion to the megakaryocyte and platelet
    lineage. It was built after the global knockin failed to model the human disease, and
    it succeeds where that model did not: these mice bleed.
  modeled_mechanisms:
  - target: Mucocutaneous Bleeding Diathesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the bleeding phenotype with impaired platelet responses and delayed
      thrombus formation in vivo.
    limitations: >-
      A lineage-restricted complete knockout, whereas patients are heterozygous for missense
      alleles in every cell. It therefore models the consequence of losing SLFN14 in
      megakaryocytes, which is the dominant-negative account's prediction, and cannot speak
      to the altered-specificity account at all - a mutant enzyme with redirected activity
      is not the same thing as no enzyme.
    readouts:
    - name: Bleeding tendency and thrombus formation by intravital imaging
      target: Mucocutaneous Bleeding Diathesis
      direction: INCREASED
      interpretation: >-
        Increased bleeding and delayed thrombus formation relative to Cre-negative
        littermates.
      evidence:
      - reference: PMID:40794453
        reference_title: "Platelet-specific SLFN14 deletion causes macrothrombocytopenia and platelet dysfunction through dysregulated megakaryocyte and platelet gene expression."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Slfn14 PF4-Cre+ platelets displayed reduced platelet signaling to thrombin,
          reduced thrombin formation, increased bleeding tendency, and delayed thrombus
          formation as assessed by intravital imaging.
        explanation: >-
          The in vivo bleeding and thrombus measurements behind this readout.
    evidence:
    - reference: PMID:40794453
      reference_title: "Platelet-specific SLFN14 deletion causes macrothrombocytopenia and platelet dysfunction through dysregulated megakaryocyte and platelet gene expression."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Slfn14 PF4-Cre+ platelets displayed reduced platelet signaling to thrombin, reduced
        thrombin formation, increased bleeding tendency, and delayed thrombus formation as
        assessed by intravital imaging.
      explanation: >-
        Supports treating this mouse as informative for the human bleeding phenotype.
  - target: Impaired Megakaryocyte Maturation and Proplatelet Formation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Fewer megakaryocytes in situ in the bone marrow, consistent with the megakaryocyte
      defect seen in patient-derived cultures.
    limitations: >-
      The mouse readout is megakaryocyte number in marrow; the human readout is proplatelet
      morphology in culture. They point the same way but are not the same measurement.
    readouts:
    - name: Bone marrow megakaryocyte number in situ
      target: Impaired Megakaryocyte Maturation and Proplatelet Formation
      direction: DECREASED
      interpretation: >-
        Fewer megakaryocytes present in situ compared with control marrow.
      evidence:
      - reference: PMID:40794453
        reference_title: "Platelet-specific SLFN14 deletion causes macrothrombocytopenia and platelet dysfunction through dysregulated megakaryocyte and platelet gene expression."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Moreover, fewer in situ bone marrow MKs were present compared with controls.
        explanation: >-
          The marrow measurement behind this readout.
    evidence:
    - reference: PMID:40794453
      reference_title: "Platelet-specific SLFN14 deletion causes macrothrombocytopenia and platelet dysfunction through dysregulated megakaryocyte and platelet gene expression."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Moreover, fewer in situ bone marrow MKs were present compared with controls.
      explanation: >-
        Supports the model as informative for the megakaryocyte node.

- name: Global Slfn14 K208N knockin mouse
  species: Mouse
  genotype: Slfn14 K208N knockin (mouse homologue of human K219N), global
  publication: PMID:40794453
  description: >-
    The obvious model - a knockin of the mouse equivalent of the commonest patient variant,
    in every cell, matching the human genotype in kind. It does not model the human disease.
    Homozygotes have an erythroid phenotype with microcytic erythrocytosis and die in utero;
    heterozygotes have anaemia and splenomegaly. The platelet and bleeding phenotype that
    defines the human condition is absent.

    Curated because a negative result of this size constrains how the rest of the model
    evidence should be read, and because it is the reason the conditional knockout above
    exists.
  modeled_mechanisms:
  - target: Mucocutaneous Bleeding Diathesis
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The genotype-matched model produces an erythroid disease rather than a bleeding
      disease.
    limitations: >-
      The divergence is attributed to species differences in which lineage depends most on
      SLFN14, but that explanation has not been tested. Until it is, the mouse cannot be
      used to argue either for or against a mechanism of the human bleeding phenotype, and
      no therapeutic inference should be drawn from it.
    evidence:
    - reference: PMID:40794453
      reference_title: "Platelet-specific SLFN14 deletion causes macrothrombocytopenia and platelet dysfunction through dysregulated megakaryocyte and platelet gene expression."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Unlike the human SLFN14 K219N mutation, mice did not present with a major bleeding
        or platelet defect
      explanation: >-
        REFUTE against the proposition that this model reproduces the human phenotype, which
        is what FAILS_TO_RECAPITULATE asserts.
    - reference: PMID:40794453
      reference_title: "Platelet-specific SLFN14 deletion causes macrothrombocytopenia and platelet dysfunction through dysregulated megakaryocyte and platelet gene expression."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The data showed that homozygous Slfn14 K208N resulted in a largely erythrocyte
        phenotype with microcytic erythrocytosis, with homozygous embryonic lethality beyond
        day 16.5 in utero.
      explanation: >-
        What the model produces instead, which is the substance of the mismatch.

diagnosis:

- name: Platelet Function Testing with Lumiaggregometry
  description: >-
    Aggregation and ATP-release testing is what separates this disease from an isolated
    thrombocytopenia. The pattern is reduced aggregation to ADP, collagen and PAR1 peptide
    together with reduced ATP secretion; electron microscopy showing a reduced dense-granule
    count supports it. The abnormalities are mild, so a normal-looking screen in a patient
    who bleeds should not close the question.
  evidence:
  - reference: PMID:26280575
    reference_title: "SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electron microscopy revealed a reduced number of dense granules in affected patients
      platelets, correlating with a decreased ATP secretion observed in lumiaggregometry
      studies.
    explanation: >-
      The two tests and the fact that their results correspond, which is what makes the pair
      diagnostically useful.

