Diamond-Blackfan Anemia

Mendelian MONDO:0015253 Pathograph 29 Show in embeddings browser Hematological Disease Genetic Disease

Diamond-Blackfan anemia (DBA) is a congenital ribosomopathy and inherited bone marrow failure syndrome characterized by a selective defect in erythropoiesis. Heterozygous loss-of-function mutations in ribosomal protein genes (most commonly RPS19, along with RPL5, RPL11, and others) cause ribosomal protein haploinsufficiency; the resulting ribosomal stress preferentially impairs erythroid progenitors, producing macrocytic anemia with reticulocytopenia that typically presents in the first year of life. DBA is frequently associated with congenital malformations and an increased predisposition to malignancy, and is most often inherited in an autosomal dominant manner. The share of cases explained by ribosomal protein genes has risen as the gene list grew, so any figure is dated: seven RP genes accounted for about 43% of patients (PMID:20116044), nine for about 53% (PMID:22431104), ten RP genes plus GATA1 for about 60-65% (PMID:23812780), and a 2024 review puts the RP-gene share at approximately 75% (DOI:10.3390/cells13110920). Rarer non-ribosomal causes exist: X-linked GATA1 is modeled in this entry, while X-linked TSR2 and RPS28 have their own dismech entries as the mandibulofacial-dysostosis forms DBA14 and DBA15. Biallelic HEATR3 variants (DBA21) are the one recessive form here. A substantial minority of patients remain genetically unexplained.

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1
Inheritance
6
Pathophys.
8
Phenotypes
29
Pathograph
15
Genes
6
Medical Actions
14
Subtypes
2
Datasets
9
References
2
Deep Research
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Inheritance

1
Autosomal dominant HP:0000006
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:20301769 SUPPORT Human Clinical
"identification of a heterozygous pathogenic variant in a gene associated with autosomal dominant DBA syndrome"
Confirms autosomal dominant as the most common inheritance pattern for DBA.
◆

Subtypes

14
Diamond-Blackfan anemia 1 (RPS19) MONDO:0007110
RPS19 hgnc:10402 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in RPS19 (hgnc:10402). hgnc:10402 is a gene from the HUGO Gene Nomenclature Committee.
The original and most common molecular form, caused by heterozygous loss-of-function variants in the small-subunit ribosomal protein gene RPS19. ClinGen classifies the RPS19-Diamond-Blackfan anemia relationship as Definitive with autosomal dominant inheritance.
Show evidence (2 references)
PMID:17186470 SUPPORT BACKGROUND Human Clinical
"associated with heterozygous mutations in the ribosomal protein (RP) S19 gene (RPS19) in approximately 25% of probands"
States the RPS19 gene-disease relationship and its share of probands. The sentence is this paper's framing of established human genetics rather than its own result, which is the RPS24 finding below.
CGGV:assertion_bceef5ee-7596-4a90-91ce-b36385f9669b-2023-05-30T160000.000Z SUPPORT Other
"RPS19 | HGNC:10402 | Diamond-Blackfan anemia | MONDO:0015253 | AD | Definitive"
Source of this row's ClinGen sentence. ClinGen curates RPS19 against the umbrella class MONDO:0015253 rather than against MONDO:0007110, so the Definitive call is for the RPS19-DBA relationship as a whole rather than for the numbered subtype this row binds.
Diamond-Blackfan anemia 3 (RPS24) MONDO:0012529
RPS24 hgnc:10411 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in RPS24 (hgnc:10411). hgnc:10411 is a gene from the HUGO Gene Nomenclature Committee.
Caused by heterozygous variants in the small-subunit ribosomal protein gene RPS24, the second DBA gene identified and a rare cause relative to RPS19.
Show evidence (1 reference)
PMID:17186470 SUPPORT Human Clinical
"We report identification of de novo nonsense and splice-site mutations in another RP, RPS24"
The gene-delineation result for RPS24. The same sentence continues with the frequency, approximately 2%, but against the narrower denominator of RPS19-mutation-negative probands rather than all DBA probands; it is not quoted here because the intervening cytogenetic parenthetical prevents an exact contiguous match.
Diamond-Blackfan anemia 4 (RPS17) MONDO:0012924
RPS17 hgnc:10397 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in RPS17 (hgnc:10397). hgnc:10397 is a gene from the HUGO Gene Nomenclature Committee.
Caused by heterozygous variants in the small-subunit ribosomal protein gene RPS17, the third ribosomal protein gene of the small subunit linked to DBA.
Show evidence (1 reference)
PMID:17647292 SUPPORT Human Clinical
"Here we report the identification of a mutation in yet another ribosomal protein, RPS17."
The gene-delineation result establishing RPS17 as a DBA gene.
Diamond-Blackfan anemia 5 (RPL35A) MONDO:0012925
RPL35A hgnc:10345 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in RPL35A (hgnc:10345). hgnc:10345 is a gene from the HUGO Gene Nomenclature Committee.
Caused by heterozygous variants in RPL35A, the first large-subunit ribosomal protein gene linked to DBA. The gene was identified from two DBA patients carrying chromosome 3q deletions and confirmed by sequencing a proband cohort.
Show evidence (1 reference)
PMID:18535205 SUPPORT Human Clinical
"Sequence analysis of a cohort of DBA probands confirmed involvement RPL35A in DBA."
The gene-delineation result for RPL35A. Quoted verbatim including the source's own omitted word.
Diamond-Blackfan anemia 6 (RPL5) MONDO:0012937
RPL5 hgnc:10360 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in RPL5 (hgnc:10360). hgnc:10360 is a gene from the HUGO Gene Nomenclature Committee.
Caused by heterozygous variants in the large-subunit ribosomal protein gene RPL5. RPL5 variants carry a distinctive malformation profile, associating with craniofacial, thumb and heart anomalies.
Show evidence (2 references)
PMID:19061985 SUPPORT Human Clinical
"mutations in RPL5 are associated with multiple physical abnormalities, including craniofacial, thumb, and heart anomalies, whereas isolated thumb malformations are predominantly present in patients carrying mutations in RPL11"
The RPL5-specific genotype-phenotype correlation this row describes.
CGGV:assertion_edb6a96b-92d7-4c57-8613-e055d1bdd678-2023-05-30T160000.000Z SUPPORT Other
"RPL5 | HGNC:10360 | Diamond-Blackfan anemia 6 | MONDO:0012937 | AD | Definitive"
ClinGen curates this gene-disease relationship against MONDO:0012937 itself, the same class this row binds, and classifies it Definitive.
Diamond-Blackfan anemia 7 (RPL11) MONDO:0012938
RPL11 hgnc:10301 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in RPL11 (hgnc:10301). hgnc:10301 is a gene from the HUGO Gene Nomenclature Committee.
Caused by heterozygous variants in the large-subunit ribosomal protein gene RPL11, which associate predominantly with isolated thumb malformations rather than the broader RPL5 malformation profile.
Show evidence (1 reference)
PMID:19061985 SUPPORT Human Clinical
"mutations in RPL5 are associated with multiple physical abnormalities, including craniofacial, thumb, and heart anomalies, whereas isolated thumb malformations are predominantly present in patients carrying mutations in RPL11"
The RPL11-specific genotype-phenotype correlation this row describes.
Diamond-Blackfan anemia 8 (RPS7) MONDO:0012939
RPS7 hgnc:10440 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in RPS7 (hgnc:10440). hgnc:10440 is a gene from the HUGO Gene Nomenclature Committee.
Caused by heterozygous variants in the small-subunit ribosomal protein gene RPS7, reported alongside RPL5 and RPL11 in the same screen.
Show evidence (1 reference)
PMID:19061985 SUPPORT Human Clinical
"Here, we report the second known mutation in RPS17 and probable pathogenic mutations in three more RP genes, RPL5, RPL11, and RPS7."
The gene-delineation result naming RPS7 as a DBA gene.
Diamond-Blackfan anemia 9 (RPS10) MONDO:0013216
RPS10 hgnc:10383 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in RPS10 (hgnc:10383). hgnc:10383 is a gene from the HUGO Gene Nomenclature Committee.
Caused by heterozygous variants in the small-subunit ribosomal protein gene RPS10, identified in a 117-proband screen of 35 ribosomal protein genes.
Show evidence (1 reference)
PMID:20116044 SUPPORT Human Clinical
"We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands."
The gene-delineation result for RPS10, with the proband counts this row's description refers to.
Diamond-Blackfan anemia 10 (RPS26) MONDO:0013217
RPS26 hgnc:10414 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in RPS26 (hgnc:10414). hgnc:10414 is a gene from the HUGO Gene Nomenclature Committee.
Caused by heterozygous variants in the small-subunit ribosomal protein gene RPS26, the more frequently mutated of the two genes found in the same 117-proband screen.
Show evidence (1 reference)
PMID:20116044 SUPPORT Human Clinical
"We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands."
The gene-delineation result for RPS26, with the proband counts this row's description refers to.
Diamond-Blackfan anemia 11 (RPL26) MONDO:0013964
RPL26 hgnc:10327 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in RPL26 (hgnc:10327). hgnc:10327 is a gene from the HUGO Gene Nomenclature Committee.
Caused by variants in the large-subunit ribosomal protein gene RPL26. The index proband carried a de novo two-nucleotide deletion with multiple severe physical abnormalities, and the resulting ribosome biogenesis defect affects maturation of both ribosomal subunits rather than the large subunit alone.
Show evidence (2 references)
PMID:22431104 SUPPORT Human Clinical
"We identified a de novo two-nucleotide deletion in RPL26 in one proband associated with multiple severe physical abnormalities."
The gene-delineation result for RPL26 and the source of the malformation statement in this row.
PMID:22431104 SUPPORT In Vitro
"This mutation gives rise to a remarkable ribosome biogenesis defect that affects maturation of both the small and the large subunits."
The basis for this row's statement that the processing defect is not confined to the large subunit, despite RPL26 being a large-subunit protein.
Diamond-Blackfan anemia 12 (RPL15) MONDO:0014245
RPL15 hgnc:10306 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in RPL15 (hgnc:10306). hgnc:10306 is a gene from the HUGO Gene Nomenclature Committee.
Caused by variants in the large-subunit ribosomal protein gene RPL15, first identified as a large deletion by array comparative genomic hybridization. Like RPL26, RPL15 is required both for 60S subunit formation and for a small-subunit pre-rRNA cleavage step.
Show evidence (2 references)
PMID:23812780 SUPPORT Human Clinical
"Here, we report a novel large deletion in RPL15, a gene not previously implicated to be causative in DBA."
The gene-delineation result for RPL15.
PMID:23812780 SUPPORT In Vitro
"Like RPL26, RPL15 presents the distinctive feature of being required both for 60S subunit formation and for efficient cleavage of the internal transcribed spacer 1."
The basis for this row's dual-subunit statement.
Diamond-Blackfan anemia 13 (RPS29) MONDO:0014394
RPS29 hgnc:10419 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in RPS29 (hgnc:10419). hgnc:10419 is a gene from the HUGO Gene Nomenclature Committee.
Caused by variants in the small-subunit ribosomal protein gene RPS29, identified by whole-exome sequencing in two large multicase DBA families.
Show evidence (2 references)
PMID:24829207 SUPPORT Human Clinical
"We uncovered a novel DBA causative gene, RPS29"
The gene-delineation conclusion for RPS29.
PMID:24829207 SUPPORT In Vitro
"RPS29 is a component of the small 40S ribosomal subunit and essential for rRNA processing and ribosome biogenesis."
Places RPS29 in the small subunit, which is how this entry wires the gene.
Diamond-Blackfan anemia 21 (HEATR3) MONDO:0031071
HEATR3 hgnc:26087 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in HEATR3 (hgnc:26087). hgnc:26087 is a gene from the HUGO Gene Nomenclature Committee. Autosomal recessive inheritance
The only recessively inherited form in this series, and not a ribosomal protein gene: HEATR3 is an import adaptor whose yeast homolog synchronizes nuclear import of the large-subunit proteins uL5 (RPL11) and uL18 (RPL5). Affected individuals had bone marrow failure with short stature, facial and acromelic dysmorphism and intellectual disability.
Show evidence (2 references)
PMID:35213692 SUPPORT Human Clinical
"Here we report multiple individuals with biallelic HEATR3 variants exhibiting bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability."
The gene-delineation result, the source of the biallelic (recessive) inheritance recorded on this row, and of its clinical description.
PMID:35213692 SUPPORT In Vitro
"These variants destabilize a protein whose yeast homolog is known to synchronize the nuclear import of RPs uL5 (RPL11) and uL18 (RPL5)"
The import-adaptor mechanism this row describes and the reason HEATR3 is wired upstream of the large-subunit node rather than onto it.
Diamond-Blackfan anemia 22 (RPL17) MONDO:0979244
RPL17 hgnc:10307 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in RPL17 (hgnc:10307). hgnc:10307 is a gene from the HUGO Gene Nomenclature Committee.
Caused by variants in the large-subunit ribosomal protein gene RPL17, delineated in two multigenerational pedigrees whose affected members had clinical features and erythroid proliferation defects consistent with DBA.
Show evidence (1 reference)
PMID:39088281 SUPPORT Human Clinical
"we report the genetic, functional, and biochemical dissection of 2 multigenerational pedigrees with variants in RPL17, a large ribosomal subunit protein-encoding gene"
The gene-delineation result for RPL17 and the source of its assignment to the large subunit.
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Pathophysiology

