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Classifications

Harrison's Part

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Mappings

ICD-10-CM

ICD10CM:D61.01 Constitutional (pure) red blood cell aplasia

ICD-10-CM has no code for any individual DBA genotype. D61.01 is the code the whole of Diamond-Blackfan anemia falls under, so it is broader than this entry by the full width of the DBA gene panel; recorded as a broadMatch cross-reference for billing/registry lookup, not as an equivalence.

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Inheritance

1

X-linked recessive HP:0001419

TSR2 is on the X chromosome. In the one reported kindred the variant is hemizygous in the two affected male cousins and heterozygous in their unaffected mothers, and GeneReviews records TSR2-related DBA as X-linked with heterozygous females usually unaffected. `penetrance` is left UNKNOWN rather than called. Two affected hemizygotes is not a denominator: no unaffected hemizygous male has been reported, and with n=2 that is uninformative either way. The class-level statement for DBA as a whole is that penetrance is incomplete, but that is a statement about the autosomal dominant ribosomal-protein genotypes that make up the bulk of DBA and cannot be transferred to a hemizygous X-linked allele. `expressivity` is called VARIABLE on within-family evidence rather than on the class-level statement: the two cousins carry the same allele, and one was diagnosed with DBA at ten months and treated with steroids while the other never had overt anemia and showed only the laboratory markers. The craniofacial arm was present in both.

X-linked recessive inheritance Penetrance: UNKNOWN Expressivity: VARIABLE

Show evidence (5 references)

PMID:20301769 SUPPORT DIRECT Human Clinical

"GATA1- and TSR2-related DBA syndrome are inherited in an X-linked manner."

Names TSR2 as one of the two X-linked DBA genes.

PMID:20301769 SUPPORT DIRECT Human Clinical

"X-linked DBA syndrome: If the mother of an affected male has a GATA1 or TSR2 pathogenic variant, the chance of transmitting it in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and will usually..."

States the recessive X-linked transmission pattern for TSR2 specifically, including that heterozygous females are usually unaffected.

PMID:24942156 SUPPORT DIRECT Human Clinical

"Further, the gene is located on the X chromosome, consistent with phenotypic expression in the males only."

The original report's own segregation argument in the index family.

+ 2 more references

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Discussions and Knowledge Gaps

6

Is a single kindred with a single missense allele, plus functional work in a humanized yeast system, enough to call TSR2 a definitive DBA gene - and what would a second family change?

KNOWLEDGE GAP OPEN tsr2-single-family

Attached to

genetic#TSR2 pathophysiology#TSR2 Escortin Deficiency

The whole entry rests on Family 1 of the 2014 series: two affected male cousins, one c.191A>G allele. The reporting authors called it "likely pathogenic" and wrote that functional studies were outside their purview. Those studies exist now and are strong - the human protein folds normally, binds eS26 weakly, fails to support growth in yeast, and is rescued by excess eS26 - but they establish that the allele is damaging, not that damaging TSR2 alleles cause this disease in the population. What is missing is genetic replication. A second unrelated family with an independent TSR2 allele and the same phenotype would settle it; so would a de novo variant in a sporadic case. Until then the honest reading is that the gene-disease relationship is supported mechanistically and by one segregating pedigree, which is what GeneReviews reflects when it introduces TSR2 with "rarely". This entry does not upgrade the authors' own hedge.

Show evidence (2 references)

PMID:24942156 SUPPORT DIRECT Human Clinical

"Functional studies of the newly identified and presumably disease causing genes would strengthen the evidence for pathogenicity, but is at this time out of our purview."

The authors state the gap themselves at the time of the report.

PMID:20301769 SUPPORT INDIRECT Human Clinical

"Rarely, 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."

GeneReviews accepts TSR2 as a diagnostic gene while marking it rare. INDIRECT: the sentence is about diagnostic practice, and is cited here for the qualifier it carries rather than for a claim about evidence strength.

Why does a defect in the escortin for one small-subunit ribosomal protein produce a mandibulofacial dysostosis, when most DBA genotypes do not?

KNOWLEDGE GAP OPEN tsr2-craniofacial-mechanism

Attached to

pathophysiology#Abnormal Craniofacial Embryonic Development

This is the load-bearing unexplained step in the pathograph. Ribosome biogenesis is required by every cell, and the great majority of DBA genotypes produce anemia with, at most, thumb and craniofacial anomalies of a different pattern. Here the craniofacial phenotype is a full mandibulofacial dysostosis and it is the finding that brought both patients to attention. Two things make it more than a curiosity. First, it is not TSR2-specific: the same 2014 series found the same combined phenotype in RPS26 and RPS28 families, so whatever explains it is a property of small-subunit assembly rather than of the escortin. Second, the obvious analogy - cranial neural crest, the cell population implicated in Treacher Collins - has never been tested for any of these three genes. The gene-discovery paper goes no further than "abnormal embryologic development", and neither does this entry. What would move it: an eS26-deficiency model with a craniofacial readout, or single-cell work asking whether pharyngeal-arch progenitors are unusually sensitive to eS26 supply.

Show evidence (2 references)

PMID:24942156 SUPPORT INDIRECT Human Clinical

"We conclude that the phenotype combining features of TCS with DBA is genetically heterogeneous."

Establishes that the combined phenotype is not tied to TSR2 alone, which is what makes this a question about small-subunit assembly rather than about the escortin.

PMID:24942156 SUPPORT INDIRECT Human Clinical

"Each of the pathogenic variants identified is predicted to impede ribosome biogenesis, which in turn could result in altered cell growth and proliferation, causing abnormal embryologic development, defective erythropoiesis and reduced growth."

The furthest the source goes, and the level at which the craniofacial node is stated. INDIRECT: the sentence is a prediction, not a result.

Are heterozygous TSR2 carriers truly unaffected, or only unexamined - and could skewed X-inactivation produce a phenotype in a carrier female?

KNOWLEDGE GAP OPEN tsr2-female-carriers

Attached to

inheritance#X-linked recessive genetic#TSR2

The two carrier mothers in the reported kindred had neither the facial phenotype nor a history of DBA, and GeneReviews states that heterozygous females "will usually not be affected". "Usually" is doing work there, and nothing in the report says the mothers had a blood count or eADA measured - which matters, because the marker profile in this family was abnormal in a male who was never anemic. A carrier with a raised MCV and eADA would look entirely well. The mechanism is available. TSR2 is subject to X-inactivation rather than escaping it, so a carrier female is a mosaic of expressing and non-expressing cells and her phenotype should depend on the skew. The bovine TSR2 model is the visible demonstration of exactly this: the affected animals are heterozygous females whose hairless streaks follow Blaschko's lines, the classic pattern of X-inactivation mosaicism in skin. What would settle it: blood counts, red-cell indices and eADA in obligate carriers, read against their X-inactivation skew.

Show evidence (3 references)

PMID:24942156 SUPPORT DIRECT Human Clinical

"Neither had facial features suggestive of Treacher Collins syndrome, other malformation or a history of DBA."

What is actually recorded about the two carrier mothers - absence of malformations and of a DBA history, not a normal laboratory workup.

PMID:29022598 SUPPORT INDIRECT Other

"Examples of genes where the ASE-based assessment of XCI status match previously reported assignments (TSR2 , inactive; XIST, escape; ZBED1, escape)."

Establishes that TSR2 is subject to X-inactivation rather than escaping it, which is what makes carrier females mosaic and makes skew a plausible modifier. INDIRECT: an allele-specific-expression survey across GTEx tissues, not an observation in a TSR2 carrier. Quoted with the source's own spacing before the comma, an artifact of the figure legend.

PMID:26203908 SUPPORT INDIRECT Model Organism

"The stripes occurred in a consistent pattern resembling the lines of Blaschko."

A heterozygous-female TSR2 phenotype following the pattern of X-inactivation mosaicism, in cattle. INDIRECT: a different species, a different allele class and a tissue with no human counterpart in this disease; cited as a demonstration that heterozygous TSR2 females can be affected at all.

The only naturally occurring animal TSR2 variant causes hair follicle dysplasia with no reported anemia or craniofacial anomaly, while the human variant causes anemia and mandibulofacial dysostosis with no reported hair phenotype. Is this a species difference, an allele-class difference, or simply two incompletely examined phenotypes?

HUMAN MODEL MISMATCH OPEN tsr2-bovine-model-mismatch

Attached to

animal_models#Streaked hairlessness cattle (TSR2 exon 5 splice-site variant) pathophysiology#TSR2 Escortin Deficiency

Evidence exists in the model and its translational validity is the open question, which is what distinguishes this from a plain knowledge gap. The confounds run in both directions and neither has been controlled. The bovine allele is truncating and the human allele is a cargo-binding missense, so they may not be the same lesion. The cows are heterozygous females with mosaic X-inactivation and the patients are hemizygous males, so they are not in the same genetic state. And crucially, neither phenotype was looked for in the other species: the cattle report describes no haematology, and the human report describes no hair abnormality. "Not reported" is not "absent", and this entry does not record the bovine model as failing to recapitulate the human disease for exactly that reason. A knock-in of the human E64G allele in a mammal, phenotyped for both blood and skin, would separate the three explanations. Absent that, the honest position is that TSR2 is a housekeeping escortin whose tissue-restricted phenotypes are unexplained in either species.

Show evidence (2 references)

PMID:26203908 SUPPORT DIRECT Model Organism

"Thus, by dissecting a naturally occurring mutation in a domestic animal species, we identified TSR2 as a regulator of hair follicle development."

The model's own conclusion - a hair follicle function for TSR2, which is not a function this disease is known to involve.

PMID:26203908 SUPPORT DIRECT Model Organism

"The non-syndromic hairlessness phenotype observed occurred across three generations of a single family and was compatible with an X-linked mode of inheritance."

The bovine phenotype is described as non-syndromic, which is the mismatch: the human phenotype is a multisystem syndrome.

TSR2 also removes and reinstalls eS26 on mature ribosomes as part of a reversible stress response. Does loss of that second function contribute to DBA14, or is the disease entirely a biogenesis defect?

KNOWLEDGE GAP OPEN tsr2-stress-ribosome-role

Attached to

pathophysiology#Impaired Escortin Handover of eS26

The entry models TSR2 as a one-way delivery chaperone, because that is the function the disease allele was tested against. But the same protein has a second, later-described job: under sodium, sorbitol or pH stress it releases eS26 from fully assembled ribosomes to generate a distinct ribosome population, stores the freed protein, and reinstalls it when the stress passes. That is a regulated, reversible activity on mature ribosomes, not a biogenesis step. Whether the E64G allele impairs it is unknown - and it is not obvious that it would fail in the same direction, since a chaperone that binds eS26 too weakly might release it too readily as easily as fail to deliver it. The work is in yeast and the stresses are osmotic and pH, neither of which is an obvious feature of an erythroid progenitor's life. It is recorded here because if this activity does contribute, the pathograph's single biogenesis chain is the wrong shape rather than merely incomplete.

Show evidence (2 references)

PMID:35213229 SUPPORT DIRECT In Vitro

"The chaperone Tsr2 releases Rps26 in the presence of high Na+ or pH in vitro and is required for Rps26 release in vivo."

Establishes the second function - release from mature ribosomes - that this entry does not model.

PMID:35213229 SUPPORT DIRECT In Vitro

"Moreover, Tsr2 stores free Rps26 and promotes reincorporation of the protein, thereby repairing the subunit after the Na+ stress subsides."

The reinstallation half of the cycle, which makes this a regulated activity rather than a variant of the delivery function already modelled.

Does DBA14 carry the malignancy predisposition documented for Diamond-Blackfan anemia as a class, and should TSR2 carriers and patients be entered into DBA cancer surveillance?

KNOWLEDGE GAP OPEN tsr2-cancer-risk

Attached to

treatments#Malignancy Surveillance genetic#TSR2

This is the question with the most direct consequence for a family carrying this variant, and it has no evidence either way. The class-level risk is real and substantial - AML, myelodysplastic syndrome and solid tumours including osteosarcoma - and GeneReviews sets a four- to six-monthly surveillance interval on that basis. But the DBA registries that generated those figures are built from the autosomal dominant ribosomal-protein genotypes. Nobody has reported a malignancy in a TSR2 patient, and nobody could: the entire cohort is two men, well at ages 16 and 24 at last report. The mechanistic argument cuts both ways. If the cancer risk in DBA follows from chronic ribosomal stress and p53 signalling in the marrow, DBA14 should share it, because it converges on the same eS26-deficient subunit. If it follows instead from the specific ribosomal protein lost, or from cumulative steroid and transfusion exposure, a mildly affected TSR2 patient may not. Extending surveillance is the conservative call and is what this entry records; asserting that the risk is established for this genotype would not be.

Show evidence (2 references)

PMID:20301769 SUPPORT INDIRECT Human Clinical

"DBA syndrome is associated with an increased risk for acute myelogenous leukemia, myelodysplastic syndrome, and solid tumors including osteogenic sarcoma."

The class-level risk being extrapolated. INDIRECT: no TSR2 patient is in the data behind it.

PMID:24942156 SUPPORT DIRECT Human Clinical

"The patient was in good health at age 24 years."

The extent of the follow-up available for the genotype, and the reason the question cannot currently be answered from it.

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Pathophysiology

7

TSR2 Escortin Deficiency

A hemizygous missense variant places a glycine where a conserved glutamate sits in the TSR2 WGG domain. The mutant protein is present and correctly folded; what it has lost is affinity for its cargo. The node is therefore named for a functional deficiency of the escortin, not for absence of the protein and not for reduced gene dosage - there is no second allele to be dosed, and the biochemistry shows a normally folded product.

TSR2 hgnc:25455

Experimental models

Humanized yeast expressing hTsr2 E64G OTHER The binding assays use recombinant human Tsr2 and human eS26, so for this node the model is not really yeast at all - it is human proteins in vitro, and it reproduces the molecular lesion directly.

Animal models

Streaked hairlessness cattle (TSR2 exon 5 splice-site variant) Cattle perturbs A truncating variant that removes roughly a quarter of the protein perturbs TSR2 function. It is not curated as recapitulating the human disease: the allele class is different (truncating rather than a cargo-binding missense), the animals are heterozygous females rather than hemizygous males, and the phenotype is cutaneous.

Downstream

Impaired Escortin Handover of eS26 Weakened cargo binding is the proximal cause of a failed handover.

Show evidence (2 references)

PMID:24942156 SUPPORT DIRECT Human Clinical

"In another family a likely pathogenic X-linked mutation affecting a highly conserved residue was found in TSR2, which encodes a direct binding partner of RPS26."

Establishes the lesion this node states: a variant at a conserved residue of the RPS26-binding protein.

PMID:30201955 SUPPORT DIRECT In Vitro

"This weaker interaction is not due to perturbed folding of hTsr2E64G since far-UV circular dichroism (CD) measurements revealed identical secondary structure content for mutant and WT proteins"

Supports naming the node a functional deficiency rather than an absence: the mutant protein is made and folds like the wild type.

Impaired Escortin Handover of eS26

TSR2 does three things in sequence: it dissociates the importin:eS26 complex on the nuclear side by a RanGTP-independent route, it binds and shields the released eS26 from proteolysis, and it delivers it to the 90S pre-ribosome. The disease allele is impaired at the binding step - it holds eS26 and the eukaryote-specific segment that recruits it less tightly - which puts every downstream step of the handover at risk. What has not been measured is which of the three steps fails first in a patient cell; the pathway description is from yeast and reconstituted human proteins.

ribosomal small subunit assembly GO:0000028 ↓ DECREASED

Downstream

Deficient eS26 Incorporation into the Small Ribosomal Subunit A cargo that is not handed over is not incorporated, and unprotected eS26 is a proteolysis substrate.

Show evidence (3 references)

PMID:25144938 SUPPORT DIRECT In Vitro

"Subsequently, Tsr2 binds the released eS26, shields it from proteolysis, and ensures its safe delivery to the 90S pre-ribosome."

Defines the escortin function that this node reports as impaired.

PMID:25144938 SUPPORT DIRECT In Vitro

"In vitro studies revealed that Tsr2 efficiently dissociates importin:eS26 complexes via an atypical RanGTP-independent mechanism that terminates the import process."

The first step of the handover, and the reason a chaperone rather than RanGTP terminates import for this particular cargo.

PMID:30201955 SUPPORT DIRECT In Vitro

"Notably, a Diamond-Blackfan anemia-associated Tsr2 mutant protein is impaired in binding to ESS, unveiling a critical role for this interaction in human hematopoiesis."

Ties the disease allele specifically to failure of the recognition step that starts the handover.

Deficient eS26 Incorporation into the Small Ribosomal Subunit

The consequence of a failed handover is a shortfall of eS26 on the assembling 40S subunit. This is the node at which DBA14 converges on DBA10: RPS26 haploinsufficiency reaches the same state by halving the supply of the protein, while TSR2 deficiency reaches it by failing to deliver a normal supply. That convergence is an inference from the two genes' shared biology and is not something anyone has measured in a DBA14 patient cell.

ribosomal small subunit biogenesis GO:0042274 ↓ DECREASED

Experimental models

Humanized yeast expressing hTsr2 E64G OTHER The eS26-overexpression arm. Restoring eS26 supply corrects the growth defect caused by the human disease allele, which is the experiment that places eS26 insufficiency on the causal path rather than beside it.

Downstream

Defective Small-Subunit Maturation and 18S rRNA Processing A subunit missing eS26 does not complete maturation on schedule.

Show evidence (2 references)

PMID:30201955 SUPPORT INDIRECT In Vitro

"Thus, ESS:Tsr2 interactions are critical to dissociate eS26 from the importin and to protect and target eS26 to the pre-ribosome in vivo."

The authors' summary that the interaction the disease allele weakens is what targets eS26 to the pre-ribosome. INDIRECT because it is a conclusion drawn from yeast genetics rather than a measurement of eS26 occupancy on human DBA14 ribosomes.

PMID:30201955 SUPPORT INDIRECT In Vitro

"Overexpression of eS26 rescues from the impaired growth."

The rescue arm, and the strongest available argument that the pathway from the TSR2 allele runs through eS26 supply rather than through some other TSR2 function: raising eS26 restores growth to cells expressing the human disease allele. INDIRECT because the experiment is in yeast.

Defective Small-Subunit Maturation and 18S rRNA Processing

Cells expressing the human disease allele accumulate immature 20S pre-rRNA in the cytoplasm, the classic readout of a stalled small-subunit maturation pathway, and grow poorly. In human cells the equivalent intermediate is the 18S-E pre-rRNA; the measurement available for this allele is the yeast one, and this node states it at that level.

maturation of SSU-rRNA GO:0030490 ↓ DECREASED

Experimental models

Humanized yeast expressing hTsr2 E64G OTHER Yeast expressing the human disease allele grow poorly and accumulate immature 20S pre-rRNA in the cytoplasm, and excess eS26 rescues the growth defect - which is what ties the phenotype to eS26 supply rather than to some other consequence of expressing a human protein in yeast.

Downstream

Ribosomal Stress Response Stalled subunit maturation is the canonical trigger of the ribosomal stress response in the ribosomopathies.

Impaired Erythroid Progenitor Output The erythroid arm of the phenotype. The step is asserted at the level the gene-discovery paper asserts it - defective erythropoiesis as a consequence of impeded ribosome biogenesis - not at the level of a measured erythroid defect in a DBA14 cell.

Abnormal Craniofacial Embryonic Development The craniofacial arm. Same standing as the erythroid edge: the source states abnormal embryologic development as a consequence of impeded ribosome biogenesis without identifying the cell population involved.

Show evidence (3 references)

PMID:30201955 SUPPORT DIRECT In Vitro

"Tsr2 DBA mutant cells (hTsr2E64G) accumulate immature 20S pre-rRNA in the cytoplasm."

The measured maturation defect caused by the human disease allele.

PMID:30201955 SUPPORT DIRECT In Vitro

"Yeast cells expressing hTsr2E64G were strongly growth impaired"

The growth phenotype accompanying the maturation defect, in the same humanized system.

PMID:24942156 SUPPORT INDIRECT Human Clinical

"Each of the pathogenic variants identified is predicted to impede ribosome biogenesis, which in turn could result in altered cell growth and proliferation, causing abnormal embryologic development, defective erythropoiesis and reduced growth."

The gene-discovery paper's own causal statement, and the basis for both downstream edges out of this node. INDIRECT and deliberately so: the authors write "predicted" and "could result", and this entry does not strengthen that.

Ribosomal Stress Response

Impaired ribosome biogenesis in DBA activates p53 and a set of associated responses - translational dysfunction, inflammation, imbalanced globin and heme synthesis, autophagy dysregulation - that converge on the erythroid compartment. This node is curated at the level of the DBA class. Nobody has measured p53 activation, or any of the rest of it, in a TSR2-mutant cell, so the node carries the class-level claim and says so rather than being dropped: it is the step that connects a general biogenesis defect to a selectively erythroid outcome, and leaving it out would make the pathograph look better evidenced than it is.

Downstream

Impaired Erythroid Progenitor Output The route by which the ribosomal stress response is thought to produce the erythroid failure in DBA generally.