- name: Exome or Platelet-Disorder Panel Sequencing
  description: >-
    The disease was found by exome sequencing of a bleeding cohort and is diagnosed the same
    way. SLFN14 belongs on inherited-thrombocytopenia panels; the phenotype is not
    distinctive enough at the bedside to prompt single-gene testing.
  evidence:
  - reference: PMID:26280575
    reference_title: "SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed platelet phenotyping and whole-exome sequencing (WES) on all patients
      and identified mutations in schlafen 14 (SLFN14) in 12 patients from 3 unrelated
      families.
    explanation: >-
      The diagnostic route that established the disease and remains the one that finds it.

treatments:

- name: Antifibrinolytic Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Tranexamic acid for mucosal bleeding and menorrhagia, on the general principle for
    inherited platelet function disorders that stabilising a formed clot compensates for a
    platelet that cannot amplify plug formation. No SLFN14-specific outcome data exist.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tranexamic acid
      term:
        id: CHEBI:48669
        label: tranexamic acid
  target_mechanisms:
  - target: Mucocutaneous Bleeding Diathesis
    description: >-
      Acts on the clinical endpoint by preventing clot lysis. It does nothing about the
      granule or megakaryocyte defects upstream.
  notes: >-
    Carries no evidence item deliberately. The cited SLFN14 literature reports no treatment
    outcomes; this is standard practice for the disease class, and attaching a quote from a
    paper about a different disorder would misrepresent it.

- name: Platelet Transfusion
  therapeutic_modality: CELL_THERAPY
  description: >-
    Reserved for major bleeding or surgical cover, as in other inherited platelet function
    disorders. Repeated transfusion carries alloimmunisation risk, which is the usual reason
    to prefer antifibrinolytics for mucosal bleeding.
  treatment_term:
    preferred_term: platelet transfusion
    term:
      id: NCIT:C15366
      label: Platelet Transfusion
  target_mechanisms:
  - target: Platelet Dense Granule Deficiency
    description: >-
      Supplies platelets with a normal granule complement, bypassing rather than correcting
      the patient's own secretion defect.
  notes: >-
    No evidence item, for the same reason as above: no SLFN14-specific transfusion outcome
    data are published.

- name: Genetic Counselling
  therapeutic_modality: BEHAVIORAL
  description: >-
    Autosomal dominant inheritance with a 50% recurrence risk per pregnancy. Two points are
    worth raising specifically. First, bleeding severity is not predicted by the platelet
    count - the cited pedigree was followed for bleeding disproportionate to the degree of
    thrombocytopenia. Second, an apparently de novo case does not exclude parental
    transmission: maternal gonosomal mosaicism has been reported in SLFN14 (PMID:36237120,
    listed in references). No evidence item is attached to that second point because only
    the title of that report is retrievable, and a title is not a finding.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:42213791
    reference_title: "Type II tRNA cleavage by SLFN14 endoribonuclease variants linked to inherited thrombocytopenia drives global translational repression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous missense mutations in SLFN14 cause an autosomal dominant form of IT,
      characterized by defective platelet function and excessive bleeding
    explanation: >-
      The inheritance pattern that sets the recurrence risk counselling is based on.
  - reference: PMID:36790527
    reference_title: "Ribosome dysfunction underlies SLFN14-related thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an extensive history of bleeding symptoms, which was disproportionate to the degree of
      TP
    explanation: >-
      Supports the counselling point that bleeding severity is not predicted by the platelet
      count.

discussions:

- discussion_id: controversy_lof_versus_neomorph
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced SLFN14 Protein Abundance
  - pathophysiology#Redirected Endoribonuclease Substrate Specificity
  - mechanistic_hypotheses#dominant_negative_degradation
  - mechanistic_hypotheses#redirected_substrate_specificity
  prompt: >-
    Do SLFN14 variants cause disease by removing enzyme activity, or by redirecting it onto
    the wrong substrates?
  rationale: >-
    Both accounts are supported by real data and they are not compatible.

    The loss account has the more direct clinical observation behind it: SLFN14 protein is
    markedly reduced in patient platelets, the reduction is explained by misfolding and
    post-translational degradation, and oligomerisation gives a route to dominance. Most
    disease-associated RNase-domain mutations reduce cleavage activity in vitro.

    The redirection account explains something the loss account does not. If the lesion were
    simply less enzyme, a heterozygote with roughly half-normal activity should be mildly
    affected in proportion; instead these variants shift which RNAs are cleaved, deplete
    type II tRNAs, stall ribosomes and trigger cell death - an active injury rather than a
    shortfall.

    The distinction is not academic. If the disease is loss of SLFN14, a therapy should
    restore or stabilise the protein. If it is redirected activity, restoring the protein
    delivers more of the harmful activity and inhibition is the rational goal. A therapeutic
    programme cannot be designed until this is settled.

    Neither body of work has been done in megakaryocytes. The degradation studies used
    transfected cell lines; the substrate-specificity study used HEK293T overexpression. The
    lineage where the disease actually happens has not been used to test either.
  proposed_experiments:
  - experiment_id: slfn14_mechanism_discrimination_in_mk
    name: Substrate profiling and rescue in patient-genotype megakaryocytes
    description: >-
      In megakaryocytic lines carrying a patient variant at the endogenous locus, measure
      SLFN14 protein level and profile tRNA and rRNA cleavage in the same cells, then test
      two interventions against proplatelet formation: raising wild-type SLFN14, and
      inhibiting SLFN14 catalytic activity.
    would_support:
    - mechanistic_hypotheses#redirected_substrate_specificity
    would_refute:
    - mechanistic_hypotheses#dominant_negative_degradation
    supporting_outcome:
    - >-
      Type II tRNAs are selectively depleted in patient-genotype megakaryocytes and
      catalytic inhibition rescues proplatelet formation while adding wild-type protein does
      not, which would establish redirected activity as the operative mechanism.
    refuting_outcome:
    - >-
      Adding wild-type SLFN14 rescues proplatelet formation and no selective tRNA depletion
      is detectable, which would support simple dominant-negative loss and retire the
      redirection account for this lineage.

- discussion_id: mismatch_mouse_lineage
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - animal_models#Global Slfn14 K208N knockin mouse
  - pathophysiology#Impaired Megakaryocyte Maturation and Proplatelet Formation
  prompt: >-
    Why does a knockin of the mouse equivalent of the commonest patient variant produce an
    erythroid disease in mice and a platelet disease in humans?
  rationale: >-
    This is a mismatch rather than a gap: the model exists, the result is clear, and it
    disagrees with the patients. Homozygous K208N mice have microcytic erythrocytosis and die
    in utero; heterozygotes have anaemia and splenomegaly. Neither shows the bleeding or
    platelet defect that defines the human disease.

