Bone Marrow Failure Syndrome 5

Mendelian MONDO:0032573 Pathograph 15 Show in embeddings browser Inherited bone marrow failure syndrome Bone marrow failure syndrome

Bone marrow failure syndrome 5 (BMFS5), also called germline p53 (TP53) activation syndrome, is an inherited bone marrow failure syndrome caused by heterozygous germline frameshift variants near the 3' end of TP53 that truncate the p53 C-terminal domain. It was defined in 2018 in two unrelated individuals with de novo variants that both removed the last 32 residues of p53; the truncated protein had augmented, not reduced, transcriptional activity. The presentation mimics Diamond-Blackfan anaemia (DBA): anaemia with a paucity of erythroid precursors (pure red cell aplasia), beginning within the first year of life where onset is reported, together with hypogammaglobulinaemia, growth retardation and microcephaly. Later reports added intellectual disability, seizures, short stature, cellular radiosensitivity and transient neutropenia. The literature is small. Four case reports describe seven individuals. Every allele whose position the abstracts state is a C-terminal frameshift; the 2022 abstract describing two further patients (PMID:35084091) calls their de novo variants activating without naming them. Corticosteroid response is inconsistent (one responder, two non-responders), two patients became transfusion independent on L-leucine, and one patient is reported cured by matched-sibling haematopoietic stem cell transplantation. BMFS5 is the mechanistic inverse of Li-Fraumeni syndrome. Li-Fraumeni variants mostly inactivate the p53 DNA-binding domain and predispose to cancer; the BMFS5 alleles truncate the C-terminal domain and raise p53 transcriptional output. None of the four case-report abstracts reports a malignancy, and no source located for this entry addresses cancer risk in carriers, so the entry records no cancer phenotype and treats cancer risk as an open question. The C-terminally truncated p53-delta-31 mouse, which predates the human syndrome, has increased p53 activity and aplastic anaemia with features of dyskeratosis congenita when homozygous, but heterozygous mice are only mildly affected.

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1
Inheritance
3
Pathophys.
14
Phenotypes
1
Hypotheses
3
Gaps
15
Pathograph
1
Genes
1
Variants
4
Medical Actions
1
Models
8
References
1
Deep Research
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Classifications

Harrison's Part
ONCOLOGY HEMATOLOGY GENETICS ENVIRONMENT DISEASE
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Inheritance

1
Autosomal dominant HP:0000006
A single heterozygous germline allele is sufficient. The four patients whose origin the abstracts state (PMID:30146126, PMID:35084091) carried de novo variants, and none of the four abstracts reports transmission from an affected parent, so dominant inheritance rests on heterozygosity and on the activating mechanism rather than on observed segregation. The two French patients carry the same allele; their abstract does not say whether they are related or whether either parent was tested.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:35362179 SUPPORT Human Clinical
"who had a germline heterozygous C-terminal frameshift variant in TP53 similar to others that activate the transcription factor"
Documents a heterozygous germline allele as sufficient for the phenotype.
PMID:42104732 SUPPORT Human Clinical
"We report two French patients who both harbored a heterozygous TP53 deletion (NM_000546.5: c.1077delA; p.(Ser362AlafsTer8))."
Two further affected individuals, each heterozygous.
PMID:35084091 SUPPORT Human Clinical
"We describe two patients with the phenotype of DBA (onset of macrocytic anemia within the first year of life, paucity of erythroid precursors in bone marrow) and germline de novo variants in the TP53 gene."
Records de novo origin in two more patients, consistent with a dominant-acting allele arising without family history.
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Mechanistic Hypotheses

1
Constitutive p53 activation drives the non-haematological features
p53_activation_extrahematopoietic EMERGING
Evidence balance 1 support
The erythroid defect is experimentally linked to the truncated p53 in zebrafish and human iPSCs. The growth, microcephaly, pigmentary, gonadal and radiosensitivity features are not: they are attributed to p53 activation by analogy with mouse strains carrying p53-hyperactivating alleles, and the immunoglobulin defect has no proposed mechanism in the sources cited here. The authors of the defining report state that the role of p53 activation in each clinical feature remains unknown. Edges in this group are proposals carried by mouse data, not demonstrations in patients.
Pathograph links
p53 Pathway Hyperactivation -> Growth delay Proposed, not demonstrated in patients. Mice with broad p53 hyperactivation show developmental defects attributed to excess apoptosis or reduced proliferation in specific embryonic and neonatal compartments; the authors of the defining report state that the role of p53 activation in each clinical feature remains unknown.
p53 Pathway Hyperactivation -> Microcephaly Proposed, not demonstrated in patients. Mouse strains with p53 hyperactivation show excess apoptosis or reduced proliferation in the embryonic neuroepithelium and neonatal cerebellum.
p53 Pathway Hyperactivation -> Cellular radiosensitivity Proposed. In p53-delta-31 mouse cells loss of the C-terminal domain strengthened the cell-cycle arrest and apoptotic responses to irradiation; the patient's radiosensitivity assay is not described in the cited abstract.
p53 Pathway Hyperactivation -> Hypogonadism Proposed. Homozygous p53-delta-31 male mice are hypogonadal; one founding patient had hypogonadism.
p53 Pathway Hyperactivation -> Reticular skin pigmentation Proposed. Mouse strains with p53 hyperactivation, including p53-delta-31, develop skin hyperpigmentation from accumulation of epidermal melanocytes; one founding patient had reticular pigmentation.
Show evidence (1 reference)
PMID:30146126 SUPPORT BACKGROUND Human Clinical
"However, the exact role of p53 activation in each clinical feature remains unknown."
The source's own statement of the open question this hypothesis addresses.
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Discussions and Knowledge Gaps

3
Do carriers of C-terminal truncating, activating TP53 alleles have an increased cancer risk, and is any tumour surveillance warranted?
KNOWLEDGE GAP OPEN bmfs5_cancer_risk
Attached to
disease#Bone Marrow Failure Syndrome 5 genetic#TP53
Inherited bone marrow failure syndromes as a class carry an increased risk of malignancy, and germline TP53 is the Li-Fraumeni gene, so a TP53 result on a marrow-failure panel invites Li-Fraumeni-style surveillance. But the BMFS5 alleles act in the opposite direction from Li-Fraumeni alleles, and the developmental-syndrome literature attributes cancer risk to loss of p53 activity rather than to its increase. None of the four case-report abstracts (PMID:30146126, PMID:35084091, PMID:35362179, PMID:42104732) reports a malignancy; with seven patients and follow-up durations not stated in those abstracts, absence of reported cancer is not evidence of absent risk. Whether somatic loss of the activating allele, or clonal selection for p53-pathway escape under constitutive p53 pressure, creates a myeloid risk in these patients is untested.
Proposed experiments
Longitudinal follow-up of reported carriers for malignancy and clonal haematopoiesis
bmfs5_longitudinal_followup
Pool the reported patients through a bone marrow failure registry and follow them for malignancy, with serial marrow or blood sequencing for somatic TP53-pathway clones.
Would support
disease#Bone Marrow Failure Syndrome 5
Supporting outcome
  • Cancer-free follow-up into adulthood with no expanding p53-pathway escape clones would support managing carriers without Li-Fraumeni surveillance.
Refuting outcome
  • Malignancy, or clonal expansion of cells that have lost or inactivated the activating allele, would argue for marrow surveillance.
Show evidence (2 references)
PMID:30146126 SUPPORT BACKGROUND Human Clinical
"Inherited bone-marrow-failure syndromes (IBMFSs) include heterogeneous genetic disorders characterized by bone-marrow failure, congenital anomalies, and an increased risk of malignancy."
The class-level cancer risk that makes the question unavoidable.
PMID:30624728 SUPPORT REVIEW SYNTHESIS Human Clinical
"Of note, while Li-Fraumeni syndrome is caused by mutations in TP53, these mutations are typically loss-of-function or dominant-negative, consistent with this syndrome being linked to increased cancer risk due to loss of p53 activity, rather than developmental defects or premature aging due to..."
The review's distinction between the two allelic classes, the reason Li-Fraumeni cancer risk is not imported into this entry.
How does constitutive p53 activation produce hypogammaglobulinaemia, microcephaly and growth failure in these patients?
KNOWLEDGE GAP OPEN bmfs5_extrahematopoietic_mechanism
Attached to
phenotypes#Hypogammaglobulinemia mechanistic_hypotheses#p53_activation_extrahematopoietic
Only the erythroid defect has been reproduced experimentally with the patient allele. The growth and microcephaly edges in this entry rest on mouse strains with broad p53 hyperactivation, and nothing cited here addresses the B-cell or immunoglobulin defect at all, so hypogammaglobulinaemia is left unwired. The defining report itself names this as unknown.
Show evidence (1 reference)
PMID:30146126 SUPPORT BACKGROUND Human Clinical
"However, the exact role of p53 activation in each clinical feature remains unknown."
The authors' own statement of the gap.
Why is a single C-terminal truncating TP53 allele sufficient for marrow failure in humans when heterozygous p53-delta-31 mice are only mildly affected?
HUMAN MODEL MISMATCH OPEN bmfs5_heterozygous_dosage
Attached to
animal_models#Mouse pathophysiology#p53 Pathway Hyperactivation
The mouse reproduces the direction of effect but needs two copies for the severe phenotype, while every reported patient is heterozygous. Candidate explanations - greater human sensitivity of erythroid progenitors to p53 dosage, species differences in p53 target programmes, or the one-residue difference between the 31- and 32-residue truncations - are untested. In the mouse, lowering Mdm4 converts the mild heterozygote into a severe one, so MDM4 or MDM2 dosage is a plausible human modifier, but no source here tests it in patients.
Show evidence (2 references)
PMID:23770245 SUPPORT Model Organism
"Heterozygous p53+/Δ31 mice were only mildly affected, but decreased levels of Mdm4, a negative regulator of p53, led to a dramatic aggravation of their symptoms."
The model side of the mismatch.
PMID:35362179 SUPPORT Human Clinical
"who had a germline heterozygous C-terminal frameshift variant in TP53 similar to others that activate the transcription factor"
The human side: a heterozygous allele is sufficient.
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Pathophysiology