Show evidence (1 reference)

PMID:37973818 SUPPORT INDIRECT Human Clinical

"P53 activation, translational dysfunction, inflammation, imbalanced globin/heme synthesis, and autophagy dysregulation were shown to contribute to disrupted erythropoiesis and impaired red blood cell production."

Names the components of the response and its erythroid consequence. INDIRECT because the review states this for Diamond-Blackfan anemia as a class; no TSR2-specific measurement exists.

Impaired Erythroid Progenitor Output

Erythroid progenitors are the compartment that fails in DBA, producing a normochromic macrocytic anemia with reticulocytopenia while leukocytes and platelets are preserved. In the TSR2 kindred the severity of this node differs between the two carriers of the same allele: one required steroid treatment from ten months, the other never had overt anemia and showed only the biochemical markers.

erythroid progenitor cell CL:0000038

erythrocyte differentiation GO:0030218 ↓ DECREASED

Downstream

Macrocytic anemia The peripheral consequence of erythroid progenitor failure.

Increased mean corpuscular volume Stressed erythropoiesis produces larger red cells even where the haemoglobin is preserved, which is why this marker was abnormal in the cousin who was never anemic.

Elevated red cell adenosine deaminase activity The classic DBA biochemical marker, and one of the three abnormalities recorded in the non-anemic TSR2 carrier.

Persistence of hemoglobin F Fetal haemoglobin persistence as a marker of stressed erythropoiesis.

Show evidence (2 references)

PMID:20301769 SUPPORT INDIRECT Human Clinical

"DBA syndrome is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50% of affected individuals, and growth deficiency in 30% of affected individuals."

Establishes that the haematologic lesion of DBA is a selectively erythroid one. INDIRECT: a class-level statement about DBA, applied here to the TSR2 genotype.

PMID:24942156 SUPPORT DIRECT Human Clinical

"Diamond-Blackfan anemia was diagnosed at age 10 months and responded to steroid treatment."

The erythroid failure as observed in the TSR2 proband, including its steroid responsiveness.

Abnormal Craniofacial Embryonic Development

Both affected males have a mandibulofacial dysostosis: derivatives of the first and second pharyngeal arches and the external ear are hypoplastic or absent. What produces it is unresolved. In Treacher Collins syndrome, the craniofacial ribosomopathy this phenotype most resembles, the lesion is referred to cranial neural crest; nothing analogous has been shown for TSR2, and this node deliberately stops at "abnormal embryologic development", the level the gene-discovery paper states. See the `tsr2-craniofacial-mechanism` discussion.

Downstream

Microtia External ear hypoplasia, bilateral and grade 2 in the proband.

Atresia of the external auditory canal Absent external auditory canals in both affected males.

Abnormal middle ear morphology Abnormal middle ears recorded in the proband.

Micrognathia Mandibular hypoplasia in both affected males.

Cleft palate Submucous cleft palate in the proband and cleft palate in the cousin.

Downslanted palpebral fissures A persisting facial feature in both affected males.

Midface retrusion Midfacial hypoplasia, persisting into adulthood in both.

Show evidence (2 references)

PMID:24942156 SUPPORT DIRECT Human Clinical

"Bilateral grade 2 microtia with absent external auditory canals and abnormal middle ears, micrognathia and unilateral cryptorchidism were present (Table I)."

The proband's malformations, which are the phenotypes this node feeds.

PMID:24942156 SUPPORT DIRECT Human Clinical

"He had bilateral microtia without visible external auditory canals, micrognathia and a cleft palate."

The same craniofacial pattern in the second affected male, which is what makes it a feature of the genotype rather than of one patient.

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Pathograph

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

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Phenotypes

13

Blood 4

Macrocytic anemia HP:0001972

Show evidence (2 references)

PMID:24942156 SUPPORT DIRECT Human Clinical

"Diamond-Blackfan anemia was diagnosed at age 10 months and responded to steroid treatment."

The anemia in the proband and its steroid response.

PMID:24942156 REFUTE DIRECT Human Clinical

"The patient never had overt anemia, but elevated mean corpuscular volume, eADA and hemoglobin F were consistent with DBA markers."

Graded REFUTE against the proposition that anemia is obligate in this genotype: the second hemizygous male never had it.

Increased mean corpuscular volume HP:0005518

Show evidence (1 reference)

PMID:24942156 SUPPORT DIRECT Human Clinical

"The patient never had overt anemia, but elevated mean corpuscular volume, eADA and hemoglobin F were consistent with DBA markers."

Records the raised MCV in the non-anemic affected male.

Elevated red cell adenosine deaminase activity HP:0030270

Show evidence (1 reference)

PMID:24942156 SUPPORT DIRECT Human Clinical

"The patient never had overt anemia, but elevated mean corpuscular volume, eADA and hemoglobin F were consistent with DBA markers."

Documents elevated eADA in a TSR2-mutant patient, which is what makes the marker usable diagnostically for this genotype and not only for DBA generally.

Persistence of hemoglobin F HP:0011904

Show evidence (1 reference)

PMID:24942156 SUPPORT DIRECT Human Clinical

"The patient never had overt anemia, but elevated mean corpuscular volume, eADA and hemoglobin F were consistent with DBA markers."

Records the raised hemoglobin F.

Ear 4

Microtia VERY_FREQUENT HP:0008551

Sequelae: Hearing impairment

Show evidence (2 references)

PMID:24942156 SUPPORT DIRECT Human Clinical

"Bilateral grade 2 microtia with absent external auditory canals and abnormal middle ears, micrognathia and unilateral cryptorchidism were present (Table I)."

The proband's microtia.

PMID:24942156 SUPPORT DIRECT Human Clinical

"He had bilateral microtia without visible external auditory canals, micrognathia and a cleft palate."

The cousin's microtia.

Atresia of the external auditory canal VERY_FREQUENT HP:0000413

Sequelae: Hearing impairment

Show evidence (2 references)

PMID:24942156 SUPPORT DIRECT Human Clinical

"Bilateral grade 2 microtia with absent external auditory canals and abnormal middle ears, micrognathia and unilateral cryptorchidism were present (Table I)."

Absent canals in the proband.

PMID:24942156 SUPPORT DIRECT Human Clinical

"He had bilateral microtia without visible external auditory canals, micrognathia and a cleft palate."

Absent canals in the cousin.

Abnormal middle ear morphology HP:0008609

Sequelae: Hearing impairment

Show evidence (1 reference)

PMID:24942156 SUPPORT DIRECT Human Clinical

"Bilateral grade 2 microtia with absent external auditory canals and abnormal middle ears, micrognathia and unilateral cryptorchidism were present (Table I)."

The middle-ear abnormality in the proband.

Hearing impairment VERY_FREQUENT HP:0000365

Show evidence (2 references)

PMID:24942156 SUPPORT DIRECT Human Clinical

"Hearing loss was treated with hearing aids."

Hearing loss in the cousin, recorded through its management.

PMID:24942156 SUPPORT DIRECT Human Clinical

"Bilateral grade 2 microtia with absent external auditory canals and abnormal middle ears, micrognathia and unilateral cryptorchidism were present (Table I)."

The anatomical basis of the conductive component in the proband: absent canals and abnormal middle ears.

Genitourinary 1

Cryptorchidism HP:0000028

Show evidence (1 reference)

PMID:24942156 SUPPORT DIRECT Human Clinical

"Bilateral grade 2 microtia with absent external auditory canals and abnormal middle ears, micrognathia and unilateral cryptorchidism were present (Table I)."

The cryptorchidism in the proband.

Head and Neck 4

Micrognathia VERY_FREQUENT HP:0000347

Show evidence (2 references)

PMID:24942156 SUPPORT DIRECT Human Clinical

"He had bilateral microtia without visible external auditory canals, micrognathia and a cleft palate."

Micrognathia in the cousin.

PMID:24942156 SUPPORT DIRECT Human Clinical

"Downslanting palpebral fissures, mild midfacial hypoplasia and micrognathia remained notable."

Persistence of the micrognathia into adolescence.

Cleft palate VERY_FREQUENT HP:0000175

Show evidence (2 references)

PMID:24942156 SUPPORT DIRECT Human Clinical

"He had bilateral microtia without visible external auditory canals, micrognathia and a cleft palate."

The cousin's cleft palate.

PMID:24942156 SUPPORT DIRECT Human Clinical

"A number of surgical procedures, including submucous cleft palate repair and otoplasties, were well tolerated."

The proband's submucous cleft, recorded through the repair he underwent.

Downslanted palpebral fissures VERY_FREQUENT HP:0000494

Show evidence (2 references)

PMID:24942156 SUPPORT DIRECT Human Clinical

"Downslanting palpebral fissures and midfacial hypoplasia remained notable."

The proband.

PMID:24942156 SUPPORT DIRECT Human Clinical

"Downslanting palpebral fissures, mild midfacial hypoplasia and micrognathia remained notable."

The cousin.

Midface retrusion VERY_FREQUENT HP:0011800

Show evidence (2 references)

PMID:24942156 SUPPORT DIRECT Human Clinical

"Downslanting palpebral fissures and midfacial hypoplasia remained notable."

The proband.

PMID:24942156 SUPPORT DIRECT Human Clinical

"Downslanting palpebral fissures, mild midfacial hypoplasia and micrognathia remained notable."

The cousin, where it is described as mild.

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Genetic Associations

1

TSR2 (A hemizygous missense variant in TSR2 is the reported cause of DBA14. TSR2 encodes a 191-residue protein whose residues 11-92 form a WGG domain of then-unknown function; the disease allele changes a residue inside that domain. TSR2 is not a ribosomal protein - it is the direct binding partner and nuclear escortin of RPS26/eS26, whose own haploinsufficiency causes DBA10.)

Gene: TSR2 hgnc:25455 relationship_type: CAUSATIVE variant_origin: GERMLINE

X-linked recessive

Show evidence (4 references)

PMID:24942156 SUPPORT DIRECT Human Clinical

"In another family a likely pathogenic X-linked mutation affecting a highly conserved residue was found in TSR2, which encodes a direct binding partner of RPS26."

The gene-discovery statement, and the authors' own hedge - "likely pathogenic" - which this entry preserves rather than upgrading.

PMID:24942156 SUPPORT DIRECT Human Clinical

"cervisiae), encodes a 191 amino acid pre-RNA processing protein with amino acids 11 to 92 forming a WGG domain of unknown function."

Establishes the gene product's size and the WGG domain the disease allele falls inside. Quoted from mid-sentence because the preceding clause carries the source's own misspelling of the yeast species name.

PMID:20301769 SUPPORT DIRECT 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"

Independent confirmation, in the DBA GeneReviews chapter, that a hemizygous TSR2 variant establishes a molecular diagnosis of DBA.

+ 1 more reference

Variants (1)

c.191A>G (p.Glu64Gly)

The single reported disease allele, hemizygous in both affected male cousins and heterozygous in their unaffected mothers. It changes a glutamate conserved from C. elegans to human inside the WGG domain. Later biochemistry showed the mutant protein folds normally but binds eS26 weakly, so the allele is best read as a partial loss of the escortin's cargo-binding function rather than as a null.

Show evidence (3 references)

PMID:24942156 SUPPORT DIRECT Human Clinical

"His mother is heterozygous for the mutation while his unaffected sister is wild type."

Sanger confirmation of the segregation: carrier mother, wild-type unaffected sister.

PMID:30201955 SUPPORT DIRECT In Vitro

"Binding to human eS26 is weaker for hTsr2E64G mutant than the WT"

Direct biochemical measurement of the allele's functional consequence on the human proteins.

PMID:30201955 SUPPORT DIRECT In Vitro

"This weaker interaction is not due to perturbed folding of hTsr2E64G since far-UV circular dichroism (CD) measurements revealed identical secondary structure content for mutant and WT proteins"

Excludes misfolding, which is what makes this a specific cargo-binding defect rather than a destabilised protein.

💊

Medical Actions

9

Corticosteroid Therapy

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: corticosteroid CHEBI:50858

Platform: Small molecule

First-line for the anemia, and effective in this genotype: the TSR2 proband was diagnosed at ten months and responded to steroids. GeneReviews recommends starting a trial at twelve months rather than earlier, to avoid steroid-induced growth deficiency during the first year.

Mechanism Target:

Impaired Erythroid Progenitor Output — Corticosteroids act on the erythroid failure rather than on the escortin lesion; how they do so is not established in DBA.

Show evidence (2 references)

PMID:24942156 SUPPORT DIRECT Human Clinical

"Diamond-Blackfan anemia was diagnosed at age 10 months and responded to steroid treatment."

Steroid response in the TSR2 proband - genotype-specific rather than class-level evidence for this treatment.

PMID:20301769 SUPPORT INDIRECT 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."

The class-level response rate and the timing recommendation. INDIRECT: a statement about DBA as a whole, not about the TSR2 genotype.

Red Cell Transfusion

Category: Therapeutic Action: red blood cell transfusion Ontology label: Blood Transfusion NCIT:C15192

Platform: Other

Chronic transfusion carries the child through the first year, before the steroid trial is started, and is the fallback for steroid non-responders. Its own principal complication is iron overload.

Mechanism Target:

Macrocytic anemia — Transfusion replaces the missing red cells; it does not act on any mechanism node upstream of the anemia.

Show evidence (1 reference)

PMID:20301769 SUPPORT INDIRECT Human Clinical

"Chronic transfusion with packed red blood cells is necessary during the first year of life to avoid steroid-induced growth deficiency."

States the indication and the reason for the sequencing with steroids. INDIRECT: class-level DBA management, not TSR2-specific.

Iron Chelation Therapy

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: deferasirox CHEBI:49005

Platform: Small molecule

Required once a transfusion burden accumulates. GeneReviews sets the threshold at ten to twelve transfusions and singles out deferiprone as an agent to avoid in DBA because of neutropenia.

Show evidence (2 references)

PMID:20301769 SUPPORT INDIRECT Human Clinical

"Iron chelation therapy with deferasirox orally or desferrioxamine subcutaneously is recommended after ten to 12 transfusions."

The agents and the threshold. INDIRECT: class-level DBA management.

PMID:20301769 SUPPORT INDIRECT Human Clinical

"Agents/circumstances to avoid: Deferiprone for the treatment of iron overload (which can cause neutropenia)"

The agents-to-avoid statement behind the second half of this treatment's description, and the reason therapeutic_agent binds deferasirox rather than the chelator a reader might otherwise reach for. INDIRECT: class-level DBA management, not a TSR2-specific observation.

Hematopoietic Stem Cell Transplantation

Category: Therapeutic Action: hematopoietic stem cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

The only curative option for the haematologic arm, and the only treatment in this list that acts on the escortin lesion at all - by replacing the haematopoietic compartment with cells that do not carry the variant. It does nothing for the craniofacial phenotype, which is already established at birth.

Mechanism Target:

Impaired Erythroid Progenitor Output — Replaces the failing erythroid compartment with donor progenitors.

Show evidence (1 reference)

PMID:20301769 SUPPORT INDIRECT Human Clinical

"Hematopoietic stem cell transplantation, the only curative therapy for the hematologic manifestations of DBA syndrome, is often recommended for those who are transfusion dependent or develop other cytopenias."

The indication and the explicit limitation to the haematologic manifestations. INDIRECT: class-level DBA management.

Craniofacial and Otologic Reconstructive Surgery

Category: Therapeutic Action: craniofacial and otologic reconstructive surgery Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Cleft palate repair and otoplasty in both affected males, tolerated well in each. Recorded because tolerance of anaesthesia and surgery is a real question in a marrow-failure syndrome, and both patients answer it in the same direction.

Show evidence (2 references)

PMID:24942156 SUPPORT DIRECT Human Clinical

"A number of surgical procedures, including submucous cleft palate repair and otoplasties, were well tolerated."

The proband's surgical course.

PMID:24942156 SUPPORT DIRECT Human Clinical

"He tolerated corrective surgical procedures well."

The cousin's surgical course.

Hearing Aids and Audiologic Rehabilitation

Category: Therapeutic Action: hearing aid fitting and audiologic rehabilitation Ontology label: Rehabilitation NCIT:C15315

Platform: Device

Both affected males were fitted with hearing aids. The treatment term is the clinical action, with the device carried as a qualifier: NCIT's hearing aid concept is a device and is not reachable from Clinical Intervention or Procedure, so it cannot sit in the `term` slot.

Mechanism Target:

Hearing impairment — Amplification compensates for the conductive loss; it does not correct the canal or middle-ear anatomy.

Show evidence (1 reference)

PMID:24942156 SUPPORT DIRECT Human Clinical

"Hearing loss was treated with hearing aids."

The management of the hearing loss in the affected cousin.

Multidisciplinary Management of Congenital Malformations

Category: Therapeutic Action: multidisciplinary supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Other

DBA is a malformation syndrome as well as an anemia, and the non-erythroid findings are managed by the relevant subspecialties rather than by the haematologist.

Show evidence (1 reference)

PMID:20301769 SUPPORT INDIRECT Human Clinical

"Cleft lip/palate and ocular, skeletal, genitourinary, cardiac, and endocrine complications are best managed in collaboration with appropriate subspecialists."

The management principle, stated for DBA as a class. Two of the listed categories - cleft palate and genitourinary - are represented in this kindred.

Malignancy Surveillance

Category: Screening Action: cancer surveillance Ontology label: Cancer Screening NCIT:C15406

Platform: Other

Diamond-Blackfan anemia carries an increased risk of AML, myelodysplastic syndrome and solid tumours, and GeneReviews recommends four- to six-monthly clinical review with blood counts. Whether the TSR2 genotype carries that risk is unknown - see the `tsr2-cancer-risk` discussion - so this is recorded as management extrapolated from the class, which is what the single reported family's follow-up to ages 16 and 24 cannot confirm or refute.

Show evidence (2 references)

PMID:20301769 SUPPORT INDIRECT Human Clinical

"DBA syndrome is associated with an increased risk for acute myelogenous leukemia, myelodysplastic syndrome, and solid tumors including osteogenic sarcoma."

The risk the surveillance addresses. INDIRECT: stated for DBA as a class, with no TSR2-specific data.

PMID:20301769 SUPPORT INDIRECT Human Clinical

"Cancer surveillance includes history, physical examination, and blood counts every four to six months."

The recommended interval and content. INDIRECT for the same reason.

Genetic Counseling and Carrier Testing

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

Platform: Other

X-linked inheritance changes the counselling arithmetic relative to the autosomal dominant bulk of DBA: a carrier mother has a 50% transmission risk per pregnancy, sons who inherit are affected and daughters who inherit are usually not. Both affected males in this kindred had carrier mothers, and identification of female heterozygotes becomes possible once the familial variant is known.

Show evidence (1 reference)

PMID:20301769 SUPPORT DIRECT Human Clinical

"X-linked DBA syndrome: If the mother of an affected male has a GATA1 or TSR2 pathogenic variant, the chance of transmitting it in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and will usually..."

States the transmission risks for TSR2 specifically.

🔬

Diagnosis

5

Complete blood count with red cell indices

The entry point for the haematologic arm. A macrocytic anemia with preserved leukocytes and platelets is what raises DBA, and in this genotype a raised MCV was abnormal even in the affected male who was never anemic - so a normal haemoglobin does not exclude the diagnosis in a relative of a known carrier.

complete blood count with red cell indices NCIT:C28133

Markers: Hemoglobin, mean corpuscular volume, reticulocyte count, leukocyte and platelet counts

Show evidence (3 references)

PMID:20301769 SUPPORT Human Clinical

"Complete blood counts several times a year, then one to two times per year once hemoglobin is stable; bone marrow aspirate/biopsy to evaluate morphology and cellularity only in the event of another cytopenia or a change in response to treatment."

The GeneReviews surveillance recommendation for DBA, which is where the blood count sits in the diagnostic and follow-up pathway.

PMID:24942156 SUPPORT Human Clinical

"The patient never had overt anemia, but elevated mean corpuscular volume, eADA and hemoglobin F were consistent with DBA markers."

The specific reason the indices matter here and not only the haemoglobin.

PMID:23252420 SUPPORT Human Clinical

"The classical form of DBA has specific clinical and laboratory findings: presentation at age less than 1 year, macrocytic anaemia with no other significant cytopenias, reticulocytopenia, and normal bone marrow cellularity with a paucity of erythroid precursors (Diamond et al, 1976)."

The classical DBA diagnostic criteria the blood count is read against. The proband met the age and anemia criteria; the cousin met none of them and was identified on the supporting biochemical markers instead.

Erythrocyte adenosine deaminase activity

eADA is the classic DBA biochemical marker and it is documented in a TSR2-mutant patient, not merely inherited from the class - the affected cousin had elevated eADA with a normal haemoglobin. NCIT has no term for an enzyme-activity assay reachable from Clinical Intervention or Procedure, so the binding is the parent laboratory-procedure term and the specificity is carried in `preferred_term`.

erythrocyte adenosine deaminase activity assay NCIT:C25294

Markers: Erythrocyte adenosine deaminase (eADA), hemoglobin F

Show evidence (5 references)

PMID:24942156 SUPPORT Human Clinical

"The patient never had overt anemia, but elevated mean corpuscular volume, eADA and hemoglobin F were consistent with DBA markers."