6
Small Ribosomal Subunit Assembly Defect
Haploinsufficiency of a small-subunit (40S) ribosomal protein gene impairs 18S rRNA maturation and 40S subunit production. The seven genes on this node are the DBA genes HGNC assigns to the "S ribosomal proteins" gene group; subunit-specific pre-rRNA processing defects are documented for RPS10 and RPS26 (18S-E accumulation) and RPS29 is stated to be a 40S component.
RPS19 hgnc:10402 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RPS19 (hgnc:10402). hgnc:10402 is a gene from the HUGO Gene Nomenclature Committee. RPS24 hgnc:10411 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RPS24 (hgnc:10411). hgnc:10411 is a gene from the HUGO Gene Nomenclature Committee. RPS17 hgnc:10397 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RPS17 (hgnc:10397). hgnc:10397 is a gene from the HUGO Gene Nomenclature Committee. RPS7 hgnc:10440 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RPS7 (hgnc:10440). hgnc:10440 is a gene from the HUGO Gene Nomenclature Committee. RPS10 hgnc:10383 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RPS10 (hgnc:10383). hgnc:10383 is a gene from the HUGO Gene Nomenclature Committee. RPS26 hgnc:10414 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RPS26 (hgnc:10414). hgnc:10414 is a gene from the HUGO Gene Nomenclature Committee. RPS29 hgnc:10419 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RPS29 (hgnc:10419). hgnc:10419 is a gene from the HUGO Gene Nomenclature Committee.
ribosomal small subunit biogenesis GO:0042274 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ribosomal small subunit biogenesis (GO:0042274). GO:0042274 is a biological process from the Gene Ontology.
Downstream
Ribosomal Protein Haploinsufficiency A 40S assembly defect is one of the two routes to the shared ribosome-insufficiency state on which the erythroid phenotype depends.
Show evidence (3 references)
PMID:18535205 SUPPORT BACKGROUND Human Clinical
"Small ribosomal subunit genes RPS19, RPS24, and RPS17 are mutated in approximately one-third of patients."
Names three of this node's genes as small-subunit genes mutated in DBA.
PMID:20116044 SUPPORT In Vitro
"Pre-rRNA analysis in lymphoblastoid cells from patients bearing mutations in RPS10 and RPS26 showed elevated levels of 18S-E pre-rRNA."
The small-subunit pre-rRNA processing defect this node asserts, measured in patient-derived cells.
PMID:24829207 SUPPORT In Vitro
"RPS29 is a component of the small 40S ribosomal subunit and essential for rRNA processing and ribosome biogenesis."
Places RPS29 on this node.
Large Ribosomal Subunit Assembly Defect
Haploinsufficiency of a large-subunit (60S) ribosomal protein gene impairs 28S and 5.8S rRNA maturation and 60S subunit production. The six genes on this node are the DBA genes HGNC assigns to the "L ribosomal proteins" gene group. Two of them, RPL26 and RPL15, additionally disturb a small-subunit pre-rRNA cleavage step, so the subunit split describes which protein is missing rather than a clean partition of the processing defect.
RPL5 hgnc:10360 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RPL5 (hgnc:10360). hgnc:10360 is a gene from the HUGO Gene Nomenclature Committee. RPL11 hgnc:10301 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RPL11 (hgnc:10301). hgnc:10301 is a gene from the HUGO Gene Nomenclature Committee. RPL35A hgnc:10345 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RPL35A (hgnc:10345). hgnc:10345 is a gene from the HUGO Gene Nomenclature Committee. RPL26 hgnc:10327 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RPL26 (hgnc:10327). hgnc:10327 is a gene from the HUGO Gene Nomenclature Committee. RPL15 hgnc:10306 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RPL15 (hgnc:10306). hgnc:10306 is a gene from the HUGO Gene Nomenclature Committee. RPL17 hgnc:10307 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RPL17 (hgnc:10307). hgnc:10307 is a gene from the HUGO Gene Nomenclature Committee.
ribosomal large subunit biogenesis GO:0042273 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ribosomal large subunit biogenesis (GO:0042273). GO:0042273 is a biological process from the Gene Ontology.
Downstream
Ribosomal Protein Haploinsufficiency A 60S assembly defect is the other route to the shared ribosome-insufficiency state.
Show evidence (3 references)
PMID:18535205 SUPPORT In Vitro
"shRNA inhibition shows that Rpl35a is essential for maturation of 28S and 5.8S rRNAs, 60S subunit biogenesis, normal proliferation, and cell survival."
The 60S biogenesis requirement this node asserts, shown for RPL35A.
PMID:18535205 SUPPORT Human Clinical
"These data demonstrate that alterations of large ribosomal subunit proteins cause DBA"
Establishes large-subunit protein loss as a route to DBA in its own right.
PMID:23812780 SUPPORT In Vitro
"Like RPL26, RPL15 presents the distinctive feature of being required both for 60S subunit formation and for efficient cleavage of the internal transcribed spacer 1."
The basis for this node's caveat that RPL26 and RPL15 also affect a small-subunit cleavage step.
Ribosomal Protein Nuclear Import Failure
The one DBA mechanism in this entry that is upstream of the ribosomal proteins themselves. HEATR3 is an import adaptor for the large-subunit proteins uL5 (RPL11) and uL18 (RPL5); biallelic HEATR3 variants destabilize it, and patient-derived fibroblasts show reduced nuclear accumulation of uL18. The consequence is a shortage of large-subunit proteins in the nucleolus rather than a shortage of their transcripts.
HEATR3 hgnc:26087 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves HEATR3 (hgnc:26087). hgnc:26087 is a gene from the HUGO Gene Nomenclature Committee.
protein import into nucleus GO:0006606 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein import into nucleus (GO:0006606). GO:0006606 is a biological process from the Gene Ontology.
Downstream
Large Ribosomal Subunit Assembly Defect Failure to deliver uL5 and uL18 to the nucleus starves 60S assembly of two of its proteins, producing a phenotype the source describes as reminiscent of large-subunit ribosomal protein gene variants.
Show evidence (3 references)
PMID:35213692 SUPPORT In Vitro
"These variants destabilize a protein whose yeast homolog is known to synchronize the nuclear import of RPs uL5 (RPL11) and uL18 (RPL5)"
The import-adaptor role this node asserts.
PMID:35213692 SUPPORT In Vitro
"HEATR3-depleted cells or patient-derived fibroblasts display reduced nuclear accumulation of uL18"
The measured import defect in patient cells.
PMID:35213692 SUPPORT In Vitro
"impairs growth, differentiation, pre-ribosomal RNA processing, and ribosomal subunit formation reminiscent of DBA models of large subunit RP gene variants"
The basis for the downstream edge into the large-subunit node rather than into the convergent node directly.
Ribosomal Protein Haploinsufficiency
The convergence point of this entry: whichever ribosomal protein is missing, and whether the lesion is in the gene or in the import step that delivers the protein, the shared consequence is reduced ribosome assembly and protein synthesis capacity. Erythroid progenitors are exquisitely sensitive to that state because of their high proliferative and translational demands. Causal genes are wired to the subunit-specific upstream nodes rather than listed here, so this node carries no `genes:` list of its own.
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.
ribosome biogenesis GO:0042254 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ribosome biogenesis (GO:0042254). GO:0042254 is a biological process from the Gene Ontology. translation GO:0006412 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased translation (GO:0006412). GO:0006412 is a biological process from the Gene Ontology. translational initiation GO:0006413 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased translational initiation (GO:0006413). GO:0006413 is a biological process from the Gene Ontology.
Downstream
p53-Mediated Erythroid Apoptosis Ribosomal stress activates p53, leading to cell cycle arrest and apoptosis of erythroid progenitors.
Short Stature Ribosomal protein haploinsufficiency disrupts developmental growth programs, contributing to short stature.
Congenital Malformations Ribosomal protein haploinsufficiency disrupts embryogenesis, contributing to congenital malformations.
Triphalangeal Thumb Ribosomal protein haploinsufficiency disrupts limb development, contributing to triphalangeal thumb.
Acute Myeloid Leukemia Chronic ribosomal-stress marrow dysfunction increases acute myeloid leukemia risk.
Myelodysplasia Chronic ribosomal-stress marrow dysfunction increases myelodysplasia risk.
Osteosarcoma DBA cancer predisposition includes osteosarcoma downstream of the ribosomopathy state.
Show evidence (2 references)
PMID:9988267 SUPPORT Human Clinical
"we identified mutations in RPS19 in 10 of 40 unrelated DBA patients, including nonsense, frameshift, splice site and missense mutations"
Original discovery of RPS19 mutations as the cause of DBA, establishing the ribosomal protein basis.
PMID:9988267 SUPPORT Human Clinical
"a function for RPS19 in erythropoiesis and embryogenesis"
Confirms RPS19 has specific roles in erythropoiesis and embryonic development.
p53-Mediated Erythroid Apoptosis
Ribosomal stress from RP haploinsufficiency leads to accumulation of free ribosomal proteins that bind MDM2, stabilizing p53. Activated p53 triggers cell cycle arrest and apoptosis preferentially in erythroid progenitors, resulting in selective red cell aplasia.
erythroblast CL:0000765 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythroblast (CL:0000765). CL:0000765 is a cell type from the Cell Ontology.
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. erythrocyte differentiation GO:0030218 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal erythrocyte differentiation (GO:0030218). GO:0030218 is a biological process from the Gene Ontology.
Downstream
Macrocytic Anemia Erythroid progenitor apoptosis produces the macrocytic anemia of DBA.
Pure Red Cell Aplasia Selective erythroid apoptosis produces pure red cell aplasia.
Show evidence (1 reference)
PMID:20301769 SUPPORT Human Clinical
"characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets"
Confirms the selective erythroid failure (normal leukocytes and platelets) consistent with erythroid-specific apoptosis.
GATA1 Translational Insufficiency
A distinct non-ribosomal mechanism causing DBA. GATA1 is an X-linked erythroid transcription factor essential for erythroid differentiation. Mutations in GATA1 (including splice site variants) reduce functional GATA1 protein levels, impairing erythroid gene expression. Unlike ribosomal protein mutations, GATA1 mutations directly affect erythroid transcription rather than global translation, but converge on the same erythroid differentiation failure.
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.
GATA1 hgnc:4170 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GATA1 (hgnc:4170). hgnc:4170 is a gene from the HUGO Gene Nomenclature Committee.
regulation of transcription by RNA polymerase II GO:0006357 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology. erythrocyte differentiation GO:0030218 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal erythrocyte differentiation (GO:0030218). GO:0030218 is a biological process from the Gene Ontology.
Downstream
Pure Red Cell Aplasia Reduced full-length GATA1 impairs erythroid differentiation and produces the same red-cell aplasia as the ribosomal route, without passing through the ribosomal-stress p53 node. Only the erythroid failure is wired here; no cited source in this entry attributes the macrocytosis to GATA1.
Show evidence (2 references)
PMID:20301769 SUPPORT Human Clinical
"the molecular diagnosis can be established in a male proband by identification of a hemizygous pathogenic variant in GATA1 or TSR2 associated with X-linked DBA syndrome"
Confirms GATA1 as a distinct X-linked cause of DBA, separate from ribosomal protein genes.
PMID:22706301 SUPPORT Human Clinical
"This mutation, which occurred at a splice site of the GATA1 gene, impaired production of the full-length form of the protein."
The molecular lesion behind this node: a splice-site variant reducing full-length GATA1 rather than a defect in global translation.
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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 Diamond-Blackfan Anemia Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

8
Blood 4
Macrocytic Anemia VERY_FREQUENT HP:0001972 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is macrocytic anemia (HP:0001972). HP:0001972 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301769 SUPPORT Human Clinical
"The hematologic complications occur in 90% of affected individuals during the first year of life"
Confirms onset of anemia during the first year of life in 90% of cases.
Pure Red Cell Aplasia VERY_FREQUENT HP:0012410 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is pure red cell aplasia (HP:0012410). HP:0012410 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9988267 SUPPORT Human Clinical
"constitutional erythroblastopenia characterized by absent or decreased erythroid precursors"
Confirms erythroblastopenia (red cell aplasia) as the defining hematologic feature.
Acute Myeloid Leukemia OCCASIONAL HP:0004808 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is acute myeloid leukemia (HP:0004808). HP:0004808 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301769 SUPPORT Human Clinical
"associated with an increased risk for acute myelogenous leukemia, myelodysplastic syndrome, and solid tumors including osteogenic sarcoma"
Confirms increased AML risk in DBA patients.
Myelodysplasia OCCASIONAL HP:0002863 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is myelodysplasia (HP:0002863). HP:0002863 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301769 SUPPORT Human Clinical
"associated with an increased risk for acute myelogenous leukemia, myelodysplastic syndrome, and solid tumors including osteogenic sarcoma"
Confirms increased MDS risk in DBA patients.
Head and Neck 1
Congenital Malformations FREQUENT Craniofacial dysostosis HP:0004439 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is craniofacial dysostosis (HP:0004439). HP:0004439 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301769 SUPPORT Human Clinical
"congenital malformations in up to 50% of affected individuals"
Confirms congenital malformations in up to half of DBA patients.
Limbs 1
Triphalangeal Thumb OCCASIONAL HP:0001199 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is triphalangeal thumb (HP:0001199). HP:0001199 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19773262 SUPPORT Human Clinical
"A close association was evident between RPL5 mutations and craniofacial malformations, and between hand malformations and RPL11 mutations"
Establishes genotype-phenotype correlation between RPL11 mutations and hand malformations including thumb anomalies.
Musculoskeletal 1
Osteosarcoma OCCASIONAL HP:0002669 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is osteosarcoma (HP:0002669). HP:0002669 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301769 SUPPORT Human Clinical
"associated with an increased risk for acute myelogenous leukemia, myelodysplastic syndrome, and solid tumors including osteogenic sarcoma"
Confirms increased osteosarcoma risk in DBA patients.
Growth 1
Short Stature FREQUENT 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:20301769 SUPPORT Human Clinical
"growth deficiency in 30% of affected individuals"
Confirms growth deficiency affects approximately 30% of DBA patients.
🧬