3
TP53 C-Terminal Domain Truncation
Heterozygous germline frameshift variants near the 3' end of TP53 remove the C-terminal domain while leaving the core DNA-binding domain intact. In the defining report both variants produced the same truncation, deleting 32 residues, and the mutant protein showed augmented transcriptional activity. This is the opposite direction of effect from the DNA-binding-domain variants of Li-Fraumeni syndrome. Recorded as GAIN_OF_FUNCTION following the sources' own wording ("activating", "gain-of-function"); the reported effect is increased transactivation by the truncated protein, not a novel activity.
TP53 hgnc:11998 ↑ INCREASED HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves increased TP53 (hgnc:11998). hgnc:11998 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
Heterozygous germline C-terminal frameshift TP53 alleles, de novo where origin is reported.
DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981). GO:0000981 is a molecular function from the Gene Ontology.
Downstream
p53 Pathway Hyperactivation Loss of the C-terminal domain increases p53 transcriptional output.
Show evidence (4 references)
PMID:30146126 SUPPORT Human Clinical
"In contrast, the variants found in the two individuals studied here caused the same truncation of the protein, resulting in the loss of 32 residues from the C-terminal domain (CTD)."
Defines the lesion in the two founding patients.
PMID:30146126 SUPPORT In Vitro
"Unexpectedly, the p53 mutant had augmented transcriptional activities, an observation not previously described in humans."
Establishes the direction of effect: the truncated p53 transactivates more, not less, which is what makes this a p53-activating rather than a p53-losing disorder.
PMID:30146126 SUPPORT BACKGROUND Human Clinical
"Most of these mutations affect the core DNA-binding domain, leading to compromised transcriptional activities."
The contrast with Li-Fraumeni alleles that the authors draw, which is why this entry is kept separate from Li-Fraumeni syndrome.
+ 1 more reference
p53 Pathway Hyperactivation
The central node. Constitutively augmented p53 target-gene transactivation in every cell carrying the allele. The authors of the defining report frame the disease as confirming that p53 activation itself can cause an inherited bone marrow failure syndrome, rather than only accompanying the ribosomal, telomere or DNA-repair defects of other such syndromes. Here p53 activation is the primary lesion rather than a downstream consequence.
Constitutive p53 activation drives the non-haematological features
signal transduction by p53 class mediator GO:0072331 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased signal transduction by p53 class mediator (GO:0072331). GO:0072331 is a biological process from the Gene Ontology.
Animal models
p53-delta-31 knock-in mouse Mouse partially recapitulates Loss of the C-terminal domain increases p53 activity and, in homozygotes, causes aplastic anaemia.
Downstream
Impaired Erythropoiesis Expression of the truncated p53 impairs erythrocyte production.
Growth delay Proposed, not demonstrated in patients. Mice with broad p53 hyperactivation show developmental defects attributed to excess apoptosis or reduced proliferation in specific embryonic and neonatal compartments; the authors of the defining report state that the role of p53 activation in each clinical feature remains unknown. Constitutive p53 activation drives the non-haematological features
Microcephaly Proposed, not demonstrated in patients. Mouse strains with p53 hyperactivation show excess apoptosis or reduced proliferation in the embryonic neuroepithelium and neonatal cerebellum. Constitutive p53 activation drives the non-haematological features
Cellular radiosensitivity Proposed. In p53-delta-31 mouse cells loss of the C-terminal domain strengthened the cell-cycle arrest and apoptotic responses to irradiation; the patient's radiosensitivity assay is not described in the cited abstract. Constitutive p53 activation drives the non-haematological features
Hypogonadism Proposed. Homozygous p53-delta-31 male mice are hypogonadal; one founding patient had hypogonadism. Constitutive p53 activation drives the non-haematological features
Reticular skin pigmentation Proposed. Mouse strains with p53 hyperactivation, including p53-delta-31, develop skin hyperpigmentation from accumulation of epidermal melanocytes; one founding patient had reticular pigmentation. Constitutive p53 activation drives the non-haematological features
Show evidence (2 references)
PMID:35362179 SUPPORT Human Clinical
"who had a germline heterozygous C-terminal frameshift variant in TP53 similar to others that activate the transcription factor"
Places a third patient's variant in the activating class.
PMID:36198537 SUPPORT REVIEW SYNTHESIS Human Clinical
"This discovery confirms the hypothesis that p53 activation causes IBMFS."
Review by the senior author of the defining report, stating the organising claim of the entry.
Impaired Erythropoiesis
Failure of erythroid production with a paucity of erythroid precursors in the marrow, the Diamond-Blackfan-like core of the syndrome. In patients the erythroid lineage is the consistently affected one; neutropenia, where reported, was transient.
erythroid progenitor cell CL:0000038 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythroid progenitor cell (CL:0000038). CL:0000038 is a cell type from the Cell Ontology.
erythrocyte differentiation GO:0030218 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased erythrocyte differentiation (GO:0030218). GO:0030218 is a biological process from the Gene Ontology.
Downstream
Pure red cell aplasia Erythroid failure presents as red cell aplasia with anaemia.
Macrocytic anemia The anaemia that results from erythroid failure, macrocytic in the two patients of PMID:35084091.
Normocytic anemia The anaemia that results from erythroid failure, normocytic in the two French patients.
Show evidence (2 references)
PMID:35084091 SUPPORT Human Clinical
"We describe two patients with the phenotype of DBA (onset of macrocytic anemia within the first year of life, paucity of erythroid precursors in bone marrow) and germline de novo variants in the TP53 gene."
Marrow-level human evidence for the erythroid precursor deficit.
PMID:30146126 SUPPORT Model Organism
"When we expressed this mutant in zebrafish and human-induced pluripotent stem cells, we observed impaired erythrocyte production."
Experimental reproduction of the erythroid defect by the mutant protein.
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Pathograph

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

14
Blood 5
Pure red cell aplasia HP:0012410 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pure red cell aplasia (HP:0012410), qualified as infantile onset. HP:0012410 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (3 references)
PMID:37834388 SUPPORT REVIEW SYNTHESIS Human Clinical
"Both patients exhibited pure red cell aplasia, growth delays, hypogammaglobulinemia, microcephaly, and telomere length between the 1st and 10th percentile"
Review summary of the two founding patients, both with pure red cell aplasia.
PMID:35362179 SUPPORT Human Clinical
"Here we report a patient with red cell aplasia, which was steroid responsive"
Red cell aplasia in the third reported patient.
PMID:35084091 SUPPORT Human Clinical
"We describe two patients with the phenotype of DBA (onset of macrocytic anemia within the first year of life, paucity of erythroid precursors in bone marrow) and germline de novo variants in the TP53 gene."
Erythroid precursor paucity with onset in the first year of life, supporting the infantile onset recorded here.
Macrocytic anemia HP:0001972 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocytic anemia (HP:0001972), qualified as infantile onset. HP:0001972 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (1 reference)
PMID:35084091 SUPPORT Human Clinical
"We describe two patients with the phenotype of DBA (onset of macrocytic anemia within the first year of life, paucity of erythroid precursors in bone marrow) and germline de novo variants in the TP53 gene."
Macrocytic anaemia with infantile onset in two patients.
Normocytic anemia HP:0001897 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Normocytic anemia (HP:0001897). HP:0001897 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42104732 SUPPORT Human Clinical
"They exhibited normocytic anemia, transient neutropenia at presentation, and distinct neurological impairments."
Normocytic anaemia in two patients.
Transient neutropenia Decreased total neutrophil count HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neutropenia, annotated with Decreased total neutrophil count (HP:0001875), qualified as temporality transient. HP:0001875 is a phenotype from the Human Phenotype Ontology.
Temporal: TRANSIENT
Show evidence (1 reference)
PMID:42104732 SUPPORT Human Clinical
"They exhibited normocytic anemia, transient neutropenia at presentation, and distinct neurological impairments."
Transient neutropenia in two patients.
Hypogammaglobulinemia Decreased circulating immunoglobulin concentration HP:0004313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogammaglobulinemia, annotated with Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30146126 SUPPORT Human Clinical
"Here, we report unique de novo TP53 germline variants found in two individuals with an IBMFS accompanied by hypogammaglobulinemia, growth retardation, and microcephaly mimicking DBA and DC."
Hypogammaglobulinaemia in both founding patients.
Endocrine 1
Hypogonadism HP:0000135 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogonadism (HP:0000135). HP:0000135 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37834388 SUPPORT REVIEW SYNTHESIS Human Clinical
"one patient also presented reticular skin pigmentation, hypogonadism, and tooth anomalies"
Review summary of the founding report; one patient only.
Head and Neck 2
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30146126 SUPPORT Human Clinical
"Here, we report unique de novo TP53 germline variants found in two individuals with an IBMFS accompanied by hypogammaglobulinemia, growth retardation, and microcephaly mimicking DBA and DC."
Microcephaly in both founding patients.
PMID:35362179 SUPPORT Human Clinical
"as well as intellectual disability, seizures, microcephaly, short stature, cellular radiosensitivity, and normal telomere lengths"
Microcephaly in the third reported patient.
Tooth anomalies Abnormality of the dentition HP:0000164 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tooth anomalies, annotated with Abnormality of the dentition (HP:0000164). HP:0000164 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37834388 SUPPORT REVIEW SYNTHESIS Human Clinical
"one patient also presented reticular skin pigmentation, hypogonadism, and tooth anomalies"
Review summary of the founding report; one patient only.
Integument 1
Reticular skin pigmentation Reticular hyperpigmentation HP:0007588 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reticular skin pigmentation, annotated with Reticular hyperpigmentation (HP:0007588). HP:0007588 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37834388 SUPPORT REVIEW SYNTHESIS Human Clinical
"one patient also presented reticular skin pigmentation, hypogonadism, and tooth anomalies"
Review summary of the founding report; one patient only.
Nervous System 2
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35362179 SUPPORT Human Clinical
"as well as intellectual disability, seizures, microcephaly, short stature, cellular radiosensitivity, and normal telomere lengths"
Intellectual disability in the third reported patient.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizures, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35362179 SUPPORT Human Clinical
"as well as intellectual disability, seizures, microcephaly, short stature, cellular radiosensitivity, and normal telomere lengths"
Seizures in the third reported patient.
Cellular 1
Cellular radiosensitivity Increased sensitivity to ionizing radiation HP:0011133 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cellular radiosensitivity, annotated with Increased sensitivity to ionizing radiation (HP:0011133). HP:0011133 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35362179 SUPPORT Human Clinical
"as well as intellectual disability, seizures, microcephaly, short stature, cellular radiosensitivity, and normal telomere lengths"
Cellular radiosensitivity in the third reported patient.
Growth 2
Growth delay HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth retardation, annotated with Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Sequelae: Short stature
Show evidence (1 reference)
PMID:30146126 SUPPORT Human Clinical
"Here, we report unique de novo TP53 germline variants found in two individuals with an IBMFS accompanied by hypogammaglobulinemia, growth retardation, and microcephaly mimicking DBA and DC."
Growth retardation in both founding patients.
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35362179 SUPPORT Human Clinical
"as well as intellectual disability, seizures, microcephaly, short stature, cellular radiosensitivity, and normal telomere lengths"
Short stature in the third reported patient.
🧬