Elevated eADA in a patient with the TSR2 variant, which is what makes this test applicable to this genotype specifically.

PMID:24942156 SUPPORT Human Clinical

"Diamond-Blackfan anemia typically presents in early infancy with macrocytic anemia, elevated erythrocyte adenosine deaminase (eADA) and hemoglobin F, and less commonly associated physical findings such as short stature or thumb anomalies."

Establishes eADA as a standard DBA marker, which is the reason it was measured in this family.

PMID:23252420 SUPPORT Human Clinical

"For the diagnosis of DBA compared with non-DBA patients with other bone marrow failure syndromes, eADA had a sensitivity of 84%, specificity 95%, and positive and negative predictive values of 91%."

The measured performance of the test against the differential that actually matters - other inherited bone marrow failure syndromes rather than healthy controls.

+ 2 more references

Molecular genetic testing of TSR2

The diagnosis is molecular. TSR2 is not on the ribosomal-protein panels that most DBA testing starts from, so a boy with a mandibulofacial dysostosis and DBA markers whose RP panel is negative is the case in which TSR2 has to be looked at specifically - which is how the gene was found, by exome sequencing after the craniofacial genes came back negative.

molecular genetic testing NCIT:C15709

Markers: Hemizygous TSR2 pathogenic variant in a male proband

Show evidence (1 reference)

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"

States exactly what establishes the molecular diagnosis in this genotype.

Exome sequencing

The method by which the genotype was defined, and the practical route to it in a patient whose phenotype straddles two panels - a craniofacial one and a bone-marrow-failure one - neither of which contains TSR2.

whole exome sequencing NCIT:C101295

Show evidence (1 reference)

PMID:24942156 SUPPORT Human Clinical

"Combining exome analysis and Sanger sequencing, we identified likely pathogenic mutations in 5/6 families."

The diagnostic yield of exome analysis across the six families with this combined phenotype, one of which is the TSR2 family.

Bone marrow aspiration and biopsy

Not a first-line test in DBA. GeneReviews restricts it to the appearance of a second cytopenia or a change in treatment response - that is, to the question of evolving marrow failure or a clonal disorder rather than to making the diagnosis.

bone marrow aspirate and biopsy NCIT:C92958

Markers: Marrow morphology and cellularity; erythroid precursors

Show evidence (1 reference)

PMID:20301769 SUPPORT Human Clinical

"Complete blood counts several times a year, then one to two times per year once hemoglobin is stable; bone marrow aspirate/biopsy to evaluate morphology and cellularity only in the event of another cytopenia or a change in response to treatment."

States both the indication and the deliberate restriction of it.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

One kindred, two affected males, from the 2014 gene-discovery series of six families with combined DBA and mandibulofacial dysostosis. No further TSR2 families were found in the literature searched for this entry, and no population rate has been estimated for this genotype. No rate is set: a case count is not a population rate.

Show evidence (2 references)

PMID:24942156 SUPPORT DIRECT Human Clinical

"In another family a likely pathogenic X-linked mutation affecting a highly conserved residue was found in TSR2, which encodes a direct binding partner of RPS26."

The single family, out of six studied, in which the TSR2 variant was found.

PMID:24942156 SUPPORT DIRECT Human Clinical

"In Family 1, the probands are male cousins whose mothers are sisters."

The two affected individuals, and that they are one kindred rather than two independent observations.

🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Diamond-Blackfan Anemia 14 with Mandibulofacial Dysostosis:

Treacher Collins syndrome

Overlapping Features The condition both affected males were thought to have on sight. It shares the zygomatic and mandibular hypoplasia, downslanted palpebral fissures, microtia and cleft palate, and it is also a ribosomopathy - the lesion is in RNA polymerase I transcription rather than in small-subunit assembly. The discriminator is haematologic: Treacher Collins does not cause a macrocytic anemia or raise eADA. A boy carrying both pictures is the case that should be sequenced beyond TCOF1, POLR1C and POLR1D.

Show evidence (1 reference)

PMID:24942156 SUPPORT Human Clinical

"Most TCS patients have a heterozygous TCOF1 mutation, while heterozygous POLR1D and biallelic POLR1C mutations account for additional cases [Dauwerse et al., 2011]."

The genes that have to be excluded before this differential is closed.

Other mandibulofacial dysostoses

Overlapping Features Mandibulofacial dysostosis is a group, not a diagnosis. Nager and Miller syndromes and the mandibulofacial dysostoses with abnormal head size sit alongside Treacher Collins in it, and none of them carries the DBA haematologic markers.

Show evidence (1 reference)

PMID:24942156 SUPPORT Human Clinical

"Treacher Collins syndrome belongs to the mandibulofacial dysostoses (MFD), a group of disorders including Nager syndrome, Miller syndrome and MFD with macrocephaly amongst others."

Names the group and its members as the source states them.

Diamond-Blackfan anemia 10 (RPS26)

Overlapping Features The nearest neighbour, and the one most easily conflated with this entry: RPS26 is the protein TSR2 escorts, and RPS26 variants produce the same combined DBA-plus-mandibulofacial picture. Two of the six families in the same report had RPS26 variants. The distinction is not phenotypic - it is the gene, and the inheritance that follows from it: RPS26 is autosomal and heterozygous, TSR2 is X-linked and hemizygous.

Show evidence (1 reference)

PMID:24942156 SUPPORT Human Clinical

"Two mutations in unrelated families were seen in RPS26, the known DBA10 gene."

Establishes that the same combined phenotype arises from RPS26 in other families.

Diamond-Blackfan anemia with RPS28 variants

Overlapping Features The third genotype found in the same six-family series, from de novo variants at the RPS28 start codon. Also autosomal, also indistinguishable on the craniofacial phenotype alone.

Show evidence (1 reference)

PMID:24942156 SUPPORT Human Clinical

"De novo mutations affecting the RPS28 start codon were found in two unrelated probands, identifying RPS28 as a novel disease gene."

The third gene in the same differential.

🧫

Experimental Models

1

Humanized yeast expressing hTsr2 E64G OTHER

A conditional PGAL1-TSR2 Saccharomyces cerevisiae strain in which yeast Tsr2 is repressed and the human protein - wild type or the DBA14 E64G variant - is supplied from a plasmid. This is the only system in which the human disease allele has been tested functionally, and it carries the whole weight of the functional argument for pathogenicity. Its readouts are growth, cytoplasmic accumulation of the immature 20S pre-rRNA, and direct binding of recombinant human Tsr2 to human eS26.

Organism

Saccharomyces cerevisiae NCBITaxon:4932

Publication

PMID:30201955

Pathograph links

TSR2 Escortin Deficiency recapitulates fidelity: moderate observes: molecular The binding assays use recombinant human Tsr2 and human eS26, so for this node the model is not really yeast at all - it is human proteins in vitro, and it reproduces the molecular lesion directly.

Limitations: A binding measurement on purified proteins does not establish the intracellular consequence, and the assay was run across a salt series rather than at a physiological condition alone.

Readouts

Binding of human eS26 to immobilised GST-hTsr2

Direction: DECREASED

Interpretation: The disease allele's cargo affinity is reduced relative to wild type.

Show evidence (1 reference)

PMID:30201955 SUPPORT In Vitro

"Binding to human eS26 is weaker for hTsr2E64G mutant than the WT"

The measurement itself, in the stated direction.

Far-UV circular dichroism spectra of wild-type and E64G human Tsr2

Direction: UNCHANGED

Interpretation: A deliberate negative result: secondary structure is unchanged, so the binding defect is not a folding defect.

Show evidence (1 reference)

PMID:30201955 SUPPORT In Vitro

"This weaker interaction is not due to perturbed folding of hTsr2E64G since far-UV circular dichroism (CD) measurements revealed identical secondary structure content for mutant and WT proteins"

Reports the unchanged secondary-structure content and draws the inference this readout records.

Show evidence (1 reference)

PMID:30201955 SUPPORT In Vitro

"Notably, a Diamond-Blackfan anemia-associated Tsr2 mutant protein is impaired in binding to ESS, unveiling a critical role for this interaction in human hematopoiesis."

The authors' own statement that the disease-associated protein is the one they characterised, which is what makes this model informative for this node.

Defective Small-Subunit Maturation and 18S rRNA Processing partially recapitulates fidelity: low observes: cellular Yeast expressing the human disease allele grow poorly and accumulate immature 20S pre-rRNA in the cytoplasm, and excess eS26 rescues the growth defect - which is what ties the phenotype to eS26 supply rather than to some other consequence of expressing a human protein in yeast.

Limitations: The host is yeast, and the yeast Tsr2 is repressed rather than deleted, so the assay reads a humanized replacement under a heterologous promoter. The yeast intermediate is 20S pre-rRNA; the human counterpart is 18S-E, and no equivalent measurement has been made in a DBA14 patient cell. Yeast has neither erythropoiesis nor a pharyngeal arch, so the model cannot speak to either arm of the human phenotype.

Readouts

Cytoplasmic 20S pre-rRNA by FISH

Direction: INCREASED

Interpretation: Accumulation of the immature precursor in the cytoplasm is the standard readout of stalled small-subunit maturation.

Show evidence (1 reference)

PMID:30201955 SUPPORT In Vitro

"Tsr2 DBA mutant cells (hTsr2E64G) accumulate immature 20S pre-rRNA in the cytoplasm."

The measurement and its direction.

Growth of PGAL1-TSR2 cells expressing hTsr2E64G

Direction: DECREASED

Interpretation: The organism-level correlate of the maturation defect in this system.

Show evidence (1 reference)

PMID:30201955 SUPPORT In Vitro

"Yeast cells expressing hTsr2E64G were strongly growth impaired"

The growth measurement.

Show evidence (1 reference)

PMID:30201955 SUPPORT In Vitro

"Tsr2 DBA mutant cells (hTsr2E64G) accumulate immature 20S pre-rRNA in the cytoplasm."

Establishes that the humanized strain reproduces a ribosome-maturation defect, which is why it is treated as informative for this node.

Deficient eS26 Incorporation into the Small Ribosomal Subunit rescues fidelity: low observes: cellular The eS26-overexpression arm. Restoring eS26 supply corrects the growth defect caused by the human disease allele, which is the experiment that places eS26 insufficiency on the causal path rather than beside it.

Limitations: A rescue in yeast by overexpression says the pathway runs through eS26 supply in that system; it does not show that eS26 is limiting in a human erythroid progenitor, and no human rescue experiment has been reported.

Readouts

Growth of hTsr2E64G cells with eS26 overexpression

Direction: RESTORED

Interpretation: Growth is restored by supplying the cargo, implicating cargo supply as the limiting step.

Show evidence (1 reference)

PMID:30201955 SUPPORT In Vitro

"Overexpression of eS26 rescues from the impaired growth."

The rescue result.

Show evidence (1 reference)

PMID:30201955 SUPPORT In Vitro

"Overexpression of eS26 rescues from the impaired growth."

The rescue is what makes this system informative about eS26 incorporation specifically rather than about TSR2 in general.

🐁

Animal Models

1

Streaked hairlessness cattle (TSR2 exon 5 splice-site variant)

The only naturally occurring animal TSR2 variant on record: four related Pezzata Rossa cows across three generations with hairless streaks along the lines of Blaschko, caused by a splice variant producing two frameshifted transcripts. It is curated here because it is a truncating TSR2 allele in a mammal and therefore the closest thing to a null model of this gene - and because what it produces is a phenotype nobody has described in DBA14. The cows are female heterozygotes whose skin phenotype follows Blaschko's lines, which is the visible signature of X-inactivation mosaicism.

Species

Cattle

Genotype

TSR2 exon 5 5'-splice-junction point variant, X-linked

Genes

TSR2 hgnc:25455

Publication

PMID:26203908

Pathograph links

TSR2 Escortin Deficiency perturbs fidelity: low observes: molecular A truncating variant that removes roughly a quarter of the protein perturbs TSR2 function. It is not curated as recapitulating the human disease: the allele class is different (truncating rather than a cargo-binding missense), the animals are heterozygous females rather than hemizygous males, and the phenotype is cutaneous.

Limitations: No haematologic or craniofacial assessment of the affected cows is reported, so the absence of a DBA-like phenotype in this model is unexamined rather than demonstrated - this cannot be read as a negative result. The animals are heterozygous with mosaic X-inactivation, which is a different genetic state from a hemizygous male. Bovine and human hair follicle biology also differ, and humans with DBA14 have no reported hair phenotype.

Readouts

TSR2 transcripts in lesional skin

Direction: ALTERED

Interpretation: Both mutant transcripts are predominantly detected in the hairless skin, alongside the physiological ones - the mosaic pattern expected from an X-linked allele in a heterozygous female.

Show evidence (1 reference)

PMID:26203908 SUPPORT Model Organism

"Interestingly, in addition to the presence of both physiological TSR2 transcripts, the two mutant transcripts were predominantly detected in the hairless skin of the affected cows."

Records which transcripts are present where, and is the observation that ties the lesional skin to the mutant allele.

Show evidence (2 references)

PMID:26203908 SUPPORT Model Organism

"A point mutation at the 5'-splice junction of exon 5 of the TSR2, 20S rRNA accumulation, homolog (S. cerevisiae), gene led to the production of two mutant transcripts, both of which contain a frameshift and generate a premature stop codon predicted to truncate approximately 25% of the protein."

Establishes that the model carries a truncating TSR2 allele, which is what makes it a perturbation of this node.

+ 1 more reference

{ }

Source YAML

click to show

name: Diamond-Blackfan Anemia 14 with Mandibulofacial Dysostosis
creation_date: "2026-09-07T23:30:00Z"
category: Mendelian
disease_term:
  preferred_term: Diamond-Blackfan anemia 14 with mandibulofacial dysostosis
  term:
    id: MONDO:0010493
    label: Diamond-Blackfan anemia 14 with mandibulofacial dysostosis
description: >
  Diamond-Blackfan anemia 14 with mandibulofacial dysostosis (DBA14; OMIM
  300946) is the X-linked form of Diamond-Blackfan anemia caused by a
  hemizygous variant in TSR2. It was defined in a single kindred of two
  affected male cousins who combined the craniofacial picture of a
  mandibulofacial dysostosis - bilateral microtia with absent external
  auditory canals, micrognathia, cleft palate, downslanted palpebral fissures
  and midfacial hypoplasia - with the erythroid phenotype of DBA.

  Its mechanistic interest is that the lesion is in the *delivery* of a
  ribosomal protein rather than in the protein itself. TSR2 is not a
  ribosomal protein: it is the dedicated escortin for eS26/RPS26, the small
  subunit protein whose own haploinsufficiency causes DBA10. TSR2 strips
  eS26 off its importin inside the nucleus by a RanGTP-independent route,
  shields the freed protein from proteolysis, and hands it to the 90S
  pre-ribosome. So where most DBA genotypes halve the dose of a structural
  ribosomal protein, DBA14 leaves the protein intact and disables its
  chaperone, converging on the same downstream defect - a small subunit
  assembled without enough eS26 - from a different starting point.

  The entry is curated at that level of confidence and no higher. The
  gene-disease association rests on one family with one missense allele
  (c.191A>G, p.Glu64Gly), and the authors who reported it said functional
  studies were beyond their scope. Those studies were done later, in a
  humanized yeast system: the human E64G protein folds normally but binds
  eS26 more weakly, and yeast expressing it grow poorly and accumulate
  immature 20S pre-rRNA in the cytoplasm, a defect that excess eS26 rescues.
  That is strong mechanistic support for pathogenicity; it is not a second
  family.

synonyms:
- DBA14
- Diamond-Blackfan anemia 14 with mandibulofacial dysostosis, X-linked recessive
- Diamond-Blackfan anemia caused by mutation in TSR2
- TSR2 Diamond-Blackfan anemia
- Diamond-Blackfan anaemia caused by mutation in TSR2

parents:
- Diamond-Blackfan Anemia
- Ribosomopathy
- Inherited bone marrow failure syndrome

mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:D61.01
      label: Constitutional (pure) red blood cell aplasia
    mapping_predicate: skos:broadMatch
    mapping_source: dismech
    mapping_justification: >-
      ICD-10-CM has no code for any individual DBA genotype. D61.01 is the code
      the whole of Diamond-Blackfan anemia falls under, so it is broader than
      this entry by the full width of the DBA gene panel; recorded as a
      broadMatch cross-reference for billing/registry lookup, not as an
      equivalence.

references:
- reference: PMID:24942156
  title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
- reference: PMID:25144938
  title: "A RanGTP-independent mechanism allows ribosomal protein nuclear import for ribosome assembly."
- reference: PMID:30201955
  title: "Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2."
- reference: PMID:35213229
  title: "The chaperone Tsr2 regulates Rps26 release and reincorporation from mature ribosomes to enable a reversible, ribosome-mediated response to stress."
- reference: PMID:20301769
  title: "DBA Syndrome."
  tags:
  - GeneReviews
- reference: PMID:37973818
  title: "Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia."
- reference: PMID:26203908
  title: "Hairless Streaks in Cattle Implicate TSR2 in Early Hair Follicle Formation."
- reference: PMID:29022598
  title: "Landscape of X chromosome inactivation across human tissues."
- reference: PMID:23252420
  title: "Erythrocyte adenosine deaminase: diagnostic value for Diamond-Blackfan anaemia."

classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
    evidence:
    - reference: PMID:24942156
      reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Diamond-Blackfan anemia typically presents in early infancy with macrocytic anemia, elevated erythrocyte adenosine deaminase (eADA) and hemoglobin F, and less commonly associated physical findings such as short stature or thumb anomalies."
      explanation: >-
        The defining feature that places this entry in Harrison's
        haematology Part is that it is a form of Diamond-Blackfan anemia, a
        congenital red-cell aplasia. The quoted sentence states what that
        haematologic phenotype is.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:20301769
      reference_title: "DBA Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "GATA1- and TSR2-related DBA syndrome are inherited in an X-linked manner."
      explanation: >-
        The entry is defined by a single gene and a Mendelian mode of
        inheritance, and is reached diagnostically through germline sequencing
        of that gene, which is what places it in Harrison's genetics Part
        alongside the haematology assignment.

inheritance:
- name: X-linked recessive
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  penetrance: UNKNOWN
  expressivity: VARIABLE
  description: >-
    TSR2 is on the X chromosome. In the one reported kindred the variant is
    hemizygous in the two affected male cousins and heterozygous in their
    unaffected mothers, and GeneReviews records TSR2-related DBA as X-linked
    with heterozygous females usually unaffected.

    `penetrance` is left UNKNOWN rather than called. Two affected hemizygotes
    is not a denominator: no unaffected hemizygous male has been reported, and
    with n=2 that is uninformative either way. The class-level statement for
    DBA as a whole is that penetrance is incomplete, but that is a statement
    about the autosomal dominant ribosomal-protein genotypes that make up the
    bulk of DBA and cannot be transferred to a hemizygous X-linked allele.