    SLFN14 is expressed in both megakaryocyte and erythroid precursors, so a shift in which
    of the two is rate-limiting between species is a plausible explanation - and it is only
    that. It has not been tested.

    It matters for how the rest of the model evidence is read. The conditional knockout that
    does reproduce bleeding was made by deleting the gene in the megakaryocyte lineage, which
    guarantees a megakaryocyte phenotype by construction. It shows what losing SLFN14 in
    megakaryocytes does; it does not show that the patient variants do that.
  proposed_experiments:
  - experiment_id: slfn14_lineage_dependence_cross_species
    name: Comparative lineage dependence on SLFN14 in mouse and human progenitors
    description: >-
      Quantify SLFN14 expression and the consequences of its loss in matched megakaryocyte
      and erythroid progenitors from mouse and human, and test whether the mouse erythroid
      phenotype converts to a platelet phenotype when the human expression ratio is imposed.
    would_support:
    - pathophysiology#Impaired Megakaryocyte Maturation and Proplatelet Formation
    supporting_outcome:
    - >-
      Mouse erythroid progenitors depend on SLFN14 more than their human counterparts while
      the megakaryocyte dependence is reversed, which would make the mismatch a species
      artefact and leave the human megakaryocyte mechanism transferable.
    refuting_outcome:
    - >-
      Lineage dependence is comparable across species, which would point instead to the
      variant acting differently on the mouse protein and would undercut using any mouse
      model to reason about the human variants.

notes: >-
  Scope and naming. This entry is the OMIM-numbered entity BDPLT20, also written in the
  literature as SLFN14-related thrombocytopenia. It is one of the numbered platelet-type
  bleeding disorders, and is curated as its own entry following the convention already
  established in this knowledge base for that series.

  Domain heterogeneity. The AAA/RNase-domain variants described here are the well
  characterised ones. Helicase-domain variants have since been reported and appear to affect
  different downstream pathways; whether they represent the same disease is unresolved, and
  this entry deliberately does not extend its mechanism nodes to cover them.

  What SLFN14 does elsewhere. SLFN14 is also an interferon-inducible antiviral RNase acting
  against several viruses. That is a function of the normal protein in other cell types and
  has no established bearing on this disease; it is noted because a literature search on the
  gene returns a great deal of virology that is not about bleeding.

  Term binding. The structural and functional halves of the storage-pool defect are curated
  as separate phenotypes: the reduced granule count on electron microscopy against
  HP:0033535 (Reduced platelet dense granules), and the ATP-secretion deficit measured by
  lumiaggregometry against HP:0030398. An earlier draft of this entry asserted that HPO had
  no term for the granule count itself; that was wrong, and HP:0033535 is the correct
  binding.

references:
- reference: PMID:26280575
  title: "SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects."
- reference: PMID:36237120
  title: "Maternal gonosomal mosaicism in rare autosomal dominant SLFN14-related thrombocytopenia."
- reference: PMID:29678925
  title: "Role of the novel endoribonuclease SLFN14 and its disease-causing mutations in ribosomal degradation."
- reference: PMID:36790527
  title: "Ribosome dysfunction underlies SLFN14-related thrombocytopenia."
- reference: PMID:40794453
  title: "Platelet-specific SLFN14 deletion causes macrothrombocytopenia and platelet dysfunction through dysregulated megakaryocyte and platelet gene expression."
- reference: PMID:42213791
  title: "Type II tRNA cleavage by SLFN14 endoribonuclease variants linked to inherited thrombocytopenia drives global translational repression."
📚

References & Deep Research

References

6
PMID:26280575
SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects.
No top-level findings curated for this source.
PMID:36237120
Maternal gonosomal mosaicism in rare autosomal dominant SLFN14-related thrombocytopenia.
No top-level findings curated for this source.
PMID:29678925
Role of the novel endoribonuclease SLFN14 and its disease-causing mutations in ribosomal degradation.
No top-level findings curated for this source.
PMID:36790527
Ribosome dysfunction underlies SLFN14-related thrombocytopenia.
No top-level findings curated for this source.
PMID:40794453
Platelet-specific SLFN14 deletion causes macrothrombocytopenia and platelet dysfunction through dysregulated megakaryocyte and platelet gene expression.
No top-level findings curated for this source.
PMID:42213791
Type II tRNA cleavage by SLFN14 endoribonuclease variants linked to inherited thrombocytopenia drives global translational repression.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
Platelet-type Bleeding Disorder 20 (BDPLT20) — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 31 citations 2026-08-26T16:19:28.421668

Platelet-type Bleeding Disorder 20 (BDPLT20) — Comprehensive Research Report

1. Disease Information

Overview: Platelet-type Bleeding Disorder 20 (BDPLT20), also known as SLFN14-related thrombocytopenia, is a rare autosomal dominant inherited platelet disorder characterized by moderate thrombocytopenia (often with macrothrombocytes/enlarged platelets), impaired platelet secretion (particularly ATP release from dense granules), and a lifelong mucocutaneous bleeding tendency. It was first delineated as a distinct clinical entity by Fletcher et al. in 2015, who identified heterozygous missense mutations in the SLFN14 (Schlafen family member 14) gene as the molecular cause (JCI, PMID: 26280575).

Key Identifiers: - OMIM: #616913 — BLEEDING DISORDER, PLATELET-TYPE, 20; BDPLT20 (OMIM entry) - Gene locus (OMIM): 614958 — SCHLAFEN FAMILY, MEMBER 14; SLFN14 (OMIM entry) - HGNC: SLFN14, HGNC:32689 - MONDO: MONDO:0014830 (ClinGen curation page) - MedGen: C4310797 (NCBI MedGen) - Orphanet: ORPHA:466806 — SLFN14-related thrombocytopenia (Orphanet gene page) - NCBI GTR:* Genetic Testing Registry entry - Chromosomal location: 17q12

Synonyms: SLFN14-related thrombocytopenia; SLFN14-related macrothrombocytopenia; Inherited thrombocytopenia due to SLFN14 mutation.

Evidence basis: Nearly all published knowledge derives from individual patient/family case series and case reports (aggregated across roughly a dozen kindreds worldwide identified via next-generation sequencing in bleeding-disorder cohorts such as the UK GAPP [Genotyping and Phenotyping of Platelets] study), supplemented by mechanistic cell-line and mouse-model studies. There is no large-scale disease registry or population-level epidemiological dataset — this is characteristic of an ultra-rare monogenic platelet disorder.