Genetic Associations

1
TP53
Gene: TP53 hgnc:11998 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TP53 (hgnc:11998). hgnc:11998 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:30146126 SUPPORT Human Clinical
"These findings together with close similarities to published knock-in mouse models of TP53 lacking the CTD demonstrate that the CTD-truncation mutations of TP53 cause IBMFS"
The defining report's causal conclusion for C-terminal truncating TP53 alleles.
PMID:35084091 SUPPORT Human Clinical
"We describe two patients with the phenotype of DBA (onset of macrocytic anemia within the first year of life, paucity of erythroid precursors in bone marrow) and germline de novo variants in the TP53 gene."
Independent replication in two further de novo patients.
🔬

Variants

1
TP53 c.1077delA p.(Ser362AlafsTer8)
Gene: TP53 hgnc:11998 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TP53 (hgnc:11998). hgnc:11998 is a gene from the HUGO Gene Nomenclature Committee. frameshift
Carried in the heterozygous state by both French patients (PMID:42104732). A frameshift at codon 362 falls in the C-terminal region whose truncation defines the syndrome. The cDNA changes of the founding patients and of the two patients of PMID:35084091 are not given in their abstracts.
Show evidence (1 reference)
PMID:42104732 SUPPORT Human Clinical
"We report two French patients who both harbored a heterozygous TP53 deletion (NM_000546.5: c.1077delA; p.(Ser362AlafsTer8))."
Names the allele with its transcript reference.
💊

Medical Actions

4
Red Blood Cell Transfusion
Action: red blood cell transfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is red blood cell transfusion, annotated with Packed Red Blood Cell Transfusion (NCIT:C15409). NCIT:C15409 is a clinical intervention from the NCI Thesaurus. Ontology label: Packed Red Blood Cell Transfusion NCIT:C15409
Platform: Other
Supportive treatment of the anaemia. Transfusion dependence is implied in the reports that describe patients becoming transfusion independent after other therapy; no source here describes transfusion regimens or iron overload in this disease.
Show evidence (1 reference)
PMID:35084091 SUPPORT Human Clinical
"Both patients became transfusion independent, probably due to L-leucine therapy."
Becoming transfusion independent presupposes prior transfusion support.
Corticosteroid Therapy
Action: systemic corticosteroid therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is systemic corticosteroid therapy (NCIT:C122080). NCIT:C122080 is a clinical intervention from the NCI Thesaurus. Ontology label: Systemic Corticosteroid Therapy NCIT:C122080
Agent: corticosteroid CHEBI:50858 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses corticosteroid (CHEBI:50858). CHEBI:50858 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Tried in these patients because of the Diamond-Blackfan-like presentation. Response is inconsistent across the three patients for whom it is reported: the 2022 single patient was steroid responsive, and neither French patient responded.
Show evidence (2 references)
PMID:35362179 SUPPORT Human Clinical
"Here we report a patient with red cell aplasia, which was steroid responsive"
Steroid-responsive red cell aplasia in one patient.
PMID:42104732 REFUTE Human Clinical
"Neither patient responded to a corticosteroid trial."
Two non-responders, so a steroid response cannot be assumed.
L-Leucine
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: L-leucine CHEBI:15603 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses L-leucine (CHEBI:15603). CHEBI:15603 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Both patients of PMID:35084091 became transfusion independent, which the authors attribute, with hedging, to L-leucine. Two uncontrolled observations; causality is not established.
Show evidence (1 reference)
PMID:35084091 SUPPORT Human Clinical
"Both patients became transfusion independent, probably due to L-leucine therapy."
Transfusion independence in two patients on L-leucine, attributed to it by the authors with explicit uncertainty.
Hematopoietic Stem Cell Transplantation
Action: hematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hematopoietic stem cell transplantation, annotated with Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
One French patient received a matched-sibling transplant and remained transfusion independent at last follow-up, reported as the only patient cured by transplantation to date. A single case. The abstract does not say whether the sibling donor was tested for the TP53 allele.
Show evidence (2 references)
PMID:42104732 SUPPORT Human Clinical
"One patient underwent hematopoietic stem cell transplantation from a matched sibling donor and remained transfusion-independent at last follow-up."
Single-patient outcome after matched-sibling transplantation.
PMID:42104732 SUPPORT Human Clinical
"presents the only patient to date cured by hematopoietic stem cell transplantation"
States that this is the only transplanted patient reported.
🔬

Diagnosis

3
Bone Marrow Examination
Shows the paucity of erythroid precursors that places these patients in the Diamond-Blackfan differential.
Show evidence (1 reference)
PMID:35084091 SUPPORT Human Clinical
"We describe two patients with the phenotype of DBA (onset of macrocytic anemia within the first year of life, paucity of erythroid precursors in bone marrow) and germline de novo variants in the TP53 gene."
The marrow finding that defines the DBA-like phenotype.
Germline TP53 Testing in DBA-Like Anaemia Without a Ribosomal Protein Variant
The practical diagnostic point. TP53 belongs on the gene list for infantile pure red cell aplasia once ribosomal protein genes are negative. The founding variants were found by whole-exome sequencing. A TP53 result must be read by allele class: a C-terminal truncation points here, while a DNA-binding-domain variant points to Li-Fraumeni syndrome, with entirely different surveillance consequences.
Show evidence (2 references)
PMID:35084091 SUPPORT Human Clinical
"The possible role of TP53 variants should be considered in patients with DBA-like phenotype and no mutations in RP genes."
The source's diagnostic recommendation.
PMID:36198537 SUPPORT REVIEW SYNTHESIS Human Clinical
"We discovered germline TP53 activating mutations in IBMFS cases mimicking Diamond-Blackfan anemia using whole-exome sequencing."
Records whole-exome sequencing as the discovery method.
Telomere Length Measurement
Not a discriminator. The founding patients had telomere lengths between the 1st and 10th percentile, and the 2022 single patient had normal telomere lengths, so telomere length neither confirms nor excludes this diagnosis and does not by itself separate it from dyskeratosis congenita.
Show evidence (2 references)
PMID:37834388 SUPPORT REVIEW SYNTHESIS Human Clinical
"Both patients exhibited pure red cell aplasia, growth delays, hypogammaglobulinemia, microcephaly, and telomere length between the 1st and 10th percentile"
Telomere lengths in the founding patients.
PMID:35362179 SUPPORT Human Clinical
"as well as intellectual disability, seizures, microcephaly, short stature, cellular radiosensitivity, and normal telomere lengths"
Normal telomere lengths in a third patient.
📊

Prevalence

1
Worldwide published cases
Cases In Literature Ultra Rare
Seven individuals in four case reports, 2018 to 2026 (two each in PMID:30146126, PMID:35084091 and PMID:42104732, one in PMID:35362179). The 2022 single-patient report described its patient as the third reported individual, so it apparently did not count the two patients of the same year's other report. This is a literature count, not a population rate; no prevalence estimate exists.
Show evidence (2 references)
PMID:35362179 SUPPORT Human Clinical
"This is the third reported individual with a germline p53 activation syndrome"
States the case count at the time of this report.
PMID:42104732 SUPPORT Human Clinical
"We report two French patients who both harbored a heterozygous TP53 deletion"
Adds two further patients to the published count.
🐁

Animal Models

1
p53-delta-31 knock-in mouse
A knock-in that removes the p53 C-terminal domain, published five years before the human syndrome and cited by its authors as closely similar. The human alleles delete 32 residues; the mouse allele deletes 31.
Species
Mouse
Genotype
Trp53 nonsense allele encoding p53 lacking its last 31 residues (p53Δ31)
Publication
PMID:23770245
Pathograph links
p53 Pathway Hyperactivation partially recapitulates fidelity: moderate Loss of the C-terminal domain increases p53 activity and, in homozygotes, causes aplastic anaemia.
Limitations: The severe phenotype requires homozygosity: heterozygous p53+/Δ31 mice are only mildly affected, whereas every reported patient is heterozygous. The homozygous mice model dyskeratosis congenita, with short telomeres and pulmonary fibrosis, more closely than they model the Diamond-Blackfan-like erythroid failure of the human disease.
Readouts
p53 activity and marrow failure
Direction: INCREASED
Interpretation: Increased p53 activity with aplastic anaemia in homozygous mice.
Show evidence (1 reference)
PMID:23770245 SUPPORT Model Organism
"Here, we show that homozygous mutant mice expressing p53Δ31, a p53 lacking the C-terminal domain, exhibit increased p53 activity and suffer from aplastic anemia and pulmonary fibrosis, hallmarks of syndromes caused by short telomeres."
Reports the activity readout and the marrow phenotype.
Show evidence (2 references)
PMID:23770245 SUPPORT Model Organism
"Heterozygous p53+/Δ31 mice were only mildly affected, but decreased levels of Mdm4, a negative regulator of p53, led to a dramatic aggravation of their symptoms."
The dosage caveat on this model, and a pointer to MDM4 level as a modifier of a heterozygous C-terminal truncation.
+ 1 more reference
{ }

Source YAML

click to show 
name: Bone Marrow Failure Syndrome 5
creation_date: "2026-10-13T20:15:41Z"
category: Mendelian
disease_term:
  preferred_term: bone marrow failure syndrome 5
  term:
    id: MONDO:0032573
    label: bone marrow failure syndrome 5
description: >
  Bone marrow failure syndrome 5 (BMFS5), also called germline p53 (TP53)
  activation syndrome, is an inherited bone marrow failure syndrome caused by
  heterozygous germline frameshift variants near the 3' end of TP53 that
  truncate the p53 C-terminal domain. It was defined in 2018 in two unrelated
  individuals with de novo variants that both removed the last 32 residues of
  p53; the truncated protein had augmented, not reduced, transcriptional
  activity. The presentation mimics Diamond-Blackfan anaemia (DBA):
  anaemia with a paucity of erythroid precursors (pure red cell aplasia),
  beginning within the first year of life where onset is reported, together
  with hypogammaglobulinaemia, growth retardation and microcephaly. Later
  reports added intellectual disability, seizures, short stature, cellular
  radiosensitivity and transient neutropenia.

  The literature is small. Four case reports describe seven individuals.
  Every allele whose position the abstracts state is a C-terminal
  frameshift; the 2022 abstract describing two further patients
  (PMID:35084091) calls their de novo variants activating without naming
  them.
  Corticosteroid response is inconsistent (one responder, two
  non-responders), two patients became transfusion independent on L-leucine,
  and one patient is reported cured by matched-sibling haematopoietic stem
  cell transplantation.