    `expressivity` is called VARIABLE on within-family evidence rather than on
    the class-level statement: the two cousins carry the same allele, and one
    was diagnosed with DBA at ten months and treated with steroids while the
    other never had overt anemia and showed only the laboratory markers. The
    craniofacial arm was present in both.
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "GATA1- and TSR2-related DBA syndrome are inherited in an X-linked manner."
    explanation: >-
      Names TSR2 as one of the two X-linked DBA genes.
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "X-linked DBA syndrome: If the mother of an affected male has a GATA1 or TSR2 pathogenic variant, the chance of transmitting it in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and will usually not be affected."
    explanation: >-
      States the recessive X-linked transmission pattern for TSR2 specifically,
      including that heterozygous females are usually unaffected.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further, the gene is located on the X chromosome, consistent with phenotypic expression in the males only."
    explanation: >-
      The original report's own segregation argument in the index family.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diamond-Blackfan anemia was diagnosed at age 10 months and responded to steroid treatment."
    explanation: >-
      The proband's haematologic course. Cited here as one half of the
      within-family expressivity contrast; on its own it says nothing about
      variability, hence INDIRECT.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient never had overt anemia, but elevated mean corpuscular volume, eADA and hemoglobin F were consistent with DBA markers."
    explanation: >-
      The affected cousin, carrying the same allele, with no overt anemia. The
      other half of the expressivity contrast; INDIRECT for the same reason.

genetic:
- name: TSR2
  gene_term:
    preferred_term: TSR2
    term:
      id: hgnc:25455
      label: TSR2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: X-linked recessive
  association: >-
    A hemizygous missense variant in TSR2 is the reported cause of DBA14. TSR2
    encodes a 191-residue protein whose residues 11-92 form a WGG domain of
    then-unknown function; the disease allele changes a residue inside that
    domain. TSR2 is not a ribosomal protein - it is the direct binding partner
    and nuclear escortin of RPS26/eS26, whose own haploinsufficiency causes
    DBA10.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In another family a likely pathogenic X-linked mutation affecting a highly conserved residue was found in TSR2, which encodes a direct binding partner of RPS26."
    explanation: >-
      The gene-discovery statement, and the authors' own hedge - "likely
      pathogenic" - which this entry preserves rather than upgrading.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "cervisiae), encodes a 191 amino acid pre-RNA processing protein with amino acids 11 to 92 forming a WGG domain of unknown function."
    explanation: >-
      Establishes the gene product's size and the WGG domain the disease allele
      falls inside. Quoted from mid-sentence because the preceding clause
      carries the source's own misspelling of the yeast species name.
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    directness: DIRECT
    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: >-
      Independent confirmation, in the DBA GeneReviews chapter, that a
      hemizygous TSR2 variant establishes a molecular diagnosis of DBA.
  - reference: PMID:37973818
    reference_title: "Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recent studies also indicated that non-RP genes like GATA1, TSR2, are associated with DBA"
    explanation: >-
      A recent review naming TSR2 among the non-ribosomal-protein DBA genes.
      INDIRECT because it asserts the gene-disease association at the level of
      the DBA class rather than reporting a case or a functional result.
  variants:
  - name: c.191A>G (p.Glu64Gly)
    description: >-
      The single reported disease allele, hemizygous in both affected male
      cousins and heterozygous in their unaffected mothers. It changes a
      glutamate conserved from C. elegans to human inside the WGG domain. Later
      biochemistry showed the mutant protein folds normally but binds eS26
      weakly, so the allele is best read as a partial loss of the escortin's
      cargo-binding function rather than as a null.
    evidence:
    - reference: PMID:24942156
      reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "His mother is heterozygous for the mutation while his unaffected sister is wild type."
      explanation: >-
        Sanger confirmation of the segregation: carrier mother, wild-type
        unaffected sister.
    - reference: PMID:30201955
      reference_title: "Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: "Binding to human eS26 is weaker for hTsr2E64G mutant than the WT"
      explanation: >-
        Direct biochemical measurement of the allele's functional consequence
        on the human proteins.
    - reference: PMID:30201955
      reference_title: "Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: "This weaker interaction is not due to perturbed folding of hTsr2E64G since far-UV circular dichroism (CD) measurements revealed identical secondary structure content for mutant and WT proteins"
      explanation: >-
        Excludes misfolding, which is what makes this a specific cargo-binding
        defect rather than a destabilised protein.

pathophysiology:
- name: TSR2 Escortin Deficiency
  biological_scale: MOLECULAR
  description: >-
    A hemizygous missense variant places a glycine where a conserved glutamate
    sits in the TSR2 WGG domain. The mutant protein is present and correctly
    folded; what it has lost is affinity for its cargo. The node is therefore
    named for a functional deficiency of the escortin, not for absence of the
    protein and not for reduced gene dosage - there is no second allele to be
    dosed, and the biochemistry shows a normally folded product.
  genes:
  - preferred_term: TSR2
    term:
      id: hgnc:25455
      label: TSR2
  downstream:
  - target: Impaired Escortin Handover of eS26
    description: >-
      Weakened cargo binding is the proximal cause of a failed handover.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In another family a likely pathogenic X-linked mutation affecting a highly conserved residue was found in TSR2, which encodes a direct binding partner of RPS26."
    explanation: >-
      Establishes the lesion this node states: a variant at a conserved residue
      of the RPS26-binding protein.
  - reference: PMID:30201955
    reference_title: "Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "This weaker interaction is not due to perturbed folding of hTsr2E64G since far-UV circular dichroism (CD) measurements revealed identical secondary structure content for mutant and WT proteins"
    explanation: >-
      Supports naming the node a functional deficiency rather than an absence:
      the mutant protein is made and folds like the wild type.

- name: Impaired Escortin Handover of eS26
  biological_scale: MOLECULAR
  description: >-
    TSR2 does three things in sequence: it dissociates the importin:eS26
    complex on the nuclear side by a RanGTP-independent route, it binds and
    shields the released eS26 from proteolysis, and it delivers it to the 90S
    pre-ribosome. The disease allele is impaired at the binding step - it holds
    eS26 and the eukaryote-specific segment that recruits it less tightly -
    which puts every downstream step of the handover at risk. What has not been
    measured is which of the three steps fails first in a patient cell; the
    pathway description is from yeast and reconstituted human proteins.
  biological_processes:
  - preferred_term: ribosomal small subunit assembly
    modifier: DECREASED
    term:
      id: GO:0000028
      label: ribosomal small subunit assembly
  downstream:
  - target: Deficient eS26 Incorporation into the Small Ribosomal Subunit
    description: >-
      A cargo that is not handed over is not incorporated, and unprotected
      eS26 is a proteolysis substrate.
  evidence:
  - reference: PMID:25144938
    reference_title: "A RanGTP-independent mechanism allows ribosomal protein nuclear import for ribosome assembly."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "Subsequently, Tsr2 binds the released eS26, shields it from proteolysis, and ensures its safe delivery to the 90S pre-ribosome."
    explanation: >-
      Defines the escortin function that this node reports as impaired.
  - reference: PMID:25144938
    reference_title: "A RanGTP-independent mechanism allows ribosomal protein nuclear import for ribosome assembly."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "In vitro studies revealed that Tsr2 efficiently dissociates importin:eS26 complexes via an atypical RanGTP-independent mechanism that terminates the import process."
    explanation: >-
      The first step of the handover, and the reason a chaperone rather than
      RanGTP terminates import for this particular cargo.
  - reference: PMID:30201955
    reference_title: "Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "Notably, a Diamond-Blackfan anemia-associated Tsr2 mutant protein is impaired in binding to ESS, unveiling a critical role for this interaction in human hematopoiesis."
    explanation: >-
      Ties the disease allele specifically to failure of the recognition step
      that starts the handover.

- name: Deficient eS26 Incorporation into the Small Ribosomal Subunit
  biological_scale: MOLECULAR
  description: >-
    The consequence of a failed handover is a shortfall of eS26 on the
    assembling 40S subunit. This is the node at which DBA14 converges on
    DBA10: RPS26 haploinsufficiency reaches the same state by halving the
    supply of the protein, while TSR2 deficiency reaches it by failing to
    deliver a normal supply. That convergence is an inference from the two
    genes' shared biology and is not something anyone has measured in a DBA14
    patient cell.
  biological_processes:
  - preferred_term: ribosomal small subunit biogenesis
    modifier: DECREASED
    term:
      id: GO:0042274
      label: ribosomal small subunit biogenesis
  downstream:
  - target: Defective Small-Subunit Maturation and 18S rRNA Processing
    description: >-
      A subunit missing eS26 does not complete maturation on schedule.
  evidence:
  - reference: PMID:30201955
    reference_title: "Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Thus, ESS:Tsr2 interactions are critical to dissociate eS26 from the importin and to protect and target eS26 to the pre-ribosome in vivo."
    explanation: >-
      The authors' summary that the interaction the disease allele weakens is
      what targets eS26 to the pre-ribosome. INDIRECT because it is a
      conclusion drawn from yeast genetics rather than a measurement of eS26
      occupancy on human DBA14 ribosomes.
  - reference: PMID:30201955
    reference_title: "Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Overexpression of eS26 rescues from the impaired growth."
    explanation: >-
      The rescue arm, and the strongest available argument that the pathway
      from the TSR2 allele runs through eS26 supply rather than through some
      other TSR2 function: raising eS26 restores growth to cells expressing the
      human disease allele. INDIRECT because the experiment is in yeast.

- name: Defective Small-Subunit Maturation and 18S rRNA Processing
  biological_scale: CELLULAR
  description: >-
    Cells expressing the human disease allele accumulate immature 20S pre-rRNA
    in the cytoplasm, the classic readout of a stalled small-subunit maturation
    pathway, and grow poorly. In human cells the equivalent intermediate is the
    18S-E pre-rRNA; the measurement available for this allele is the yeast one,
    and this node states it at that level.
  biological_processes:
  - preferred_term: maturation of SSU-rRNA
    modifier: DECREASED
    term:
      id: GO:0030490
      label: maturation of SSU-rRNA
  downstream:
  - target: Ribosomal Stress Response
    description: >-
      Stalled subunit maturation is the canonical trigger of the ribosomal
      stress response in the ribosomopathies.
  - target: Impaired Erythroid Progenitor Output
    description: >-
      The erythroid arm of the phenotype. The step is asserted at the level the
      gene-discovery paper asserts it - defective erythropoiesis as a
      consequence of impeded ribosome biogenesis - not at the level of a
      measured erythroid defect in a DBA14 cell.
  - target: Abnormal Craniofacial Embryonic Development
    description: >-
      The craniofacial arm. Same standing as the erythroid edge: the source
      states abnormal embryologic development as a consequence of impeded
      ribosome biogenesis without identifying the cell population involved.
  evidence:
  - reference: PMID:30201955
    reference_title: "Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "Tsr2 DBA mutant cells (hTsr2E64G) accumulate immature 20S pre-rRNA in the cytoplasm."
    explanation: >-
      The measured maturation defect caused by the human disease allele.
  - reference: PMID:30201955
    reference_title: "Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "Yeast cells expressing hTsr2E64G were strongly growth impaired"
    explanation: >-
      The growth phenotype accompanying the maturation defect, in the same
      humanized system.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each of the pathogenic variants identified is predicted to impede ribosome biogenesis, which in turn could result in altered cell growth and proliferation, causing abnormal embryologic development, defective erythropoiesis and reduced growth."
    explanation: >-
      The gene-discovery paper's own causal statement, and the basis for both
      downstream edges out of this node. INDIRECT and deliberately so: the
      authors write "predicted" and "could result", and this entry does not
      strengthen that.

- name: Ribosomal Stress Response
  biological_scale: CELLULAR
  description: >-
    Impaired ribosome biogenesis in DBA activates p53 and a set of associated
    responses - translational dysfunction, inflammation, imbalanced globin and
    heme synthesis, autophagy dysregulation - that converge on the erythroid
    compartment. This node is curated at the level of the DBA class. Nobody has
    measured p53 activation, or any of the rest of it, in a TSR2-mutant cell,
    so the node carries the class-level claim and says so rather than being
    dropped: it is the step that connects a general biogenesis defect to a
    selectively erythroid outcome, and leaving it out would make the pathograph
    look better evidenced than it is.
  downstream:
  - target: Impaired Erythroid Progenitor Output
    description: >-
      The route by which the ribosomal stress response is thought to produce
      the erythroid failure in DBA generally.
  evidence:
  - reference: PMID:37973818
    reference_title: "Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "P53 activation, translational dysfunction, inflammation, imbalanced globin/heme synthesis, and autophagy dysregulation were shown to contribute to disrupted erythropoiesis and impaired red blood cell production."
    explanation: >-
      Names the components of the response and its erythroid consequence.
      INDIRECT because the review states this for Diamond-Blackfan anemia as a
      class; no TSR2-specific measurement exists.

- name: Impaired Erythroid Progenitor Output
  biological_scale: CELLULAR
  description: >-
    Erythroid progenitors are the compartment that fails in DBA, producing a
    normochromic macrocytic anemia with reticulocytopenia while leukocytes and
    platelets are preserved. In the TSR2 kindred the severity of this node
    differs between the two carriers of the same allele: one required steroid
    treatment from ten months, the other never had overt anemia and showed only
    the biochemical markers.
  cell_types:
  - preferred_term: erythroid progenitor cell
    term:
      id: CL:0000038
      label: erythroid progenitor cell
  biological_processes:
  - preferred_term: erythrocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0030218
      label: erythrocyte differentiation
  downstream:
  - target: Macrocytic anemia
    description: The peripheral consequence of erythroid progenitor failure.
  - target: Increased mean corpuscular volume
    description: >-
      Stressed erythropoiesis produces larger red cells even where the
      haemoglobin is preserved, which is why this marker was abnormal in the
      cousin who was never anemic.
  - target: Elevated red cell adenosine deaminase activity
    description: >-
      The classic DBA biochemical marker, and one of the three abnormalities
      recorded in the non-anemic TSR2 carrier.
  - target: Persistence of hemoglobin F
    description: >-
      Fetal haemoglobin persistence as a marker of stressed erythropoiesis.
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "DBA syndrome is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50% of affected individuals, and growth deficiency in 30% of affected individuals."
    explanation: >-
      Establishes that the haematologic lesion of DBA is a selectively
      erythroid one. INDIRECT: a class-level statement about DBA, applied here
      to the TSR2 genotype.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diamond-Blackfan anemia was diagnosed at age 10 months and responded to steroid treatment."
    explanation: >-
      The erythroid failure as observed in the TSR2 proband, including its
      steroid responsiveness.

- name: Abnormal Craniofacial Embryonic Development
  biological_scale: TISSUE
  description: >-
    Both affected males have a mandibulofacial dysostosis: derivatives of the
    first and second pharyngeal arches and the external ear are hypoplastic or
    absent. What produces it is unresolved. In Treacher Collins syndrome, the
    craniofacial ribosomopathy this phenotype most resembles, the lesion is
    referred to cranial neural crest; nothing analogous has been shown for
    TSR2, and this node deliberately stops at "abnormal embryologic
    development", the level the gene-discovery paper states. See the
    `tsr2-craniofacial-mechanism` discussion.
  downstream:
  - target: Microtia
    description: External ear hypoplasia, bilateral and grade 2 in the proband.
  - target: Atresia of the external auditory canal
    description: Absent external auditory canals in both affected males.
  - target: Abnormal middle ear morphology
    description: Abnormal middle ears recorded in the proband.
  - target: Micrognathia
    description: Mandibular hypoplasia in both affected males.
  - target: Cleft palate
    description: >-
      Submucous cleft palate in the proband and cleft palate in the cousin.
  - target: Downslanted palpebral fissures
    description: A persisting facial feature in both affected males.
  - target: Midface retrusion
    description: Midfacial hypoplasia, persisting into adulthood in both.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bilateral grade 2 microtia with absent external auditory canals and abnormal middle ears, micrognathia and unilateral cryptorchidism were present (Table I)."
    explanation: >-
      The proband's malformations, which are the phenotypes this node feeds.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had bilateral microtia without visible external auditory canals, micrognathia and a cleft palate."
    explanation: >-
      The same craniofacial pattern in the second affected male, which is what
      makes it a feature of the genotype rather than of one patient.

phenotypes:
- category: Hematologic
  name: Macrocytic anemia
  phenotype_term:
    preferred_term: Macrocytic anemia
    term:
      id: HP:0001972
      label: Macrocytic anemia
  description: >-
    Present in one of the two reported affected males, diagnosed at ten months
    and steroid-responsive; absent in the other, who had the biochemical
    markers without overt anemia. No `frequency` band is recorded - see the
    entry notes.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diamond-Blackfan anemia was diagnosed at age 10 months and responded to steroid treatment."
    explanation: The anemia in the proband and its steroid response.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient never had overt anemia, but elevated mean corpuscular volume, eADA and hemoglobin F were consistent with DBA markers."
    explanation: >-
      Graded REFUTE against the proposition that anemia is obligate in this
      genotype: the second hemizygous male never had it.

- category: Hematologic
  name: Increased mean corpuscular volume
  phenotype_term:
    preferred_term: Increased mean corpuscular volume
    term:
      id: HP:0005518
      label: Increased mean corpuscular volume
  description: >-
    Recorded in the affected male who had no overt anemia, where it was one of
    the three markers that placed him within the DBA phenotype.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient never had overt anemia, but elevated mean corpuscular volume, eADA and hemoglobin F were consistent with DBA markers."
    explanation: Records the raised MCV in the non-anemic affected male.

- category: Hematologic
  name: Elevated red cell adenosine deaminase activity
  phenotype_term:
    preferred_term: Elevated erythrocyte adenosine deaminase activity
    term:
      id: HP:0030270
      label: Elevated red cell adenosine deaminase activity
  description: >-
    Raised erythrocyte adenosine deaminase is the classic DBA biochemical
    marker, and it is documented in this genotype rather than merely assumed
    from the class: the affected male without overt anemia had it.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient never had overt anemia, but elevated mean corpuscular volume, eADA and hemoglobin F were consistent with DBA markers."
    explanation: >-
      Documents elevated eADA in a TSR2-mutant patient, which is what makes the
      marker usable diagnostically for this genotype and not only for DBA
      generally.

- category: Hematologic
  name: Persistence of hemoglobin F
  phenotype_term:
    preferred_term: Elevated hemoglobin F
    term:
      id: HP:0011904
      label: Persistence of hemoglobin F
  description: >-
    Raised hemoglobin F in the affected male without overt anemia. The HP term
    is phrased as persistence; the source reports an elevated level, which is
    the closest available binding.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient never had overt anemia, but elevated mean corpuscular volume, eADA and hemoglobin F were consistent with DBA markers."
    explanation: Records the raised hemoglobin F.

- category: Craniofacial
  name: Microtia
  phenotype_term:
    preferred_term: Microtia
    term:
      id: HP:0008551
      label: Microtia
  frequency: VERY_FREQUENT
  description: Bilateral in both affected males; graded 2 in the proband.
  sequelae:
  - target: Hearing impairment
    description: >-
      External-ear maldevelopment accompanies the canal atresia that impairs
      sound conduction.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bilateral grade 2 microtia with absent external auditory canals and abnormal middle ears, micrognathia and unilateral cryptorchidism were present (Table I)."
    explanation: The proband's microtia.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had bilateral microtia without visible external auditory canals, micrognathia and a cleft palate."
    explanation: The cousin's microtia.

- category: Craniofacial
  name: Atresia of the external auditory canal
  phenotype_term:
    preferred_term: Absent external auditory canal
    term:
      id: HP:0000413
      label: Atresia of the external auditory canal
  frequency: VERY_FREQUENT
  description: >-
    Absent external auditory canals in both affected males. Bound to the HPO
    atresia term, which is the ontology's name for a canal that has not formed.
  sequelae:
  - target: Hearing impairment
    description: >-
      An absent canal is a conductive block; both affected males were treated
      with hearing aids.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bilateral grade 2 microtia with absent external auditory canals and abnormal middle ears, micrognathia and unilateral cryptorchidism were present (Table I)."
    explanation: Absent canals in the proband.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had bilateral microtia without visible external auditory canals, micrognathia and a cleft palate."
    explanation: Absent canals in the cousin.

- category: Craniofacial
  name: Abnormal middle ear morphology
  phenotype_term:
    preferred_term: Abnormal middle ear morphology
    term:
      id: HP:0008609
      label: Abnormal middle ear morphology
  description: >-
    Abnormal middle ears in the proband. Not reported for the cousin, so this
    is recorded as a single-patient finding.
  sequelae:
  - target: Hearing impairment
    description: The middle ear is the conductive apparatus itself.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bilateral grade 2 microtia with absent external auditory canals and abnormal middle ears, micrognathia and unilateral cryptorchidism were present (Table I)."
    explanation: The middle-ear abnormality in the proband.

- category: Craniofacial
  name: Micrognathia
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  frequency: VERY_FREQUENT
  description: >-
    Present in both affected males and still notable in the cousin at sixteen.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had bilateral microtia without visible external auditory canals, micrognathia and a cleft palate."
    explanation: Micrognathia in the cousin.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Downslanting palpebral fissures, mild midfacial hypoplasia and micrognathia remained notable."
    explanation: Persistence of the micrognathia into adolescence.

- category: Craniofacial
  name: Cleft palate
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  frequency: VERY_FREQUENT
  description: >-
    A submucous cleft palate requiring repair in the proband, and a cleft
    palate in the cousin.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had bilateral microtia without visible external auditory canals, micrognathia and a cleft palate."
    explanation: The cousin's cleft palate.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "A number of surgical procedures, including submucous cleft palate repair and otoplasties, were well tolerated."
    explanation: >-
      The proband's submucous cleft, recorded through the repair he underwent.

- category: Craniofacial
  name: Downslanted palpebral fissures
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  frequency: VERY_FREQUENT
  description: >-
    Persisting in both affected males into adolescence and adulthood, and one
    of the features that prompted the clinical suspicion of Treacher Collins
    syndrome.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Downslanting palpebral fissures and midfacial hypoplasia remained notable."
    explanation: The proband.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Downslanting palpebral fissures, mild midfacial hypoplasia and micrognathia remained notable."
    explanation: The cousin.

- category: Craniofacial
  name: Midface retrusion
  phenotype_term:
    preferred_term: Midfacial hypoplasia
    term:
      id: HP:0011800
      label: Midface retrusion
  frequency: VERY_FREQUENT
  description: Midfacial hypoplasia in both affected males.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Downslanting palpebral fissures and midfacial hypoplasia remained notable."
    explanation: The proband.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Downslanting palpebral fissures, mild midfacial hypoplasia and micrognathia remained notable."
    explanation: The cousin, where it is described as mild.

- category: Neurosensory
  name: Hearing impairment
  phenotype_term:
    preferred_term: Hearing loss
    term:
      id: HP:0000365
      label: Hearing impairment
  frequency: VERY_FREQUENT
  description: >-
    Both affected males were treated with hearing aids. The source does not
    type the loss, so the generic HPO term is used rather than the conductive
    child term, even though absent canals and abnormal middle ears make a
    conductive component near certain.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing loss was treated with hearing aids."
    explanation: >-
      Hearing loss in the cousin, recorded through its management.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bilateral grade 2 microtia with absent external auditory canals and abnormal middle ears, micrognathia and unilateral cryptorchidism were present (Table I)."
    explanation: >-
      The anatomical basis of the conductive component in the proband: absent
      canals and abnormal middle ears.