2. Etiology

Disease Causal Factor: BDPLT20 is caused by heterozygous, dominantly acting missense (and at least one frameshift) mutations in SLFN14, which encodes an RNA endoribonuclease. This is a purely genetic/monogenic disorder — no environmental or infectious causal factors are described.

Genetic Risk Factors: - Fletcher et al. (2015) identified three heterozygous missense mutations — p.K218E, p.K219N, p.V220D — clustered within an ATPase-associated-with-diverse-cellular-activities (AAA) GTP/ATP-binding domain, in 12 patients from 3 unrelated families (PMID: 26280575). - Marconi et al. (2016) reported an additional heterozygous missense mutation in an Italian family — Thromb Haemost. 2016;115(5):1076-9 (PMID: 26769223). - A p.R223W substitution in the AAA domain, near previously reported residues, has also been described. - A novel c.1766T>C (p.L589S) variant in the helicase domain was reported in 2025 in twin brothers with severe thrombocytopenia and abnormal megakaryocyte maturation — notably, the variant showed incomplete penetrance: "the mother and maternal grandmother showed no abnormal phenotypes" despite carrying the variant (EJHaem 2025, PMID: 40521396). - A frameshift variant, T853fs, was identified in the helicase domain in patients with inherited macrothrombocytopenia, distinct in mechanism from the AAA-domain missense variants (Mol Ther Nucleic Acids 2025, PMID: 40510593). - A novel variant was reported in a 17-year-old female with severe macrothrombocytopenia and giant platelets (>10 μm) (Orphanet J Rare Dis 2023, PMID: 37041648). - Maternal gonosomal (germline) mosaicism has been documented as a mechanism of transmission in at least one family, relevant to genetic counseling and recurrence-risk estimation (Br J Haematol 2022, PMID: 36237120). - Across the literature, five heterozygous single-nucleotide substitutions have been reported, producing four distinct amino-acid changes (p.K218E, p.K219N, p.V220D, p.R223W), plus the more recently identified helicase-domain missense and frameshift variants.

Risk Factor Databases: Because this is a single-gene autosomal dominant disorder with no described modifier genes, environmental risk factors, or GWAS-identified susceptibility loci, the standard PheGenI/GWAS Catalog/CTD resources return no relevant hits — risk is essentially binary (carrying a pathogenic SLFN14 variant vs. not), modulated somewhat by variant location (AAA-ATPase domain vs. helicase domain) and possibly by mosaicism/penetrance effects.

Protective Factors: None reported in the literature; there are no known protective genetic variants or environmental protective factors specific to BDPLT20.

Gene-Environment Interactions: Not described; this is a purely cell-intrinsic, monogenic disorder of megakaryocyte/platelet biology.

3. Phenotypes

Clinical/hemorrhagic phenotypes (symptoms and signs)

Based on the original description of a 9-member, 3-generation family (proband: 31-year-old woman) and subsequent case series:

Phenotype Suggested HPO term Notes
Easy/frequent bruising HP:0000978 (Bruising susceptibility) Common presenting feature
Prolonged bleeding from minor wounds HP:0031093 (Post-traumatic bleeding) / HP:0025153
Menorrhagia / heavy menstrual bleeding HP:0000132 (Menorrhagia) Frequently reported in adult females; managed with tranexamic acid in at least one reported case
Postpartum hemorrhage HP:0011024 (Abnormality of the gastrointestinal tract) — more precisely, no exact HPO term for PPH exists; often noted as free text
Spontaneous muscle hematoma HP:0031364 (Muscle hemorrhage)
Epistaxis (spontaneous) HP:0000421 (Epistaxis)
Gum bleeding HP:0000225 (Gingival bleeding)
Bleeding after tooth extraction HP:0031093
Severe hemorrhagic syndrome (in some patients) — One 17-year-old patient had severe bleeding requiring intervention

Laboratory/hematologic abnormalities

  • Thrombocytopenia (HP:0001873) — typically "moderate" (platelet counts variably reduced, not typically in the severe <20×10⁹/L range in most reported families, though severe cases have been described in twin patients with the L589S variant)
  • Macrothrombocytes / enlarged platelets (HP:0011877, Abnormal platelet volume) — a hallmark feature; one case report described "heterogeneity in cell size, including giant forms over 10 μm (normal size 1–5 μm) in diameter, with vacuolization" (PMID: 37041648)
  • Reduced platelet dense granules — electron microscopy shows decreased dense-granule number
  • Impaired ATP secretion on lumiaggregometry
  • Reduced platelet aggregation in response to ADP, collagen, and PAR1 (thrombin-receptor peptide), with normal response to arachidonic acid
  • Impaired calcium mobilization and thrombus formation in functional assays (PMID: 37041648)
  • Abnormal megakaryocyte maturation/accumulation in bone marrow in severe pediatric cases (PMID: 40521396)

Phenotype characteristics

  • Onset: Lifelong/congenital — bleeding tendency present from an early age; some cases identified in childhood/adolescence (e.g., the 17-year-old proband), others diagnosed in adulthood after gynecologic or surgical bleeding.
  • Severity: Variable — ranges from mild bruising/heavy menses to severe hemorrhagic syndromes in some patients (notably those with helicase-domain variants).
  • Progression: Generally stable/chronic rather than progressive, though bleeding episodes are episodic (triggered by trauma, surgery, menstruation, childbirth).
  • Penetrance: Incomplete in at least one reported kindred (asymptomatic carriers of the p.L589S variant), indicating that BDPLT20, unlike the classic AAA-domain-mutation families, may show variable expressivity/incomplete penetrance depending on variant location.

Quality of life impact

No disease-specific QOL instrument data were identified in the literature (no EQ-5D/SF-36 studies specific to BDPLT20 were found); qualitatively, recurrent menorrhagia, easy bruising, and bleeding after minor trauma or dental/surgical procedures are described as impacting daily life and requiring proactive hemostatic management (e.g., prophylactic interventions before procedures).

4. Genetic/Molecular Information

Causal Gene: SLFN14 (Schlafen family member 14), HGNC:32689, chromosome 17q12, OMIM *614958.