  BMFS5 is the mechanistic inverse of Li-Fraumeni syndrome. Li-Fraumeni
  variants mostly inactivate the p53 DNA-binding domain and predispose to
  cancer; the BMFS5 alleles truncate the C-terminal domain and raise p53
  transcriptional output. None of the four case-report abstracts reports a
  malignancy, and no source located for this entry addresses cancer risk in
  carriers, so the entry records no cancer phenotype and treats cancer risk
  as an open question. The C-terminally truncated p53-delta-31 mouse, which
  predates the human syndrome, has increased p53 activity and aplastic
  anaemia with features of dyskeratosis congenita when homozygous, but
  heterozygous mice are only mildly affected.
synonyms:
- BMFS5
- germline p53 activation syndrome
- germline TP53 activation syndrome
parents:
- Inherited bone marrow failure syndrome
- Bone marrow failure syndrome
notes: >-
  No GeneReviews chapter names this disease (`just check-genereviews --online`
  returned NO_CHAPTER for the name, MONDO label and synonyms). ClinGen has no
  gene-disease validity assertion for TP53 in this disease; the cached ClinGen
  TP53 record is for Li-Fraumeni syndrome. All four case reports were read as
  PubMed abstracts only, so variant nomenclature for the first five patients,
  exact onset ages and follow-up durations are not recorded here.
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
    evidence:
    - reference: PMID:30146126
      reference_title: "De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here, we report unique de novo TP53 germline variants found in two individuals with an IBMFS accompanied by hypogammaglobulinemia, growth retardation, and microcephaly mimicking DBA and DC."
      explanation: >
        An inherited bone marrow failure syndrome, placing it in Harrison's
        haematology/oncology Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:30146126
      reference_title: "De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here, we report unique de novo TP53 germline variants found in two individuals with an IBMFS accompanied by hypogammaglobulinemia, growth retardation, and microcephaly mimicking DBA and DC."
      explanation: >
        A germline monogenic disorder, placing it in Harrison's genetics Part.

inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    A single heterozygous germline allele is sufficient. The four patients
    whose origin the abstracts state (PMID:30146126, PMID:35084091) carried
    de novo variants, and none of the four abstracts reports transmission
    from an affected parent, so dominant inheritance rests on heterozygosity
    and on the activating mechanism rather than on observed segregation. The
    two French patients carry the same allele; their abstract does not say
    whether they are related or whether either parent was tested.
  evidence:
  - reference: PMID:35362179
    reference_title: "The germline p53 activation syndrome: A new patient further refines the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "who had a germline heterozygous C-terminal frameshift variant in TP53 similar to others that activate the transcription factor"
    explanation: >
      Documents a heterozygous germline allele as sufficient for the
      phenotype.
  - reference: PMID:42104732
    reference_title: "Germline TP53 Mutations Causing Diamond-Blackfan Anemia: A French Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two French patients who both harbored a heterozygous TP53 deletion (NM_000546.5: c.1077delA; p.(Ser362AlafsTer8))."
    explanation: >
      Two further affected individuals, each heterozygous.
  - reference: PMID:35084091
    reference_title: "De novo TP53 germline activating mutations in two patients with the phenotype mimicking Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe two patients with the phenotype of DBA (onset of macrocytic anemia within the first year of life, paucity of erythroid precursors in bone marrow) and germline de novo variants in the TP53 gene."
    explanation: >
      Records de novo origin in two more patients, consistent with a
      dominant-acting allele arising without family history.

prevalence:
- population: Worldwide published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Seven individuals in four case reports, 2018 to 2026 (two each in
    PMID:30146126, PMID:35084091 and PMID:42104732, one in PMID:35362179). The
    2022 single-patient report described its patient as the third reported
    individual, so it apparently did not count the two patients of the same
    year's other report. This is a literature count, not a population rate;
    no prevalence estimate exists.
  evidence:
  - reference: PMID:35362179
    reference_title: "The germline p53 activation syndrome: A new patient further refines the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the third reported individual with a germline p53 activation syndrome"
    explanation: >
      States the case count at the time of this report.
  - reference: PMID:42104732
    reference_title: "Germline TP53 Mutations Causing Diamond-Blackfan Anemia: A French Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two French patients who both harbored a heterozygous TP53 deletion"
    explanation: >
      Adds two further patients to the published count.

pathophysiology:
- name: TP53 C-Terminal Domain Truncation
  biological_scale: MOLECULAR
  description: >
    Heterozygous germline frameshift variants near the 3' end of TP53 remove
    the C-terminal domain while leaving the core DNA-binding domain intact. In
    the defining report both variants produced the same truncation, deleting
    32 residues, and the mutant protein showed augmented transcriptional
    activity. This is the opposite direction of effect from the
    DNA-binding-domain variants of Li-Fraumeni syndrome. Recorded as
    GAIN_OF_FUNCTION following the sources' own wording ("activating",
    "gain-of-function"); the reported effect is increased transactivation by
    the truncated protein, not a novel activity.
  genes:
  - preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
    modifier: INCREASED
  genetic_context:
    description: >-
      Heterozygous germline C-terminal frameshift TP53 alleles, de novo where
      origin is reported.
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific
    modifier: INCREASED
    term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence:
  - reference: PMID:30146126
    reference_title: "De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, the variants found in the two individuals studied here caused the same truncation of the protein, resulting in the loss of 32 residues from the C-terminal domain (CTD)."
    explanation: >
      Defines the lesion in the two founding patients.
  - reference: PMID:30146126
    reference_title: "De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Unexpectedly, the p53 mutant had augmented transcriptional activities, an observation not previously described in humans."
    explanation: >
      Establishes the direction of effect: the truncated p53 transactivates
      more, not less, which is what makes this a p53-activating rather than a
      p53-losing disorder.
  - reference: PMID:30146126
    reference_title: "De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Most of these mutations affect the core DNA-binding domain, leading to compromised transcriptional activities."
    explanation: >
      The contrast with Li-Fraumeni alleles that the authors draw, which is why
      this entry is kept separate from Li-Fraumeni syndrome.
  - reference: PMID:42104732
    reference_title: "Germline TP53 Mutations Causing Diamond-Blackfan Anemia: A French Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recently, gain-of-function mutations in TP53 have been identified as a novel cause of Diamond-Blackfan anemia."
    explanation: >
      The source for the GAIN_OF_FUNCTION category label.
  downstream:
  - target: p53 Pathway Hyperactivation
    description: >
      Loss of the C-terminal domain increases p53 transcriptional output.
    evidence:
    - reference: PMID:37834388
      reference_title: "p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These results clearly established that a loss of the p53 C-terminal domain led to increased p53 activity."
      explanation: >
        The review's summary of the p53-delta-31 mouse data, in which
        deleting the last 31 residues stabilised p53 and increased target-gene
        transactivation. Graded MODEL_ORGANISM because the underlying data are
        from mouse cells.

- name: p53 Pathway Hyperactivation
  biological_scale: CELLULAR
  description: >
    The central node. Constitutively augmented p53 target-gene transactivation
    in every cell carrying the allele. The authors of the defining report frame
    the disease as confirming that p53 activation itself can cause an inherited
    bone marrow failure syndrome, rather than only accompanying the ribosomal,
    telomere or DNA-repair defects of other such syndromes. Here p53 activation
    is the primary lesion rather than a downstream consequence.
  biological_processes:
  - preferred_term: signal transduction by p53 class mediator
    modifier: INCREASED
    term:
      id: GO:0072331
      label: signal transduction by p53 class mediator
  evidence:
  - reference: PMID:35362179
    reference_title: "The germline p53 activation syndrome: A new patient further refines the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "who had a germline heterozygous C-terminal frameshift variant in TP53 similar to others that activate the transcription factor"
    explanation: >
      Places a third patient's variant in the activating class.
  - reference: PMID:36198537
    reference_title: "[Bone marrow failure and TP53 activating mutations]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "This discovery confirms the hypothesis that p53 activation causes IBMFS."
    explanation: >
      Review by the senior author of the defining report, stating the
      organising claim of the entry.
  downstream:
  - target: Impaired Erythropoiesis
    description: >
      Expression of the truncated p53 impairs erythrocyte production.
    evidence:
    - reference: PMID:30146126
      reference_title: "De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "When we expressed this mutant in zebrafish and human-induced pluripotent stem cells, we observed impaired erythrocyte production."
      explanation: >
        The functional link between the mutant protein and the erythroid
        defect. The sentence covers both a zebrafish (in vivo) and a human
        iPSC (in vitro) system; it is graded MODEL_ORGANISM for the
        zebrafish arm, and the iPSC result is the in vitro half of the same
        sentence.
  - target: Growth delay
    description: >
      Proposed, not demonstrated in patients. Mice with broad p53
      hyperactivation show developmental defects attributed to excess
      apoptosis or reduced proliferation in specific embryonic and neonatal
      compartments; the authors of the defining report state that the role of
      p53 activation in each clinical feature remains unknown.
    hypothesis_groups:
    - p53_activation_extrahematopoietic
    evidence:
    - reference: PMID:30624728
      reference_title: "The role of p53 in developmental syndromes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: "Analyses from a variety of mouse strains demonstrate that inappropriately activating p53 during embryonic and early postnatal development triggers a host of developmental defects."
      explanation: >
        Mouse-only support for p53 hyperactivation causing developmental
        defects; the extension to this human feature is inference.
  - target: Microcephaly
    description: >
      Proposed, not demonstrated in patients. Mouse strains with p53
      hyperactivation show excess apoptosis or reduced proliferation in the
      embryonic neuroepithelium and neonatal cerebellum.
    hypothesis_groups:
    - p53_activation_extrahematopoietic
    evidence:
    - reference: PMID:30624728
      reference_title: "The role of p53 in developmental syndromes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: "Excessive apoptosis and/or decreased proliferation have been detected in certain cell compartments in these mouse strains, such as the embryonic neuroepithelium and the neonatal bone marrow and cerebellum"
      explanation: >
        Mouse-only cellular basis for a neural growth defect under p53
        hyperactivation; the extension to human microcephaly in this
        syndrome is inference.
  - target: Cellular radiosensitivity
    description: >
      Proposed. In p53-delta-31 mouse cells loss of the C-terminal domain
      strengthened the cell-cycle arrest and apoptotic responses to
      irradiation; the patient's radiosensitivity assay is not described in
      the cited abstract.
    hypothesis_groups:
    - p53_activation_extrahematopoietic
    evidence:
    - reference: PMID:37834388
      reference_title: "p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: "an increased apoptotic response was observed in irradiated p53Δ31/Δ31 thymocytes"
      explanation: >
        Mouse evidence that C-terminal truncation heightens the p53 response
        to ionising radiation.
  - target: Hypogonadism
    description: >
      Proposed. Homozygous p53-delta-31 male mice are hypogonadal; one
      founding patient had hypogonadism.
    hypothesis_groups:
    - p53_activation_extrahematopoietic
    evidence:
    - reference: PMID:37834388
      reference_title: "p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: "Upon dissection, p53Δ31/Δ31 mice exhibited cerebellar hypoplasia, hypogonadism in males, and hypertrophic hearts typical of anemic animals."
      explanation: >
        Mouse-only support; the extension to the patient is inference.
  - target: Reticular skin pigmentation
    description: >
      Proposed. Mouse strains with p53 hyperactivation, including
      p53-delta-31, develop skin hyperpigmentation from accumulation of
      epidermal melanocytes; one founding patient had reticular pigmentation.
    hypothesis_groups:
    - p53_activation_extrahematopoietic
    evidence:
    - reference: PMID:30624728
      reference_title: "The role of p53 in developmental syndromes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: "A number of mouse strains with p53 hyperactivation exhibit hyperpigmentation defects in which the skin on the paws, tails, and ears darkens during the early postnatal period due to the progressive accumulation of melanocytes in the epidermis"
      explanation: >
        Mouse-only support; the reticular pattern seen in the patient is not
        modelled.