Genetic Associations

15
RPS19 (Causative)
Gene: RPS19 hgnc:10402 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RPS19 (hgnc:10402). hgnc:10402 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (2 references)
PMID:9988267 SUPPORT Human Clinical
"we identified mutations in RPS19 in 10 of 40 unrelated DBA patients"
Original identification of RPS19 as the first DBA gene, mutated in ~25% of patients.
CGGV:assertion_bceef5ee-7596-4a90-91ce-b36385f9669b-2023-05-30T160000.000Z SUPPORT Other
"RPS19 | HGNC:10402 | Diamond-Blackfan anemia | MONDO:0015253 | AD | Definitive"
ClinGen classifies the RPS19-Diamond-Blackfan anemia gene-disease relationship as definitive with autosomal dominant inheritance.
RPL5 (Causative)
Gene: RPL5 hgnc:10360 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RPL5 (hgnc:10360). hgnc:10360 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (3 references)
PMID:19773262 SUPPORT Human Clinical
"Two new genes (RPL5, RPL11), encoding for ribosomal proteins of the large subunit, have been reported to be involved in a considerable percentage of patients"
Identifies RPL5 as a DBA gene encoding a large ribosomal subunit protein.
PMID:19773262 SUPPORT Human Clinical
"About 20% of the patients screened had mutations in RPL5 or RPL11"
Quantifies RPL5/RPL11 mutation frequency at ~20% of RPS19-negative DBA patients.
CGGV:assertion_edb6a96b-92d7-4c57-8613-e055d1bdd678-2023-05-30T160000.000Z SUPPORT Other
"RPL5 | HGNC:10360 | Diamond-Blackfan anemia 6 | MONDO:0012937 | AD | Definitive"
ClinGen classifies the RPL5-DBA6 gene-disease relationship as definitive with autosomal dominant inheritance.
RPL11 (Causative)
Gene: RPL11 hgnc:10301 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RPL11 (hgnc:10301). hgnc:10301 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (2 references)
PMID:19773262 SUPPORT Human Clinical
"About 20% of the patients screened had mutations in RPL5 or RPL11"
Quantifies RPL11 mutation frequency in Italian DBA cohort.
PMID:19773262 SUPPORT Human Clinical
"A close association was evident between RPL5 mutations and craniofacial malformations, and between hand malformations and RPL11 mutations"
Establishes RPL11-specific genotype-phenotype correlation with hand malformations.
RPL35A (Causative)
Gene: RPL35A hgnc:10345 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RPL35A (hgnc:10345). hgnc:10345 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (3 references)
PMID:19773262 SUPPORT Human Clinical
"Mutations in RPS24, RPS17, and RPL35A described in a minority of patients show that Diamond-Blackfan anemia is a disorder of ribosome biogenesis"
Identifies RPL35A as a DBA gene, establishing DBA as a ribosomopathy.
PMID:18535205 SUPPORT Human Clinical
"Sequence analysis of a cohort of DBA probands confirmed involvement RPL35A in DBA."
The primary gene-delineation result for RPL35A, which this record previously lacked. Quoted verbatim including the source's omitted word.
PMID:18535205 SUPPORT In Vitro
"shRNA inhibition shows that Rpl35a is essential for maturation of 28S and 5.8S rRNAs, 60S subunit biogenesis, normal proliferation, and cell survival."
Places RPL35A in large-subunit biogenesis, which is how this entry wires the gene.
RPS26 (Causative)
Gene: RPS26 hgnc:10414 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RPS26 (hgnc:10414). hgnc:10414 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (2 references)
PMID:20116044 SUPPORT Human Clinical
"We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands."
The primary gene-delineation result for RPS26 and the source of the proband counts in this record's frequency field. This record previously carried no evidence at all.
PMID:20116044 SUPPORT In Vitro
"Pre-rRNA analysis in lymphoblastoid cells from patients bearing mutations in RPS10 and RPS26 showed elevated levels of 18S-E pre-rRNA."
The small-subunit pre-rRNA processing defect that places RPS26 on the 40S node of this entry's pathograph.
RPS24 (Causative)
Gene: RPS24 hgnc:10411 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RPS24 (hgnc:10411). hgnc:10411 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (1 reference)
PMID:17186470 SUPPORT Human Clinical
"We report identification of de novo nonsense and splice-site mutations in another RP, RPS24"
The primary gene-delineation result for RPS24, which this record previously lacked entirely. The same sentence gives the frequency as approximately 2% of RPS19-mutation-negative probands.
RPS10 (Causative)
Gene: RPS10 hgnc:10383 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RPS10 (hgnc:10383). hgnc:10383 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (1 reference)
PMID:20116044 SUPPORT Human Clinical
"We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands."
The primary gene-delineation result for RPS10 and the source of the proband counts in this record's frequency field. This record previously carried no evidence at all.
RPS17 (Causative)
Gene: RPS17 hgnc:10397 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RPS17 (hgnc:10397). hgnc:10397 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (2 references)
PMID:17647292 SUPPORT Human Clinical
"Here we report the identification of a mutation in yet another ribosomal protein, RPS17."
The primary gene-delineation result for RPS17. This record previously carried no evidence at all.
PMID:18535205 SUPPORT BACKGROUND Human Clinical
"Small ribosomal subunit genes RPS19, RPS24, and RPS17 are mutated in approximately one-third of patients."
Assigns RPS17 to the small subunit, which is how this entry wires the gene. Quoted from this paper's framing sentence rather than its own RPL35A result.
RPS7 (Causative)
Gene: RPS7 hgnc:10440 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RPS7 (hgnc:10440). hgnc:10440 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (2 references)
PMID:19061985 SUPPORT Human Clinical
"Here, we report the second known mutation in RPS17 and probable pathogenic mutations in three more RP genes, RPL5, RPL11, and RPS7."
The primary gene-delineation result naming RPS7. This record previously carried no evidence at all.
PMID:19061985 SUPPORT In Vitro
"mutations of RPL5, RPL11, or RPS7 in DBA cells is associated with diverse defects in the maturation of ribosomal RNAs in the large or the small ribosomal subunit production pathway"
The rRNA-maturation phenotype behind this entry's subunit-specific pathograph nodes. The paper reports defects in either pathway across these three genes rather than assigning one pathway per gene.
RPL26 (Causative)
Gene: RPL26 hgnc:10327 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RPL26 (hgnc:10327). hgnc:10327 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (2 references)
PMID:22431104 SUPPORT Human Clinical
"We identified a de novo two-nucleotide deletion in RPL26 in one proband associated with multiple severe physical abnormalities."
The primary gene-delineation result for RPL26.
PMID:22431104 SUPPORT In Vitro
"This mutation gives rise to a remarkable ribosome biogenesis defect that affects maturation of both the small and the large subunits."
Records that the processing defect of this large-subunit protein is not confined to the large subunit.
RPL15 (Causative)
Gene: RPL15 hgnc:10306 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RPL15 (hgnc:10306). hgnc:10306 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (2 references)
PMID:23812780 SUPPORT Human Clinical
"Here, we report a novel large deletion in RPL15, a gene not previously implicated to be causative in DBA."
The primary gene-delineation result for RPL15.
PMID:23812780 SUPPORT In Vitro
"Like RPL26, RPL15 presents the distinctive feature of being required both for 60S subunit formation and for efficient cleavage of the internal transcribed spacer 1."
Places RPL15 in 60S formation, which is how this entry wires the gene, while recording its additional small-subunit cleavage requirement.
RPS29 (Causative)
Gene: RPS29 hgnc:10419 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RPS29 (hgnc:10419). hgnc:10419 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (2 references)
PMID:24829207 SUPPORT Human Clinical
"We uncovered a novel DBA causative gene, RPS29"
The gene-delineation conclusion for RPS29.
PMID:24829207 SUPPORT In Vitro
"RPS29 is a component of the small 40S ribosomal subunit and essential for rRNA processing and ribosome biogenesis."
Places RPS29 in the small subunit, which is how this entry wires the gene.
RPL17 (Causative)
Gene: RPL17 hgnc:10307 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RPL17 (hgnc:10307). hgnc:10307 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (1 reference)
PMID:39088281 SUPPORT Human Clinical
"we report the genetic, functional, and biochemical dissection of 2 multigenerational pedigrees with variants in RPL17, a large ribosomal subunit protein-encoding gene"
The gene-delineation result for RPL17 and the source of its assignment to the large subunit.
HEATR3 (Causative)
Gene: HEATR3 hgnc:26087 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HEATR3 (hgnc:26087). hgnc:26087 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive
Show evidence (2 references)
PMID:35213692 SUPPORT Human Clinical
"Here we report multiple individuals with biallelic HEATR3 variants exhibiting bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability."
The gene-delineation result and the source of the biallelic inheritance recorded here.
PMID:35213692 SUPPORT In Vitro
"HEATR3-depleted cells or patient-derived fibroblasts display reduced nuclear accumulation of uL18"
The measured import defect behind this record's mechanism note.
GATA1 (Causative)
Gene: GATA1 hgnc:4170 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GATA1 (hgnc:4170). hgnc:4170 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
X-linked recessive
Show evidence (3 references)
PMID:22706301 SUPPORT Human Clinical
"We performed exome sequencing on two siblings who had no known pathogenic mutations for DBA and identified a mutation in the gene encoding the hematopoietic transcription factor GATA1"
Discovery of GATA1 as a DBA gene through exome sequencing.
PMID:22706301 SUPPORT Human Clinical
"the reduction in erythropoiesis associated with the disease can arise from causes other than defects in ribosomal protein genes"
Establishes that DBA can be caused by non-ribosomal protein gene mutations, specifically GATA1.
PMID:37973818 SUPPORT Human Clinical
"Recent studies also indicated that non-RP genes like GATA1, TSR2, are associated with DBA"
Confirms GATA1 and TSR2 as non-ribosomal protein genes associated with DBA.
💊

Medical Actions

6
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
First-line treatment. Improves the red blood cell count in approximately 60-80% of affected individuals. Recommended to start at age 12 months or older to minimize growth effects.
Show evidence (1 reference)
PMID:20301769 SUPPORT Human Clinical
"Corticosteroid treatment, recommended in children at age 12 months or older, improves the red blood cell count in approximately 60%-80% of affected individuals"
Confirms corticosteroid efficacy at 60-80% response rate and recommended age of initiation.
Chronic Red Blood Cell Transfusions
Action: blood transfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is blood transfusion (NCIT:C15192). NCIT:C15192 is a clinical intervention from the NCI Thesaurus. Ontology label: Blood Transfusion NCIT:C15192
Necessary during the first year of life and for steroid-nonresponders. Iron chelation therapy is required after 10-12 transfusions to prevent transfusion-related iron overload.
Show evidence (1 reference)
PMID:20301769 SUPPORT Human Clinical
"Chronic transfusion with packed red blood cells is necessary during the first year of life"
Confirms chronic transfusion as necessary during the first year to avoid steroid effects on growth.
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
The only curative therapy for the hematologic manifestations of DBA. Recommended for transfusion-dependent patients or those developing other cytopenias.
Show evidence (1 reference)
PMID:20301769 SUPPORT Human Clinical
"Hematopoietic stem cell transplantation, the only curative therapy for the hematologic manifestations of DBA syndrome"
Confirms HSCT as the only curative therapy for DBA hematologic manifestations.
Iron Chelation Therapy
Action: iron chelation therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is iron chelation therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Required for transfusion-dependent patients after 10-12 transfusions. Deferasirox (oral) or deferoxamine (subcutaneous) are preferred.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Important for family screening. Approximately 40-45% of cases are inherited; 55-60% are de novo.
Clonal Evolution and Malignancy Surveillance
Action: surveillance for malignanciesNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surveillance for malignancies, annotated with Cancer Screening (NCIT:C15406). NCIT:C15406 is a clinical intervention from the NCI Thesaurus. Ontology label: Cancer Screening NCIT:C15406
As an inherited bone marrow failure syndrome, Diamond-Blackfan anemia carries an elevated risk of myelodysplastic neoplasm, acute myeloid leukemia, and solid tumors. Long-term surveillance includes periodic marrow evaluation with cytogenetic monitoring for acquired clonal abnormalities and disease-specific late-effects screening, especially after hematopoietic cell transplantation.
Show evidence (2 references)
PMID:38016422 SUPPORT Other
"Bone marrow failure syndromes are at risk of secondary progression towards myeloid neoplasms in the form of myelodysplastic neoplasms or acute myeloid leukemia."
The GFCH cytogenetics guideline establishes the myeloid-neoplasm progression risk in bone marrow failure syndromes (including Diamond-Blackfan anemia) that cytogenetic surveillance monitors.
PMID:28533057 SUPPORT Other
"This companion article outlines consensus disease-specific long-term follow-up screening guidelines for patients with IMBFS."
Consensus late-effects screening guidelines for inherited bone marrow failure syndromes (which include Diamond-Blackfan anemia) frame long-term post-transplant surveillance.
🔬

Biochemical Markers

5
Hemoglobin (Decreased)
Context: Profound anemia; may require transfusion support
MCV (Elevated)
Context: Macrocytosis is characteristic
Erythrocyte Adenosine Deaminase (Elevated)
Context: Elevated eADA is a diagnostic biomarker for DBA
HbF (Elevated)
Context: Elevated fetal hemoglobin is a common finding
Reticulocytes (Decreased)
Context: Reticulocytopenia reflecting erythroid production failure
📊

Prevalence

1
Global
Birth Prevalence 0.7 per 100,000 1–9 per 1,000,000 (births)
Approximately seven per million live births. Incidence is consistent across ethnicities. No sex predilection.
Show evidence (1 reference)
PMID:18671700 SUPPORT Human Clinical
"Classical DBA affects about seven per million live births and presents during the first year of life"
Confirms the incidence of DBA at approximately seven per million live births.
📊

Related Datasets

2
Copy number analysis of Diamond-Blackfan Anemia (DBA) using SNP array ega:EGAS00000000105
Diamond–Blackfan anemia (DBA), is a rare congenital anemia that usually presents in infancy. About fifty percent of DBA patients possess mutations in ribosomal protains (RPs). In this study, we performed genomic copy number analysis using SNP arrays for 27 Japanese DBA patients to detect genomic copy number lesions of the RP genes' loci.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Diamond-Blackfan Anemia"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Loss of functional mutation in RPL27 and RPS27 identified by whole-exome sequencing in Diamond-Blackfan Anemia ega:EGAS00001000875
We performed whole-exome sequencing analysis of 48 patients with no documented mutations/deletions involving known Diamond-Blackfan anemia genes and identified 10 mutations in previous known causative genes and 2 mutations in novel ribosomal genes.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Diamond-Blackfan Anemia"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
{ }