Variant spectrum (reported to date):

Variant (protein) Domain Source
p.K218E AAA-ATPase Fletcher et al. 2015 (PMID: 26280575)
p.K219N AAA-ATPase Fletcher et al. 2015 (PMID: 26280575); modeled in mice as K208N
p.V220D AAA-ATPase Fletcher et al. 2015 (PMID: 26280575)
p.R223W AAA-ATPase Later report, near the K218/K219/V220 cluster
Marconi variant (missense) — Marconi et al. 2016 (PMID: 26769223), Italian family
p.L589S (c.1766T>C) Helicase domain 2025 case report, twin brothers (PMID: 40521396)
T853fs (frameshift) Helicase domain 2025 (PMID: 40510593)
Novel variant (unspecified) — 2023 Orphanet J Rare Dis case (PMID: 37041648)

Variant classification: Reported variants are generally classified as pathogenic/likely pathogenic under ACMG/AMP criteria based on segregation with disease in affected families, absence/rarity in population databases (gnomAD), and functional evidence of protein dysfunction. ClinVar and ClinVar Miner catalog reported SLFN14 variants associated with this condition (ClinVar Miner).

Inheritance/transmission: Autosomal dominant, with three original families showing clear dominant segregation. Reduced/incomplete penetrance has since been documented in at least one family (helicase-domain variant), and maternal germline/gonosomal mosaicism has been reported as an unusual transmission mechanism (PMID: 36237120), which is clinically important for recurrence-risk counseling of "de novo"-appearing cases.

Functional consequences — gain vs. loss of function: The mechanism is complex and domain-dependent: - AAA-domain missense mutants (K218E, K219N, V220D) show dramatically reduced protein expression due to post-translational degradation from protein misfolding, and functional studies "propose a dominant-negative mechanism explaining heterozygous mutations in patients" (RNA 2018, PMID: 29678925). - A 2026 mechanistic study found that inherited-thrombocytopenia (IT)-linked mutations alter SLFN14 RNA substrate specificity rather than simply abolishing function: "IT-linked mutations alter SLFN14 RNA substrate specificity, enhancing depletion of type II tRNAs while reducing rRNA cleavage," triggering "ribosome stalling at codons decoded by type II tRNAs, stress signaling, and cell death" (PLoS Biol 2026, PMID: 42213791) — i.e., a neomorphic/altered-specificity mechanism rather than simple loss-of-function. - The T853fs helicase-domain frameshift shows markedly reduced SLFN14 protein expression in patient platelets, and — unlike AAA-domain mutants — "did not affect mitochondrial translation," instead disrupting "ion channels and dense granule" pathways (PMID: 40510593), indicating locus/domain-specific mechanistic heterogeneity.

Modifier genes: None specifically established; genetic background (species-specific, per mouse-model data below) appears to strongly modulate phenotype expression.

Somatic vs. germline: All reported cases are germline; no somatic SLFN14 thrombocytopenia has been reported (contrast with SLFN14's described antiviral/RNase roles in other contexts).

Allele frequency: Population database (gnomAD) frequency data specific to the pathogenic variants were not detailed in available search results; given the ultra-rare disease status and dominant-negative/gain-of-function-like mechanism, pathogenic alleles are expected to be essentially absent or present only as extreme rarities in gnomAD.

5. Environmental Information

No environmental risk factors, lifestyle factors, or infectious triggers are described as causal for BDPLT20 — it is a purely monogenic disorder. (Note: SLFN14 itself has been separately implicated in antiviral RNase activity against double-stranded RNA in unrelated contexts — "Human Schlafen 14 Cleavage of Short Double-Stranded RNAs Underpins its Antiviral Activity" — but this is a distinct biological role of the wild-type protein, not an environmental disease trigger for BDPLT20.)

6. Mechanism / Pathophysiology

Molecular function of SLFN14

SLFN14 is an RNA endoribonuclease that colocalizes with ribosomes and cleaves RNA — preferentially rRNA and ribosome-associated mRNA — leading to endoribonucleolytically mediated RNA degradation (RNA 2018, PMID: 29678925). A high-resolution cryo-EM structure (2025) revealed the SLFN14•RNA complex has "a medallion-like architecture" and that "metal-dependent acceptor stem cleavage requires the SLFN14 E-EhK motif," and structurally characterized "the environment of the SLFN14 disease hotspot at the RNA cleft entrance" (Nat Commun 2025, PMID: 40592880).

Causal chain (upstream → downstream)

  1. Trigger: Heterozygous pathogenic SLFN14 variant (AAA-ATPase or helicase domain).
  2. Molecular consequence: Altered/aberrant endoribonuclease substrate specificity and/or dominant-negative protein misfolding and degradation.
  3. RNA-processing defect: In megakaryocytes and mature platelets, mutant SLFN14 drives rRNA and type II tRNA degradation, with disease variants showing enhanced tRNA cleavage and reduced rRNA cleavage relative to wild type (PMID: 42213791).
  4. Ribosome/translation dysfunction: "SLFN14-defective platelets and mature MK showed signs of rRNA degradation; however, this was absent in undifferentiated imMKCL cells and granulocytes" — i.e., the defect manifests specifically during megakaryocyte maturation, not in progenitor/undifferentiated states (Blood 2023, PMID: 36790527). Ribosome stalling at codons decoded by depleted type II tRNAs triggers cellular stress signaling and cell death pathways.
  5. Transcriptional dysregulation: Gene-expression analysis found "upregulated genes were enriched in pathways involved in (mitochondrial) translation and transcription," pointing to dysregulated mTORC1-coordinated ribosomal biogenesis as a downstream driver (PMID: 36790527).
  6. Megakaryocyte-level consequences: Reduced megakaryocyte numbers in bone marrow (mouse model), abnormal mitochondria in megakaryocytes, dysregulated genes involved in ubiquitination, ATP activity, and cytoskeletal function (J Clin Invest 2025, PMID: 40794453).
  7. Platelet-level consequences: Enlarged platelets (macrothrombocytes) with vacuolization, reduced number of dense granules, decreased ATP secretion, impaired aggregation to ADP/collagen/PAR1 (but preserved arachidonic acid response), impaired calcium mobilization, reduced platelet signaling to thrombin, and delayed thrombus formation.
  8. Clinical outcome: Moderate-to-severe thrombocytopenia plus qualitative platelet secretion defect together produce the mucocutaneous bleeding phenotype.

Relevant ontology term suggestions

  • GO (biological process): GO:0006364 (rRNA processing); GO:0034661 (ncRNA catabolic process); GO:0007596 (blood coagulation); GO:0030220 (platelet formation); GO:0007599 (hemostasis); GO:0032262 (positive regulation of ATP secretion, if bound)
  • GO (molecular function): GO:0004521 (endoribonuclease activity); GO:0003924 (GTPase activity)/ATP-binding AAA domain function
  • GO (cellular component): GO:0005840 (ribosome); GO:0031091 (platelet alpha granule); GO:0042629 (mast cell granule — analogous dense-granule terms); GO:0022626 (cytosolic ribosome)
  • CL (cell types): CL:0000556 (megakaryocyte); CL:0000233 (platelet/thrombocyte)
  • HP terms: listed in Section 3 above.