- name: Impaired Erythropoiesis
  biological_scale: CELLULAR
  description: >
    Failure of erythroid production with a paucity of erythroid precursors in
    the marrow, the Diamond-Blackfan-like core of the syndrome. In patients
    the erythroid lineage is the consistently affected one; neutropenia, where
    reported, was transient.
  cell_types:
  - preferred_term: erythroid progenitor cell
    term:
      id: CL:0000038
      label: erythroid progenitor cell
  biological_processes:
  - preferred_term: erythrocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0030218
      label: erythrocyte differentiation
  evidence:
  - reference: PMID:35084091
    reference_title: "De novo TP53 germline activating mutations in two patients with the phenotype mimicking Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe two patients with the phenotype of DBA (onset of macrocytic anemia within the first year of life, paucity of erythroid precursors in bone marrow) and germline de novo variants in the TP53 gene."
    explanation: >
      Marrow-level human evidence for the erythroid precursor deficit.
  - reference: PMID:30146126
    reference_title: "De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "When we expressed this mutant in zebrafish and human-induced pluripotent stem cells, we observed impaired erythrocyte production."
    explanation: >
      Experimental reproduction of the erythroid defect by the mutant protein.
  downstream:
  - target: Pure red cell aplasia
    description: Erythroid failure presents as red cell aplasia with anaemia.
  - target: Macrocytic anemia
    description: >
      The anaemia that results from erythroid failure, macrocytic in the two
      patients of PMID:35084091.
  - target: Normocytic anemia
    description: >
      The anaemia that results from erythroid failure, normocytic in the two
      French patients.

mechanistic_hypotheses:
- hypothesis_group_id: p53_activation_extrahematopoietic
  hypothesis_label: Constitutive p53 activation drives the non-haematological features
  status: EMERGING
  description: >
    The erythroid defect is experimentally linked to the truncated p53 in
    zebrafish and human iPSCs. The growth, microcephaly, pigmentary, gonadal
    and radiosensitivity features are not: they are attributed to p53
    activation by analogy with mouse strains carrying p53-hyperactivating
    alleles, and the immunoglobulin defect has no proposed mechanism in the
    sources cited here. The authors of the defining report state that the role of p53
    activation in each clinical feature remains unknown. Edges in this group
    are proposals carried by mouse data, not demonstrations in patients.
  evidence:
  - reference: PMID:30146126
    reference_title: "De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "However, the exact role of p53 activation in each clinical feature remains unknown."
    explanation: >
      The source's own statement of the open question this hypothesis
      addresses.

phenotypes:
- category: Hematologic
  name: Pure red cell aplasia
  description: >
    The defining feature. Reported as pure red cell aplasia in both founding
    patients and as red cell aplasia in the 2022 single-patient report; the
    two patients of the other 2022 report had a paucity of erythroid
    precursors on marrow examination, and both French patients were diagnosed
    with TP53-associated Diamond-Blackfan anaemia. Onset was within the first
    year of life in the two patients for whom the abstracts state it.
  phenotype_term:
    preferred_term: Pure red cell aplasia
    term:
      id: HP:0012410
      label: Pure red cell aplasia
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:37834388
    reference_title: "p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Both patients exhibited pure red cell aplasia, growth delays, hypogammaglobulinemia, microcephaly, and telomere length between the 1st and 10th percentile"
    explanation: >
      Review summary of the two founding patients, both with pure red cell
      aplasia.
  - reference: PMID:35362179
    reference_title: "The germline p53 activation syndrome: A new patient further refines the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report a patient with red cell aplasia, which was steroid responsive"
    explanation: >
      Red cell aplasia in the third reported patient.
  - reference: PMID:35084091
    reference_title: "De novo TP53 germline activating mutations in two patients with the phenotype mimicking Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe two patients with the phenotype of DBA (onset of macrocytic anemia within the first year of life, paucity of erythroid precursors in bone marrow) and germline de novo variants in the TP53 gene."
    explanation: >
      Erythroid precursor paucity with onset in the first year of life,
      supporting the infantile onset recorded here.

- category: Hematologic
  name: Macrocytic anemia
  description: >
    Reported in the two patients of PMID:35084091. The two French patients
    instead had normocytic anaemia, so red cell size is not a reliable
    discriminator from other causes of DBA-like anaemia here.
  phenotype_term:
    preferred_term: Macrocytic anemia
    term:
      id: HP:0001972
      label: Macrocytic anemia
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:35084091
    reference_title: "De novo TP53 germline activating mutations in two patients with the phenotype mimicking Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe two patients with the phenotype of DBA (onset of macrocytic anemia within the first year of life, paucity of erythroid precursors in bone marrow) and germline de novo variants in the TP53 gene."
    explanation: >
      Macrocytic anaemia with infantile onset in two patients.

- category: Hematologic
  name: Normocytic anemia
  description: >
    Reported in both French patients (PMID:42104732), in contrast to the
    macrocytosis of PMID:35084091.
  phenotype_term:
    preferred_term: Normocytic anemia
    term:
      id: HP:0001897
      label: Normocytic anemia
  evidence:
  - reference: PMID:42104732
    reference_title: "Germline TP53 Mutations Causing Diamond-Blackfan Anemia: A French Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They exhibited normocytic anemia, transient neutropenia at presentation, and distinct neurological impairments."
    explanation: >
      Normocytic anaemia in two patients.

- category: Hematologic
  name: Transient neutropenia
  description: >
    Neutropenia at presentation that resolved, in both French patients. Not
    reported in the earlier abstracts.
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
    temporality: TRANSIENT
  evidence:
  - reference: PMID:42104732
    reference_title: "Germline TP53 Mutations Causing Diamond-Blackfan Anemia: A French Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They exhibited normocytic anemia, transient neutropenia at presentation, and distinct neurological impairments."
    explanation: >
      Transient neutropenia in two patients.

- category: Immunologic
  name: Hypogammaglobulinemia
  description: >
    Present in both founding patients. Its mechanism is not addressed by any
    source cited here, so it is left unwired in the pathograph and carried as
    a knowledge gap.
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:30146126
    reference_title: "De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report unique de novo TP53 germline variants found in two individuals with an IBMFS accompanied by hypogammaglobulinemia, growth retardation, and microcephaly mimicking DBA and DC."
    explanation: >
      Hypogammaglobulinaemia in both founding patients.

- category: Growth
  name: Growth delay
  description: >
    Growth retardation in both founding patients; the third reported patient
    had short stature.
  phenotype_term:
    preferred_term: Growth retardation
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:30146126
    reference_title: "De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report unique de novo TP53 germline variants found in two individuals with an IBMFS accompanied by hypogammaglobulinemia, growth retardation, and microcephaly mimicking DBA and DC."
    explanation: >
      Growth retardation in both founding patients.
  sequelae:
  - target: Short stature
    description: Growth failure manifesting as short stature.

- category: Growth
  name: Short stature
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:35362179
    reference_title: "The germline p53 activation syndrome: A new patient further refines the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "as well as intellectual disability, seizures, microcephaly, short stature, cellular radiosensitivity, and normal telomere lengths"
    explanation: >
      Short stature in the third reported patient.

- category: Neurological
  name: Microcephaly
  description: >
    Present in both founding patients and the third reported patient.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:30146126
    reference_title: "De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report unique de novo TP53 germline variants found in two individuals with an IBMFS accompanied by hypogammaglobulinemia, growth retardation, and microcephaly mimicking DBA and DC."
    explanation: >
      Microcephaly in both founding patients.
  - reference: PMID:35362179
    reference_title: "The germline p53 activation syndrome: A new patient further refines the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "as well as intellectual disability, seizures, microcephaly, short stature, cellular radiosensitivity, and normal telomere lengths"
    explanation: >
      Microcephaly in the third reported patient.

- category: Neurological
  name: Intellectual disability
  description: >
    Reported in the third patient. The French report describes distinct
    neurological impairments in both its patients without specifying them in
    the abstract.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:35362179
    reference_title: "The germline p53 activation syndrome: A new patient further refines the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "as well as intellectual disability, seizures, microcephaly, short stature, cellular radiosensitivity, and normal telomere lengths"
    explanation: >
      Intellectual disability in the third reported patient.

- category: Neurological
  name: Seizure
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:35362179
    reference_title: "The germline p53 activation syndrome: A new patient further refines the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "as well as intellectual disability, seizures, microcephaly, short stature, cellular radiosensitivity, and normal telomere lengths"
    explanation: >
      Seizures in the third reported patient.

- category: Cellular
  name: Cellular radiosensitivity
  description: >
    Reported in the third patient. Consistent with a hyperactive p53 response
    to DNA damage, but the cited abstract does not report the assay or link it
    mechanistically.
  phenotype_term:
    preferred_term: Cellular radiosensitivity
    term:
      id: HP:0011133
      label: Increased sensitivity to ionizing radiation
  evidence:
  - reference: PMID:35362179
    reference_title: "The germline p53 activation syndrome: A new patient further refines the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "as well as intellectual disability, seizures, microcephaly, short stature, cellular radiosensitivity, and normal telomere lengths"
    explanation: >
      Cellular radiosensitivity in the third reported patient.

- category: Integument
  name: Reticular skin pigmentation
  description: >
    Reported in one of the two founding patients, a dyskeratosis
    congenita-like feature.
  phenotype_term:
    preferred_term: Reticular skin pigmentation
    term:
      id: HP:0007588
      label: Reticular hyperpigmentation
  evidence:
  - reference: PMID:37834388
    reference_title: "p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "one patient also presented reticular skin pigmentation, hypogonadism, and tooth anomalies"
    explanation: >
      Review summary of the founding report; one patient only.

- category: Endocrine
  name: Hypogonadism
  description: Reported in one of the two founding patients.
  phenotype_term:
    preferred_term: Hypogonadism
    term:
      id: HP:0000135
      label: Hypogonadism
  evidence:
  - reference: PMID:37834388
    reference_title: "p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "one patient also presented reticular skin pigmentation, hypogonadism, and tooth anomalies"
    explanation: >
      Review summary of the founding report; one patient only.