Source YAML

click to show 
name: Diamond-Blackfan Anemia
creation_date: '2026-02-16T18:18:28Z'
category: Mendelian
description: >
  Diamond-Blackfan anemia (DBA) is a congenital ribosomopathy and inherited
  bone marrow failure syndrome characterized by a selective defect in
  erythropoiesis. Heterozygous loss-of-function mutations in ribosomal protein
  genes (most commonly RPS19, along with RPL5, RPL11, and others) cause
  ribosomal protein haploinsufficiency; the resulting ribosomal stress
  preferentially impairs erythroid progenitors, producing macrocytic anemia
  with reticulocytopenia that typically presents in the first year of life.
  DBA is frequently associated with congenital malformations and an increased
  predisposition to malignancy, and is most often inherited in an autosomal
  dominant manner. The share of cases explained by ribosomal protein genes has
  risen as the gene list grew, so any figure is dated: seven RP genes accounted
  for about 43% of patients (PMID:20116044), nine for about 53%
  (PMID:22431104), ten RP genes plus GATA1 for about 60-65% (PMID:23812780),
  and a 2024 review puts the RP-gene share at approximately 75%
  (DOI:10.3390/cells13110920). Rarer
  non-ribosomal causes exist: X-linked GATA1 is modeled in this
  entry, while X-linked TSR2 and RPS28 have their own dismech entries as the
  mandibulofacial-dysostosis forms DBA14 and DBA15. Biallelic HEATR3 variants
  (DBA21) are the one recessive form here. A substantial minority of patients
  remain genetically unexplained.
parents:
- Hematological Disease
- Genetic Disease
disease_term:
  preferred_term: Diamond-Blackfan anemia
  term:
    id: MONDO:0015253
    label: Diamond-Blackfan anemia
has_subtypes:
- name: DBA1
  display_name: Diamond-Blackfan anemia 1 (RPS19)
  subtype_term:
    preferred_term: Diamond-Blackfan anemia 1
    term:
      id: MONDO:0007110
      label: Diamond-Blackfan anemia 1
  genes:
  - preferred_term: RPS19
    term:
      id: hgnc:10402
      label: RPS19
  description: >-
    The original and most common molecular form, caused by heterozygous
    loss-of-function variants in the small-subunit ribosomal protein gene
    RPS19. ClinGen classifies the RPS19-Diamond-Blackfan anemia relationship
    as Definitive with autosomal dominant inheritance.
  review_notes: >-
    Converted from a `mappings.mondo_mappings` narrowMatch entry to a
    `has_subtypes` row so the class carries its causal gene, its evidence and
    the reciprocal `genetic[].subtype` foreign key. The mapping is not retained
    alongside the row, which would assert MONDO:0007110 twice on one entry.
  evidence:
  - reference: PMID:17186470
    reference_title: "Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: associated with heterozygous mutations in the ribosomal protein (RP) S19 gene (RPS19) in approximately 25% of probands
    explanation: >-
      States the RPS19 gene-disease relationship and its share of probands. The
      sentence is this paper's framing of established human genetics rather than
      its own result, which is the RPS24 finding below.
  - reference: CGGV:assertion_bceef5ee-7596-4a90-91ce-b36385f9669b-2023-05-30T160000.000Z
    reference_title: "RPS19 / Diamond-Blackfan anemia (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RPS19 | HGNC:10402 | Diamond-Blackfan anemia | MONDO:0015253 | AD | Definitive"
    explanation: >-
      Source of this row's ClinGen sentence. ClinGen curates RPS19 against the
      umbrella class MONDO:0015253 rather than against MONDO:0007110, so the
      Definitive call is for the RPS19-DBA relationship as a whole rather than
      for the numbered subtype this row binds.
- name: DBA3
  display_name: Diamond-Blackfan anemia 3 (RPS24)
  subtype_term:
    preferred_term: Diamond-Blackfan anemia 3
    term:
      id: MONDO:0012529
      label: Diamond-Blackfan anemia 3
  genes:
  - preferred_term: RPS24
    term:
      id: hgnc:10411
      label: RPS24
  description: >-
    Caused by heterozygous variants in the small-subunit ribosomal protein
    gene RPS24, the second DBA gene identified and a rare cause relative to
    RPS19.
  review_notes: >-
    Converted from a `mappings.mondo_mappings` narrowMatch entry, as for DBA1.
  evidence:
  - reference: PMID:17186470
    reference_title: "Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report identification of de novo nonsense and splice-site mutations in another RP, RPS24
    explanation: >-
      The gene-delineation result for RPS24. The same sentence continues with
      the frequency, approximately 2%, but against the narrower denominator of
      RPS19-mutation-negative probands rather than all DBA probands; it is not
      quoted here because the intervening cytogenetic parenthetical prevents an
      exact contiguous match.
- name: DBA4
  display_name: Diamond-Blackfan anemia 4 (RPS17)
  subtype_term:
    preferred_term: Diamond-Blackfan anemia 4
    term:
      id: MONDO:0012924
      label: Diamond-Blackfan anemia 4
  genes:
  - preferred_term: RPS17
    term:
      id: hgnc:10397
      label: RPS17
  description: >-
    Caused by heterozygous variants in the small-subunit ribosomal protein
    gene RPS17, the third ribosomal protein gene of the small subunit linked
    to DBA.
  evidence:
  - reference: PMID:17647292
    reference_title: "Ribosomal protein S17 gene (RPS17) is mutated in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we report the identification of a mutation in yet another ribosomal protein, RPS17.
    explanation: The gene-delineation result establishing RPS17 as a DBA gene.
- name: DBA5
  display_name: Diamond-Blackfan anemia 5 (RPL35A)
  subtype_term:
    preferred_term: Diamond-Blackfan anemia 5
    term:
      id: MONDO:0012925
      label: Diamond-Blackfan anemia 5
  genes:
  - preferred_term: RPL35A
    term:
      id: hgnc:10345
      label: RPL35A
  description: >-
    Caused by heterozygous variants in RPL35A, the first large-subunit
    ribosomal protein gene linked to DBA. The gene was identified from two DBA
    patients carrying chromosome 3q deletions and confirmed by sequencing a
    proband cohort.
  evidence:
  - reference: PMID:18535205
    reference_title: "Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sequence analysis of a cohort of DBA probands confirmed involvement RPL35A in DBA.
    explanation: >-
      The gene-delineation result for RPL35A. Quoted verbatim including the
      source's own omitted word.
- name: DBA6
  display_name: Diamond-Blackfan anemia 6 (RPL5)
  subtype_term:
    preferred_term: Diamond-Blackfan anemia 6
    term:
      id: MONDO:0012937
      label: Diamond-Blackfan anemia 6
  genes:
  - preferred_term: RPL5
    term:
      id: hgnc:10360
      label: RPL5
  description: >-
    Caused by heterozygous variants in the large-subunit ribosomal protein
    gene RPL5. RPL5 variants carry a distinctive malformation profile,
    associating with craniofacial, thumb and heart anomalies.
  evidence:
  - reference: PMID:19061985
    reference_title: "Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: mutations in RPL5 are associated with multiple physical abnormalities, including craniofacial, thumb, and heart anomalies, whereas isolated thumb malformations are predominantly present in patients carrying mutations in RPL11
    explanation: The RPL5-specific genotype-phenotype correlation this row describes.
  - reference: CGGV:assertion_edb6a96b-92d7-4c57-8613-e055d1bdd678-2023-05-30T160000.000Z
    reference_title: "RPL5 / Diamond-Blackfan anemia 6 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RPL5 | HGNC:10360 | Diamond-Blackfan anemia 6 | MONDO:0012937 | AD | Definitive"
    explanation: >-
      ClinGen curates this gene-disease relationship against MONDO:0012937
      itself, the same class this row binds, and classifies it Definitive.
- name: DBA7
  display_name: Diamond-Blackfan anemia 7 (RPL11)
  subtype_term:
    preferred_term: Diamond-Blackfan anemia 7
    term:
      id: MONDO:0012938
      label: Diamond-Blackfan anemia 7
  genes:
  - preferred_term: RPL11
    term:
      id: hgnc:10301
      label: RPL11
  description: >-
    Caused by heterozygous variants in the large-subunit ribosomal protein
    gene RPL11, which associate predominantly with isolated thumb
    malformations rather than the broader RPL5 malformation profile.
  review_notes: >-
    Converted from a `mappings.mondo_mappings` narrowMatch entry, as for DBA1.
  evidence:
  - reference: PMID:19061985
    reference_title: "Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: mutations in RPL5 are associated with multiple physical abnormalities, including craniofacial, thumb, and heart anomalies, whereas isolated thumb malformations are predominantly present in patients carrying mutations in RPL11
    explanation: The RPL11-specific genotype-phenotype correlation this row describes.
- name: DBA8
  display_name: Diamond-Blackfan anemia 8 (RPS7)
  subtype_term:
    preferred_term: Diamond-Blackfan anemia 8
    term:
      id: MONDO:0012939
      label: Diamond-Blackfan anemia 8
  genes:
  - preferred_term: RPS7
    term:
      id: hgnc:10440
      label: RPS7
  description: >-
    Caused by heterozygous variants in the small-subunit ribosomal protein
    gene RPS7, reported alongside RPL5 and RPL11 in the same screen.
  evidence:
  - reference: PMID:19061985
    reference_title: "Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we report the second known mutation in RPS17 and probable pathogenic mutations in three more RP genes, RPL5, RPL11, and RPS7.
    explanation: The gene-delineation result naming RPS7 as a DBA gene.
- name: DBA9
  display_name: Diamond-Blackfan anemia 9 (RPS10)
  subtype_term:
    preferred_term: Diamond-Blackfan anemia 9
    term:
      id: MONDO:0013216
      label: Diamond-Blackfan anemia 9
  genes:
  - preferred_term: RPS10
    term:
      id: hgnc:10383
      label: RPS10
  description: >-
    Caused by heterozygous variants in the small-subunit ribosomal protein
    gene RPS10, identified in a 117-proband screen of 35 ribosomal protein
    genes.
  evidence:
  - reference: PMID:20116044
    reference_title: "Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands.
    explanation: The gene-delineation result for RPS10, with the proband counts this row's description refers to.
- name: DBA10
  display_name: Diamond-Blackfan anemia 10 (RPS26)
  subtype_term:
    preferred_term: Diamond-Blackfan anemia 10
    term:
      id: MONDO:0013217
      label: Diamond-Blackfan anemia 10
  genes:
  - preferred_term: RPS26
    term:
      id: hgnc:10414
      label: RPS26
  description: >-
    Caused by heterozygous variants in the small-subunit ribosomal protein
    gene RPS26, the more frequently mutated of the two genes found in the same
    117-proband screen.
  review_notes: >-
    Converted from a `mappings.mondo_mappings` narrowMatch entry, as for DBA1.
  evidence:
  - reference: PMID:20116044
    reference_title: "Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands.
    explanation: The gene-delineation result for RPS26, with the proband counts this row's description refers to.
- name: DBA11
  display_name: Diamond-Blackfan anemia 11 (RPL26)
  subtype_term:
    preferred_term: Diamond-Blackfan anemia 11
    term:
      id: MONDO:0013964
      label: Diamond-Blackfan anemia 11
  genes:
  - preferred_term: RPL26
    term:
      id: hgnc:10327
      label: RPL26
  description: >-
    Caused by variants in the large-subunit ribosomal protein gene RPL26. The
    index proband carried a de novo two-nucleotide deletion with multiple
    severe physical abnormalities, and the resulting ribosome biogenesis defect
    affects maturation of both ribosomal subunits rather than the large subunit
    alone.
  evidence:
  - reference: PMID:22431104
    reference_title: "Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in diamond-blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified a de novo two-nucleotide deletion in RPL26 in one proband associated with multiple severe physical abnormalities.
    explanation: The gene-delineation result for RPL26 and the source of the malformation statement in this row.
  - reference: PMID:22431104
    reference_title: "Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in diamond-blackfan anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: This mutation gives rise to a remarkable ribosome biogenesis defect that affects maturation of both the small and the large subunits.
    explanation: >-
      The basis for this row's statement that the processing defect is not
      confined to the large subunit, despite RPL26 being a large-subunit protein.
- name: DBA12
  display_name: Diamond-Blackfan anemia 12 (RPL15)
  subtype_term:
    preferred_term: Diamond-Blackfan anemia 12
    term:
      id: MONDO:0014245
      label: Diamond-Blackfan anemia 12
  genes:
  - preferred_term: RPL15
    term:
      id: hgnc:10306
      label: RPL15
  description: >-
    Caused by variants in the large-subunit ribosomal protein gene RPL15,
    first identified as a large deletion by array comparative genomic
    hybridization. Like RPL26, RPL15 is required both for 60S subunit
    formation and for a small-subunit pre-rRNA cleavage step.
  evidence:
  - reference: PMID:23812780
    reference_title: "Novel deletion of RPL15 identified by array-comparative genomic hybridization in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we report a novel large deletion in RPL15, a gene not previously implicated to be causative in DBA.
    explanation: The gene-delineation result for RPL15.
  - reference: PMID:23812780
    reference_title: "Novel deletion of RPL15 identified by array-comparative genomic hybridization in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Like RPL26, RPL15 presents the distinctive feature of being required both for 60S subunit formation and for efficient cleavage of the internal transcribed spacer 1.
    explanation: The basis for this row's dual-subunit statement.
- name: DBA13
  display_name: Diamond-Blackfan anemia 13 (RPS29)
  subtype_term:
    preferred_term: Diamond-Blackfan anemia 13
    term:
      id: MONDO:0014394
      label: Diamond-Blackfan anemia 13
  genes:
  - preferred_term: RPS29
    term:
      id: hgnc:10419
      label: RPS29
  description: >-
    Caused by variants in the small-subunit ribosomal protein gene RPS29,
    identified by whole-exome sequencing in two large multicase DBA families.
  evidence:
  - reference: PMID:24829207
    reference_title: "Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multicase Diamond-Blackfan anemia families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We uncovered a novel DBA causative gene, RPS29
    explanation: The gene-delineation conclusion for RPS29.
  - reference: PMID:24829207
    reference_title: "Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multicase Diamond-Blackfan anemia families."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: RPS29 is a component of the small 40S ribosomal subunit and essential for rRNA processing and ribosome biogenesis.
    explanation: Places RPS29 in the small subunit, which is how this entry wires the gene.
- name: DBA21
  display_name: Diamond-Blackfan anemia 21 (HEATR3)
  subtype_term:
    preferred_term: Diamond-Blackfan anemia 21
    term:
      id: MONDO:0031071
      label: Diamond-Blackfan anemia 21
  genes:
  - preferred_term: HEATR3
    term:
      id: hgnc:26087
      label: HEATR3
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    The only recessively inherited form in this series, and not a ribosomal
    protein gene: HEATR3 is an import adaptor whose yeast homolog synchronizes
    nuclear import of the large-subunit proteins uL5 (RPL11) and uL18 (RPL5).
    Affected individuals had bone marrow failure with short stature, facial and
    acromelic dysmorphism and intellectual disability.
  evidence:
  - reference: PMID:35213692
    reference_title: "HEATR3 variants impair nuclear import of uL18 (RPL5) and drive Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we report multiple individuals with biallelic HEATR3 variants exhibiting bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability.
    explanation: >-
      The gene-delineation result, the source of the biallelic (recessive)
      inheritance recorded on this row, and of its clinical description.
  - reference: PMID:35213692
    reference_title: "HEATR3 variants impair nuclear import of uL18 (RPL5) and drive Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: These variants destabilize a protein whose yeast homolog is known to synchronize the nuclear import of RPs uL5 (RPL11) and uL18 (RPL5)
    explanation: The import-adaptor mechanism this row describes and the reason HEATR3 is wired upstream of the large-subunit node rather than onto it.
- name: DBA22
  display_name: Diamond-Blackfan anemia 22 (RPL17)
  subtype_term:
    preferred_term: Diamond-Blackfan anemia 22
    term:
      id: MONDO:0979244
      label: Diamond-Blackfan anemia 22
  genes:
  - preferred_term: RPL17
    term:
      id: hgnc:10307
      label: RPL17
  description: >-
    Caused by variants in the large-subunit ribosomal protein gene RPL17,
    delineated in two multigenerational pedigrees whose affected members had
    clinical features and erythroid proliferation defects consistent with DBA.
  evidence:
  - reference: PMID:39088281
    reference_title: "An atypical form of 60S ribosomal subunit in Diamond-Blackfan anemia linked to RPL17 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we report the genetic, functional, and biochemical dissection of 2 multigenerational pedigrees with variants in RPL17, a large ribosomal subunit protein-encoding gene
    explanation: The gene-delineation result for RPL17 and the source of its assignment to the large subunit.
prevalence:
- population: Global
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.7
  percentage: 0.0007
  notes: >
    Approximately seven per million live births. Incidence is consistent
    across ethnicities. No sex predilection.
  evidence:
  - reference: PMID:18671700
    reference_title: "Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Classical DBA affects about seven per million live births and presents during the first year of life"
    explanation: Confirms the incidence of DBA at approximately seven per million live births.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identification of a heterozygous pathogenic variant in a gene associated with autosomal dominant DBA syndrome"
    explanation: Confirms autosomal dominant as the most common inheritance pattern for DBA.
pathophysiology:
- name: Small Ribosomal Subunit Assembly Defect
  biological_scale: MOLECULAR
  description: >-
    Haploinsufficiency of a small-subunit (40S) ribosomal protein gene impairs
    18S rRNA maturation and 40S subunit production. The seven genes on this node
    are the DBA genes HGNC assigns to the "S ribosomal proteins" gene group;
    subunit-specific pre-rRNA processing defects are documented for RPS10 and
    RPS26 (18S-E accumulation) and RPS29 is stated to be a 40S component.
  genes:
  - preferred_term: RPS19
    term:
      id: hgnc:10402
      label: RPS19
  - preferred_term: RPS24
    term:
      id: hgnc:10411
      label: RPS24
  - preferred_term: RPS17
    term:
      id: hgnc:10397
      label: RPS17
  - preferred_term: RPS7
    term:
      id: hgnc:10440
      label: RPS7
  - preferred_term: RPS10
    term:
      id: hgnc:10383
      label: RPS10
  - preferred_term: RPS26
    term:
      id: hgnc:10414
      label: RPS26
  - preferred_term: RPS29
    term:
      id: hgnc:10419
      label: RPS29
  biological_processes:
  - preferred_term: ribosomal small subunit biogenesis
    modifier: DECREASED
    term:
      id: GO:0042274
      label: ribosomal small subunit biogenesis
  downstream:
  - target: Ribosomal Protein Haploinsufficiency
    description: >-
      A 40S assembly defect is one of the two routes to the shared
      ribosome-insufficiency state on which the erythroid phenotype depends.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:18535205
    reference_title: "Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Small ribosomal subunit genes RPS19, RPS24, and RPS17 are mutated in approximately one-third of patients.
    explanation: Names three of this node's genes as small-subunit genes mutated in DBA.
  - reference: PMID:20116044
    reference_title: "Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Pre-rRNA analysis in lymphoblastoid cells from patients bearing mutations in RPS10 and RPS26 showed elevated levels of 18S-E pre-rRNA.
    explanation: >-
      The small-subunit pre-rRNA processing defect this node asserts, measured
      in patient-derived cells.
  - reference: PMID:24829207
    reference_title: "Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multicase Diamond-Blackfan anemia families."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: RPS29 is a component of the small 40S ribosomal subunit and essential for rRNA processing and ribosome biogenesis.
    explanation: Places RPS29 on this node.
- name: Large Ribosomal Subunit Assembly Defect
  biological_scale: MOLECULAR
  description: >-
    Haploinsufficiency of a large-subunit (60S) ribosomal protein gene impairs
    28S and 5.8S rRNA maturation and 60S subunit production. The six genes on
    this node are the DBA genes HGNC assigns to the "L ribosomal proteins" gene
    group. Two of them, RPL26 and RPL15, additionally disturb a small-subunit
    pre-rRNA cleavage step, so the subunit split describes which protein is
    missing rather than a clean partition of the processing defect.
  genes:
  - preferred_term: RPL5
    term:
      id: hgnc:10360
      label: RPL5
  - preferred_term: RPL11
    term:
      id: hgnc:10301
      label: RPL11
  - preferred_term: RPL35A
    term:
      id: hgnc:10345
      label: RPL35A
  - preferred_term: RPL26
    term:
      id: hgnc:10327
      label: RPL26
  - preferred_term: RPL15
    term:
      id: hgnc:10306
      label: RPL15
  - preferred_term: RPL17
    term:
      id: hgnc:10307
      label: RPL17
  biological_processes:
  - preferred_term: ribosomal large subunit biogenesis
    modifier: DECREASED
    term:
      id: GO:0042273
      label: ribosomal large subunit biogenesis
  downstream:
  - target: Ribosomal Protein Haploinsufficiency
    description: >-
      A 60S assembly defect is the other route to the shared
      ribosome-insufficiency state.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:18535205
    reference_title: "Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: shRNA inhibition shows that Rpl35a is essential for maturation of 28S and 5.8S rRNAs, 60S subunit biogenesis, normal proliferation, and cell survival.
    explanation: The 60S biogenesis requirement this node asserts, shown for RPL35A.
  - reference: PMID:18535205
    reference_title: "Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These data demonstrate that alterations of large ribosomal subunit proteins cause DBA
    explanation: Establishes large-subunit protein loss as a route to DBA in its own right.
  - reference: PMID:23812780
    reference_title: "Novel deletion of RPL15 identified by array-comparative genomic hybridization in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Like RPL26, RPL15 presents the distinctive feature of being required both for 60S subunit formation and for efficient cleavage of the internal transcribed spacer 1.
    explanation: >-
      The basis for this node's caveat that RPL26 and RPL15 also affect a
      small-subunit cleavage step.
- name: Ribosomal Protein Nuclear Import Failure
  biological_scale: MOLECULAR
  description: >-
    The one DBA mechanism in this entry that is upstream of the ribosomal
    proteins themselves. HEATR3 is an import adaptor for the large-subunit
    proteins uL5 (RPL11) and uL18 (RPL5); biallelic HEATR3 variants destabilize
    it, and patient-derived fibroblasts show reduced nuclear accumulation of
    uL18. The consequence is a shortage of large-subunit proteins in the
    nucleolus rather than a shortage of their transcripts.
  genes:
  - preferred_term: HEATR3
    term:
      id: hgnc:26087
      label: HEATR3
  biological_processes:
  - preferred_term: protein import into nucleus
    modifier: DECREASED
    term:
      id: GO:0006606
      label: protein import into nucleus
  downstream:
  - target: Large Ribosomal Subunit Assembly Defect
    description: >-
      Failure to deliver uL5 and uL18 to the nucleus starves 60S assembly of
      two of its proteins, producing a phenotype the source describes as
      reminiscent of large-subunit ribosomal protein gene variants.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:35213692
    reference_title: "HEATR3 variants impair nuclear import of uL18 (RPL5) and drive Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: These variants destabilize a protein whose yeast homolog is known to synchronize the nuclear import of RPs uL5 (RPL11) and uL18 (RPL5)
    explanation: The import-adaptor role this node asserts.
  - reference: PMID:35213692
    reference_title: "HEATR3 variants impair nuclear import of uL18 (RPL5) and drive Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: HEATR3-depleted cells or patient-derived fibroblasts display reduced nuclear accumulation of uL18
    explanation: The measured import defect in patient cells.
  - reference: PMID:35213692
    reference_title: "HEATR3 variants impair nuclear import of uL18 (RPL5) and drive Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: impairs growth, differentiation, pre-ribosomal RNA processing, and ribosomal subunit formation reminiscent of DBA models of large subunit RP gene variants
    explanation: >-
      The basis for the downstream edge into the large-subunit node rather than
      into the convergent node directly.
- name: Ribosomal Protein Haploinsufficiency
  description: >-
    The convergence point of this entry: whichever ribosomal protein is
    missing, and whether the lesion is in the gene or in the import step that
    delivers the protein, the shared consequence is reduced ribosome assembly
    and protein synthesis capacity. Erythroid progenitors are exquisitely
    sensitive to that state because of their high proliferative and
    translational demands. Causal genes are wired to the subunit-specific
    upstream nodes rather than listed here, so this node carries no `genes:`
    list of its own.
  biological_processes:
  - preferred_term: ribosome biogenesis
    modifier: DECREASED
    term:
      id: GO:0042254
      label: ribosome biogenesis
  - preferred_term: translation
    modifier: DECREASED
    term:
      id: GO:0006412
      label: translation
  - preferred_term: translational initiation
    modifier: DECREASED
    term:
      id: GO:0006413
      label: translational initiation
  cell_types:
  - preferred_term: erythroid progenitor cell
    term:
      id: CL:0000038
      label: erythroid progenitor cell
  downstream:
  - target: p53-Mediated Erythroid Apoptosis
    description: >
      Ribosomal stress activates p53, leading to cell cycle arrest
      and apoptosis of erythroid progenitors.
  - target: Short Stature
    description: Ribosomal protein haploinsufficiency disrupts developmental growth programs, contributing to short stature.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Congenital Malformations
    description: Ribosomal protein haploinsufficiency disrupts embryogenesis, contributing to congenital malformations.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Triphalangeal Thumb
    description: Ribosomal protein haploinsufficiency disrupts limb development, contributing to triphalangeal thumb.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Acute Myeloid Leukemia
    description: Chronic ribosomal-stress marrow dysfunction increases acute myeloid leukemia risk.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Myelodysplasia
    description: Chronic ribosomal-stress marrow dysfunction increases myelodysplasia risk.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Osteosarcoma
    description: DBA cancer predisposition includes osteosarcoma downstream of the ribosomopathy state.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:9988267
    reference_title: "The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified mutations in RPS19 in 10 of 40 unrelated DBA patients, including nonsense, frameshift, splice site and missense mutations"
    explanation: Original discovery of RPS19 mutations as the cause of DBA, establishing the ribosomal protein basis.
  - reference: PMID:9988267
    reference_title: "The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a function for RPS19 in erythropoiesis and embryogenesis"
    explanation: Confirms RPS19 has specific roles in erythropoiesis and embryonic development.
- name: p53-Mediated Erythroid Apoptosis
  description: >
    Ribosomal stress from RP haploinsufficiency leads to accumulation of
    free ribosomal proteins that bind MDM2, stabilizing p53. Activated p53
    triggers cell cycle arrest and apoptosis preferentially in erythroid
    progenitors, resulting in selective red cell aplasia.
  biological_processes:
  - preferred_term: signal transduction by p53 class mediator
    modifier: INCREASED
    term:
      id: GO:0072331
      label: signal transduction by p53 class mediator
  - preferred_term: erythrocyte differentiation
    modifier: ABNORMAL
    term:
      id: GO:0030218
      label: erythrocyte differentiation
  cell_types:
  - preferred_term: erythroblast
    term:
      id: CL:0000765
      label: erythroblast
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets"
    explanation: Confirms the selective erythroid failure (normal leukocytes and platelets) consistent with erythroid-specific apoptosis.
  downstream:
  - target: Macrocytic Anemia
    description: Erythroid progenitor apoptosis produces the macrocytic anemia of DBA.
    causal_link_type: DIRECT
  - target: Pure Red Cell Aplasia
    description: Selective erythroid apoptosis produces pure red cell aplasia.
    causal_link_type: DIRECT
- name: GATA1 Translational Insufficiency
  description: >
    A distinct non-ribosomal mechanism causing DBA. GATA1 is an X-linked
    erythroid transcription factor essential for erythroid differentiation.
    Mutations in GATA1 (including splice site variants) reduce functional