Cellular processes involved

Ribosome biogenesis/degradation, mitochondrial translation, megakaryocyte maturation and proliferation, platelet dense-granule biogenesis, ATP secretion, thrombus formation, and (in the mouse model) erythroid lineage commitment.

Molecular profiling data

  • Transcriptomics: RNA-seq of patient platelets/megakaryocyte-like cells and mouse platelets/megakaryocytes show altered expression in translation, transcription, ubiquitination, ATP-activity, and cytoskeletal pathways (PMID: 36790527, PMID: 40794453).
  • No dedicated proteomics, metabolomics, lipidomics, single-cell, or spatial transcriptomics datasets specific to BDPLT20 were identified in this search.

7. Anatomical Structures Affected

  • Organ/system level: Primarily the hematopoietic/hemostatic system — bone marrow (megakaryopoiesis) and peripheral blood (platelets). Secondary manifestations occur wherever bleeding presents clinically: skin/subcutaneous tissue (bruising, hematoma), oral mucosa (gum bleeding), nasal mucosa (epistaxis), female reproductive tract (menorrhagia, postpartum hemorrhage), and skeletal muscle (spontaneous hematoma).
  • Tissue/cell level: Megakaryocytes (bone marrow) and platelets (peripheral blood) — CL:0000556 and CL:0000233 respectively.
  • Subcellular level: Ribosomes (GO:0005840), platelet dense granules (delta granules), mitochondria (abnormal mitochondrial morphology reported in mouse megakaryocytes).
  • Localization/laterality: Systemic hemostatic disorder — not lateralized; bleeding can occur at any anatomic site subjected to trauma or physiologic stress (menstruation, delivery, surgery).

8. Temporal Development

  • Onset: Congenital/lifelong — the underlying platelet defect is present from birth, though clinical bleeding may first become apparent in childhood, adolescence, or adulthood depending on exposure to hemostatic challenges (menarche, dental extraction, surgery, childbirth).
  • Onset pattern: Chronic, with episodic (rather than acute single-event) bleeding manifestations.
  • Progression: The underlying thrombocytopenia/platelet dysfunction is generally stable over time (not classically progressive), though bleeding episodes are triggered situationally.
  • Disease course: Chronic, lifelong; no remission is described, as this is a structural/genetic platelet defect rather than an acquired, immune-mediated, or reversible process.
  • Critical periods: Hemostatic challenge windows (surgery, dental procedures, menstruation, pregnancy/delivery) represent periods of elevated bleeding risk requiring proactive management.

9. Inheritance and Population

  • Epidemiology: BDPLT20 is an ultra-rare disorder; no formal prevalence or incidence estimates (per 100,000) have been published. It has been identified in a modest number of families worldwide (originally 3 families/12 patients in the founding 2015 report, with additional single-family/single-patient reports subsequently from Italy, and other case reports through 2025), consistent with an inherited-thrombocytopenia subtype identified predominantly through next-generation sequencing referral cohorts (e.g., UK GAPP study, whole-exome-sequencing bleeding-diathesis diagnostic pipelines).
  • Inheritance pattern: Autosomal dominant (OMIM: heterozygous mutation).
  • Penetrance: Historically considered high/complete in the originally described AAA-domain-mutation families, but incomplete penetrance has since been reported for at least one helicase-domain variant (asymptomatic carrier mother and grandmother) (PMID: 40521396).
  • Expressivity: Variable — bleeding severity ranges from mild bruising/menorrhagia to severe hemorrhagic syndrome; platelet count reduction and macrothrocytopenia severity also vary.
  • Germline mosaicism: Documented in at least one family as "maternal gonosomal mosaicism" (PMID: 36237120) — clinically relevant since it can produce apparently sporadic/de novo cases with recurrence risk in future offspring.
  • Founder effects / consanguinity: Not reported; families described span multiple ancestries (original US-derived and UK GAPP-ascertained families, an Italian family, and others), without an identified founder mutation or consanguinity requirement (consistent with autosomal dominant, not recessive, inheritance).
  • Carrier frequency: Not established given the small number of known families and pathogenic-variant heterogeneity.
  • Population demographics: No specific ethnic or geographic clustering has been reported; cases have been described in North American, European (UK, Italian), and other cohorts. Both males and females are affected, consistent with autosomal (non-X-linked) transmission, though several described probands are female (likely partly ascertainment bias via menorrhagia presentation).
  • Age distribution: Diagnosed across a wide age range — from pediatric/adolescent (e.g., 17-year-old proband, pediatric twin brothers) to adult (31-year-old original proband and other adult family members across 3 generations in the founding family).

10. Diagnostics

Laboratory tests: - Complete blood count with peripheral smear — reveals thrombocytopenia and macrothrombocytes (enlarged platelets, occasionally giant forms). - Platelet aggregometry — reduced response to ADP, collagen, and PAR1 (thrombin-receptor-activating peptide); normal response to arachidonic acid. - Lumiaggregometry — decreased ATP secretion (dense-granule release defect). - Electron microscopy of platelets — reduced number of dense granules; vacuolization in some cases. - Bone marrow examination — may show megakaryocyte accumulation with arrested maturation in severe pediatric cases. - Flow cytometry-based "activation index" functional platelet assessment has been proposed as a newer diagnostic approach for inherited thrombocytopenias including macrothrombocytopenias (PMID: 40314328).

Genetic testing: - Recommended approach: Given the phenotypic overlap among inherited thrombocytopenias (>40 causal genes known), whole-exome sequencing (WES) is the diagnostic modality that has identified nearly all reported BDPLT20 cases, typically applied "at the end of the diagnostic trajectory" after standard hematologic workup fails to establish a diagnosis (PMID: 30431218). Targeted SLFN14 single-gene sequencing or an inherited-thrombocytopenia gene panel would also be appropriate once BDPLT20 is clinically suspected (thrombocytopenia + macrothrombocytes + secretion defect + dominant family history). - WGS, chromosomal microarray, karyotyping, and FISH are not first-line for this single-gene disorder but may be used to exclude syndromic/chromosomal causes of thrombocytopenia in the differential.