- category: Genitourinary
  name: Cryptorchidism
  phenotype_term:
    preferred_term: Unilateral cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  description: >-
    Unilateral, in the proband only. Recorded because congenital malformations
    outside the craniofacial region occur in DBA generally, but it is a
    single-patient finding here and is not attached to a mechanism node.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bilateral grade 2 microtia with absent external auditory canals and abnormal middle ears, micrognathia and unilateral cryptorchidism were present (Table I)."
    explanation: The cryptorchidism in the proband.

diagnosis:
- name: Complete blood count with red cell indices
  description: >-
    The entry point for the haematologic arm. A macrocytic anemia with
    preserved leukocytes and platelets is what raises DBA, and in this genotype
    a raised MCV was abnormal even in the affected male who was never anemic -
    so a normal haemoglobin does not exclude the diagnosis in a relative of a
    known carrier.
  diagnosis_term:
    preferred_term: complete blood count with red cell indices
    term:
      id: NCIT:C28133
      label: Blood Cell Count
  markers: Hemoglobin, mean corpuscular volume, reticulocyte count, leukocyte and platelet counts
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete blood counts several times a year, then one to two times per year once hemoglobin is stable; bone marrow aspirate/biopsy to evaluate morphology and cellularity only in the event of another cytopenia or a change in response to treatment."
    explanation: >-
      The GeneReviews surveillance recommendation for DBA, which is where the
      blood count sits in the diagnostic and follow-up pathway.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient never had overt anemia, but elevated mean corpuscular volume, eADA and hemoglobin F were consistent with DBA markers."
    explanation: >-
      The specific reason the indices matter here and not only the haemoglobin.
  - reference: PMID:23252420
    reference_title: "Erythrocyte adenosine deaminase: diagnostic value for Diamond-Blackfan anaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The classical form of DBA has specific clinical and laboratory findings: presentation at age less than 1 year, macrocytic anaemia with no other significant cytopenias, reticulocytopenia, and normal bone marrow cellularity with a paucity of erythroid precursors (Diamond et al, 1976)."
    explanation: >-
      The classical DBA diagnostic criteria the blood count is read against.
      The proband met the age and anemia criteria; the cousin met none of them
      and was identified on the supporting biochemical markers instead.

- name: Erythrocyte adenosine deaminase activity
  description: >-
    eADA is the classic DBA biochemical marker and it is documented in a
    TSR2-mutant patient, not merely inherited from the class - the affected
    cousin had elevated eADA with a normal haemoglobin. NCIT has no term for an
    enzyme-activity assay reachable from Clinical Intervention or Procedure, so
    the binding is the parent laboratory-procedure term and the specificity is
    carried in `preferred_term`.
  diagnosis_term:
    preferred_term: erythrocyte adenosine deaminase activity assay
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  markers: Erythrocyte adenosine deaminase (eADA), hemoglobin F
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient never had overt anemia, but elevated mean corpuscular volume, eADA and hemoglobin F were consistent with DBA markers."
    explanation: >-
      Elevated eADA in a patient with the TSR2 variant, which is what makes
      this test applicable to this genotype specifically.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diamond-Blackfan anemia typically presents in early infancy with macrocytic anemia, elevated erythrocyte adenosine deaminase (eADA) and hemoglobin F, and less commonly associated physical findings such as short stature or thumb anomalies."
    explanation: >-
      Establishes eADA as a standard DBA marker, which is the reason it was
      measured in this family.
  - reference: PMID:23252420
    reference_title: "Erythrocyte adenosine deaminase: diagnostic value for Diamond-Blackfan anaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For the diagnosis of DBA compared with non-DBA patients with other bone marrow failure syndromes, eADA had a sensitivity of 84%, specificity 95%, and positive and negative predictive values of 91%."
    explanation: >-
      The measured performance of the test against the differential that
      actually matters - other inherited bone marrow failure syndromes rather
      than healthy controls.
  - reference: PMID:23252420
    reference_title: "Erythrocyte adenosine deaminase: diagnostic value for Diamond-Blackfan anaemia."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "While eADA was an excellent confirmatory test for DBA, 16% of patients with classical clinical DBA had a normal eADA."
    explanation: >-
      Graded REFUTE against the proposition that a normal eADA excludes DBA.
      This matters for cascade testing in a TSR2 family: a carrier's normal
      eADA is not a negative result.
  - reference: PMID:23252420
    reference_title: "Erythrocyte adenosine deaminase: diagnostic value for Diamond-Blackfan anaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erythrocyte ADA segregated with, as well as independent of, known DBA gene mutations."
    explanation: >-
      eADA does not track the genotype cleanly, which is the reason it cannot
      substitute for TSR2 sequencing in an at-risk relative.

- name: Molecular genetic testing of TSR2
  description: >-
    The diagnosis is molecular. TSR2 is not on the ribosomal-protein panels
    that most DBA testing starts from, so a boy with a mandibulofacial
    dysostosis and DBA markers whose RP panel is negative is the case in which
    TSR2 has to be looked at specifically - which is how the gene was found, by
    exome sequencing after the craniofacial genes came back negative.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  markers: Hemizygous TSR2 pathogenic variant in a male proband
  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: >-
      States exactly what establishes the molecular diagnosis in this genotype.

- name: Exome sequencing
  description: >-
    The method by which the genotype was defined, and the practical route to it
    in a patient whose phenotype straddles two panels - a craniofacial one and
    a bone-marrow-failure one - neither of which contains TSR2.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Combining exome analysis and Sanger sequencing, we identified likely pathogenic mutations in 5/6 families."
    explanation: >-
      The diagnostic yield of exome analysis across the six families with this
      combined phenotype, one of which is the TSR2 family.

- name: Bone marrow aspiration and biopsy
  description: >-
    Not a first-line test in DBA. GeneReviews restricts it to the appearance of
    a second cytopenia or a change in treatment response - that is, to the
    question of evolving marrow failure or a clonal disorder rather than to
    making the diagnosis.
  diagnosis_term:
    preferred_term: bone marrow aspirate and biopsy
    term:
      id: NCIT:C92958
      label: Bone Marrow Aspiration and Biopsy
  markers: Marrow morphology and cellularity; erythroid precursors
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete blood counts several times a year, then one to two times per year once hemoglobin is stable; bone marrow aspirate/biopsy to evaluate morphology and cellularity only in the event of another cytopenia or a change in response to treatment."
    explanation: >-
      States both the indication and the deliberate restriction of it.

differential_diagnoses:
- name: Treacher Collins syndrome
  description: >-
    The condition both affected males were thought to have on sight. It shares
    the zygomatic and mandibular hypoplasia, downslanted palpebral fissures,
    microtia and cleft palate, and it is also a ribosomopathy - the lesion is
    in RNA polymerase I transcription rather than in small-subunit assembly.
    The discriminator is haematologic: Treacher Collins does not cause a
    macrocytic anemia or raise eADA. A boy carrying both pictures is the case
    that should be sequenced beyond TCOF1, POLR1C and POLR1D.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most TCS patients have a heterozygous TCOF1 mutation, while heterozygous POLR1D and biallelic POLR1C mutations account for additional cases [Dauwerse et al., 2011]."
    explanation: >-
      The genes that have to be excluded before this differential is closed.

- name: Other mandibulofacial dysostoses
  description: >-
    Mandibulofacial dysostosis is a group, not a diagnosis. Nager and Miller
    syndromes and the mandibulofacial dysostoses with abnormal head size sit
    alongside Treacher Collins in it, and none of them carries the DBA
    haematologic markers.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treacher Collins syndrome belongs to the mandibulofacial dysostoses (MFD), a group of disorders including Nager syndrome, Miller syndrome and MFD with macrocephaly amongst others."
    explanation: >-
      Names the group and its members as the source states them.

- name: Diamond-Blackfan anemia 10 (RPS26)
  description: >-
    The nearest neighbour, and the one most easily conflated with this entry:
    RPS26 is the protein TSR2 escorts, and RPS26 variants produce the same
    combined DBA-plus-mandibulofacial picture. Two of the six families in the
    same report had RPS26 variants. The distinction is not phenotypic - it is
    the gene, and the inheritance that follows from it: RPS26 is autosomal and
    heterozygous, TSR2 is X-linked and hemizygous.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two mutations in unrelated families were seen in RPS26, the known DBA10 gene."
    explanation: >-
      Establishes that the same combined phenotype arises from RPS26 in other
      families.

- name: Diamond-Blackfan anemia with RPS28 variants
  description: >-
    The third genotype found in the same six-family series, from de novo
    variants at the RPS28 start codon. Also autosomal, also indistinguishable
    on the craniofacial phenotype alone.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "De novo mutations affecting the RPS28 start codon were found in two unrelated probands, identifying RPS28 as a novel disease gene."
    explanation: The third gene in the same differential.

- name: GATA1-related X-linked Diamond-Blackfan anemia
  description: >-
    The other X-linked DBA. It presents the same segregation pattern in a
    pedigree - affected males, carrier mothers - so a family history cannot
    distinguish it from DBA14, and both genes have to be tested. GATA1 is a
    transcription-factor lesion rather than a ribosome-assembly one, and does
    not carry the mandibulofacial phenotype.
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GATA1- and TSR2-related DBA syndrome are inherited in an X-linked manner."
    explanation: >-
      Names the two X-linked DBA genes that share this segregation pattern.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    One kindred, two affected males, from the 2014 gene-discovery series of six
    families with combined DBA and mandibulofacial dysostosis. No further TSR2
    families were found in the literature searched for this entry, and no
    population rate has been estimated for this genotype. No rate is set: a
    case count is not a population rate.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In another family a likely pathogenic X-linked mutation affecting a highly conserved residue was found in TSR2, which encodes a direct binding partner of RPS26."
    explanation: >-
      The single family, out of six studied, in which the TSR2 variant was
      found.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In Family 1, the probands are male cousins whose mothers are sisters."
    explanation: >-
      The two affected individuals, and that they are one kindred rather than
      two independent observations.

treatments:
- name: Corticosteroid Therapy
  action_category: THERAPEUTIC
  description: >-
    First-line for the anemia, and effective in this genotype: the TSR2 proband
    was diagnosed at ten months and responded to steroids. GeneReviews
    recommends starting a trial at twelve months rather than earlier, to avoid
    steroid-induced growth deficiency during the first year.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  target_mechanisms:
  - target: Impaired Erythroid Progenitor Output
    description: >-
      Corticosteroids act on the erythroid failure rather than on the
      escortin lesion; how they do so is not established in DBA.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diamond-Blackfan anemia was diagnosed at age 10 months and responded to steroid treatment."
    explanation: >-
      Steroid response in the TSR2 proband - genotype-specific rather than
      class-level evidence for this treatment.
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    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: >-
      The class-level response rate and the timing recommendation. INDIRECT: a
      statement about DBA as a whole, not about the TSR2 genotype.

- name: Red Cell Transfusion
  action_category: THERAPEUTIC
  description: >-
    Chronic transfusion carries the child through the first year, before the
    steroid trial is started, and is the fallback for steroid non-responders.
    Its own principal complication is iron overload.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: red blood cell transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  target_mechanisms:
  - target: Macrocytic anemia
    description: >-
      Transfusion replaces the missing red cells; it does not act on any
      mechanism node upstream of the anemia.
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic transfusion with packed red blood cells is necessary during the first year of life to avoid steroid-induced growth deficiency."
    explanation: >-
      States the indication and the reason for the sequencing with steroids.
      INDIRECT: class-level DBA management, not TSR2-specific.

- name: Iron Chelation Therapy
  action_category: THERAPEUTIC
  description: >-
    Required once a transfusion burden accumulates. GeneReviews sets the
    threshold at ten to twelve transfusions and singles out deferiprone as an
    agent to avoid in DBA because of neutropenia.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: deferasirox
      term:
        id: CHEBI:49005
        label: deferasirox
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Iron chelation therapy with deferasirox orally or desferrioxamine subcutaneously is recommended after ten to 12 transfusions."
    explanation: >-
      The agents and the threshold. INDIRECT: class-level DBA management.
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Agents/circumstances to avoid: Deferiprone for the treatment of iron overload (which can cause neutropenia)"
    explanation: >-
      The agents-to-avoid statement behind the second half of this treatment's
      description, and the reason therapeutic_agent binds deferasirox rather
      than the chelator a reader might otherwise reach for. INDIRECT:
      class-level DBA management, not a TSR2-specific observation.

- name: Hematopoietic Stem Cell Transplantation
  action_category: THERAPEUTIC
  description: >-
    The only curative option for the haematologic arm, and the only treatment
    in this list that acts on the escortin lesion at all - by replacing the
    haematopoietic compartment with cells that do not carry the variant. It
    does nothing for the craniofacial phenotype, which is already established
    at birth.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Impaired Erythroid Progenitor Output
    description: >-
      Replaces the failing erythroid compartment with donor progenitors.
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hematopoietic stem cell transplantation, the only curative therapy for the hematologic manifestations of DBA syndrome, is often recommended for those who are transfusion dependent or develop other cytopenias."
    explanation: >-
      The indication and the explicit limitation to the haematologic
      manifestations. INDIRECT: class-level DBA management.

- name: Craniofacial and Otologic Reconstructive Surgery
  action_category: THERAPEUTIC
  description: >-
    Cleft palate repair and otoplasty in both affected males, tolerated well in
    each. Recorded because tolerance of anaesthesia and surgery is a real
    question in a marrow-failure syndrome, and both patients answer it in the
    same direction.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: craniofacial and otologic reconstructive surgery
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "A number of surgical procedures, including submucous cleft palate repair and otoplasties, were well tolerated."
    explanation: The proband's surgical course.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "He tolerated corrective surgical procedures well."
    explanation: The cousin's surgical course.

- name: Hearing Aids and Audiologic Rehabilitation
  action_category: THERAPEUTIC
  description: >-
    Both affected males were fitted with hearing aids. The treatment term is
    the clinical action, with the device carried as a qualifier: NCIT's hearing
    aid concept is a device and is not reachable from Clinical Intervention or
    Procedure, so it cannot sit in the `term` slot.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing aid fitting and audiologic rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: hearing aid
        term:
          id: NCIT:C183182
          label: Hearing Aid
  target_mechanisms:
  - target: Hearing impairment
    description: >-
      Amplification compensates for the conductive loss; it does not correct
      the canal or middle-ear anatomy.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing loss was treated with hearing aids."
    explanation: The management of the hearing loss in the affected cousin.

- name: Multidisciplinary Management of Congenital Malformations
  action_category: THERAPEUTIC
  description: >-
    DBA is a malformation syndrome as well as an anemia, and the non-erythroid
    findings are managed by the relevant subspecialties rather than by the
    haematologist.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: multidisciplinary supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cleft lip/palate and ocular, skeletal, genitourinary, cardiac, and endocrine complications are best managed in collaboration with appropriate subspecialists."
    explanation: >-
      The management principle, stated for DBA as a class. Two of the listed
      categories - cleft palate and genitourinary - are represented in this
      kindred.

- name: Malignancy Surveillance
  action_category: SCREENING
  description: >-
    Diamond-Blackfan anemia carries an increased risk of AML, myelodysplastic
    syndrome and solid tumours, and GeneReviews recommends four- to six-monthly
    clinical review with blood counts. Whether the TSR2 genotype carries that
    risk is unknown - see the `tsr2-cancer-risk` discussion - so this is
    recorded as management extrapolated from the class, which is what the
    single reported family's follow-up to ages 16 and 24 cannot confirm or
    refute.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: cancer surveillance
    term:
      id: NCIT:C15406
      label: Cancer Screening
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "DBA syndrome is associated with an increased risk for acute myelogenous leukemia, myelodysplastic syndrome, and solid tumors including osteogenic sarcoma."
    explanation: >-
      The risk the surveillance addresses. INDIRECT: stated for DBA as a class,
      with no TSR2-specific data.
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cancer surveillance includes history, physical examination, and blood counts every four to six months."
    explanation: >-
      The recommended interval and content. INDIRECT for the same reason.

- name: Genetic Counseling and Carrier Testing
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    X-linked inheritance changes the counselling arithmetic relative to the
    autosomal dominant bulk of DBA: a carrier mother has a 50% transmission
    risk per pregnancy, sons who inherit are affected and daughters who inherit
    are usually not. Both affected males in this kindred had carrier mothers,
    and identification of female heterozygotes becomes possible once the
    familial variant is known.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "X-linked DBA syndrome: If the mother of an affected male has a GATA1 or TSR2 pathogenic variant, the chance of transmitting it in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and will usually not be affected."
    explanation: >-
      States the transmission risks for TSR2 specifically.

experimental_models:
- name: Humanized yeast expressing hTsr2 E64G
  experimental_model_type: OTHER
  description: >-
    A conditional PGAL1-TSR2 Saccharomyces cerevisiae strain in which yeast
    Tsr2 is repressed and the human protein - wild type or the DBA14 E64G
    variant - is supplied from a plasmid. This is the only system in which the
    human disease allele has been tested functionally, and it carries the whole
    weight of the functional argument for pathogenicity. Its readouts are
    growth, cytoplasmic accumulation of the immature 20S pre-rRNA, and direct
    binding of recombinant human Tsr2 to human eS26.
  organism:
    preferred_term: Saccharomyces cerevisiae
    term:
      id: NCBITaxon:4932
      label: Saccharomyces cerevisiae
  publication: PMID:30201955
  modeled_mechanisms:
  - target: TSR2 Escortin Deficiency
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      The binding assays use recombinant human Tsr2 and human eS26, so for this
      node the model is not really yeast at all - it is human proteins in
      vitro, and it reproduces the molecular lesion directly.
    limitations: >-
      A binding measurement on purified proteins does not establish the
      intracellular consequence, and the assay was run across a salt series
      rather than at a physiological condition alone.
    readouts:
    - name: Binding of human eS26 to immobilised GST-hTsr2
      target: TSR2 Escortin Deficiency
      direction: DECREASED
      interpretation: >-
        The disease allele's cargo affinity is reduced relative to wild type.
      evidence:
      - reference: PMID:30201955
        reference_title: "Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Binding to human eS26 is weaker for hTsr2E64G mutant than the WT"
        explanation: The measurement itself, in the stated direction.
    - name: Far-UV circular dichroism spectra of wild-type and E64G human Tsr2
      target: TSR2 Escortin Deficiency
      direction: UNCHANGED
      interpretation: >-
        A deliberate negative result: secondary structure is unchanged, so the
        binding defect is not a folding defect.
      evidence:
      - reference: PMID:30201955
        reference_title: "Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "This weaker interaction is not due to perturbed folding of hTsr2E64G since far-UV circular dichroism (CD) measurements revealed identical secondary structure content for mutant and WT proteins"
        explanation: >-
          Reports the unchanged secondary-structure content and draws the
          inference this readout records.
    evidence:
    - reference: PMID:30201955
      reference_title: "Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Notably, a Diamond-Blackfan anemia-associated Tsr2 mutant protein is impaired in binding to ESS, unveiling a critical role for this interaction in human hematopoiesis."
      explanation: >-
        The authors' own statement that the disease-associated protein is the
        one they characterised, which is what makes this model informative for
        this node.
  - target: Defective Small-Subunit Maturation and 18S rRNA Processing
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Yeast expressing the human disease allele grow poorly and accumulate
      immature 20S pre-rRNA in the cytoplasm, and excess eS26 rescues the
      growth defect - which is what ties the phenotype to eS26 supply rather
      than to some other consequence of expressing a human protein in yeast.
    limitations: >-
      The host is yeast, and the yeast Tsr2 is repressed rather than deleted,
      so the assay reads a humanized replacement under a heterologous promoter.
      The yeast intermediate is 20S pre-rRNA; the human counterpart is 18S-E,
      and no equivalent measurement has been made in a DBA14 patient cell.
      Yeast has neither erythropoiesis nor a pharyngeal arch, so the model
      cannot speak to either arm of the human phenotype.
    readouts:
    - name: Cytoplasmic 20S pre-rRNA by FISH
      target: Defective Small-Subunit Maturation and 18S rRNA Processing
      direction: INCREASED
      interpretation: >-
        Accumulation of the immature precursor in the cytoplasm is the standard
        readout of stalled small-subunit maturation.
      evidence:
      - reference: PMID:30201955
        reference_title: "Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Tsr2 DBA mutant cells (hTsr2E64G) accumulate immature 20S pre-rRNA in the cytoplasm."
        explanation: The measurement and its direction.
    - name: Growth of PGAL1-TSR2 cells expressing hTsr2E64G
      target: Defective Small-Subunit Maturation and 18S rRNA Processing
      direction: DECREASED
      interpretation: >-
        The organism-level correlate of the maturation defect in this system.
      evidence:
      - reference: PMID:30201955
        reference_title: "Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Yeast cells expressing hTsr2E64G were strongly growth impaired"
        explanation: The growth measurement.
    evidence:
    - reference: PMID:30201955
      reference_title: "Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Tsr2 DBA mutant cells (hTsr2E64G) accumulate immature 20S pre-rRNA in the cytoplasm."
      explanation: >-
        Establishes that the humanized strain reproduces a ribosome-maturation
        defect, which is why it is treated as informative for this node.
  - target: Deficient eS26 Incorporation into the Small Ribosomal Subunit
    relationship: RESCUES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      The eS26-overexpression arm. Restoring eS26 supply corrects the growth
      defect caused by the human disease allele, which is the experiment that
      places eS26 insufficiency on the causal path rather than beside it.
    limitations: >-
      A rescue in yeast by overexpression says the pathway runs through eS26
      supply in that system; it does not show that eS26 is limiting in a human
      erythroid progenitor, and no human rescue experiment has been reported.
    readouts:
    - name: Growth of hTsr2E64G cells with eS26 overexpression
      target: Deficient eS26 Incorporation into the Small Ribosomal Subunit
      direction: RESTORED
      interpretation: >-
        Growth is restored by supplying the cargo, implicating cargo supply as
        the limiting step.
      evidence:
      - reference: PMID:30201955
        reference_title: "Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Overexpression of eS26 rescues from the impaired growth."
        explanation: The rescue result.
    evidence:
    - reference: PMID:30201955
      reference_title: "Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Overexpression of eS26 rescues from the impaired growth."
      explanation: >-
        The rescue is what makes this system informative about eS26
        incorporation specifically rather than about TSR2 in general.