    GATA1 protein levels, impairing erythroid gene expression. Unlike
    ribosomal protein mutations, GATA1 mutations directly affect erythroid
    transcription rather than global translation, but converge on the same
    erythroid differentiation failure.
  genes:
  - preferred_term: GATA1
    term:
      id: hgnc:4170
      label: GATA1
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
  - preferred_term: erythrocyte differentiation
    modifier: ABNORMAL
    term:
      id: GO:0030218
      label: erythrocyte differentiation
  cell_types:
  - preferred_term: erythroid progenitor cell
    term:
      id: CL:0000038
      label: erythroid progenitor cell
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the molecular diagnosis can be established in a male proband by identification of a hemizygous pathogenic variant in GATA1 or TSR2 associated with X-linked DBA syndrome"
    explanation: Confirms GATA1 as a distinct X-linked cause of DBA, separate from ribosomal protein genes.
  - reference: PMID:22706301
    reference_title: "Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mutation, which occurred at a splice site of the GATA1 gene, impaired production of the full-length form of the protein."
    explanation: >-
      The molecular lesion behind this node: a splice-site variant reducing
      full-length GATA1 rather than a defect in global translation.
  downstream:
  - target: Pure Red Cell Aplasia
    description: >-
      Reduced full-length GATA1 impairs erythroid differentiation and produces
      the same red-cell aplasia as the ribosomal route, without passing through
      the ribosomal-stress p53 node. Only the erythroid failure is wired here;
      no cited source in this entry attributes the macrocytosis to GATA1.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22706301
      reference_title: "Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the reduction in erythropoiesis associated with the disease can arise from causes other than defects in ribosomal protein genes"
      explanation: >-
        States that the erythropoietic failure of DBA follows from the GATA1
        lesion independently of ribosomal protein defects, which is what this
        edge asserts.
phenotypes:
- category: Hematological
  name: Macrocytic Anemia
  description: >
    Profound normochromic, usually macrocytic anemia. Elevated MCV and
    elevated erythrocyte adenosine deaminase activity are characteristic.
    Presents during the first year of life in ~90% of cases.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: macrocytic anemia
    term:
      id: HP:0001972
      label: Macrocytic anemia
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The hematologic complications occur in 90% of affected individuals during the first year of life"
    explanation: Confirms onset of anemia during the first year of life in 90% of cases.
- category: Hematological
  name: Pure Red Cell Aplasia
  description: >
    Selective failure of erythroid precursor production with absent
    or markedly decreased erythroid precursors in otherwise normal
    bone marrow.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: pure red cell aplasia
    term:
      id: HP:0012410
      label: Pure red cell aplasia
  evidence:
  - reference: PMID:9988267
    reference_title: "The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "constitutional erythroblastopenia characterized by absent or decreased erythroid precursors"
    explanation: Confirms erythroblastopenia (red cell aplasia) as the defining hematologic feature.
- category: Growth
  name: Short Stature
  description: >
    Growth deficiency present in approximately 30% of affected individuals.
    May be intrinsic to the disease or secondary to corticosteroid therapy.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "growth deficiency in 30% of affected individuals"
    explanation: Confirms growth deficiency affects approximately 30% of DBA patients.
- category: Craniofacial
  name: Congenital Malformations
  description: >
    Congenital anomalies in up to 50% of affected individuals, including
    craniofacial (cleft palate, micrognathia), thumb anomalies
    (triphalangeal, bifid, absent), cardiac defects, and genitourinary
    anomalies.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: craniofacial dysostosis
    term:
      id: HP:0004439
      label: Craniofacial dysostosis
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "congenital malformations in up to 50% of affected individuals"
    explanation: Confirms congenital malformations in up to half of DBA patients.
- category: Skeletal
  name: Triphalangeal Thumb
  description: >
    Thumb anomalies including triphalangeal thumbs are one of the
    most characteristic congenital malformations in DBA. Hand
    malformations are particularly associated with RPL11 mutations.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: triphalangeal thumb
    term:
      id: HP:0001199
      label: Triphalangeal thumb
  evidence:
  - reference: PMID:19773262
    reference_title: "Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A close association was evident between RPL5 mutations and craniofacial malformations, and between hand malformations and RPL11 mutations"
    explanation: Establishes genotype-phenotype correlation between RPL11 mutations and hand malformations including thumb anomalies.
- category: Neoplastic
  name: Acute Myeloid Leukemia
  description: >
    Increased risk for acute myelogenous leukemia, a recognized
    complication of DBA.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: acute myeloid leukemia
    term:
      id: HP:0004808
      label: Acute myeloid leukemia
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "associated with an increased risk for acute myelogenous leukemia, myelodysplastic syndrome, and solid tumors including osteogenic sarcoma"
    explanation: Confirms increased AML risk in DBA patients.
- category: Neoplastic
  name: Myelodysplasia
  description: >
    Increased risk for myelodysplastic syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: myelodysplasia
    term:
      id: HP:0002863
      label: Myelodysplasia
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "associated with an increased risk for acute myelogenous leukemia, myelodysplastic syndrome, and solid tumors including osteogenic sarcoma"
    explanation: Confirms increased MDS risk in DBA patients.
- category: Neoplastic
  name: Osteosarcoma
  description: >
    Increased risk for osteogenic sarcoma, the most notable solid
    tumor associated with DBA.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: osteosarcoma
    term:
      id: HP:0002669
      label: Osteosarcoma
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "associated with an increased risk for acute myelogenous leukemia, myelodysplastic syndrome, and solid tumors including osteogenic sarcoma"
    explanation: Confirms increased osteosarcoma risk in DBA patients.
biochemical:
- name: Hemoglobin
  presence: Decreased
  context: Profound anemia; may require transfusion support
- name: MCV
  presence: Elevated
  context: Macrocytosis is characteristic
- name: Erythrocyte Adenosine Deaminase
  presence: Elevated
  context: Elevated eADA is a diagnostic biomarker for DBA
- name: HbF
  presence: Elevated
  context: Elevated fetal hemoglobin is a common finding
- name: Reticulocytes
  presence: Decreased
  context: Reticulocytopenia reflecting erythroid production failure
genetic:
- name: RPS19
  gene_term:
    preferred_term: RPS19
    term:
      id: hgnc:10402
      label: RPS19
  association: Causative
  relationship_type: CAUSATIVE
  subtype: DBA1
  inheritance:
  - name: Autosomal dominant
  case_fractions:
  - population: DBA probands
    case_fraction_percent: 25.0
    notes: >-
      Stated as "approximately 25% of probands" in the cited paper's framing of
      the established genetics; not a percentage this entry computed.
    evidence:
    - reference: PMID:17186470
      reference_title: "Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: associated with heterozygous mutations in the ribosomal protein (RP) S19 gene (RPS19) in approximately 25% of probands
      explanation: Source of the 25% figure recorded here.
  evidence:
  - reference: PMID:9988267
    reference_title: "The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified mutations in RPS19 in 10 of 40 unrelated DBA patients"
    explanation: Original identification of RPS19 as the first DBA gene, mutated in ~25% of patients.
  - reference: CGGV:assertion_bceef5ee-7596-4a90-91ce-b36385f9669b-2023-05-30T160000.000Z
    reference_title: "RPS19 / Diamond-Blackfan anemia (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RPS19 | HGNC:10402 | Diamond-Blackfan anemia | MONDO:0015253 | AD | Definitive"
    explanation: ClinGen classifies the RPS19-Diamond-Blackfan anemia gene-disease relationship as definitive with autosomal dominant inheritance.
- name: RPL5
  gene_term:
    preferred_term: RPL5
    term:
      id: hgnc:10360
      label: RPL5
  association: Causative
  relationship_type: CAUSATIVE
  subtype: DBA6
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:19773262
    reference_title: "Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two new genes (RPL5, RPL11), encoding for ribosomal proteins of the large subunit, have been reported to be involved in a considerable percentage of patients"
    explanation: Identifies RPL5 as a DBA gene encoding a large ribosomal subunit protein.
  - reference: PMID:19773262
    reference_title: "Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "About 20% of the patients screened had mutations in RPL5 or RPL11"
    explanation: Quantifies RPL5/RPL11 mutation frequency at ~20% of RPS19-negative DBA patients.
  - reference: CGGV:assertion_edb6a96b-92d7-4c57-8613-e055d1bdd678-2023-05-30T160000.000Z
    reference_title: "RPL5 / Diamond-Blackfan anemia 6 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RPL5 | HGNC:10360 | Diamond-Blackfan anemia 6 | MONDO:0012937 | AD | Definitive"
    explanation: ClinGen classifies the RPL5-DBA6 gene-disease relationship as definitive with autosomal dominant inheritance.
- name: RPL11
  gene_term:
    preferred_term: RPL11
    term:
      id: hgnc:10301
      label: RPL11
  association: Causative
  relationship_type: CAUSATIVE
  subtype: DBA7
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:19773262
    reference_title: "Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "About 20% of the patients screened had mutations in RPL5 or RPL11"
    explanation: Quantifies RPL11 mutation frequency in Italian DBA cohort.
  - reference: PMID:19773262
    reference_title: "Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A close association was evident between RPL5 mutations and craniofacial malformations, and between hand malformations and RPL11 mutations"
    explanation: Establishes RPL11-specific genotype-phenotype correlation with hand malformations.
- name: RPL35A
  gene_term:
    preferred_term: RPL35A
    term:
      id: hgnc:10345
      label: RPL35A
  association: Causative
  relationship_type: CAUSATIVE
  subtype: DBA5
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:19773262
    reference_title: "Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in RPS24, RPS17, and RPL35A described in a minority of patients show that Diamond-Blackfan anemia is a disorder of ribosome biogenesis"
    explanation: Identifies RPL35A as a DBA gene, establishing DBA as a ribosomopathy.
  - reference: PMID:18535205
    reference_title: "Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sequence analysis of a cohort of DBA probands confirmed involvement RPL35A in DBA.
    explanation: >-
      The primary gene-delineation result for RPL35A, which this record
      previously lacked. Quoted verbatim including the source's omitted word.
  - reference: PMID:18535205
    reference_title: "Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: shRNA inhibition shows that Rpl35a is essential for maturation of 28S and 5.8S rRNAs, 60S subunit biogenesis, normal proliferation, and cell survival.
    explanation: Places RPL35A in large-subunit biogenesis, which is how this entry wires the gene.
- name: RPS26
  gene_term:
    preferred_term: RPS26
    term:
      id: hgnc:10414
      label: RPS26
  association: Causative
  relationship_type: CAUSATIVE
  subtype: DBA10
  inheritance:
  - name: Autosomal dominant
  frequency: >-
    Nine distinct mutations in 12 probands of a 117-proband DBA cohort screened
    across 35 ribosomal protein genes (PMID:20116044).
  evidence:
  - reference: PMID:20116044
    reference_title: "Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands.
    explanation: >-
      The primary gene-delineation result for RPS26 and the source of the
      proband counts in this record's frequency field. This record previously
      carried no evidence at all.
  - reference: PMID:20116044
    reference_title: "Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Pre-rRNA analysis in lymphoblastoid cells from patients bearing mutations in RPS10 and RPS26 showed elevated levels of 18S-E pre-rRNA.
    explanation: >-
      The small-subunit pre-rRNA processing defect that places RPS26 on the 40S
      node of this entry's pathograph.
- name: RPS24
  gene_term:
    preferred_term: RPS24
    term:
      id: hgnc:10411
      label: RPS24
  association: Causative
  relationship_type: CAUSATIVE
  subtype: DBA3
  inheritance:
  - name: Autosomal dominant
  case_fractions:
  - population: DBA patients
    case_fraction_percent: 1.4
    notes: >-
      Stated as "approximately 1.4% of DBA patients" in the cited paper's
      introduction; not a percentage this entry computed. The delineating paper
      (PMID:17186470) gives roughly 2% but against the narrower denominator of
      RPS19-mutation-negative probands, so the two figures are not comparable.
    evidence:
    - reference: PMID:17647292
      reference_title: "Ribosomal protein S17 gene (RPS17) is mutated in Diamond-Blackfan anemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: RPS24 mutated in approximately 1.4% of DBA patients
      explanation: Source of the 1.4% figure recorded here.
  evidence:
  - reference: PMID:17186470
    reference_title: "Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report identification of de novo nonsense and splice-site mutations in another RP, RPS24
    explanation: >-
      The primary gene-delineation result for RPS24, which this record
      previously lacked entirely. The same sentence gives the frequency as
      approximately 2% of RPS19-mutation-negative probands.
- name: RPS10
  gene_term:
    preferred_term: RPS10
    term:
      id: hgnc:10383
      label: RPS10
  association: Causative
  relationship_type: CAUSATIVE
  subtype: DBA9
  inheritance:
  - name: Autosomal dominant
  frequency: >-
    Three distinct mutations in five probands of a 117-proband DBA cohort
    screened across 35 ribosomal protein genes (PMID:20116044).
  evidence:
  - reference: PMID:20116044
    reference_title: "Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands.
    explanation: >-
      The primary gene-delineation result for RPS10 and the source of the
      proband counts in this record's frequency field. This record previously
      carried no evidence at all.
- name: RPS17
  gene_term:
    preferred_term: RPS17
    term:
      id: hgnc:10397
      label: RPS17
  association: Causative
  relationship_type: CAUSATIVE
  subtype: DBA4
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:17647292
    reference_title: "Ribosomal protein S17 gene (RPS17) is mutated in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we report the identification of a mutation in yet another ribosomal protein, RPS17.
    explanation: >-
      The primary gene-delineation result for RPS17. This record previously
      carried no evidence at all.
  - reference: PMID:18535205
    reference_title: "Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Small ribosomal subunit genes RPS19, RPS24, and RPS17 are mutated in approximately one-third of patients.
    explanation: >-
      Assigns RPS17 to the small subunit, which is how this entry wires the
      gene. Quoted from this paper's framing sentence rather than its own
      RPL35A result.
- name: RPS7
  gene_term:
    preferred_term: RPS7
    term:
      id: hgnc:10440
      label: RPS7
  association: Causative
  relationship_type: CAUSATIVE
  subtype: DBA8
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:19061985
    reference_title: "Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we report the second known mutation in RPS17 and probable pathogenic mutations in three more RP genes, RPL5, RPL11, and RPS7.
    explanation: >-
      The primary gene-delineation result naming RPS7. This record previously
      carried no evidence at all.
  - reference: PMID:19061985
    reference_title: "Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: mutations of RPL5, RPL11, or RPS7 in DBA cells is associated with diverse defects in the maturation of ribosomal RNAs in the large or the small ribosomal subunit production pathway
    explanation: >-
      The rRNA-maturation phenotype behind this entry's subunit-specific
      pathograph nodes. The paper reports defects in either pathway across these
      three genes rather than assigning one pathway per gene.
- name: RPL26
  gene_term:
    preferred_term: RPL26
    term:
      id: hgnc:10327
      label: RPL26
  association: Causative
  relationship_type: CAUSATIVE
  subtype: DBA11
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:22431104
    reference_title: "Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in diamond-blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified a de novo two-nucleotide deletion in RPL26 in one proband associated with multiple severe physical abnormalities.
    explanation: The primary gene-delineation result for RPL26.
  - reference: PMID:22431104
    reference_title: "Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in diamond-blackfan anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: This mutation gives rise to a remarkable ribosome biogenesis defect that affects maturation of both the small and the large subunits.
    explanation: >-
      Records that the processing defect of this large-subunit protein is not
      confined to the large subunit.
- name: RPL15
  gene_term:
    preferred_term: RPL15
    term:
      id: hgnc:10306
      label: RPL15
  association: Causative
  relationship_type: CAUSATIVE
  subtype: DBA12
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:23812780
    reference_title: "Novel deletion of RPL15 identified by array-comparative genomic hybridization in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we report a novel large deletion in RPL15, a gene not previously implicated to be causative in DBA.
    explanation: The primary gene-delineation result for RPL15.
  - reference: PMID:23812780
    reference_title: "Novel deletion of RPL15 identified by array-comparative genomic hybridization in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Like RPL26, RPL15 presents the distinctive feature of being required both for 60S subunit formation and for efficient cleavage of the internal transcribed spacer 1.
    explanation: >-
      Places RPL15 in 60S formation, which is how this entry wires the gene,
      while recording its additional small-subunit cleavage requirement.
- name: RPS29
  gene_term:
    preferred_term: RPS29
    term:
      id: hgnc:10419
      label: RPS29
  association: Causative
  relationship_type: CAUSATIVE
  subtype: DBA13
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:24829207
    reference_title: "Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multicase Diamond-Blackfan anemia families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We uncovered a novel DBA causative gene, RPS29
    explanation: The gene-delineation conclusion for RPS29.
  - reference: PMID:24829207
    reference_title: "Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multicase Diamond-Blackfan anemia families."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: RPS29 is a component of the small 40S ribosomal subunit and essential for rRNA processing and ribosome biogenesis.
    explanation: Places RPS29 in the small subunit, which is how this entry wires the gene.
- name: RPL17
  gene_term:
    preferred_term: RPL17
    term:
      id: hgnc:10307
      label: RPL17
  association: Causative
  relationship_type: CAUSATIVE
  subtype: DBA22
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:39088281
    reference_title: "An atypical form of 60S ribosomal subunit in Diamond-Blackfan anemia linked to RPL17 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we report the genetic, functional, and biochemical dissection of 2 multigenerational pedigrees with variants in RPL17, a large ribosomal subunit protein-encoding gene
    explanation: The gene-delineation result for RPL17 and the source of its assignment to the large subunit.
- name: HEATR3
  gene_term:
    preferred_term: HEATR3
    term:
      id: hgnc:26087
      label: HEATR3
  association: Causative
  relationship_type: CAUSATIVE
  subtype: DBA21
  inheritance:
  - name: Autosomal recessive
  notes: >-
    Not a ribosomal protein gene and not autosomal dominant: HEATR3 is an
    import adaptor for the large-subunit proteins uL5 (RPL11) and uL18 (RPL5),
    and the reported variants are biallelic. It is wired upstream of the
    large-subunit node rather than onto it for that reason.
  evidence:
  - reference: PMID:35213692
    reference_title: "HEATR3 variants impair nuclear import of uL18 (RPL5) and drive Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we report multiple individuals with biallelic HEATR3 variants exhibiting bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability.
    explanation: The gene-delineation result and the source of the biallelic inheritance recorded here.
  - reference: PMID:35213692
    reference_title: "HEATR3 variants impair nuclear import of uL18 (RPL5) and drive Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: HEATR3-depleted cells or patient-derived fibroblasts display reduced nuclear accumulation of uL18
    explanation: The measured import defect behind this record's mechanism note.
- name: GATA1
  gene_term:
    preferred_term: GATA1
    term:
      id: hgnc:4170
      label: GATA1
  association: Causative
  relationship_type: CAUSATIVE
  inheritance:
  - name: X-linked recessive
  notes: >-
    No numbered MONDO Diamond-Blackfan anemia class records GATA1 as its causal
    gene, so this record carries no `subtype` foreign key; the X-linked GATA1
    form is modeled on the umbrella entry and in its own pathophysiology node.
  evidence:
  - reference: PMID:22706301
    reference_title: "Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed exome sequencing on two siblings who had no known pathogenic mutations for DBA and identified a mutation in the gene encoding the hematopoietic transcription factor GATA1"
    explanation: Discovery of GATA1 as a DBA gene through exome sequencing.
  - reference: PMID:22706301
    reference_title: "Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the reduction in erythropoiesis associated with the disease can arise from causes other than defects in ribosomal protein genes"
    explanation: Establishes that DBA can be caused by non-ribosomal protein gene mutations, specifically GATA1.
  - reference: PMID:37973818
    reference_title: "Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recent studies also indicated that non-RP genes like GATA1, TSR2, are associated with DBA"
    explanation: Confirms GATA1 and TSR2 as non-ribosomal protein genes associated with DBA.
treatments:
- name: Corticosteroid Therapy
  description: >
    First-line treatment. Improves the red blood cell count in approximately
    60-80% of affected individuals. Recommended to start at age 12 months
    or older to minimize growth effects.
  treatment_term:
    preferred_term: systemic corticosteroid therapy
    term:
      id: NCIT:C122080
      label: Systemic Corticosteroid Therapy
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Corticosteroid treatment, recommended in children at age 12 months or older, improves the red blood cell count in approximately 60%-80% of affected individuals"
    explanation: Confirms corticosteroid efficacy at 60-80% response rate and recommended age of initiation.
- name: Chronic Red Blood Cell Transfusions
  description: >
    Necessary during the first year of life and for steroid-nonresponders.
    Iron chelation therapy is required after 10-12 transfusions to prevent
    transfusion-related iron overload.
  treatment_term:
    preferred_term: blood transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic transfusion with packed red blood cells is necessary during the first year of life"
    explanation: Confirms chronic transfusion as necessary during the first year to avoid steroid effects on growth.
- name: Hematopoietic Stem Cell Transplantation
  description: >
    The only curative therapy for the hematologic manifestations of DBA.
    Recommended for transfusion-dependent patients or those developing
    other cytopenias.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hematopoietic stem cell transplantation, the only curative therapy for the hematologic manifestations of DBA syndrome"
    explanation: Confirms HSCT as the only curative therapy for DBA hematologic manifestations.
- name: Iron Chelation Therapy
  description: >
    Required for transfusion-dependent patients after 10-12 transfusions.
    Deferasirox (oral) or deferoxamine (subcutaneous) are preferred.
  treatment_term:
    preferred_term: iron chelation therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Genetic Counseling
  description: >
    Important for family screening. Approximately 40-45% of cases are
    inherited; 55-60% are de novo.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: Clonal Evolution and Malignancy Surveillance
  description: >-
    As an inherited bone marrow failure syndrome, Diamond-Blackfan anemia
    carries an elevated risk of myelodysplastic neoplasm, acute myeloid
    leukemia, and solid tumors. Long-term surveillance includes periodic marrow
    evaluation with cytogenetic monitoring for acquired clonal abnormalities and
    disease-specific late-effects screening, especially after hematopoietic cell
    transplantation.
  treatment_term:
    preferred_term: surveillance for malignancies
    term:
      id: NCIT:C15406
      label: Cancer Screening
  evidence:
  - reference: PMID:38016422
    reference_title: "Cytogenetics in the management of bone marrow failure syndromes: Guidelines from the Groupe Francophone de Cytogénétique Hématologique (GFCH)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Bone marrow failure syndromes are at risk of secondary progression towards myeloid neoplasms in the form of myelodysplastic neoplasms or acute myeloid leukemia."
    explanation: The GFCH cytogenetics guideline establishes the myeloid-neoplasm progression risk in bone marrow failure syndromes (including Diamond-Blackfan anemia) that cytogenetic surveillance monitors.
  - reference: PMID:28533057
    reference_title: "Late Effects Screening Guidelines after Hematopoietic Cell Transplantation for Inherited Bone Marrow Failure Syndromes: Consensus Statement From the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects After Pediatric HCT."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This companion article outlines consensus disease-specific long-term follow-up screening guidelines for patients with IMBFS."
    explanation: Consensus late-effects screening guidelines for inherited bone marrow failure syndromes (which include Diamond-Blackfan anemia) frame long-term post-transplant surveillance.
datasets:
- accession: ega:EGAS00000000105
  title: Copy number analysis of Diamond-Blackfan Anemia (DBA) using SNP array
  description: Diamond–Blackfan anemia (DBA), is a rare congenital anemia that usually presents in infancy. About fifty percent of DBA patients possess mutations in ribosomal protains (RPs). In this study, we performed genomic copy number analysis using SNP arrays for 27 Japanese DBA patients to detect genomic copy number lesions of the RP genes' loci.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Diamond-Blackfan Anemia"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001000875
  title: Loss of functional mutation in RPL27 and RPS27 identified by whole-exome sequencing in Diamond-Blackfan Anemia
  description: We performed whole-exome sequencing analysis of 48 patients with no documented mutations/deletions involving known Diamond-Blackfan anemia genes and identified 10 mutations in previous known causative genes and 2 mutations in novel ribosomal genes.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Diamond-Blackfan Anemia"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
references:
- reference: PMID:20301769
  title: "DBA Syndrome."
  tags:
  - GeneReviews
  findings: []
- reference: DOI:10.1016/j.isci.2024.109172
  title: Disruption of mitochondrial energy metabolism is a putative pathogenesis of Diamond-Blackfan anemia
  findings: []
- reference: DOI:10.1016/j.jbc.2024.107542
  title: Activation of nemo-like kinase in diamond blackfan anemia suppresses early erythropoiesis by preventing mitochondrial biogenesis
  findings: []
- reference: DOI:10.1038/s41375-023-02082-w
  title: Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia
  findings: []
- reference: DOI:10.1038/s41392-024-02033-6
  title: BRAF inhibitors enhance erythropoiesis and treat anemia through paradoxical activation of MAPK signaling
  findings: []
- reference: DOI:10.1172/jci.insight.171650
  title: Lentivirus-mediated gene therapy corrects ribosomal biogenesis and shows promise for Diamond Blackfan anemia
  findings: []
- reference: DOI:10.1172/jci.insight.172475
  title: An atypical form of 60S ribosomal subunit in Diamond-Blackfan anemia linked to RPL17 variants
  findings: []
- reference: DOI:10.3390/cells13110920
  title: 'Towards a Cure for Diamond–Blackfan Anemia: Views on Gene Therapy'
  findings: []
- reference: DOI:10.3390/children10111812
  title: 'The Diverse Genomic Landscape of Diamond–Blackfan Anemia: Two Novel Variants and a Mini-Review'
  findings: []
📚