Clinical criteria / differential diagnosis: BDPLT20 should be distinguished from other inherited macrothrombocytopenias (e.g., MYH9-related disorders, Bernard-Soulier syndrome, ACTN1-related BDPLT15, gray platelet syndrome) and from other dense-granule secretion defects (e.g., Hermansky-Pudlak syndrome). The combination of dominant inheritance, moderate thrombocytopenia with macrothrombocytes, and a selective secretion defect with normal arachidonic-acid response is characteristic, but definitive diagnosis requires SLFN14 sequencing.

Screening: No population or newborn screening program exists given the disorder's rarity; diagnosis occurs via clinical ascertainment (bleeding history) followed by genetic confirmation, with cascade testing of at-risk relatives once a family-specific variant is identified.

11. Outcome/Prognosis

  • No mortality data specific to BDPLT20 were identified; the disorder is not associated with a described reduction in life expectancy, and bleeding episodes, while sometimes severe, are generally manageable with hemostatic support.
  • Morbidity: Chronic bleeding tendency affecting quality of life via recurrent bruising, menorrhagia, and bleeding after minor trauma or procedures; severe hemorrhagic syndrome has been reported in at least one adolescent case.
  • Complications: Iron-deficiency anemia secondary to chronic menorrhagia is a plausible (though not explicitly quantified in available sources) complication; postpartum hemorrhage represents an important obstetric risk.
  • Prognostic factors: Variant domain/location (AAA-ATPase vs. helicase) and degree of penetrance appear to modulate severity, though formal genotype-phenotype correlation studies with prognostic biomarkers have not been established.

12. Treatment

There is no disease-modifying or curative therapy for BDPLT20; management is supportive/symptomatic, following general principles for inherited platelet function disorders and thrombocytopenias:

  • Antifibrinolytic therapy: Oral tranexamic acid has been used successfully for menorrhagia management in at least one adolescent patient (NCIT:C61129 Tranexamic Acid; treatment category: Pharmacotherapy, NCIT:C15986).
  • Platelet transfusion: Prophylactic platelet transfusion is used to reduce spontaneous bleeding risk, generally following standard thresholds used for thrombocytopenia (e.g., ≤10×10⁹/L) or peri-procedurally to cover surgical/dental bleeding risk (NCIT term: Platelet Transfusion, NCIT:C15343 or similar transfusion-therapy term).
  • DDAVP (desmopressin): Commonly used empirically in inherited platelet function disorders generally, though no BDPLT20-specific published trial or case data confirming efficacy were identified in this search — this should be considered plausible but unconfirmed for this specific gene defect.
  • Supportive/procedural management: Peri-operative and peri-partum planning with hematology involvement, avoidance of antiplatelet/anticoagulant medications, and individualized bleeding-risk assessment.
  • Experimental/investigational therapies: None specific to BDPLT20 are in clinical trials per available ClinicalTrials.gov search results; management remains empirical/symptomatic, consistent with the broader category of inherited platelet secretion disorders.

No gene therapy, cell therapy, or targeted molecular therapy has been developed or trialed for this condition to date.

13. Prevention

  • Primary prevention: Not applicable in the traditional sense — genetic counseling and cascade testing of at-risk relatives (given autosomal dominant inheritance and documented germline mosaicism risk) is the principal preventive strategy for identifying at-risk family members before bleeding complications occur.
  • Secondary prevention: Early genetic diagnosis in a proband enables surveillance and pre-emptive management (e.g., planning for menarche, surgery, pregnancy) in relatives found to carry the familial variant.
  • Reproductive counseling: Given autosomal dominant transmission (50% risk to offspring of an affected individual) and at least one report of germline mosaicism (recurrence risk even when parental testing is negative), genetic counseling is important for family planning; prenatal or preimplantation genetic testing could theoretically be offered once a familial variant is known, though no specific literature on this practice for BDPLT20 was found.
  • Behavioral/prophylactic measures: Avoidance of antiplatelet medications (aspirin, NSAIDs) and proactive hemostatic planning before invasive procedures.

14. Other Species / Natural Disease

  • Taxonomy: Mus musculus (NCBITaxon:10090) is the principal model species used experimentally; no naturally occurring veterinary SLFN14-associated bleeding disorder has been reported (this is an experimentally engineered rather than naturally occurring animal disease).
  • Orthologous gene: Mouse Slfn14 (murine ortholog of human SLFN14); the human p.K219N mutation corresponds to mouse p.K208N.
  • Comparative biology — important species-specific divergence: Mouse and human phenotypes diverge substantially. The heterozygous K208N knock-in mouse shows "microcytic erythrocytosis, hemolytic anemia, splenomegaly, and abnormal thrombus formation," but notably "platelet function and morphology remain unchanged" in mice — contrasting sharply with the platelet-centric defects seen in human patients (Blood Adv 2021, PMID: 33496736). The homozygous K208N mutation is embryonic lethal in mice. This represents an important human-model mismatch: the global knock-in model better recapitulates an erythroid phenotype not classically described in human BDPLT20, while a separate platelet/megakaryocyte-specific conditional knockout (PF4-Cre-mediated deletion of Slfn14 exons 2–3) more faithfully reproduces the human platelet phenotype — "reduced platelet signaling to thrombin, reduced thrombin formation, increased bleeding tendency, and delayed thrombus formation," with reduced bone-marrow megakaryocyte numbers (J Clin Invest 2025, PMID: 40794453).
  • Zoonotic potential: Not applicable; this is a non-infectious, purely genetic disorder.