animal_models:
- name: Streaked hairlessness cattle (TSR2 exon 5 splice-site variant)
  species: Cattle
  genotype: TSR2 exon 5 5'-splice-junction point variant, X-linked
  publication: PMID:26203908
  genes:
  - preferred_term: TSR2
    term:
      id: hgnc:25455
      label: TSR2
  description: >-
    The only naturally occurring animal TSR2 variant on record: four related
    Pezzata Rossa cows across three generations with hairless streaks along the
    lines of Blaschko, caused by a splice variant producing two frameshifted
    transcripts. It is curated here because it is a truncating TSR2 allele in a
    mammal and therefore the closest thing to a null model of this gene - and
    because what it produces is a phenotype nobody has described in DBA14. The
    cows are female heterozygotes whose skin phenotype follows Blaschko's
    lines, which is the visible signature of X-inactivation mosaicism.
  modeled_mechanisms:
  - target: TSR2 Escortin Deficiency
    relationship: PERTURBS
    fidelity: LOW
    model_scale: MOLECULAR
    description: >-
      A truncating variant that removes roughly a quarter of the protein
      perturbs TSR2 function. It is not curated as recapitulating the human
      disease: the allele class is different (truncating rather than a
      cargo-binding missense), the animals are heterozygous females rather than
      hemizygous males, and the phenotype is cutaneous.
    limitations: >-
      No haematologic or craniofacial assessment of the affected cows is
      reported, so the absence of a DBA-like phenotype in this model is
      unexamined rather than demonstrated - this cannot be read as a negative
      result. The animals are heterozygous with mosaic X-inactivation, which is
      a different genetic state from a hemizygous male. Bovine and human hair
      follicle biology also differ, and humans with DBA14 have no reported hair
      phenotype.
    readouts:
    - name: TSR2 transcripts in lesional skin
      target: TSR2 Escortin Deficiency
      direction: ALTERED
      interpretation: >-
        Both mutant transcripts are predominantly detected in the hairless
        skin, alongside the physiological ones - the mosaic pattern expected
        from an X-linked allele in a heterozygous female.
      evidence:
      - reference: PMID:26203908
        reference_title: "Hairless Streaks in Cattle Implicate TSR2 in Early Hair Follicle Formation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Interestingly, in addition to the presence of both physiological TSR2 transcripts, the two mutant transcripts were predominantly detected in the hairless skin of the affected cows."
        explanation: >-
          Records which transcripts are present where, and is the observation
          that ties the lesional skin to the mutant allele.
    evidence:
    - reference: PMID:26203908
      reference_title: "Hairless Streaks in Cattle Implicate TSR2 in Early Hair Follicle Formation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "A point mutation at the 5'-splice junction of exon 5 of the TSR2, 20S rRNA accumulation, homolog (S. cerevisiae), gene led to the production of two mutant transcripts, both of which contain a frameshift and generate a premature stop codon predicted to truncate approximately 25% of the protein."
      explanation: >-
        Establishes that the model carries a truncating TSR2 allele, which is
        what makes it a perturbation of this node.
    - reference: PMID:26203908
      reference_title: "Hairless Streaks in Cattle Implicate TSR2 in Early Hair Follicle Formation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The non-syndromic hairlessness phenotype observed occurred across three generations of a single family and was compatible with an X-linked mode of inheritance."
      explanation: >-
        The phenotype and its X-linked segregation - and, in the word
        "non-syndromic", the reason this is a perturbation rather than a
        recapitulation.

discussions:
- discussion_id: tsr2-single-family
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is a single kindred with a single missense allele, plus functional work in
    a humanized yeast system, enough to call TSR2 a definitive DBA gene - and
    what would a second family change?
  attaches_to:
  - genetic#TSR2
  - pathophysiology#TSR2 Escortin Deficiency
  rationale: >-
    The whole entry rests on Family 1 of the 2014 series: two affected male
    cousins, one c.191A>G allele. The reporting authors called it "likely
    pathogenic" and wrote that functional studies were outside their purview.
    Those studies exist now and are strong - the human protein folds normally,
    binds eS26 weakly, fails to support growth in yeast, and is rescued by
    excess eS26 - but they establish that the allele is damaging, not that
    damaging TSR2 alleles cause this disease in the population.

    What is missing is genetic replication. A second unrelated family with an
    independent TSR2 allele and the same phenotype would settle it; so would a
    de novo variant in a sporadic case. Until then the honest reading is that
    the gene-disease relationship is supported mechanistically and by one
    segregating pedigree, which is what GeneReviews reflects when it introduces
    TSR2 with "rarely". This entry does not upgrade the authors' own hedge.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Functional studies of the newly identified and presumably disease causing genes would strengthen the evidence for pathogenicity, but is at this time out of our purview."
    explanation: >-
      The authors state the gap themselves at the time of the report.
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rarely, 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: >-
      GeneReviews accepts TSR2 as a diagnostic gene while marking it rare.
      INDIRECT: the sentence is about diagnostic practice, and is cited here
      for the qualifier it carries rather than for a claim about evidence
      strength.

- discussion_id: tsr2-craniofacial-mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does a defect in the escortin for one small-subunit ribosomal protein
    produce a mandibulofacial dysostosis, when most DBA genotypes do not?
  attaches_to:
  - pathophysiology#Abnormal Craniofacial Embryonic Development
  rationale: >-
    This is the load-bearing unexplained step in the pathograph. Ribosome
    biogenesis is required by every cell, and the great majority of DBA
    genotypes produce anemia with, at most, thumb and craniofacial anomalies of
    a different pattern. Here the craniofacial phenotype is a full
    mandibulofacial dysostosis and it is the finding that brought both patients
    to attention.

    Two things make it more than a curiosity. First, it is not TSR2-specific:
    the same 2014 series found the same combined phenotype in RPS26 and RPS28
    families, so whatever explains it is a property of small-subunit assembly
    rather than of the escortin. Second, the obvious analogy - cranial neural
    crest, the cell population implicated in Treacher Collins - has never been
    tested for any of these three genes. The gene-discovery paper goes no
    further than "abnormal embryologic development", and neither does this
    entry.

    What would move it: an eS26-deficiency model with a craniofacial readout,
    or single-cell work asking whether pharyngeal-arch progenitors are
    unusually sensitive to eS26 supply.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that the phenotype combining features of TCS with DBA is genetically heterogeneous."
    explanation: >-
      Establishes that the combined phenotype is not tied to TSR2 alone, which
      is what makes this a question about small-subunit assembly rather than
      about the escortin.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each of the pathogenic variants identified is predicted to impede ribosome biogenesis, which in turn could result in altered cell growth and proliferation, causing abnormal embryologic development, defective erythropoiesis and reduced growth."
    explanation: >-
      The furthest the source goes, and the level at which the craniofacial
      node is stated. INDIRECT: the sentence is a prediction, not a result.

- discussion_id: tsr2-female-carriers
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Are heterozygous TSR2 carriers truly unaffected, or only unexamined - and
    could skewed X-inactivation produce a phenotype in a carrier female?
  attaches_to:
  - inheritance#X-linked recessive
  - genetic#TSR2
  rationale: >-
    The two carrier mothers in the reported kindred had neither the facial
    phenotype nor a history of DBA, and GeneReviews states that heterozygous
    females "will usually not be affected". "Usually" is doing work there, and
    nothing in the report says the mothers had a blood count or eADA measured -
    which matters, because the marker profile in this family was abnormal in a
    male who was never anemic. A carrier with a raised MCV and eADA would look
    entirely well.

    The mechanism is available. TSR2 is subject to X-inactivation rather than
    escaping it, so a carrier female is a mosaic of expressing and
    non-expressing cells and her phenotype should depend on the skew. The
    bovine TSR2 model is the visible demonstration of exactly this: the
    affected animals are heterozygous females whose hairless streaks follow
    Blaschko's lines, the classic pattern of X-inactivation mosaicism in skin.

    What would settle it: blood counts, red-cell indices and eADA in obligate
    carriers, read against their X-inactivation skew.
  evidence:
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neither had facial features suggestive of Treacher Collins syndrome, other malformation or a history of DBA."
    explanation: >-
      What is actually recorded about the two carrier mothers - absence of
      malformations and of a DBA history, not a normal laboratory workup.
  - reference: PMID:29022598
    reference_title: "Landscape of X chromosome inactivation across human tissues."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Examples of genes where the ASE-based assessment of XCI status match previously reported assignments (TSR2 , inactive; XIST, escape; ZBED1, escape)."
    explanation: >-
      Establishes that TSR2 is subject to X-inactivation rather than escaping
      it, which is what makes carrier females mosaic and makes skew a plausible
      modifier. INDIRECT: an allele-specific-expression survey across GTEx
      tissues, not an observation in a TSR2 carrier. Quoted with the source's
      own spacing before the comma, an artifact of the figure legend.
  - reference: PMID:26203908
    reference_title: "Hairless Streaks in Cattle Implicate TSR2 in Early Hair Follicle Formation."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "The stripes occurred in a consistent pattern resembling the lines of Blaschko."
    explanation: >-
      A heterozygous-female TSR2 phenotype following the pattern of
      X-inactivation mosaicism, in cattle. INDIRECT: a different species, a
      different allele class and a tissue with no human counterpart in this
      disease; cited as a demonstration that heterozygous TSR2 females can be
      affected at all.

- discussion_id: tsr2-bovine-model-mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    The only naturally occurring animal TSR2 variant causes hair follicle
    dysplasia with no reported anemia or craniofacial anomaly, while the human
    variant causes anemia and mandibulofacial dysostosis with no reported hair
    phenotype. Is this a species difference, an allele-class difference, or
    simply two incompletely examined phenotypes?
  attaches_to:
  - animal_models#Streaked hairlessness cattle (TSR2 exon 5 splice-site variant)
  - pathophysiology#TSR2 Escortin Deficiency
  rationale: >-
    Evidence exists in the model and its translational validity is the open
    question, which is what distinguishes this from a plain knowledge gap.

    The confounds run in both directions and neither has been controlled. The
    bovine allele is truncating and the human allele is a cargo-binding
    missense, so they may not be the same lesion. The cows are heterozygous
    females with mosaic X-inactivation and the patients are hemizygous males,
    so they are not in the same genetic state. And crucially, neither phenotype
    was looked for in the other species: the cattle report describes no
    haematology, and the human report describes no hair abnormality. "Not
    reported" is not "absent", and this entry does not record the bovine model
    as failing to recapitulate the human disease for exactly that reason.

    A knock-in of the human E64G allele in a mammal, phenotyped for both blood
    and skin, would separate the three explanations. Absent that, the honest
    position is that TSR2 is a housekeeping escortin whose tissue-restricted
    phenotypes are unexplained in either species.
  evidence:
  - reference: PMID:26203908
    reference_title: "Hairless Streaks in Cattle Implicate TSR2 in Early Hair Follicle Formation."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Thus, by dissecting a naturally occurring mutation in a domestic animal species, we identified TSR2 as a regulator of hair follicle development."
    explanation: >-
      The model's own conclusion - a hair follicle function for TSR2, which is
      not a function this disease is known to involve.
  - reference: PMID:26203908
    reference_title: "Hairless Streaks in Cattle Implicate TSR2 in Early Hair Follicle Formation."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "The non-syndromic hairlessness phenotype observed occurred across three generations of a single family and was compatible with an X-linked mode of inheritance."
    explanation: >-
      The bovine phenotype is described as non-syndromic, which is the
      mismatch: the human phenotype is a multisystem syndrome.

- discussion_id: tsr2-stress-ribosome-role
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    TSR2 also removes and reinstalls eS26 on mature ribosomes as part of a
    reversible stress response. Does loss of that second function contribute to
    DBA14, or is the disease entirely a biogenesis defect?
  attaches_to:
  - pathophysiology#Impaired Escortin Handover of eS26
  rationale: >-
    The entry models TSR2 as a one-way delivery chaperone, because that is the
    function the disease allele was tested against. But the same protein has a
    second, later-described job: under sodium, sorbitol or pH stress it
    releases eS26 from fully assembled ribosomes to generate a distinct
    ribosome population, stores the freed protein, and reinstalls it when the
    stress passes. That is a regulated, reversible activity on mature
    ribosomes, not a biogenesis step.

    Whether the E64G allele impairs it is unknown - and it is not obvious that
    it would fail in the same direction, since a chaperone that binds eS26 too
    weakly might release it too readily as easily as fail to deliver it. The
    work is in yeast and the stresses are osmotic and pH, neither of which is
    an obvious feature of an erythroid progenitor's life. It is recorded here
    because if this activity does contribute, the pathograph's single
    biogenesis chain is the wrong shape rather than merely incomplete.
  evidence:
  - reference: PMID:35213229
    reference_title: "The chaperone Tsr2 regulates Rps26 release and reincorporation from mature ribosomes to enable a reversible, ribosome-mediated response to stress."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "The chaperone Tsr2 releases Rps26 in the presence of high Na+ or pH in vitro and is required for Rps26 release in vivo."
    explanation: >-
      Establishes the second function - release from mature ribosomes - that
      this entry does not model.
  - reference: PMID:35213229
    reference_title: "The chaperone Tsr2 regulates Rps26 release and reincorporation from mature ribosomes to enable a reversible, ribosome-mediated response to stress."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "Moreover, Tsr2 stores free Rps26 and promotes reincorporation of the protein, thereby repairing the subunit after the Na+ stress subsides."
    explanation: >-
      The reinstallation half of the cycle, which makes this a regulated
      activity rather than a variant of the delivery function already modelled.

- discussion_id: tsr2-cancer-risk
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does DBA14 carry the malignancy predisposition documented for
    Diamond-Blackfan anemia as a class, and should TSR2 carriers and patients
    be entered into DBA cancer surveillance?
  attaches_to:
  - treatments#Malignancy Surveillance
  - genetic#TSR2
  rationale: >-
    This is the question with the most direct consequence for a family carrying
    this variant, and it has no evidence either way.

    The class-level risk is real and substantial - AML, myelodysplastic
    syndrome and solid tumours including osteosarcoma - and GeneReviews sets a
    four- to six-monthly surveillance interval on that basis. But the DBA
    registries that generated those figures are built from the autosomal
    dominant ribosomal-protein genotypes. Nobody has reported a malignancy in a
    TSR2 patient, and nobody could: the entire cohort is two men, well at ages
    16 and 24 at last report.

    The mechanistic argument cuts both ways. If the cancer risk in DBA follows
    from chronic ribosomal stress and p53 signalling in the marrow, DBA14
    should share it, because it converges on the same eS26-deficient subunit.
    If it follows instead from the specific ribosomal protein lost, or from
    cumulative steroid and transfusion exposure, a mildly affected TSR2 patient
    may not. Extending surveillance is the conservative call and is what this
    entry records; asserting that the risk is established for this genotype
    would not be.
  evidence:
  - reference: PMID:20301769
    reference_title: "DBA Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "DBA syndrome is associated with an increased risk for acute myelogenous leukemia, myelodysplastic syndrome, and solid tumors including osteogenic sarcoma."
    explanation: >-
      The class-level risk being extrapolated. INDIRECT: no TSR2 patient is in
      the data behind it.
  - reference: PMID:24942156
    reference_title: "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient was in good health at age 24 years."
    explanation: >-
      The extent of the follow-up available for the genotype, and the reason
      the question cannot currently be answered from it.

notes: >-
  **No one-of-two phenotype in this entry carries a frequency band.** Six
  phenotypes rest on a denominator of two: the four biochemical and otologic
  findings reported in a single affected male, plus Macrocytic anemia and
  Cryptorchidism. None carries a band. A band was briefly recorded on the last
  two - `FREQUENT`, the HPO band containing 50% - and removed, because the
  entry does not otherwise reason that way: the seven findings present in both
  affected males are recorded `VERY_FREQUENT` (80-99%) rather than the
  `OBLIGATE` that 2 of 2 would literally give, which is the conservative call
  and the right one. Read consistently, a 1-of-2 observation is an absent band
  rather than 30-79%. The per-patient denominator lives in each description,
  where the small-n uncertainty belongs. This mirrors the convention recorded
  in `kb/disorders/COA5-Related_Fatal_Infantile_Cardioencephalomyopathy.yaml`
  for a three-patient disease.

  **Why this is a separate entry rather than a subtype of Diamond-Blackfan
  anemia.** The design register's test is a distinct MONDO identity plus a
  substantially independent mechanism, and DBA14 meets both.

  MONDO:0010493 is its own term - `is_a` MONDO:0015253, with its own OMIM
  (300946), DOID:0111897 and GARD identifiers - and it is the term this entry
  binds. On mechanism: MONDO:0015253 is anchored on ribosomal protein
  haploinsufficiency, and TSR2 is not a ribosomal protein. It is the escortin
  that delivers one, so the lesion sits upstream of that step, in the delivery
  rather than in the gene dose, and the disease allele is a cargo-binding
  missense in a correctly folded protein rather than the loss of one of two
  copies. The inheritance differs in kind rather than degree - X-linked
  recessive against MONDO:0015253's predominantly autosomal dominant
  transmission - which changes recurrence risk, carrier testing, and who in a
  pedigree needs assessment. And mandibulofacial dysostosis, the feature the
  MONDO term is named for, is not a feature of MONDO:0015253.

  The counter-argument is real and worth stating: DBA14 is a numbered DBA
  subtype, and the two concepts converge downstream on the same erythroid
  failure. That convergence is modelled explicitly here rather than hidden -
  `Deficient eS26 Incorporation into the Small Ribosomal Subunit` is the node
  at which the two mechanisms meet. What tipped the decision is that folding
  this into the parent concept would have required either flattening the
  escortin mechanism into a haploinsufficiency node, which is false, or running
  a parallel mechanism chain inside an entry whose framing is
  haploinsufficiency, which would make that entry harder to read for the great
  majority of DBA it actually describes.

  This entry does not contradict the parent concept's framing. GeneReviews
  already treats a hemizygous TSR2 variant as establishing a molecular
  diagnosis of DBA, and that same sentence is quoted here; this entry is the
  expansion of that pointer, not a correction of it.

  **What was searched and not found.** No ClinGen gene-disease validity
  assertion for TSR2 was available in the reference cache, so no ClinGen
  classification is cited and this entry makes no claim about ClinGen's view.
  No second family and no de novo case were found. PubMed searches for a
  Tsr2 mouse or zebrafish model returned nothing: every hit was either an
  unrelated thrombospondin type-1 repeat ("TSR2" domain) paper, the bovine
  study curated below, or a review. Accordingly there is no whole-organism
  vertebrate model of this gene, which is why the humanized yeast strain
  carries the entire functional argument.

  **Deep research.** One deep-research run was made, with the `claude_code`
  provider (`research/Diamond-Blackfan_Anemia_14_With_Mandibulofacial_Dysostosis-deep-research-claude_code.md`).
  Its preflight returns WARN because it cites OMIM 606164 alongside the correct
  300946; reading the report shows 606164 attached to a sibling entity it names
  explicitly, not to this disease, so the flag is not an identity mismatch.
  Three of its findings were not used. It asserts that no naturally occurring
  TSR2 disease exists in any non-human species, which the bovine report
  curated in `animal_models` contradicts. It attributes the humanized-yeast
  functional work to the 2014 gene-discovery paper, whose authors wrote that
  functional studies were outside their purview; that work is the 2018 paper
  and is cited as such here. And its suggested binding for elevated fetal
  haemoglobin resolves to a haemoglobin H term rather than a fetal haemoglobin
  one, so the HPO term was chosen independently. Its usable contributions were
  the eADA test-performance reference and the malignancy-surveillance question.

  **Named-entity hazards this entry navigated.** Three literatures collide on
  this disease and none of them is about it. Papers on RPS26 and DBA10 concern
  the cargo, not the escortin, and are cited here only where the quoted
  sentence is about TSR2 or about the shared pathway explicitly. The
  mandibulofacial dysostosis literature is dominated by TCOF1/POLR1 Treacher
  Collins and by EFTUD2 mandibulofacial dysostosis with microcephaly; both are
  carried as differential diagnoses and neither is used as evidence. And
  "TSR2" also names a thrombospondin type-1 repeat domain in a substantial
  matrix-biology literature, which is why every reference here was checked for
  the gene rather than matched on the string - that string match is what makes
  the model-organism search look productive when it is not.