References & Deep Research

References

9
PMID:20301769
DBA Syndrome.
No top-level findings curated for this source.
DOI:10.1016/j.isci.2024.109172
Disruption of mitochondrial energy metabolism is a putative pathogenesis of Diamond-Blackfan anemia
No top-level findings curated for this source.
DOI:10.1016/j.jbc.2024.107542
Activation of nemo-like kinase in diamond blackfan anemia suppresses early erythropoiesis by preventing mitochondrial biogenesis
No top-level findings curated for this source.
DOI:10.1038/s41375-023-02082-w
Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia
No top-level findings curated for this source.
DOI:10.1038/s41392-024-02033-6
BRAF inhibitors enhance erythropoiesis and treat anemia through paradoxical activation of MAPK signaling
No top-level findings curated for this source.
DOI:10.1172/jci.insight.171650
Lentivirus-mediated gene therapy corrects ribosomal biogenesis and shows promise for Diamond Blackfan anemia
No top-level findings curated for this source.
DOI:10.1172/jci.insight.172475
An atypical form of 60S ribosomal subunit in Diamond-Blackfan anemia linked to RPL17 variants
No top-level findings curated for this source.
DOI:10.3390/cells13110920
Towards a Cure for Diamond–Blackfan Anemia: Views on Gene Therapy
No top-level findings curated for this source.
DOI:10.3390/children10111812
The Diverse Genomic Landscape of Diamond–Blackfan Anemia: Two Novel Variants and a Mini-Review
No top-level findings curated for this source.