- category: Dental
  name: Tooth anomalies
  description: >
    Reported in one of the two founding patients. The cited summary does not
    specify the anomaly, hence the general dentition term.
  phenotype_term:
    preferred_term: Tooth anomalies
    term:
      id: HP:0000164
      label: Abnormality of the dentition
  evidence:
  - reference: PMID:37834388
    reference_title: "p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "one patient also presented reticular skin pigmentation, hypogonadism, and tooth anomalies"
    explanation: >
      Review summary of the founding report; one patient only.

genetic:
- name: TP53
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >
    Heterozygous germline frameshift variants that truncate the p53 C-terminal
    domain and increase p53 transcriptional activity. The same gene causes
    Li-Fraumeni syndrome through a different allelic class, mainly
    DNA-binding-domain variants that compromise transactivation; the two
    diseases are kept as separate entries.
  review_notes: >-
    `relationship_type: CAUSATIVE` rests on seven patients in four case
    reports, de novo origin where reported, recurrence of C-terminal
    truncation across independent families, and functional reproduction of
    the erythroid defect in zebrafish and human iPSCs. No ClinGen
    gene-disease validity assertion exists for TP53 in this disease; the
    cached ClinGen TP53 record (Definitive) is for Li-Fraumeni syndrome,
    MONDO:0018875, and is not copied here.
  evidence:
  - reference: PMID:30146126
    reference_title: "De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings together with close similarities to published knock-in mouse models of TP53 lacking the CTD demonstrate that the CTD-truncation mutations of TP53 cause IBMFS"
    explanation: >
      The defining report's causal conclusion for C-terminal truncating TP53
      alleles.
  - reference: PMID:35084091
    reference_title: "De novo TP53 germline activating mutations in two patients with the phenotype mimicking Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe two patients with the phenotype of DBA (onset of macrocytic anemia within the first year of life, paucity of erythroid precursors in bone marrow) and germline de novo variants in the TP53 gene."
    explanation: >
      Independent replication in two further de novo patients.

variants:
- name: TP53 c.1077delA p.(Ser362AlafsTer8)
  description: >-
    Carried in the heterozygous state by both French patients (PMID:42104732).
    A frameshift at codon 362 falls in the C-terminal region whose truncation
    defines the syndrome. The cDNA changes of the founding patients and of the
    two patients of PMID:35084091 are not given in their abstracts.
  gene:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  type: frameshift
  evidence:
  - reference: PMID:42104732
    reference_title: "Germline TP53 Mutations Causing Diamond-Blackfan Anemia: A French Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two French patients who both harbored a heterozygous TP53 deletion (NM_000546.5: c.1077delA; p.(Ser362AlafsTer8))."
    explanation: >-
      Names the allele with its transcript reference.

treatments:
- name: Red Blood Cell Transfusion
  description: >
    Supportive treatment of the anaemia. Transfusion dependence is implied in
    the reports that describe patients becoming transfusion independent after
    other therapy; no source here describes transfusion regimens or iron
    overload in this disease.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: red blood cell transfusion
    term:
      id: NCIT:C15409
      label: Packed Red Blood Cell Transfusion
  evidence:
  - reference: PMID:35084091
    reference_title: "De novo TP53 germline activating mutations in two patients with the phenotype mimicking Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients became transfusion independent, probably due to L-leucine therapy."
    explanation: >
      Becoming transfusion independent presupposes prior transfusion support.

- name: Corticosteroid Therapy
  description: >
    Tried in these patients because of the Diamond-Blackfan-like
    presentation. Response is inconsistent across the three
    patients for whom it is reported: the 2022 single patient was steroid
    responsive, and neither French patient responded.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: systemic corticosteroid therapy
    term:
      id: NCIT:C122080
      label: Systemic Corticosteroid Therapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  evidence:
  - reference: PMID:35362179
    reference_title: "The germline p53 activation syndrome: A new patient further refines the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report a patient with red cell aplasia, which was steroid responsive"
    explanation: >
      Steroid-responsive red cell aplasia in one patient.
  - reference: PMID:42104732
    reference_title: "Germline TP53 Mutations Causing Diamond-Blackfan Anemia: A French Report."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Neither patient responded to a corticosteroid trial."
    explanation: >
      Two non-responders, so a steroid response cannot be assumed.

- name: L-Leucine
  description: >
    Both patients of PMID:35084091 became transfusion independent, which the
    authors attribute, with hedging, to L-leucine. Two uncontrolled
    observations; causality is not established.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: L-leucine
      term:
        id: CHEBI:15603
        label: L-leucine
  evidence:
  - reference: PMID:35084091
    reference_title: "De novo TP53 germline activating mutations in two patients with the phenotype mimicking Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients became transfusion independent, probably due to L-leucine therapy."
    explanation: >
      Transfusion independence in two patients on L-leucine, attributed to it
      by the authors with explicit uncertainty.

- name: Hematopoietic Stem Cell Transplantation
  description: >
    One French patient received a matched-sibling transplant and remained
    transfusion independent at last follow-up, reported as the only patient
    cured by transplantation to date. A single case. The abstract does not say
    whether the sibling donor was tested for the TP53 allele.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  evidence:
  - reference: PMID:42104732
    reference_title: "Germline TP53 Mutations Causing Diamond-Blackfan Anemia: A French Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient underwent hematopoietic stem cell transplantation from a matched sibling donor and remained transfusion-independent at last follow-up."
    explanation: >
      Single-patient outcome after matched-sibling transplantation.
  - reference: PMID:42104732
    reference_title: "Germline TP53 Mutations Causing Diamond-Blackfan Anemia: A French Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presents the only patient to date cured by hematopoietic stem cell transplantation"
    explanation: >
      States that this is the only transplanted patient reported.

diagnosis:
- name: Bone Marrow Examination
  description: >
    Shows the paucity of erythroid precursors that places these patients in
    the Diamond-Blackfan differential.
  evidence:
  - reference: PMID:35084091
    reference_title: "De novo TP53 germline activating mutations in two patients with the phenotype mimicking Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe two patients with the phenotype of DBA (onset of macrocytic anemia within the first year of life, paucity of erythroid precursors in bone marrow) and germline de novo variants in the TP53 gene."
    explanation: >
      The marrow finding that defines the DBA-like phenotype.

- name: Germline TP53 Testing in DBA-Like Anaemia Without a Ribosomal Protein Variant
  description: >
    The practical diagnostic point. TP53 belongs on the gene list for
    infantile pure red cell aplasia once ribosomal protein genes are negative.
    The founding variants were found by whole-exome sequencing. A TP53 result
    must be read by allele class: a C-terminal truncation points here, while a
    DNA-binding-domain variant points to Li-Fraumeni syndrome, with entirely
    different surveillance consequences.
  evidence:
  - reference: PMID:35084091
    reference_title: "De novo TP53 germline activating mutations in two patients with the phenotype mimicking Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The possible role of TP53 variants should be considered in patients with DBA-like phenotype and no mutations in RP genes."
    explanation: >
      The source's diagnostic recommendation.
  - reference: PMID:36198537
    reference_title: "[Bone marrow failure and TP53 activating mutations]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "We discovered germline TP53 activating mutations in IBMFS cases mimicking Diamond-Blackfan anemia using whole-exome sequencing."
    explanation: >
      Records whole-exome sequencing as the discovery method.

- name: Telomere Length Measurement
  description: >
    Not a discriminator. The founding patients had telomere lengths between
    the 1st and 10th percentile, and the 2022 single patient had normal
    telomere lengths, so telomere length neither confirms nor excludes this
    diagnosis and does not by itself separate it from dyskeratosis congenita.
  evidence:
  - reference: PMID:37834388
    reference_title: "p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Both patients exhibited pure red cell aplasia, growth delays, hypogammaglobulinemia, microcephaly, and telomere length between the 1st and 10th percentile"
    explanation: >
      Telomere lengths in the founding patients.
  - reference: PMID:35362179
    reference_title: "The germline p53 activation syndrome: A new patient further refines the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "as well as intellectual disability, seizures, microcephaly, short stature, cellular radiosensitivity, and normal telomere lengths"
    explanation: >
      Normal telomere lengths in a third patient.

animal_models:
- name: p53-delta-31 knock-in mouse
  species: Mouse
  genotype: Trp53 nonsense allele encoding p53 lacking its last 31 residues (p53Δ31)
  publication: PMID:23770245
  description: >
    A knock-in that removes the p53 C-terminal domain, published five years
    before the human syndrome and cited by its authors as closely similar.
    The human alleles delete 32 residues; the mouse allele deletes 31.
  modeled_mechanisms:
  - target: p53 Pathway Hyperactivation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >
      Loss of the C-terminal domain increases p53 activity and, in
      homozygotes, causes aplastic anaemia.
    limitations: >-
      The severe phenotype requires homozygosity: heterozygous p53+/Δ31 mice
      are only mildly affected, whereas every reported patient is
      heterozygous. The homozygous mice model dyskeratosis congenita, with
      short telomeres and pulmonary fibrosis, more closely than they model the
      Diamond-Blackfan-like erythroid failure of the human disease.
    readouts:
    - name: p53 activity and marrow failure
      target: p53 Pathway Hyperactivation
      direction: INCREASED
      interpretation: >
        Increased p53 activity with aplastic anaemia in homozygous mice.
      evidence:
      - reference: PMID:23770245
        reference_title: "Mutant mice lacking the p53 C-terminal domain model telomere syndromes."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Here, we show that homozygous mutant mice expressing p53Δ31, a p53 lacking the C-terminal domain, exhibit increased p53 activity and suffer from aplastic anemia and pulmonary fibrosis, hallmarks of syndromes caused by short telomeres."
        explanation: Reports the activity readout and the marrow phenotype.
    evidence:
    - reference: PMID:23770245
      reference_title: "Mutant mice lacking the p53 C-terminal domain model telomere syndromes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Heterozygous p53+/Δ31 mice were only mildly affected, but decreased levels of Mdm4, a negative regulator of p53, led to a dramatic aggravation of their symptoms."
      explanation: >
        The dosage caveat on this model, and a pointer to MDM4 level as a
        modifier of a heterozygous C-terminal truncation.
    - reference: PMID:30146126
      reference_title: "De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These findings together with close similarities to published knock-in mouse models of TP53 lacking the CTD demonstrate that the CTD-truncation mutations of TP53 cause IBMFS"
      explanation: >
        The human-syndrome authors' statement that the mouse model is
        informative for this disease.