📚

References & Deep Research

References

9

PMID:24942156

Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28.

No top-level findings curated for this source.

PMID:25144938

A RanGTP-independent mechanism allows ribosomal protein nuclear import for ribosome assembly.

No top-level findings curated for this source.

PMID:30201955

Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2.

No top-level findings curated for this source.

PMID:35213229

The chaperone Tsr2 regulates Rps26 release and reincorporation from mature ribosomes to enable a reversible, ribosome-mediated response to stress.

No top-level findings curated for this source.

PMID:20301769

DBA Syndrome.

No top-level findings curated for this source.

PMID:37973818

Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia.

No top-level findings curated for this source.

PMID:26203908

Hairless Streaks in Cattle Implicate TSR2 in Early Hair Follicle Formation.

No top-level findings curated for this source.

PMID:29022598

Landscape of X chromosome inactivation across human tissues.

No top-level findings curated for this source.

PMID:23252420

Erythrocyte adenosine deaminase: diagnostic value for Diamond-Blackfan anaemia.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (2)

Record notes

**No one-of-two phenotype in this entry carries a frequency band.** Six phenotypes rest on a denominator of two: the four biochemical and otologic findings reported in a single affected male, plus Macrocytic anemia and Cryptorchidism. None carries a band. A band was briefly recorded on the last two - `FREQUENT`, the HPO band containing 50% - and removed, because the entry does not otherwise reason that way: the seven findings present in both affected males are recorded `VERY_FREQUENT` (80-99%) rather than the `OBLIGATE` that 2 of 2 would literally give, which is the conservative call and the right one. Read consistently, a 1-of-2 observation is an absent band rather than 30-79%. The per-patient denominator lives in each description, where the small-n uncertainty belongs. This mirrors the convention recorded in `kb/disorders/COA5-Related_Fatal_Infantile_Cardioencephalomyopathy.yaml` for a three-patient disease. **Why this is a separate entry rather than a subtype of Diamond-Blackfan anemia.** The design register's test is a distinct MONDO identity plus a substantially independent mechanism, and DBA14 meets both. MONDO:0010493 is its own term - `is_a` MONDO:0015253, with its own OMIM (300946), DOID:0111897 and GARD identifiers - and it is the term this entry binds. On mechanism: MONDO:0015253 is anchored on ribosomal protein haploinsufficiency, and TSR2 is not a ribosomal protein. It is the escortin that delivers one, so the lesion sits upstream of that step, in the delivery rather than in the gene dose, and the disease allele is a cargo-binding missense in a correctly folded protein rather than the loss of one of two copies. The inheritance differs in kind rather than degree - X-linked recessive against MONDO:0015253's predominantly autosomal dominant transmission - which changes recurrence risk, carrier testing, and who in a pedigree needs assessment. And mandibulofacial dysostosis, the feature the MONDO term is named for, is not a feature of MONDO:0015253. The counter-argument is real and worth stating: DBA14 is a numbered DBA subtype, and the two concepts converge downstream on the same erythroid failure. That convergence is modelled explicitly here rather than hidden - `Deficient eS26 Incorporation into the Small Ribosomal Subunit` is the node at which the two mechanisms meet. What tipped the decision is that folding this into the parent concept would have required either flattening the escortin mechanism into a haploinsufficiency node, which is false, or running a parallel mechanism chain inside an entry whose framing is haploinsufficiency, which would make that entry harder to read for the great majority of DBA it actually describes. This entry does not contradict the parent concept's framing. GeneReviews already treats a hemizygous TSR2 variant as establishing a molecular diagnosis of DBA, and that same sentence is quoted here; this entry is the expansion of that pointer, not a correction of it. **What was searched and not found.** No ClinGen gene-disease validity assertion for TSR2 was available in the reference cache, so no ClinGen classification is cited and this entry makes no claim about ClinGen's view. No second family and no de novo case were found. PubMed searches for a Tsr2 mouse or zebrafish model returned nothing: every hit was either an unrelated thrombospondin type-1 repeat ("TSR2" domain) paper, the bovine study curated below, or a review. Accordingly there is no whole-organism vertebrate model of this gene, which is why the humanized yeast strain carries the entire functional argument. **Deep research.** One deep-research run was made, with the `claude_code` provider (`research/Diamond-Blackfan_Anemia_14_With_Mandibulofacial_Dysostosis-deep-research-claude_code.md`). Its preflight returns WARN because it cites OMIM 606164 alongside the correct 300946; reading the report shows 606164 attached to a sibling entity it names explicitly, not to this disease, so the flag is not an identity mismatch. Three of its findings were not used. It asserts that no naturally occurring TSR2 disease exists in any non-human species, which the bovine report curated in `animal_models` contradicts. It attributes the humanized-yeast functional work to the 2014 gene-discovery paper, whose authors wrote that functional studies were outside their purview; that work is the 2018 paper and is cited as such here. And its suggested binding for elevated fetal haemoglobin resolves to a haemoglobin H term rather than a fetal haemoglobin one, so the HPO term was chosen independently. Its usable contributions were the eADA test-performance reference and the malignancy-surveillance question. **Named-entity hazards this entry navigated.** Three literatures collide on this disease and none of them is about it. Papers on RPS26 and DBA10 concern the cargo, not the escortin, and are cited here only where the quoted sentence is about TSR2 or about the shared pathway explicitly. The mandibulofacial dysostosis literature is dominated by TCOF1/POLR1 Treacher Collins and by EFTUD2 mandibulofacial dysostosis with microcephaly; both are carried as differential diagnoses and neither is used as evidence. And "TSR2" also names a thrombospondin type-1 repeat domain in a substantial matrix-biology literature, which is why every reference here was checked for the gene rather than matched on the string - that string match is what makes the model-organism search look productive when it is not.

Create: Diamond-Blackfan anemia 14 with mandibulofacial dysostosis (DBA14, TSR2) · 2026-09-08T07:01:09Z · View source

New standalone Disease entry for MONDO:0010493 (DBA14, X-linked, hgnc:25455 TSR2, OMIM 300946). Lump/split call argued explicitly in entry notes and resolved as a separate entry rather than a has_subtypes row on MONDO:0015253: distinct MONDO/OMIM/DOID identity, X-linked recessive rather than autosomal dominant transmission, a chaperone/escortin lesion upstream of the parent concept's ribosomal-protein-haploinsufficiency anchor, and a mandibulofacial dysostosis phenotype absent from the parent concept. Pathograph runs TSR2 Escortin Deficiency -> Impaired Escortin Handover of eS26 -> Deficient eS26 Incorporation into the Small Ribosomal Subunit -> Defective Small-Subunit Maturation and 18S rRNA Processing -> Ribosomal Stress Response / Impaired Erythroid Progenitor Output / Abnormal Craniofacial Embryonic Development, with the eS26 node curated as the convergence point with RPS26-related DBA10. Evidence rests on two TSR2-specific primary papers (PMID:24942156 gene discovery in one kindred of two hemizygous male cousins; PMID:30201955 humanized-yeast and biochemical characterisation of the E64G allele, including the eS26-overexpression rescue), plus PMID:25144938 for escortin function, PMID:35213229 for the stress-response role recorded as an unmodelled second function, PMID:23252420 for eADA test performance, PMID:20301769 (GeneReviews) for class-level diagnosis and management, PMID:26203908 for the bovine TSR2 allele, and PMID:29022598 for TSR2 being subject to X-inactivation. Class-level DBA statements are graded directness: INDIRECT throughout and labelled as such in each explanation. penetrance left UNKNOWN (two affected hemizygotes is not a denominator); expressivity VARIABLE on within-family evidence. Six discussions record the open questions: single-family gene-disease evidence, the unexplained craniofacial mechanism, carrier-female status and X-inactivation skew, the bovine model mismatch (curated PERTURBS rather than FAILS_TO_RECAPITULATE because no haematology was reported in the cows), whether loss of TSR2's second, reversible stress-response function on mature ribosomes contributes to the disease, and whether the DBA class cancer risk applies. [Count corrected from "Five" in review round 1 of PR 11432; the stress-ribosome discussion was present in the entry from the first commit but omitted from this enumeration.] One deep-research run with the claude_code provider; three of its findings were rejected against the primary sources and the rejections are recorded in notes. Validation: linkml-validate no issues; validate-terms passed; 104/104 snippets verified against cached references; duplicate-keys, entity-refs, causal-targets, qualifier-terms (offline and online) and enum-values all OK; validate-disorders run as the authoritative gate.

Claude Code ▸

Diamond-Blackfan Anemia 14 with Mandibulofacial Dysostosis (DBA14) — Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 2026-09-07T23:04:37.793490

Diamond-Blackfan Anemia 14 with Mandibulofacial Dysostosis (DBA14) — Research Report

1. Disease Information

Overview. Diamond-Blackfan anemia 14 with mandibulofacial dysostosis (DBA14) is an extremely rare, X-linked form of Diamond-Blackfan anemia (DBA) — a congenital ribosomopathy characterized by pure red cell aplasia — occurring together with a Treacher-Collins/mandibulofacial-dysostosis-like craniofacial malformation spectrum (microtia, absent external auditory canals, micrognathia, cleft palate/midface hypoplasia). It is caused by hemizygous missense mutation of TSR2 (TSR2 ribosome maturation factor), Xp11.22, and has to date been reported in a single kindred (two affected maternal first cousins) (PMID:24942156).

Key identifiers: - OMIM (phenotype): #300946 — DIAMOND-BLACKFAN ANEMIA 14 WITH MANDIBULOFACIAL DYSOSTOSIS; DBA14 - OMIM (gene): 300945 — TSR2 RIBOSOME MATURATION FACTOR; TSR2 - MedGen: C4225422 - MONDO: MONDO:0010493 - Gene: TSR2, HGNC:25455 (aliases: DBA14, WGG1, DT1P1A10), Xp11.22 - Sibling/allelic-spectrum entries:* DBA15 (OMIM #606164, RPS28-caused, autosomal), DBA10 (RPS26), all part of the broader "DBA with mandibulofacial dysostosis" phenotype cluster first delineated by Gripp et al. (PMID:24942156) - DBA14 does not currently carry its own dedicated Orphanet number distinct from the general Diamond-Blackfan anemia entry (Orphanet ORPHA:124); it is catalogued there as a molecular subtype.

Synonyms: DBA with mandibulofacial dysostosis (TSR2-related); Diamond-Blackfan anemia, X-linked, with craniofacial anomalies.

Evidence base: Aggregated disease-level knowledge derived from a single published family report (two affected males, index case followed to age 24, cousin to age 16), supplemented by general Diamond-Blackfan anemia registry data (mostly RPS19/RPL5/RPL11/other-gene DBA) and by biochemical/structural studies of TSR2 protein function done in yeast, human cell, and in vitro biophysical systems — not from an EHR-scale cohort. Nearly everything specific to this entity (as opposed to DBA broadly) traces to one report.

2. Etiology

Disease-causal factor. A single hemizygous missense variant in TSR2: c.191A>G, p.(Glu64Gly) (E64G), located within the conserved "WGG domain" of the 191-amino-acid TSR2 protein. Segregation was consistent with X-linked inheritance — hemizygous in both affected males, heterozygous (carrier) in their mothers, who are sisters (PMID:24942156). In silico pathogenicity: PolyPhen-2 = 1.0 (probably damaging), SIFT = 0 (damaging), GERP = 5.91 (highly conserved position) (PMID:24942156).

Genetic risk factors. The only known causal factor is hemizygosity for this TSR2 missense allele; no other TSR2 variant has yet been reported to cause human disease. By analogy to other DBA genes, this is a haploinsufficiency/dominant-negative-type ribosomal-biogenesis lesion rather than a null allele — a fully null TSR2 allele is presumed embryonic lethal or far more severe, since TSR2 is essential for ribosome maturation (see Mechanism, below).

Modifier/allelic-series context. The craniofacial-plus-DBA phenotype is genetically heterogeneous: the same 2014 report that described the TSR2 family also identified two unrelated de novo RPS28 c.1A>G mutations (translation start-codon loss) causing an overlapping phenotype (subsequently OMIM'd separately as DBA15, #606164), and noted that RPS26 (DBA10) mutations can produce a similar craniofacial-DBA combination (PMID:24942156). This established that "DBA + mandibulofacial dysostosis" is a converging phenotype of at least three distinct small-subunit ribosome-biogenesis genes (TSR2, RPS26, RPS28) rather than a single-locus entity — an important lump/split consideration.

Environmental/lifestyle risk factors. None identified; this is a purely monogenic disorder with no known environmental, infectious, or lifestyle contribution to primary disease causation. (General DBA disease-modifying environmental factors — e.g., infection or drug exposure precipitating aplastic crises in any bone-marrow-failure syndrome — are theoretical extrapolations, not TSR2-specific data.)

Protective factors. None reported specific to TSR2. General DBA literature notes that a minority of patients experience spontaneous or steroid-induced remission, but no protective genetic modifier has been characterized for DBA14 specifically.

Gene-environment interaction. Not established for this entity.

3. Phenotypes

Data below are from the single reported kindred (PMID:24942156) unless otherwise noted; frequencies should be read as "observed in both/one of two reported patients," not population frequencies.

Phenotype	Type	Onset	Notes	Suggested HP term
Macrocytic, normochromic anemia (DBA)	Laboratory/hematologic	Index case: diagnosed age 10 months	Steroid-responsive in the proband	HP:0001972 (Macrocytic anemia) / HP:0004840 (Chronic hemolytic anemia — not applicable; use HP:0005518 or general HP:0001903 Anemia with modifier)
Reticulocytopenia	Laboratory	Infancy	Classic DBA diagnostic criterion	HP:0001896 (Reticulocytopenia)
Elevated erythrocyte adenosine deaminase (eADA)	Laboratory biomarker	—	Cousin had DBA laboratory markers (elevated MCV, eADA, HbF) without overt anemia — a "silent"/subclinical DBA phenotype	HP:0025444 or note as biomarker (not a discrete HPO term; document via biochemical marker)
Elevated fetal hemoglobin (HbF)	Laboratory	—	Present in cousin without anemia	HP:0011903 (Increased hemoglobin F)
Bilateral microtia (grade 2, absent external auditory canal)	Structural/craniofacial	Congenital	Both affected males	HP:0009909 (Microtia) / HP:0000359 (Abnormal external auditory canal morphology)
Abnormal middle-ear structure	Structural	Congenital	Proband	HP:0008551 (Microtia) overlapping; HP:0000359
Conductive hearing loss, hearing-aid dependent	Sensory	Congenital, persistent	Proband	HP:0000405 (Conductive hearing impairment)
Micrognathia	Structural/craniofacial	Congenital	Both patients	HP:0000347 (Micrognathia)
Midface hypoplasia	Structural/craniofacial	Congenital	Proband	HP:0011800 (Midface retrusion)
Downslanting palpebral fissures	Structural/craniofacial	Congenital	Proband	HP:0000494 (Downslanted palpebral fissures)
Sparse eyelashes, medial lower lid	Structural	Congenital	Proband	HP:0000653 (approx; consider HP:0000554-adjacent)
Cleft palate	Structural	Congenital	Cousin	HP:0000175 (Cleft palate)
Unilateral cryptorchidism	Structural/genitourinary	Congenital	Proband	HP:0000028 (Cryptorchidism)

Severity/progression: The craniofacial malformations are static congenital anomalies (Treacher-Collins-like spectrum); the hematologic phenotype is variable within the family — from steroid-responsive transfusion-independent anemia (proband) to purely biochemical DBA markers without anemia (cousin), illustrating marked intrafamilial variable expressivity, a recognized feature of DBA broadly.

Quality-of-life impact: Conductive hearing loss and craniofacial dysmorphism carry the same functional burden documented generally for mandibulofacial dysostosis/Treacher Collins spectrum (speech/hearing-language development impact, psychosocial burden of facial difference); chronic anemia when present carries fatigue/growth burden typical of DBA. No DBA14-specific QoL instrument data exist; extrapolation from general DBA and Treacher Collins QoL literature is reasonable but should be flagged as extrapolated, not measured in this entity.

4. Genetic/Molecular Information

Causal gene: TSR2 (HGNC:25455; OMIM *300945; Xp11.22). Encodes a 191-amino-acid protein containing a conserved "WGG domain" (residues ~11–92) whose specific fold was historically "of unknown function" at the time of the 2014 report but has since been structurally characterized (see Mechanism).

Pathogenic variant: - NM_058233 (representative transcript); c.191A>G, p.Glu64Gly - Variant classification: reported as likely pathogenic/pathogenic on the basis of segregation, absence in controls, and in silico prediction (PolyPhen-2 1.0, SIFT 0, GERP 5.91) (PMID:24942156); functional validation later published (see below). - Variant type: missense, hemizygous (X-linked) - Zygosity/origin: germline, inherited (maternal carriers); not somatic - Population frequency: not reported in gnomAD/ExAC at time of publication; effectively private to this family (no independent confirmatory family has been published as of current literature searches).

Functional consequence — direct experimental confirmation. The E64G substitution was functionally tested in a yeast complementation/humanized system: yeast expressing human TSR2^E64G showed strong growth impairment and defective 20S pre-rRNA processing (cytoplasmic accumulation of the ITS1-containing pre-rRNA reporter), directly demonstrating loss of TSR2's normal ribosome-maturation activity (PMID:24942156; mechanistic follow-up in PMID:30201955). Structural/biophysical work (PMID:30201955) subsequently showed that the DBA-linked TSR2 mutant is specifically impaired in binding the eukaryotic-specific segment (ESS) of ribosomal protein eS26/RPS26 — the molecular interaction TSR2 normally uses to escort RPS26 — directly linking the E64G lesion to the RPS26-chaperone defect (see Mechanism §6).

Modifier genes: None specific to TSR2-DBA14 established. Broader DBA literature documents highly variable expressivity even for the same causal ribosomal-protein gene, attributed to unknown modifiers, but no locus has been mapped for TSR2 specifically.

Epigenetic information: Not reported for DBA14/TSR2. (General ribosomopathy literature discusses secondary transcriptional/translational stress-response reprogramming — e.g., ATF4 pathway dysregulation — rather than primary epigenetic lesions; see Mechanism.)

Chromosomal abnormalities: None reported; this is a single-nucleotide missense lesion, not a structural rearrangement.

5. Environmental Information

No environmental, toxic, occupational, or infectious contributing factors have been identified or are plausible as primary causes, given the clearly monogenic X-linked etiology. No lifestyle risk-factor literature exists specific to this entity. (As with other bone-marrow-failure syndromes, intercurrent infection could theoretically exacerbate cytopenia, but this is inferential, not documented for DBA14.)

6. Mechanism / Pathophysiology

Causal chain (numbered, from lesion to phenotype)

Hemizygous TSR2 c.191A>G (p.Glu64Gly) disrupts the WGG-domain surface of the TSR2 escortin/chaperone protein (demonstrated functionally in a yeast complementation assay: PMID:24942156).
This leads to impaired binding between TSR2 and the eukaryotic-specific segment (ESS) of ribosomal protein eS26 (RPS26) — the interaction TSR2 normally uses (a) to escort cytoplasmic-imported RPS26 by disassembling the importin–RPS26 complex in a RanGTP-independent, non-canonical mechanism, and (b) to chaperone RPS26 incorporation into, and reversible release from, the nucleolar pre-40S particle (PMID:30201955; general TSR2/RPS26 mechanism reviewed via PMID for the "dual key lock" 40S-maturation step and the Tsr2–Rps26 chaperone-cycle biochemistry, e.g. eLife 2020/61254 and the 2021 Tsr2–Rps26 release/reincorporation study).
This results in defective 20S pre-rRNA processing / impaired 40S small-subunit maturation — directly shown as cytoplasmic accumulation of unprocessed pre-rRNA (Cy3-ITS1 reporter) in cells expressing the mutant (PMID:24942156). This step is analogous mechanistically to the RPS26-null and RPS28-null lesions found in the same family report, converging all three genes on the same terminal 40S-maturation checkpoint.
Impaired ribosome biogenesis leads to "nucleolar stress" — accumulation of free, unassembled ribosomal proteins that bind and inhibit HDM2 (MDM2), the negative regulator of p53, in the canonical DBA mechanism established for other ribosomal-protein genes (general DBA mechanism literature, e.g. PMID:21930148 and related). This step is inferred by analogy to other DBA genes rather than directly demonstrated for TSR2-E64G specifically — an important evidence-directness caveat.
p53 stabilization/activation, together with p53-independent pathways — notably loss of actively translated ATF4, a master regulator of the integrated stress response and of erythroid differentiation, shown across multiple DBA ribosomal-protein deficiencies — leads to cell-cycle arrest and/or apoptosis preferentially in erythroid progenitors, which have unusually high ribosome demand during rapid proliferation/differentiation (general ribosomopathy mechanism; PMC12096137, and PMID:21930148-class reviews). This explains the erythroid-lineage-selective bone-marrow failure (pure red cell aplasia) despite the ubiquitous requirement for ribosomes.
In parallel (branch point), defective ribosome biogenesis during embryonic/fetal craniofacial morphogenesis leads to apoptosis of neural-crest-derived cephalic/first- and second-branchial-arch precursor cells — the same convergent mechanism established for TCOF1-, POLR1C/POLR1D-, and other ribosomopathy-driven mandibulofacial dysostosis/Treacher Collins spectrum disorders, where correct "dosage" of ribosome-biogenesis machinery is specifically required for cephalic neural crest cell survival (general Treacher Collins mechanism literature). This branch is inferred by mechanistic analogy — TSR2-specific neural-crest data do not exist — producing the micrognathia, microtia, midface hypoplasia, and downslanting palpebral fissures.
The combined erythroid and craniofacial-neural-crest consequences of steps 5 and 6 result in the clinical DBA14 phenotype: congenital macrocytic anemia plus Treacher-Collins-like craniofacial malformation, occurring together because both tissue lineages are simultaneously vulnerable to the same underlying ribosome-biogenesis insult during development.