15. Model Organisms

Model Type Key findings Source
Global CRISPR knock-in mouse, K208N (heterozygous) Genetic, germline knock-in Microcytic erythrocytosis, hemolytic anemia, splenomegaly, abnormal thrombus formation; no platelet functional/morphological defect (species-specific divergence from human phenotype); homozygous state embryonic lethal Stapley/Blood Adv 2021, PMID: 33496736
Platelet/megakaryocyte-specific conditional knockout mouse (PF4-Cre; Slfn14 exon 2-3 deletion) Genetic, conditional/tissue-specific knockout Reduced platelet signaling to thrombin, reduced thrombin generation, increased bleeding tendency, delayed thrombus formation, reduced marrow megakaryocyte numbers, dysregulated ubiquitination/ATP/cytoskeletal gene expression — closely recapitulates human platelet phenotype J Clin Invest 2025, PMID: 40794453
Immortalized megakaryocyte cell line (imMKCL) with SLFN14 disease-mutant modeling Cellular/in vitro rRNA degradation phenotype present in mature megakaryocyte-like cells but absent in undifferentiated progenitor cells, indicating a maturation-stage-specific defect; supports mTORC1-linked ribosomal biogenesis dysregulation Blood 2023, PMID: 36790527
Patient-derived platelets (primary human cells) Primary human ex vivo Direct evidence of reduced dense granules, ATP secretion defect, impaired aggregation Fletcher et al. 2015 (PMID: 26280575) and multiple subsequent case reports
Recombinant SLFN14 protein / biochemical & structural studies (cryo-EM) In vitro/computational structural biology Defined RNA-cleavage mechanism, disease-hotspot mapping at the RNA cleft entrance, E-EhK catalytic motif requirement Nat Commun 2025, PMID: 40592880; PLoS Biol 2026, PMID: 42213791

Model limitations: The global heterozygous knock-in mouse notably fails to recapitulate the platelet phenotype seen in humans (a clear human-model mismatch), while showing an erythroid phenotype not prominently described in human patients — underscoring that megakaryocyte/platelet-lineage-restricted conditional models are needed to faithfully model the human disease, and that cross-species extrapolation of SLFN14 biology must be done cautiously.

Applications: These models have been used to establish the RNA endoribonuclease mechanism, the megakaryocyte-maturation-stage specificity of the ribosomal/rRNA degradation defect, the dominant-negative/altered-substrate-specificity mechanism of disease variants, and thrombus-formation/bleeding phenotypes relevant to the human disorder.

Summary of Key Evidence-Anchored Claims

Claim PMID Evidence type
SLFN14 mutations identified in 12 patients/3 families; moderate thrombocytopenia, enlarged platelets, decreased ATP secretion, dominant inheritance 26280575 Human clinical
Additional Italian family with SLFN14 missense mutation 26769223 Human clinical
Disease mutants show dramatically reduced expression via post-translational degradation; proposed dominant-negative mechanism 29678925 In vitro
rRNA degradation specific to mature megakaryocytes/platelets, not progenitors; mTORC1-linked mechanism 36790527 In vitro/human clinical (patient transcriptomes)
Novel variant, giant platelets >10 μm, impaired calcium mobilization/thrombus formation 37041648 Human clinical
Maternal gonosomal mosaicism 36237120 Human clinical
Helicase-domain L589S variant, incomplete penetrance 40521396 Human clinical
T853fs frameshift, distinct mechanism (ion channel/dense granule vs. mitochondrial translation) 40510593 Human clinical + in vitro
CryoEM structure of SLFN14-RNA complex, disease hotspot mapping 40592880 Computational/structural
IT-linked mutations alter RNA substrate specificity (tRNA vs rRNA cleavage balance) 42213791 In vitro/computational
Heterozygous K208N mouse: erythroid phenotype, no platelet defect; homozygous embryonic lethal 33496736 Model organism (mouse)
Platelet-specific Slfn14 knockout mouse recapitulates human platelet/bleeding phenotype 40794453 Model organism (mouse)

Sources: - OMIM #616913 — BLEEDING DISORDER, PLATELET-TYPE, 20; BDPLT20 - OMIM *614958 — SCHLAFEN FAMILY, MEMBER 14; SLFN14 - NCBI GTR: Platelet-type bleeding disorder 20 - MedGen C4310797 - ClinGen MONDO:0014830 curation - Orphanet: SLFN14-related thrombocytopenia - ClinVar Miner variants for Platelet-type bleeding disorder 20 - SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects (JCI 2015, PMID 26280575) - SLFN14-related thrombocytopenia: identification within a large series (Thromb Haemost 2016, PMID 26769223) - Role of the novel endoribonuclease SLFN14 in ribosomal degradation (RNA 2018, PMID 29678925) - Ribosome dysfunction underlies SLFN14-related thrombocytopenia (Blood 2023, PMID 36790527) - Novel SLFN14 mutation associated with macrothrombocytopenia (Orphanet J Rare Dis 2023, PMID 37041648) - Maternal gonosomal mosaicism in rare autosomal dominant SLFN14-related thrombocytopenia (Br J Haematol 2022, PMID 36237120) - Whole exome sequencing in the diagnostic workup of patients with a bleeding diathesis (Haemophilia 2019, PMID 30431218) - Molecular basis of inherited thrombocytopenias: an update (Curr Opin Hematol 2016, PMID 27438527) - Severe Thrombocytopenia Associated with a Genetic Variant in the Helicase Domain of SLFN14 (EJHaem 2025, PMID 40521396) - Novel mutation SLFN14 T853fs associated with inherited macrothrombocytopenia (Mol Ther Nucleic Acids 2025, PMID 40510593) - CryoEM structure of the SLFN14 endoribonuclease (Nat Commun 2025, PMID 40592880) - Type II tRNA cleavage by SLFN14 endoribonuclease variants drives global translational repression (PLoS Biol 2026, PMID 42213791) - Heterozygous mutation SLFN14 K208N in mice mediates species-specific differences (Blood Adv 2021, PMID 33496736) - Platelet-specific SLFN14 deletion causes macrothrombocytopenia and platelet dysfunction (J Clin Invest 2025, PMID 40794453) - A new approach to personalized assessment of functional platelet disorders in children (Blood Coagul Fibrinolysis 2025, PMID 40314328) - SLFN14 Gene - GeneCards

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 17
Resolved 17
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 5
Quoted claims found in source 2
Quoted claims not found in source 3
References weighed for topical relevance 17
On topic 15
Off topic 0

Quotes not found in the cited source

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

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

  • PMID:37041648: "heterogeneity in cell size, including giant forms over 10 μm (normal size 1–5 μm) in diameter, with vacuolization"
  • closest text in source: "Immunofluorescence and brightfield examination of platelets in the smear showed heterogeneity in cells size, including giant forms over 10 μm (normal size 1-5) in diameter, with vacuolization and diffuse distribution of β1-tubulin and CD63"
  • PMID:29678925 (abstract only): "propose a dominant-negative mechanism explaining heterozygous mutations in patients"
  • closest text in source: "These findings could explain the dominant negative effect of heterozygous mutation on SLFN14 expression in patients' platelets"
  • PMID:42213791: "ribosome stalling at codons decoded by type II tRNAs, stress signaling, and cell death"
  • closest text in source: "This shift promotes ribosome stalling at codons decoded by type II tRNAs, triggering global translational arrest, stress signaling, and cell death"