discussions:
- discussion_id: bmfs5_cancer_risk
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - disease#Bone Marrow Failure Syndrome 5
  - genetic#TP53
  prompt: >-
    Do carriers of C-terminal truncating, activating TP53 alleles have an
    increased cancer risk, and is any tumour surveillance warranted?
  rationale: >-
    Inherited bone marrow failure syndromes as a class carry an increased risk
    of malignancy, and germline TP53 is the Li-Fraumeni gene, so a TP53 result
    on a marrow-failure panel invites Li-Fraumeni-style surveillance. But the
    BMFS5 alleles act in the opposite direction from Li-Fraumeni alleles, and
    the developmental-syndrome literature attributes cancer risk to loss of
    p53 activity rather than to its increase. None of the four case-report
    abstracts (PMID:30146126, PMID:35084091, PMID:35362179, PMID:42104732)
    reports a malignancy; with seven patients and follow-up durations not
    stated in those abstracts, absence of reported cancer is not evidence of
    absent risk.
    Whether somatic loss of the activating allele, or clonal selection for
    p53-pathway escape under constitutive p53 pressure, creates a myeloid
    risk in these patients is untested.
  proposed_experiments:
  - experiment_id: bmfs5_longitudinal_followup
    name: Longitudinal follow-up of reported carriers for malignancy and clonal haematopoiesis
    description: >-
      Pool the reported patients through a bone marrow failure registry and
      follow them for malignancy, with serial marrow or blood sequencing for
      somatic TP53-pathway clones.
    would_support:
    - disease#Bone Marrow Failure Syndrome 5
    supporting_outcome:
    - >-
      Cancer-free follow-up into adulthood with no expanding p53-pathway
      escape clones would support managing carriers without Li-Fraumeni
      surveillance.
    refuting_outcome:
    - >-
      Malignancy, or clonal expansion of cells that have lost or inactivated
      the activating allele, would argue for marrow surveillance.
  evidence:
  - reference: PMID:30146126
    reference_title: "De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Inherited bone-marrow-failure syndromes (IBMFSs) include heterogeneous genetic disorders characterized by bone-marrow failure, congenital anomalies, and an increased risk of malignancy."
    explanation: >-
      The class-level cancer risk that makes the question unavoidable.
  - reference: PMID:30624728
    reference_title: "The role of p53 in developmental syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Of note, while Li-Fraumeni syndrome is caused by mutations in TP53, these mutations are typically loss-of-function or dominant-negative, consistent with this syndrome being linked to increased cancer risk due to loss of p53 activity, rather than developmental defects or premature aging due to increased p53 activity"
    explanation: >-
      The review's distinction between the two allelic classes, the reason
      Li-Fraumeni cancer risk is not imported into this entry.

- discussion_id: bmfs5_extrahematopoietic_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Hypogammaglobulinemia
  - mechanistic_hypotheses#p53_activation_extrahematopoietic
  prompt: >-
    How does constitutive p53 activation produce hypogammaglobulinaemia,
    microcephaly and growth failure in these patients?
  rationale: >-
    Only the erythroid defect has been reproduced experimentally with the
    patient allele. The growth and microcephaly edges in this entry rest on
    mouse strains with broad p53 hyperactivation, and nothing cited here
    addresses the B-cell or immunoglobulin defect at all, so
    hypogammaglobulinaemia is left unwired. The defining report itself names
    this as unknown.
  evidence:
  - reference: PMID:30146126
    reference_title: "De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "However, the exact role of p53 activation in each clinical feature remains unknown."
    explanation: >-
      The authors' own statement of the gap.

- discussion_id: bmfs5_heterozygous_dosage
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - animal_models#Mouse
  - pathophysiology#p53 Pathway Hyperactivation
  prompt: >-
    Why is a single C-terminal truncating TP53 allele sufficient for marrow
    failure in humans when heterozygous p53-delta-31 mice are only mildly
    affected?
  rationale: >-
    The mouse reproduces the direction of effect but needs two copies for the
    severe phenotype, while every reported patient is heterozygous. Candidate
    explanations - greater human sensitivity of erythroid progenitors to p53
    dosage, species differences in p53 target programmes, or the one-residue
    difference between the 31- and 32-residue truncations - are untested. In
    the mouse, lowering Mdm4 converts the mild heterozygote into a severe one,
    so MDM4 or MDM2 dosage is a plausible human modifier, but no source here
    tests it in patients.
  evidence:
  - reference: PMID:23770245
    reference_title: "Mutant mice lacking the p53 C-terminal domain model telomere syndromes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Heterozygous p53+/Δ31 mice were only mildly affected, but decreased levels of Mdm4, a negative regulator of p53, led to a dramatic aggravation of their symptoms."
    explanation: >-
      The model side of the mismatch.
  - reference: PMID:35362179
    reference_title: "The germline p53 activation syndrome: A new patient further refines the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "who had a germline heterozygous C-terminal frameshift variant in TP53 similar to others that activate the transcription factor"
    explanation: >-
      The human side: a heterozygous allele is sufficient.

references:
- reference: PMID:30146126
  title: "De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome."
- reference: PMID:35084091
  title: "De novo TP53 germline activating mutations in two patients with the phenotype mimicking Diamond-Blackfan anemia."
- reference: PMID:35362179
  title: "The germline p53 activation syndrome: A new patient further refines the clinical phenotype."
- reference: PMID:42104732
  title: "Germline TP53 Mutations Causing Diamond-Blackfan Anemia: A French Report."
- reference: PMID:36198537
  title: "[Bone marrow failure and TP53 activating mutations]."
- reference: PMID:37834388
  title: "p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes."
- reference: PMID:30624728
  title: "The role of p53 in developmental syndromes."
- reference: PMID:23770245
  title: "Mutant mice lacking the p53 C-terminal domain model telomere syndromes."
📚

References & Deep Research

References

8
PMID:30146126
De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome.
No top-level findings curated for this source.
PMID:35084091
De novo TP53 germline activating mutations in two patients with the phenotype mimicking Diamond-Blackfan anemia.
No top-level findings curated for this source.
PMID:35362179
The germline p53 activation syndrome: A new patient further refines the clinical phenotype.
No top-level findings curated for this source.
PMID:42104732
Germline TP53 Mutations Causing Diamond-Blackfan Anemia: A French Report.
No top-level findings curated for this source.
PMID:36198537
[Bone marrow failure and TP53 activating mutations].
No top-level findings curated for this source.
PMID:37834388
p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes.
No top-level findings curated for this source.
PMID:30624728
The role of p53 in developmental syndromes.
No top-level findings curated for this source.
PMID:23770245
Mutant mice lacking the p53 C-terminal domain model telomere syndromes.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Bone_Marrow_Failure_Syndrome_5 · 2026-10-13T23:55:23Z · View source

New entry for bone marrow failure syndrome 5 (MONDO:0032573), germline TP53 activation syndrome caused by heterozygous C-terminal truncating TP53 frameshifts. Curated from four case-report abstracts (PMID:30146126, PMID:35084091, PMID:35362179, PMID:42104732; seven patients), three reviews (PMID:37834388, PMID:30624728, PMID:36198537) and the p53-delta-31 mouse paper (PMID:23770245). One deep-research report was used as a lead only: the falcon provider failed authentication (503 Failed to authenticate) on two attempts and on a later providers --check, so the claude_code provider was used instead; its OMIM-summary leads (infantile onset, developmental delay) were not used except where a cached abstract states them. preflight-dr exited 2 because the local mondo.db is absent. Lump/split: kept as a separate DISEASE, not a Diamond-Blackfan anaemia subtype and not a Li-Fraumeni subtype; Li-Fraumeni cancer risk not imported. Gaps recorded: cancer risk unknown (no malignancy in the four abstracts), mechanism of hypogammaglobulinaemia unknown and left unwired, extra-haematopoietic edges rest on mouse data under an EMERGING hypothesis group, heterozygous-human versus homozygous-mouse dosage mismatch, no ClinGen assertion for this disease, no GeneReviews chapter, case-report full texts not cached. Validated with just validate, validate-terms, count-verified-snippets (62/62), entity-ref, causal-target, duplicate-key, qualifier, genereviews, gene-term-mismatch, block-scalar, the ungated snippet/title/grading/retired-prose/environmental/coarse/reference-title/folded-hyphen gates, check_gene_activity_grounding --against-ref origin/main, and validate-disorders, all passing.

Claude Code ▸
Bone Marrow Failure Syndrome 5 (BMFS5; germline TP53 C-terminal activation syndrome): research report
claude-haiku-5-5, claude-sonnet-5-5 2 citations 2026-10-13T20:26:45.346745

I'm pulling the OMIM entry for BMFS5 to confirm the variants and the cancer-risk detail. After that I'll write the report from the cached primary papers.

Bone Marrow Failure Syndrome 5 (BMFS5; germline TP53 C-terminal activation syndrome): research report

Source basis. Every claim below comes from the PubMed abstracts cached in references_cache/ (PMIDs 30146126, 30624728, 35084091, 35362179, 36198537, 37834388, 42104732), or from a web-search summary of the OMIM entry, which I labelled as a lead where I used it. Full texts were not read for the case reports, and the OMIM page itself failed to load (HTTP 420). Statements that rest only on model inference are marked [inferred]. Items I could not source are marked [gap]. Nothing here was checked against ClinVar, gnomAD, HPO annotations, or ClinicalTrials.gov.

1. Disease information

  • Identifiers.
  • MONDO:0032573, from the repo stub, with parent MONDO:0000159 (bone marrow failure syndrome).
  • OMIM #618165, from the OMIM web-search summary (lead).
  • Causal gene: TP53, hgnc:11998. The stub lists it as MONDO's causal gene.
  • Orphanet, ICD-10/11, and MeSH IDs: [gap], not retrieved.
  • Definition. An autosomal dominant inherited bone marrow failure syndrome (IBMFS). It is caused by de novo germline TP53 variants that truncate the C-terminal domain (CTD) and increase p53 transcriptional activity.
  • Toki et al. (PMID:30146126, Am J Hum Genet 2018, primary, human genetics plus zebrafish and iPSC): "unique de novo TP53 germline variants found in two individuals with an IBMFS accompanied by hypogammaglobulinemia, growth retardation, and microcephaly mimicking DBA and DC."
  • Ito (PMID:36198537, review) names it "germline TP53 activation syndrome (bone marrow failure syndrome 5)".
  • Synonyms. Germline p53 activation syndrome (PMID:35362179). TP53-associated Diamond-Blackfan anemia / DBA-like phenotype (PMID:35084091, PMID:42104732).
  • Lump/split call to surface. This is a germline entity. It is distinct from Li-Fraumeni syndrome (DNA-binding-domain loss of function, cancer predisposition) and from somatic TP53-mutant myeloid neoplasms (design decisions §3a). Whether the DBA-like cases should instead sit under Diamond-Blackfan anemia (RP-gene) as a subtype is a nosology question. DBA is defined by ribosomal-protein genes, and PMID:35084091 and PMID:42104732 frame these patients as "DBA-like" or "TP53-associated DBA". I would keep BMFS5 as its own entry and cross-reference DBA.
  • Data level. The literature is aggregated case reports (n≈2 in the discovery paper, then a handful of further patients), not EHR-derived.