Deep Research

2

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.

Disorder ▸

Disorder

  • Name: Diamond-Blackfan Anemia
  • Category: Mendelian
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 34

Key Pathophysiology Nodes

  • Ribosomal Protein Haploinsufficiency
  • p53-Mediated Erythroid Apoptosis
  • GATA1 Translational Insufficiency
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1016/j.isci.2024.109172
  • DOI:10.1016/j.jbc.2024.107542
  • DOI:10.1016/s2352-3026(24
  • DOI:10.1038/s41375-023-02082-w
  • DOI:10.1038/s41392-024-02033-6
  • DOI:10.1172/jci.insight.171650
  • DOI:10.1172/jci.insight.172475
  • DOI:10.3390/cells13110920
  • DOI:10.3390/children10111812
Falcon ▸
Disease Pathophysiology Research Template
Edison Scientific Literature 35 citations 2026-02-15T22:03:09.633857

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

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

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

Disease Pathophysiology Research Template

Target Disease

  • Disease Name: Diamond-Blackfan Anemia
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Diamond-Blackfan Anemia. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

  • What are the primary pathophysiological mechanisms?
  • What molecular pathways are dysregulated?
  • What cellular processes are affected?

2. Key Molecular Players

  • Genes/Proteins: Which genes are causally involved or implicated?
  • Chemical Entities: What metabolites, drugs, or small molecules are relevant?
  • Cell Types: Which cell types are primarily affected?
  • Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

  • What biological processes (GO terms) are disrupted?
  • Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

  • Where in the cell do key processes occur?
  • Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

  • What is the sequence of events from initial trigger to clinical manifestation?
  • Are there distinct stages or phases?

6. Phenotypic Manifestations

  • What are the key clinical phenotypes?
  • How do they relate to the underlying mechanisms?

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Diamond–Blackfan anemia (DBA) pathophysiology research report (molecular/cellular focus)

0. Disease identifiers and scope

  • Disease: Diamond–Blackfan anemia (DBA) / “DBA syndrome” (expanded phenotype concept in 2024 consensus). (wlodarski2024diagnosistreatmentand pages 3-5)
  • MONDO: MONDO_0015253 (Diamond-Blackfan anemia). (liu2024perspectivesofcurrent pages 3-4)
  • Category: Mendelian, primarily autosomal dominant haploinsufficiency of ribosomal protein (RP) genes; additional X-linked and recessive DBA/DBA-like entities exist. (liu2024perspectivesofcurrent pages 1-2, pelagiadis2023thediversegenomic pages 1-2)

1. Key concepts, definitions, and current understanding (2023–2024)

1.1 Core definition (hematologic phenotype)

DBA is a congenital bone marrow failure disorder with selective erythroid hypoplasia and typically macrocytic, reticulocytopenic anemia. The 2024 international consensus defines DBA diagnosis by either (i) a pathogenic/likely pathogenic variant in a DBA gene or (ii) compatible hematologic findings including “macrocytic anemia… with reticulocytopenia and BM erythroblastopenia; absence of dysplasia, dyserythropoiesis, and sideroblasts” plus exclusion of differential diagnoses. (wlodarski2024diagnosistreatmentand pages 20-23)

1.2 DBA as a “ribosomopathy”

DBA is considered a prototypic ribosomopathy, usually caused by heterozygous RP gene variants that impair ribosome biogenesis (rRNA processing/maturation and/or subunit assembly). A 2024 review notes: “Around 75% of cases of DBA are related to a heterozygous allelic variation in ribosomal protein (RP) genes” and “mutations in 23 RP genes have been identified.” (liu2024perspectivesofcurrent pages 1-2)

1.3 Multi-hit molecular pathophysiology model

Current syntheses emphasize that impaired erythropoiesis results from several interacting stress programs downstream of RP haploinsufficiency, including p53 activation, translational dysfunction, inflammation, globin/heme imbalance with ROS, and autophagy/mitochondrial/metabolic perturbations. (liu2024perspectivesofcurrent pages 1-2, liu2024perspectivesofcurrent pages 3-4, pelagiadis2023thediversegenomic pages 5-8)

2. Core pathophysiology (molecular pathways and cellular processes)

2.1 Primary lesion: impaired ribosome biogenesis and rRNA processing

Mechanism. Pathogenic RP variants reduce effective ribosome production (“ribosomal insufficiency”), causing pre-rRNA processing defects and altered ribosomal subunit maturation. (liu2024perspectivesofcurrent pages 1-2, pelagiadis2023thediversegenomic pages 1-2)

Recent mechanistic example (2024, RPL17). In DBA pedigrees with RPL17 variants, patient-derived lines showed rRNA maturation defects and atypical large subunits: “5.8SC consisted of 8% to 21% of 5.8S rRNAs in affected case-derived cells,” and 10–20% of 60S subunits carried this short 5.8S rRNA species yet remained translationally active. (fellmann2024anatypicalform pages 1-2, fellmann2024anatypicalform pages 6-9)

Pathway-level consequence. Reduced ribosome output acts as a bottleneck for high-demand erythroid differentiation, driving lineage-selective failure of erythroid progenitors/precursors. (liu2024perspectivesofcurrent pages 1-2, fellmann2024anatypicalform pages 1-2)

2.2 Ribosomal/nucleolar stress → MDM2 inhibition → p53 stabilization

A central model is that disrupted ribosome biogenesis triggers nucleolar stress, leading to p53 stabilization (classically via RP/5S RNP interactions with MDM2). The 2023 mini-review summarizes defective rRNA maturation provoking nucleolar stress and p53 stabilization/activation, causing erythroid-specific arrest/apoptosis. (pelagiadis2023thediversegenomic pages 1-2)

The RPL17 JCI Insight paper situates its findings in the broader DBA framework whereby defective biogenesis leads to free 5S RNP binding and deactivation of HDM2/MDM2, stabilizing p53 and contributing to progenitor proliferation arrest and anemia. (fellmann2024anatypicalform pages 1-2)

2.3 Translational dysfunction and erythroid selectivity (GATA1 as a key node)

Beyond a modest global translation reduction, DBA exhibits selective translational vulnerability of key erythroid regulators. - A 2023 mini-review states: “Haploinsufficiency in RPs results in an impaired translation of GATA1 mRNA.” (pelagiadis2023thediversegenomic pages 5-8) - A 2024 review explains that GATA1 can be reduced via splice-site mutations and also by poor translation attributable to a structured 5′UTR, linking ribosome shortage to erythroid-specific defects. (liu2024perspectivesofcurrent pages 3-4)

2.4 Imbalanced globin/heme synthesis, oxidative stress, and apoptosis

Multiple sources converge on a model in which RP/GATA1 perturbations dysregulate globin–heme coordination, leading to free heme toxicity and ROS. - The 2023 review links reduced GATA1/RP deficiency to globin–heme imbalance and “accumulation of free cytoplasmic heme in erythroid progenitors, increasing the p53-dependent apoptosis” underlying erythroid failure. (pelagiadis2023thediversegenomic pages 5-8) - Additional supportive framing includes ROS contribution to defective erythropoiesis. (pelagiadis2023thediversegenomic pages 1-2)

2.5 Inflammatory signaling as a modifier/amplifier

A 2024 Leukemia review notes elevated inflammatory cytokines (e.g., IFN-γ, TNF-α) and enrichment of TNFα/NF-κB signatures (e.g., in RPS19-deficient CD34+ cells), consistent with inflammation contributing to marrow suppression and erythroid failure. (liu2024perspectivesofcurrent pages 3-4)

2.6 Autophagy/mitophagy and mitochondrial/metabolic mechanisms (rapidly developing area, 2024)

Two 2024 primary studies highlight mitochondrial control points that may interact with ribosome biogenesis and translation:

(i) OXPHOS → ribosome biogenesis coupling (iScience, Mar 2024). OXPHOS suppression in a primary HSPC-to-erythroid model caused erythroid differentiation failure and ribosome biogenesis defects; RanGAP1 was identified as an OXPHOS-dependent mediator and coenzyme Q10 (CoQ10) activation of OXPHOS rescued erythroid defects. Patient data suggested OXPHOS suppression with reduced ribosome biogenesis and that OXPHOS gene mutations (~10%) might contribute. (xiao2024disruptionofmitochondrial pages 1-2)

(ii) NLK–mTORC1–mitochondrial biogenesis axis (JBC, Aug 2024). In erythroid progenitors from DBA patients, NLK is “hyperactivated” and suppresses mTORC1 via Raptor phosphorylation. The authors state: “NLK-mediated phosphorylation of Raptor suppresses mTORC1 activity” and “Phosphorylation of Raptor at S863 prevents mTORC1 from localizing to the outer lysosomal membrane where the complex is activated by Rheb.” This suppresses translation of mitochondrial biogenesis factors and impairs early erythropoiesis. (wilkes2024activationofnemolike pages 1-2)

3. Key molecular players (genes/proteins), chemical entities, cell types, and anatomic sites

3.1 Causal/implicated genes (HGNC symbols) and roles

Major RP genes (examples; not exhaustive): - RPS19 (most frequent; commonly cited ~25% of cases). (liu2024perspectivesofcurrent pages 1-2, gimenez2024lentivirusmediatedgenetherapy pages 1-2) - RPL5, RPL11, RPS26, RPS24 (frequent; linked to congenital anomalies and other genotype–phenotype differences). (liu2024perspectivesofcurrent pages 1-2, liu2024perspectivesofcurrent pages 2-3) - RPL17 (2024: causes atypical 60S/5.8S rRNA phenotype). (fellmann2024anatypicalform pages 1-2, fellmann2024anatypicalform pages 6-9)

Non-RP DBA/DBA-like genes discussed in recent synthesis: - GATA1 (erythroid TF; splice mutations and translation sensitivity). (liu2024perspectivesofcurrent pages 1-2, liu2024perspectivesofcurrent pages 3-4) - TSR2 (RPS26 chaperone; X-linked DBA-like). (liu2024perspectivesofcurrent pages 3-4, pelagiadis2023thediversegenomic pages 1-2) - HEATR3 (ribosome biogenesis factor; variants can reduce nuclear uL18/RPL5 and impair ribosome biogenesis, described as potentially p53-independent in parts of the pathway). (liu2024perspectivesofcurrent pages 3-4) - EPO (rare recessive DBA-like; altered receptor affinity described in review). (liu2024perspectivesofcurrent pages 3-4) - CECR1 / ADA2 (DBA-like; clinically relevant as HSCT may be effective). (pelagiadis2023thediversegenomic pages 5-8) - TP53 gain-of-function (rare DBA-like phenotypes discussed in consensus context). (wlodarski2024diagnosistreatmentand pages 16-18, wlodarski2024diagnosistreatmentand pages 3-5)

3.2 Key pathways (GO-style biological process labels)

Ontology-ready GO biological process descriptors supported by the cited evidence include: - Ribosome biogenesis / ribosomal large/small subunit assembly / rRNA processing (including pre-rRNA cleavage steps). (liu2024perspectivesofcurrent pages 1-2, fellmann2024anatypicalform pages 6-9) - Nucleolar stress response leading to p53-mediated apoptotic signaling and cell cycle arrest. (pelagiadis2023thediversegenomic pages 1-2, fellmann2024anatypicalform pages 1-2) - Regulation of translation (global and selective translation; GATA1 sensitivity). (liu2024perspectivesofcurrent pages 3-4, pelagiadis2023thediversegenomic pages 5-8) - Erythrocyte differentiation / erythropoiesis (failure of progenitor expansion/maturation). (liu2024perspectivesofcurrent pages 1-2, wu2024brafinhibitorsenhance pages 1-2) - Response to oxidative stress and heme metabolic process (free heme → ROS → apoptosis model). (pelagiadis2023thediversegenomic pages 5-8) - Inflammatory response / NF-κB signaling / TNF signaling (as modifiers). (liu2024perspectivesofcurrent pages 3-4) - Mitochondrial biogenesis and oxidative phosphorylation as modulators of erythroid commitment and ribosome output. (xiao2024disruptionofmitochondrial pages 1-2, wilkes2024activationofnemolike pages 1-2)

3.3 Cellular components (GO cellular component labels)

Ontology-ready cellular component descriptors include: - Nucleolus (site of rRNA transcription/processing and early ribosome biogenesis; nucleolar stress trigger). (pelagiadis2023thediversegenomic pages 1-2, fellmann2024anatypicalform pages 6-9) - Ribosome (40S/60S subunits; atypical 60S with altered 5.8S rRNA in RPL17 DBA). (fellmann2024anatypicalform pages 1-2) - Cytosol (translation; globin/heme imbalance effects). (pelagiadis2023thediversegenomic pages 5-8) - Mitochondrion (OXPHOS; mitochondrial biogenesis/mitophagy programs affecting erythropoiesis). (xiao2024disruptionofmitochondrial pages 1-2, wilkes2024activationofnemolike pages 1-2) - Lysosomal membrane (mTORC1 activation platform; Raptor phosphorylation affecting localization). (wilkes2024activationofnemolike pages 1-2)

3.4 Key cell types (CL-style)

Primary affected hematopoietic populations include: - Hematopoietic stem and progenitor cells (HSPCs) and early erythroid progenitors. (xiao2024disruptionofmitochondrial pages 1-2, wu2024brafinhibitorsenhance pages 1-2) - Erythroid progenitors/precursors (reduced in marrow; early erythropoiesis block). (liu2024perspectivesofcurrent pages 1-2, wlodarski2024diagnosistreatmentand pages 20-23)

3.5 Anatomical locations (UBERON-style)

  • Bone marrow (erythroblastopenia; diagnostic site). (wlodarski2024diagnosistreatmentand pages 20-23)
  • Peripheral blood (macrocytosis, reticulocytopenia; HbF/eADA biomarkers). (wlodarski2024diagnosistreatmentand pages 20-23, liu2024perspectivesofcurrent pages 2-3)

3.6 Chemical entities (CHEBI-style)

  • L-leucine (branched-chain amino acid; translation/mTOR-targeted strategy; clinical trial NCT01362595). (NCT01362595 chunk 1)
  • Coenzyme Q10 (ubiquinone) (OXPHOS activator; rescued erythroid defects in model). (xiao2024disruptionofmitochondrial pages 1-2)
  • BRAF inhibitors (drug class; paradoxical MAPK activation enhances erythropoiesis, including DBA samples/models). (wu2024brafinhibitorsenhance pages 1-2)
  • Prednisone/prednisolone (glucocorticoids; standard-of-care). (wlodarski2024diagnosistreatmentand pages 8-10)
  • Iron chelators: deferoxamine (DFO), deferasirox (DFX), deferiprone (DFP). (wlodarski2024diagnosistreatmentand pages 10-11)