2. Etiology

  • Cause. Heterozygous de novo germline TP53 frameshift variants clustered in the C-terminal domain.
  • Toki: "the variants found in the two individuals studied here caused the same truncation of the protein, resulting in the loss of 32 residues from the C-terminal domain (CTD). Unexpectedly, the p53 mutant had augmented transcriptional activities, an observation not previously described in humans."
  • Kumar et al. (PMID:35362179): third reported individual, "a germline heterozygous C-terminal frameshift variant in TP53 similar to others that activate the transcription factor."
  • Moisan et al. (PMID:42104732, 2026): two French patients with NM_000546.5: c.1077delA; p.(Ser362AlafsTer8).
  • Fedorova et al. (PMID:35084091): two patients with "germline de novo variants in the TP53 gene". The abstract gives no cDNA change.
  • The Toki index-case nucleotide changes are [gap]. The shared outcome is a 32-residue CTD loss, which is consistent with the codon ~362 frameshift region. A ClinVar Miner search hit lists TP53 c.1083del p.Ser362fs, a lead that is not verified.
  • Genetic risk factors. No modifier genes or susceptibility loci identified [gap].
  • Environmental risk and protective factors; gene-environment interaction. None reported in the sources [gap].
  • Related evidence on germline p53 hyperactivation. Rakotopare & Toledo (PMID:37834388, review): "germline mutations affecting TP53 or its regulator MDM4 may cause short telomeres and alter hematopoiesis, but also revealed features of Diamond-Blackfan anemia (DBA) or Fanconi anemia (FA)."

3. Phenotypes

Frequencies cannot be given because only about 6–8 patients are reported. HPO terms below are suggestions from my own recall and are unverified, so look each up before binding it.

Phenotype Source Suggested HPO (verify)
Infantile-onset severe, transfusion-requiring anemia / red cell aplasia OMIM summary (lead); PMID:35084091 ("onset of macrocytic anemia within the first year of life, paucity of erythroid precursors in bone marrow"); PMID:35362179 ("red cell aplasia, which was steroid responsive") HP:0001903 anemia, HP:0001927/other macrocytosis terms, erythroid hypoplasia
Hypogammaglobulinemia PMID:30146126 HP:0004313
Growth retardation / short stature PMID:30146126, PMID:35362179 HP:0004322
Microcephaly PMID:30146126, PMID:35362179 HP:0000252
Intellectual disability, seizures PMID:35362179; OMIM summary lists developmental delay and seizures HP:0001249, HP:0001250
Cellular radiosensitivity PMID:35362179 no confident HPO term
Normal telomere length PMID:35362179; OMIM summary (lead) not a phenotype term
Transient neutropenia, normocytic anemia, "distinct neurological impairments" PMID:42104732 HP:0001875
  • Variability.
  • Steroid response differed across patients. One patient was steroid-responsive (PMID:35362179). Neither French patient responded (PMID:42104732).
  • Anemia was normocytic in the French patients and macrocytic in the Russian ones.
  • Neurological involvement varies.
  • Quality-of-life data: none [gap].

4. Genetic and molecular information

  • Gene. TP53, hgnc:11998, 17p13.
  • Variant class. C-terminal frameshifts that remove the last 32 residues (PMID:30146126). This is a gain-of-function / hyperactivating effect on transcription, not the dominant-negative DNA-binding-domain effect typical of Li-Fraumeni. For the KB slot, functional_impact_category: GAIN_OF_FUNCTION fits, but check whether a finer value is warranted.
  • Origin. De novo germline in all reported cases (PMID:30146126; PMID:35084091). Parental mosaicism and recurrence risk are [gap].
  • Population frequency, ACMG classification, and ClinGen gene-disease validity: [gap]. A ClinGen assertion would be worth looking up in the CGGV: cache. I did not check it.
  • Epigenetic and chromosomal findings: none reported.

5. Environmental information

None reported. A cellular radiosensitivity finding in one patient (PMID:35362179) is a cell-level observation, not an environmental risk factor. No infectious or lifestyle contributors are reported.

6. Mechanism and pathophysiology (causal chain)

  1. De novo TP53 frameshift in the C-terminal domain deletes 32 residues (PMID:30146126, human genetics).
  2. Loss of the CTD increases p53 transcriptional activity. Toki reports "the p53 mutant had augmented transcriptional activities" (in vitro). The CTD normally restrains DNA binding, so I infer the restraint is lost [inferred].
  3. p53 hyperactivation leads to impaired erythropoiesis. Expression in zebrafish and human iPSCs gave "impaired erythrocyte production" (PMID:30146126, model organism and in vitro).
  4. Impaired erythropoiesis results in early-onset red cell aplasia / anemia, a DBA-like picture.

  5. Branch, non-hematologic. Constitutive p53 activity likely leads to growth failure, microcephaly, and hypogammaglobulinemia [inferred]. The supporting data are mouse knock-ins (see section 15) and the review PMID:30624728, which states "increased p53 activity underlies the developmental defects in a wide range of genetic syndromes."

  6. Positive feedback context. In other BMFS, ribosomal, telomere, or DNA-repair defects activate p53, and p53-DREAM represses further BMFS-related genes (PMID:37834388, review, partly computational). BMFS5 is the reverse case, where p53 activation is primary and not a downstream consequence of another defect.

  7. Suggested terms (verify).
  8. GO: positive regulation of apoptotic process, GO:0043065; cell cycle arrest, GO:0007050; erythrocyte differentiation, GO:0030218.
  9. CL: erythroid progenitor / hematopoietic stem cell.
  10. Omics: no single-cell, proteomic, or metabolomic data found [gap].

7. Anatomical structures affected

  • Bone marrow (UBERON:0002371), especially the erythroid lineage.
  • Brain (microcephaly, seizures), by phenotype.
  • Immune system (humoral).
  • Growth axis.

Lateralization is not applicable.

8. Temporal development

  • Onset. Infancy. Macrocytic anemia appeared within the first year in the Russian patients (PMID:35084091); the OMIM summary says infantile onset.
  • Course and remission.
  • Two patients became transfusion-independent "probably due to L-leucine therapy" (PMID:35084091).
  • One patient was steroid-responsive (PMID:35362179).
  • Long-term natural history [gap].
  • Cancer risk. Whether CTD-truncating carriers have an elevated cancer risk is not addressed in the sources I read [gap]. This matters for surveillance counseling, because the usual Li-Fraumeni protocols may not apply to a hyperactivating allele.

9. Inheritance and population

  • Autosomal dominant, all reported variants de novo (PMID:30146126; PMID:35084091).
  • Prevalence, incidence, sex ratio, founder effects, and penetrance: [gap]. Fewer than ten patients across Japan, Russia, the USA, and France.

10. Diagnostics

  • Laboratory. Anemia with erythroid hypoplasia on marrow examination, hypogammaglobulinemia, and normal telomere length, which argues against dyskeratosis congenita (PMID:35362179).
  • Genetic testing. TP53 variants were found by exome sequencing in the discovery paper (Ito, PMID:36198537: "using whole-exome sequencing"). The practical point is that TP53 should be on DBA / IBMFS panels. PMID:35084091 states "The possible role of TP53 variants should be considered in patients with DBA-like phenotype and no mutations in RP genes."
  • Differential diagnosis. DBA (RP genes), dyskeratosis congenita (telomere biology disorders), Fanconi anemia, Li-Fraumeni syndrome (different variant class).
  • Guideline-level criteria, screening, and biomarkers: [gap].

11. Outcome and prognosis

  • Survival and life expectancy: [gap].
  • Complications: reported features include growth failure and neurodevelopmental impairment.
  • Recovery. The French report documents the "only patient to date cured by hematopoietic stem cell transplantation" from a matched sibling donor, transfusion-independent at last follow-up (PMID:42104732).

12. Treatment (all from case-level observations)

  • Transfusion support. Implied by the transfusion-dependent anemia in the OMIM summary (lead).
  • Corticosteroids. Responsive in one patient (PMID:35362179). Non-responsive in the two French patients (PMID:42104732).
  • L-leucine. Two patients became transfusion-independent, "probably due to L-leucine therapy" (PMID:35084091). This is uncontrolled and causality is uncertain.
  • Hematopoietic stem cell transplantation. One patient cured by matched-sibling HSCT (PMID:42104732). A single case.
  • NCIT. NCIT C15431 (hematopoietic cell transplantation) is already in the repo's CLAUDE.md. Other drug and supportive-care NCIT terms need a lookup. I did not run one.
  • No clinical trials were checked [gap].

13. Prevention

Genetic counseling, with a de novo origin implying a low recurrence risk, except for germline mosaicism [inferred]. Everything else is [gap].

14. Other species and natural disease

No naturally occurring animal disease was identified [gap]; OMIA was not searched.

15. Model organisms

  • Zebrafish and human iPSC. Mutant p53 expression impaired erythrocyte production (PMID:30146126).
  • Mouse. Toki points to "close similarities to published knock-in mouse models of TP53 lacking the CTD." The mouse primary papers are not cited in the abstract and I did not retrieve them.
  • Mouse p53 hyperactivation reviews. PMID:30624728 (Bowen & Attardi) reports that hematopoietic, neuronal, craniofacial, cardiovascular, and pigmentation defects arise in mice with broad p53 hyperactivation, and that many are rescued by p53 loss. This is a model-organism review and not a human phenotype source.
  • Limitation. Whether mouse CTD-deletion phenotypes map one-to-one to human BMFS5 is open; a HUMAN_MODEL_MISMATCH discussion may be warranted if curated.

Notes for curation

  1. The KB file is a stub-level placeholder. kb/disorders/Bone_Marrow_Failure_Syndrome_5.yaml currently has 8 lines, with only the name and disease_term. The seven reference-cache files are untracked.
  2. Before writing evidence snippets, run just count-verified-snippets. All quotes above come from the cached abstracts and should be re-copied exactly from the cache.
  3. Priority gaps. The Toki cDNA/protein nomenclature, ClinGen validity, cancer risk, and the mouse primary papers.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 7
Resolved 7
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 2
Quoted claims found in source 2
Quoted claims not found in source 0
References weighed for topical relevance 7
On topic 7
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 14
Resolved 13
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 0
Terms whose name was checked 2
Terms named correctly 2
Terms named as a different term 0

Obsolete terms

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

  • GO:0007050 (GO_0007050) (1 mention) - replaced by GO:0051726

13 of 14 terms resolved to a current term; the rest could not be looked up either way.