4. Disease progression model (sequence of events)

A knowledge-base-ready sequence supported by 2023–2024 evidence: 1. Germline RP haploinsufficiency (or specific non-RP gene defects) reduces effective ribosome biogenesis and/or alters rRNA processing and ribosome output. (liu2024perspectivesofcurrent pages 1-2, pelagiadis2023thediversegenomic pages 1-2, fellmann2024anatypicalform pages 6-9) 2. Ribosomal/nucleolar stress activates p53 programs via MDM2 inhibition (canonical model), promoting progenitor cell cycle arrest/apoptosis. (pelagiadis2023thediversegenomic pages 1-2, fellmann2024anatypicalform pages 1-2) 3. Selective translational insufficiency reduces key erythroid regulators such as GATA1, compromising erythroid lineage specification and maturation. (pelagiadis2023thediversegenomic pages 5-8, liu2024perspectivesofcurrent pages 3-4) 4. Downstream metabolic and proteostatic stress emerges, including globin/heme imbalance (free heme → ROS) and potentially autophagy/mitochondrial dysfunction. (pelagiadis2023thediversegenomic pages 5-8, liu2024perspectivesofcurrent pages 3-4) 5. Failure of early erythropoiesis manifests as marrow erythroid hypoplasia/erythroblastopenia and reticulocytopenic anemia, with variable congenital anomalies and cancer predisposition. (wlodarski2024diagnosistreatmentand pages 20-23, liu2024perspectivesofcurrent pages 1-2)

5. Phenotypic manifestations and mechanistic links (HP-style)

Common/important clinical phenotypes and their mechanistic relationships: - Macrocytic anemia and reticulocytopenia: direct consequence of erythroid progenitor depletion and maturation failure. (wlodarski2024diagnosistreatmentand pages 20-23) - Bone marrow erythroblastopenia: defining tissue phenotype consistent with early erythroid block. (wlodarski2024diagnosistreatmentand pages 20-23) - Congenital anomalies (subset): genotype–phenotype correlations show higher malformation rates with some large subunit genes (e.g., RPL5/RPL11) than with RPS19 in recent review synthesis. (liu2024perspectivesofcurrent pages 2-3) - Cancer predisposition (MDS/AML and solid tumors including colon cancer): increased risk is recognized and drives lifelong surveillance recommendations. (liu2024perspectivesofcurrent pages 1-2, pelagiadis2023thediversegenomic pages 1-2, wlodarski2024diagnosistreatmentand pages 3-5)

6. Recent developments (2023–2024) and latest research highlights

6.1 Ribosome structural/processing diversity in DBA (2024)

RPL17 DBA can yield an atypical translated ribosome pool with altered 5.8S rRNA length and measurable pre-rRNA processing changes, reinforcing that DBA can involve both quantity (ribosome abundance) and qualitative rRNA processing perturbations. (fellmann2024anatypicalform pages 1-2, fellmann2024anatypicalform pages 6-9)

6.2 Mitochondrial energy metabolism as a mechanistic contributor and potential target (2024)

A primary mechanistic proposal is that OXPHOS suppression can impair ribosome biogenesis and erythroid differentiation, with RanGAP1 as a mediator and CoQ10 as a rescuing intervention in model systems; patient transcriptomics suggest an OXPHOS-gene mutation signal (~10%). (xiao2024disruptionofmitochondrial pages 1-2)

6.3 Kinase signaling control of mitochondrial biogenesis in DBA (2024)

NLK hyperactivation suppresses mTORC1 and blocks translation of mitochondrial biogenesis factors (e.g., TFAM, PHB2 protein upregulation is translation-controlled), connecting ribosome insufficiency to a specific kinase→mTORC1→mitochondrial biogenesis bottleneck in early erythropoiesis. (wilkes2024activationofnemolike pages 1-2)

6.4 Small-molecule pathway modulation: paradoxical MAPK activation by BRAF inhibitors (2024)

A 2024 Signal Transduction and Targeted Therapy study reported that BRAF inhibitors can act as MAPK “amplifiers” in WT BRAF contexts, boosting progenitor proliferation; “overall cell numbers [increased] by nearly 10-fold” in culture and activity was observed in DBA patient samples and an Rpl11 haploinsufficiency DBA model. (wu2024brafinhibitorsenhance pages 1-2)

6.5 Gene therapy trajectory (2024)

Lentiviral gene addition remains a leading experimental curative approach for RPS19-deficient DBA: - A 2024 JCI Insight paper developed clinically applicable vectors (PGK.CoRPS19, EF1α.CoRPS19) and reported restoration of erythroid differentiation in patient CD34+ cells plus long-term repopulating properties and non-toxic insertion-site/safety profiles. (gimenez2024lentivirusmediatedgenetherapy pages 1-2) - A 2024 Cells review summarizes preclinical evidence that enforced RPS19 expression can “cure” anemia and prevent lethal marrow failure in mouse models and supports the rationale for autologous gene therapy to circumvent donor limitations of allogeneic HSCT. (vale2024towardsacure pages 4-6)

7. Current applications and real-world implementations (clinical practice)

7.1 Diagnostic implementation (2024 consensus)

Practical diagnostic approach includes genetic confirmation or classic hematology/BM findings with exclusion of mimics (TEC, viral PRCA, MDS with 5q-, other inherited bone marrow failure syndromes, Pearson syndrome, congenital sideroblastic/dyserythropoietic anemias). (wlodarski2024diagnosistreatmentand pages 20-23)

7.2 First-line therapy: corticosteroids

The 2024 international consensus provides specific implementation details: - Initial prednisone/prednisolone: 2 mg/kg/day (with max limits) and avoid extending the initial high-dose course beyond ~4 weeks; assess reticulocyte/Hb response at ~10–14 days. (wlodarski2024diagnosistreatmentand pages 8-10) - Initial steroid response rate ~60–80%; ~30–40% remain on durable steroid therapy. (wlodarski2024diagnosistreatmentand pages 8-10)

7.3 Chronic transfusion strategy and iron overload management

The 2024 consensus recommends higher transfusion targets than restrictive adult triggers: maintain pre-transfusion nadir ≥9–10 g/dL to support growth and quality of life, often using q3-week schedules. (wlodarski2024diagnosistreatmentand pages 8-10)

Because transfusions are the major iron source and iron overload is a major cause of death in non-transplanted patients, the consensus emphasizes MRI-based monitoring and quantitative targets/thresholds (e.g., LIC goal <3 mg Fe/g dry weight; cardiac T2* thresholds). (wlodarski2024diagnosistreatmentand pages 10-11)

7.4 Curative therapy: HSCT (and movement toward gene therapy)

  • HSCT remains the only established curative option for hematologic disease in DBA in current standard practice, but is limited by donor availability and transplant risks; consensus broadens HSCT indications and emphasizes systematic surveillance. (liu2024perspectivesofcurrent pages 1-2, wlodarski2024diagnosistreatmentand pages 3-5)
  • Gene therapy is an active translational direction for RPS19 DBA, supported by 2024 preclinical human CD34+ correction and vector safety analyses. (gimenez2024lentivirusmediatedgenetherapy pages 1-2)

7.5 Clinical trials and experimental therapeutics (implementation evidence)

L-leucine (ClinicalTrials.gov). NCT01362595 (Northwell Health) is a single-group, open-label Phase I/II trial in transfusion-dependent DBA. Dose: 700 mg/m² per dose, orally three times daily; primary efficacy endpoint at 9 months; enrollment 55; results posted 2022-12-02. (NCT01362595 chunk 1)

8. Expert opinions and authoritative analyses (2024 consensus and high-impact reviews)

  • The 2024 Lancet Haematology consensus explicitly states that the evidence base is largely non-randomized (“level C”) and therefore provides expert-derived implementation thresholds (transfusion Hb targets, steroid dose ceilings, iron MRI targets, and systematic surveillance including early colorectal cancer screening). (wlodarski2024diagnosistreatmentand pages 3-5)
  • The 2024 Leukemia review frames DBA as a multi-mechanism disorder and highlights emerging therapeutics (notably gene therapy for RPS19) while emphasizing unresolved questions such as erythroid lineage selectivity and variable penetrance/remission. (liu2024perspectivesofcurrent pages 1-2)

9. Relevant recent statistics and data (2023–2024)

9.1 Epidemiology

  • Incidence estimates:
  • ~5–7 cases per million live births (2024 review). (liu2024perspectivesofcurrent pages 1-2)
  • ~5–10 cases per million live births (2024 international consensus). (wlodarski2024diagnosistreatmentand pages 3-5)
  • Alternative expression in one 2024 primary paper: ~1 in 100,000–200,000 births. (fellmann2024anatypicalform pages 1-2)

9.2 Genetics (frequency highlights)

  • Proportion with RP-gene involvement: ~75% RP genes; ~70–80% have putatively causal haploinsufficient variants in some series/framings. (liu2024perspectivesofcurrent pages 1-2)
  • RPS19 ~25% of cases (commonly cited). (liu2024perspectivesofcurrent pages 1-2, gimenez2024lentivirusmediatedgenetherapy pages 1-2)

9.3 Biomarkers and genotype–phenotype

  • eADA elevation in ~80–85% of patients (review synthesis) and is a supportive diagnostic criterion in the 2024 consensus. (liu2024perspectivesofcurrent pages 2-3, wlodarski2024diagnosistreatmentand pages 20-23)
  • Genotype–phenotype example: malformations are more frequent with RPL5/RPL11 compared with RPS19 in review summaries. (liu2024perspectivesofcurrent pages 2-3)

9.4 Treatment outcomes

  • Steroid response: initial response ~60–80%. (wlodarski2024diagnosistreatmentand pages 8-10)
  • Treatment independence: French registry (n=222) 21% overall, 30% if initially steroid responsive, 5% if steroid non-responsive; ~70% of independence achieved in first decade. (wlodarski2024diagnosistreatmentand pages 10-11)

9.5 Malignancy risk

  • A 2023 mini-review reports 4.8-fold increased cancer risk and ~20% cumulative incidence of malignancy/MDS/AML by age 46. (pelagiadis2023thediversegenomic pages 1-2)

10. Knowledge-base-ready annotation blocks

10.1 Gene/protein annotations (HGNC symbols) with mechanistic tags

  • RPS19, RPL5, RPL11, RPS26, RPS24, RPL17: ribosome biogenesis/rRNA maturation; ribosomal stress; p53 pathway activation; erythroid differentiation failure. (liu2024perspectivesofcurrent pages 1-2, fellmann2024anatypicalform pages 1-2)
  • GATA1: erythroid transcription program; translationally sensitive node in ribosome insufficiency. (liu2024perspectivesofcurrent pages 3-4, pelagiadis2023thediversegenomic pages 5-8)
  • HEATR3, TSR2: ribosome biogenesis/assembly factors (DBA-like). (liu2024perspectivesofcurrent pages 3-4)
  • TP53: rare gain-of-function DBA-like; central stress effector. (wlodarski2024diagnosistreatmentand pages 16-18)
  • NLK, RPTOR (Raptor), MTOR: signaling module linking DBA stress to mTORC1 inhibition and mitochondrial biogenesis block. (wilkes2024activationofnemolike pages 1-2)
  • RanGAP1: OXPHOS-dependent mediator connecting mitochondrial metabolism to ribosome biogenesis in model. (xiao2024disruptionofmitochondrial pages 1-2)

10.2 GO biological process candidates (text labels)

  • ribosome biogenesis; rRNA processing; translation; regulation of translation; erythrocyte differentiation/erythropoiesis; p53-mediated apoptotic signaling; response to oxidative stress; mitochondrial oxidative phosphorylation; mitochondrial biogenesis; inflammatory response/NF-κB signaling. (liu2024perspectivesofcurrent pages 3-4, fellmann2024anatypicalform pages 6-9, xiao2024disruptionofmitochondrial pages 1-2, wilkes2024activationofnemolike pages 1-2)

10.3 CL cell type candidates (text labels)

  • hematopoietic stem cell; hematopoietic progenitor cell; erythroid progenitor cell; erythroblast. (xiao2024disruptionofmitochondrial pages 1-2, wlodarski2024diagnosistreatmentand pages 20-23)

10.4 UBERON anatomy candidates (text labels)

  • bone marrow; blood. (wlodarski2024diagnosistreatmentand pages 20-23)

10.5 HP phenotype candidates (text labels)

  • macrocytic anemia; reticulocytopenia; erythroblastopenia; congenital anomalies (craniofacial/limb/cardiac); cancer predisposition; growth impairment. (wlodarski2024diagnosistreatmentand pages 20-23, liu2024perspectivesofcurrent pages 1-2)

10.6 CHEBI chemical candidates (text labels)

  • L-leucine; coenzyme Q10 (ubiquinone); prednisone/prednisolone; deferoxamine/deferasirox/deferiprone; BRAF inhibitors. (NCT01362595 chunk 1, xiao2024disruptionofmitochondrial pages 1-2, wlodarski2024diagnosistreatmentand pages 8-10, wlodarski2024diagnosistreatmentand pages 10-11, wu2024brafinhibitorsenhance pages 1-2)

11. Evidence items (PMID-focused) and limitations

The provided 2023–2024 evidence extracts are primarily from full-text/registry materials indexed by DOI and trial identifiers, and many excerpts did not include PubMed IDs in the available text. Where PMIDs are required for mechanistic claims, additional targeted PubMed retrieval would be needed to map each mechanistic statement to a PMID explicitly (particularly for classic p53/MDM2/5S-RNP literature). Within the available context, mechanistic claims are supported by peer-reviewed primary papers and consensus/reviews with DOI/URLs (listed above) and ClinicalTrials.gov identifiers. (wlodarski2024diagnosistreatmentand pages 3-5, fellmann2024anatypicalform pages 1-2, xiao2024disruptionofmitochondrial pages 1-2, wilkes2024activationofnemolike pages 1-2, NCT01362595 chunk 1)

12. Key source list (URLs and publication dates)

  • Wlodarski MW et al. May 2024. The Lancet Haematology (international consensus). https://doi.org/10.1016/S2352-3026(24)00063-2 (wlodarski2024diagnosistreatmentand pages 3-5)
  • Liu Y, Karlsson S. Nov 2024. Leukemia (review). https://doi.org/10.1038/s41375-023-02082-w (liu2024perspectivesofcurrent pages 1-2)
  • Fellmann F et al. Aug 2024. JCI Insight (RPL17 atypical 60S). https://doi.org/10.1172/jci.insight.172475 (fellmann2024anatypicalform pages 1-2)
  • Wilkes MC et al. Aug 2024. J Biol Chem (NLK–mTORC1–mitochondria). https://doi.org/10.1016/j.jbc.2024.107542 (wilkes2024activationofnemolike pages 1-2)
  • Xiao R et al. Mar 2024. iScience (OXPHOS/RanGAP1/CoQ10). https://doi.org/10.1016/j.isci.2024.109172 (xiao2024disruptionofmitochondrial pages 1-2)
  • Wu S et al. Dec 2024. Signal Transduction and Targeted Therapy (BRAFi/MAPK/erythropoiesis). https://doi.org/10.1038/s41392-024-02033-6 (wu2024brafinhibitorsenhance pages 1-2)
  • Giménez Y et al. May 2024. JCI Insight (RPS19 lentiviral gene therapy). https://doi.org/10.1172/jci.insight.171650 (gimenez2024lentivirusmediatedgenetherapy pages 1-2)
  • ClinicalTrials.gov NCT01362595 (LeucineDBA). Results posted Dec 2, 2022; started Jun 2013. https://clinicaltrials.gov/study/NCT01362595 (NCT01362595 chunk 1)

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