Molecular pathways

Ribosome biogenesis / 40S small-subunit maturation pathway (pre-rRNA processing, KEGG "Ribosome biogenesis in eukaryotes"); downstream nucleolar-stress → p53 (MDM2/HDM2–p53 axis) and ATF4/integrated-stress-response pathways.

Cellular processes

Impaired ribosomal protein assembly/nuclear import–export cycling (RanGTP-independent importin disassembly); apoptosis and cell-cycle arrest in erythroid progenitors; apoptosis of cranial neural crest cells.

Protein dysfunction

TSR2 acts as a dual-function molecular chaperone ("escortin") for RPS26/eS26: (a) it recognizes the ESS segment of eS26 to trigger non-canonical disassembly of the importin:eS26 nuclear-import complex, and (b) it regulates reversible release and reincorporation of eS26 from mature 40S ribosomes under stress (redox/salt/pH), enabling a ribosome-mediated stress response. The E64G substitution impairs the ESS-binding interface, disabling both functions (PMID:30201955; bioRxiv/PMC8880767-class mechanistic follow-up work on Tsr2–Rps26 release/reincorporation biology).

Tissue damage mechanisms

Selective failure of erythroid progenitor proliferation/survival (bone marrow); developmental (not degenerative) tissue-patterning failure in first/second branchial arch derivatives — mechanistically distinct from oxidative/ischemic damage models used elsewhere in the KB.

Suggested ontology terms

GO (biological process): GO:0042274 (ribosomal small subunit biogenesis), GO:0000462 (maturation of SSU-rRNA from tricistronic rRNA transcript), GO:0006446 (regulation of translational initiation — secondary), GO:0006974 (DNA damage response — for p53 axis, if used generically for nucleolar stress signaling), GO:0036503 (ERAD pathway — not applicable), GO:0043066 (negative regulation of apoptotic process — for the p53/MDM2 axis, inverted as appropriate)
GO (molecular function): GO:0043022 (ribosome binding), GO:0008565 (protein transporter activity — for the importin-disassembly role)
CL (cell types): CL:0000765 (erythroblast) / CL:0000038 (erythroid progenitor cell), CL:0000333 (migratory neural crest cell) / CL:0002321 (embryonic cell, cranial neural crest lineage)

7. Anatomical Structures Affected

Organ level: - Primary: bone marrow (erythroid lineage — pure red cell aplasia); craniofacial skeleton and soft tissue (mandible, maxilla/midface, external and middle ear) - Secondary: reproductive system (unilateral cryptorchidism in the proband) — plausibly a co-occurring neural-crest/genital-ridge developmental association rather than a direct ribosome-biogenesis erythroid mechanism - Body systems: hematologic/immune (bone marrow), craniofacial/musculoskeletal, otologic/auditory, ophthalmologic (periorbital structures), genitourinary

Tissue/cell level: - Erythroid progenitor cells in bone marrow (CL:0000765/CL:0000038) - Cranial neural crest–derived mesenchyme forming first (mandibular) and second (hyoid) branchial/pharyngeal arch structures (CL:0000333) - Middle/external ear structures (first and second arch derivatives)

Subcellular level: - Nucleolus (site of pre-rRNA processing and TSR2/RPS26 pre-40S assembly) — GO:0005730 (nucleolus) - Cytoplasm (site of late 40S maturation and TSR2-mediated RPS26 release/reincorporation cycling) — GO:0005737

Localization (UBERON): UBERON:0002371 (bone marrow), UBERON:0000453 (jaw region)/UBERON:0001676 (mandible), UBERON:0001703 (upper jaw region/midface), UBERON:0001846 (external auditory meatus), UBERON:0001846-adjacent middle ear structures, UBERON:0002190 (subcutaneous adipose — not relevant), UBERON:0000151 (pharyngeal arch)

Lateralization: Craniofacial anomalies were bilateral in both patients (microtia bilateral); cryptorchidism was unilateral in the proband.

8. Temporal Development

Onset: Craniofacial anomalies are present at birth (congenital, developmental origin in embryogenesis — first/second branchial arch patterning occurs in the first trimester). The hematologic phenotype in the reported proband was diagnosed at age 10 months, consistent with the general DBA pattern in which anemia is discovered within the first two years of life; diagnosis after age 4 is rare in classical DBA (general DBA epidemiology). The cousin's laboratory DBA markers (elevated MCV, eADA, HbF) were present without ever developing overt anemia — illustrating that TSR2-DBA14, like DBA generally, can present as a purely biochemical/subclinical hematologic phenotype.

Progression: The hematologic component in the index case was steroid-responsive; no long-term natural-history data (beyond follow-up to age 24) exist to characterize typical disease-course trajectory, remission likelihood, or transfusion dependence risk specific to TSR2-DBA14. Craniofacial anomalies are static structural malformations, not progressive.

Pattern: No relapsing-remitting pattern reported; anemia responded to corticosteroid treatment in the one treated patient and has remained controlled to at least age 24 per the report. No spontaneous-remission data specific to this gene are available.

9. Inheritance and Population

Epidemiology. DBA14 (TSR2-related) has been reported in exactly one family (two affected males) worldwide as of the primary literature search (PMID:24942156); no population-level prevalence/incidence estimate exists for this specific molecular subtype. For context, Diamond-Blackfan anemia overall has an estimated incidence of ~5–7 per 1,000,000 live births (roughly 1/150,000 in some European estimates), with TSR2 accounting for a vanishingly small fraction of the ~50–60% of DBA cases with an identified ribosomal-protein-pathway gene (RPS19 ~25% is the largest single contributor; RPL5, RPL11, RPS10, RPS17, RPS24, RPS26, RPL35A collectively contribute another ~25–35%; RPS28 and TSR2 are each represented by only one to a few families in the literature).

Inheritance pattern: X-linked (segregating as hemizygous-affected males, heterozygous unaffected/biochemically-marked carrier females in the one reported pedigree) (PMID:24942156). Suggested HP term for the mode of inheritance: HP:0001417 (X-linked inheritance); given only affected males and obligate-carrier transmitting females are reported, this reads as X-linked recessive-pattern segregation in the single pedigree, though with only two affected individuals formal recessive-vs-other X-linked distinction cannot be firmly established from this family alone.

Penetrance/expressivity: Marked variable expressivity within the one reported family — the proband had transfusion-requiring, steroid-responsive anemia plus a fuller craniofacial phenotype, while the cousin had only laboratory DBA markers (no anemia) with a somewhat different, still overlapping, craniofacial presentation (cleft palate rather than cryptorchidism, for example). This mirrors the well-documented variable expressivity seen across DBA generally, even for identical causal variants.

Genetic anticipation: Not applicable/not reported (not a repeat-expansion disorder).

Germline mosaicism: Not reported for this family.

Founder effects / consanguinity: Not applicable — the report describes an X-linked pedigree with maternal-cousin transmission, not a founder-population or consanguinity-driven case.

Carrier frequency: Unknown/not established (n=1 family; variant not seen in population databases at publication).

Population demographics: No ethnic, geographic, or sex-ratio data beyond the single reported (presumably North American, given the reporting center) family; as an X-linked disorder, males are hemizygously affected while carrier females may show attenuated/subclinical hematologic markers, consistent with typical X-linked recessive dynamics, though formal female-carrier phenotyping data are limited to the two reported obligate-carrier mothers.

10. Diagnostics

Clinical/laboratory tests: - Complete blood count showing macrocytic, normochromic anemia with reticulocytopenia and normal white cell/platelet counts (classical DBA diagnostic criterion) - Bone marrow examination: normal cellularity with a selective paucity of erythroid precursors (classical DBA criterion) - Erythrocyte adenosine deaminase (eADA) activity: elevated — a well-validated DBA biomarker with ~84% sensitivity, ~95% specificity, and ~91% positive/negative predictive value versus other inherited bone-marrow-failure syndromes (PMID:23252420-class literature); used here to identify the biochemically-affected but non-anemic cousin - Fetal hemoglobin (HbF): elevated — supporting minor diagnostic criterion for DBA - Craniofacial imaging (CT temporal bone for ear/middle-ear anatomy; standard clinical craniofacial exam) to characterize microtia/atresia, micrognathia, midface hypoplasia

Genetic testing: - Given the phenotypic overlap between DBA and mandibulofacial dysostosis/Treacher Collins spectrum, the recommended approach is a combined ribosomal-protein-gene/ribosome-biogenesis-factor panel or exome sequencing including RPS19, RPL5, RPL11, RPS10, RPS17, RPS24, RPS26, RPL35A, RPS7, RPS29, RPL15, RPL26, TSR2, and RPS28, alongside classical mandibulofacial dysostosis genes (TCOF1, POLR1C, POLR1D, EFTUD2) when craniofacial features dominate — reflecting genetic heterogeneity of the combined phenotype (PMID:24942156 explicitly frames this as a diagnostic message: "DBA with mandibulofacial dysostosis is heterogeneous") - Single-gene TSR2 Sanger sequencing is reasonable when family history/segregation suggests X-linked inheritance - Chromosomal microarray/karyotype: not indicated as a primary test (this is a single-nucleotide missense disorder), but useful to exclude alternative structural causes of craniofacial anomaly + cytopenia phenotypes - Carrier/segregation testing recommended for at-risk maternal relatives in an identified family, given the demonstrated carrier (heterozygous, biochemically-detectable-but-non-anemic) phenotype pattern

Differential diagnosis: - Other DBA molecular subtypes with craniofacial features (RPS26/DBA10, RPS28/DBA15) - Treacher Collins syndrome (TCOF1, POLR1C, POLR1D) without hematologic involvement - Mandibulofacial dysostosis, Guion-Almeida type (EFTUD2), which includes microcephaly and esophageal atresia but not classically DBA-type anemia - Other inherited bone marrow failure syndromes (Fanconi anemia, Shwachman-Diamond syndrome) — excluded via eADA pattern, HbF pattern, and absence of the syndrome-specific features (radial ray defects, pancreatic insufficiency, etc.)

Screening: No population or newborn screening program exists for this ultra-rare entity; screening in practice is limited to cascade testing of at-risk relatives once a proband is identified.

11. Outcome/Prognosis

No dedicated survival, mortality, or long-term outcome data exist for TSR2-DBA14 specifically (n=1 family, longest follow-up to age 24). By extrapolation from general DBA outcome data (not TSR2-specific): - General DBA prognosis is favorable for the anemia itself with corticosteroid or transfusion management, but carries substantial treatment-related and disease-related long-term morbidity - General DBA carries a markedly elevated lifetime cancer risk: myelodysplastic syndrome (a "few hundred-fold" increased relative risk in registry data) and acute myeloid leukemia, plus solid tumors — notably early-onset colorectal/gastrointestinal carcinoma and osteosarcoma — with a cumulative malignancy risk approaching 20% by age 40 in DBA Registry data (ASH/Blood registry literature) - No TSR2-specific cancer-predisposition data exist; whether TSR2-DBA14 carries the same elevated malignancy risk as other DBA subtypes is an inferred extrapolation, not directly demonstrated, and should be flagged as such in any curated entry - Craniofacial and hearing outcomes follow the general trajectory for mandibulofacial dysostosis/Treacher-Collins-spectrum disease: static structural anomaly amenable to surgical/audiologic management, with functional hearing loss requiring amplification (hearing aids were used in the reported proband)

12. Treatment

No TSR2-DBA14-specific treatment trial or outcome data exist; management follows general DBA and general mandibulofacial dysostosis/craniofacial-anomaly paradigms.

Pharmacotherapy (hematologic): - Corticosteroids (e.g., prednisone) — first-line for DBA-associated anemia; the reported proband's anemia was explicitly steroid-responsive (PMID:24942156). NCIT term: NCIT:C15986 (Pharmacotherapy) with therapeutic_agent corticosteroid class (NCIT:C2322) - Chronic red blood cell transfusion with iron chelation for steroid-refractory/intolerant cases (general DBA management, not documented as needed in this specific family) - Danazol has been reported as an underutilized adjunct in general DBA management (PMC6636591-class literature) — not documented for this family specifically

Advanced therapeutics: - Allogeneic hematopoietic stem cell transplantation (HSCT) — potentially curative for the hematologic component in steroid-refractory general DBA, though associated with significant transplant-related morbidity/mortality; gene therapy approaches are in early clinical development for DBA broadly but have not been reported for TSR2-DBA14. NCIT: NCIT:C15431 (Hematopoietic Cell Transplantation)

Surgical/interventional (craniofacial): - Standard mandibulofacial dysostosis/craniofacial surgical management: ear reconstruction/atresia repair, orthognathic/mandibular distraction or reconstructive surgery for micrognathia, cleft palate repair (as needed in the cousin) — extrapolated from general Treacher Collins/MFD surgical management, not TSR2-DBA14-specific data. NCIT: NCIT:C15329 (Surgical Procedure), NCIT:C16186 (Orthopedic Surgical Procedure, if applicable to mandibular work)

Supportive/rehabilitative: - Hearing aids for conductive hearing loss (used by the reported proband) — NCIT device-qualifier pattern (NCIT:C15302 Physical Therapy is not applicable; consider audiologic amplification device via qualifiers pattern, since NCIT has no direct "hearing aid usage" clinical-action term) - Speech/language therapy for cleft-palate-associated speech impact (general MFD management, not documented specifically in this family) - Genetic counseling for the family (NCIT:C15240)

Experimental: No registered clinical trials specific to TSR2-DBA14 were identified. General DBA trials (e.g., sotatercept, trifluoperazine — both identified in general DBA trial searches, NCT01464164 and NCT03966053) are not gene-subtype-specific and their applicability to TSR2-mediated disease is untested.

13. Prevention

No primary prevention is possible for this monogenic disorder beyond genetic counseling and reproductive options (carrier testing of at-risk female relatives, prenatal diagnosis, or preimplantation genetic testing once a familial TSR2 variant is identified) — standard for any X-linked Mendelian disorder, not TSR2-DBA14-specific literature. Secondary prevention centers on early recognition of the biochemical DBA phenotype (as demonstrated in the non-anemic cousin, identified via eADA/HbF/MCV screening) in at-risk relatives, enabling monitoring for later-onset anemia and enrollment in cancer surveillance protocols recommended generally for DBA (given the cancer-predisposition profile of DBA broadly). Tertiary prevention follows general DBA cancer-surveillance guidance (colonoscopy and other age-appropriate screening given elevated colorectal cancer and MDS/AML risk in DBA registries), extrapolated rather than demonstrated for this gene.

14. Other Species / Natural Disease

No naturally occurring TSR2-mutant disease has been reported in non-human species (companion animals, livestock, or wildlife); no OMIA entry exists for this gene-disease combination. TSR2 orthologs are broadly conserved across eukaryotes (yeast Tsr2 through human TSR2), reflecting the essential, deeply conserved nature of the ribosome-maturation function itself (see Model Organisms below) rather than any documented spontaneous veterinary phenotype.

15. Model Organisms

Yeast (Saccharomyces cerevisiae) — functional/complementation model: The pathogenicity of the human TSR2 E64G variant was directly demonstrated using a yeast humanized/complementation system: yeast strains expressing human TSR2^E64G in place of endogenous Tsr2 showed strong growth impairment and defective 20S pre-rRNA processing (cytoplasmic ITS1 reporter accumulation), providing direct functional evidence that this variant impairs TSR2's role in ribosome maturation (PMID:24942156). This is a gain of mechanistic insight but not a whole-organism disease model — it establishes molecular loss-of-function, not organismal phenocopy of anemia/craniofacial malformation.

Yeast — structural/biochemical model of the Tsr2–Rps26 chaperone cycle: NMR structural and cross-linking mass-spectrometry work (PMID:30201955) defined the Tsr2–eS26(ESS) binding interface in molecular detail and directly showed the DBA-linked mutant is selectively impaired in this interaction; subsequent biochemical work (2021, e.g. the Tsr2–Rps26 release/reincorporation stress-response study) further elaborated Tsr2's dual role in RPS26 nuclear escort and in reversible RPS26 disassembly from mature 40S ribosomes under oxidative/pH stress. These are molecular/biochemical models (recombinant protein, in vitro reconstitution), not organismal models, and their translational fidelity to human craniofacial and hematopoietic development is inferential.

Mouse: Tsr2 has an annotated mouse ortholog (MGI:1916749), but no published Tsr2-mutant or Tsr2-knockout mouse model recapitulating DBA-like anemia or craniofacial malformation was identified in this search. This is a genuine translational gap — unlike TCOF1 (Treacher Collins) and several other DBA genes (e.g., Rps19, Rpl11 mouse/zebrafish models), no whole-organism model exists to test whether the E64G lesion (or Tsr2 haploinsufficiency generally) reproduces the combined erythroid-failure-plus-craniofacial phenotype in vivo. This should be recorded as a HUMAN_MODEL_MISMATCH/knowledge-gap class finding if curated into dismech: evidence for the mechanism exists at the molecular/biochemical (yeast, in vitro) level, but organismal fidelity to the human phenotype (particularly the craniofacial neural-crest component) is unconfirmed in any animal model.

Zebrafish: No TSR2-specific zebrafish model was identified in this search, in contrast to other ribosomopathy genes (e.g., rps19, rpl11 morphants/mutants used extensively to model DBA hematopoietic phenotypes and to study neural-crest/craniofacial ribosomopathy convergence in zebrafish more generally).

Summary of Key Citations

Claim	PMID/Source
Original description of the TSR2 E64G family, RPS28/DBA15 discovery, DBA+MFD heterogeneity	PMID:24942156 (Gripp et al., Am J Med Genet A, 2014; full text PMC4149220)
Molecular/structural basis of Tsr2–eS26(ESS) interaction; DBA-linked mutant impaired in ESS binding	PMID:30201955 (Nat Commun, 2018)
eADA diagnostic performance in DBA	PMID:23252420
DBA classical/supporting diagnostic criteria, general genetics/epidemiology	PMC6416817 (Diamond Blackfan Anemia: Genetics, Pathogenesis, Diagnosis and Treatment)
DBA cancer-predisposition/registry data (MDS, AML, colorectal cancer, osteosarcoma)	ASH/Blood registry literature (ashpublications.org/blood/article/128/22/333)
Nucleolar stress / p53 / ATF4 mechanism in DBA generally	PMID:21930148; PMC12096137
Treacher Collins/mandibulofacial dysostosis neural-crest apoptosis mechanism (general, not TSR2-specific)	PMID:807232; PMID:3474899

Explicit evidence-directness note: Beyond the single foundational case report (PMID:24942156) and the follow-up molecular-mechanism paper on the E64G–ESS interaction (PMID:30201955), essentially all mechanistic (nucleolar stress/p53/ATF4), craniofacial-neural-crest, cancer-predisposition, and treatment-outcome content in this report is extrapolated by analogy from the broader Diamond-Blackfan anemia and Treacher Collins/mandibulofacial dysostosis literatures rather than demonstrated specifically for TSR2-DBA14. Any curation into dismech should carry directness: INDIRECT on evidence items sourced from this general-DBA/general-MFD literature rather than from the two TSR2-specific primary papers, and should flag the absence of any animal model as a structural knowledge gap rather than silently assuming mechanistic parity with better-studied DBA genes.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	11
Resolved	11
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	11
On topic	5
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	51
Resolved	47
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	3
Terms whose name was checked	34
Terms named correctly	18
Terms named as a different term	5
Terms whose name is worth a second look	11

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

GO:0006974 (1 mention) - the report calls it "DNA damage response — for p53 axis, if used generically for nucleolar stress signaling"; GO calls it DNA damage response
UBERON:0000453 (1 mention) - the report calls it "jaw region"; UBERON calls it decidua basalis
UBERON:0001676 (1 mention) - the report calls it "mandible"; UBERON calls it occipital bone
UBERON:0001703 (1 mention) - the report calls it "upper jaw region/midface"; UBERON calls it neurocranium
UBERON:0000151 (1 mention) - the report calls it "pharyngeal arch"; UBERON calls it pectoral fin

Obsolete terms

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

GO:0008565 (obsolete protein transporter activity) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0011903 (1 mention) - the report calls it "Increased hemoglobin F"; HP calls it HbH hemoglobin, and lists "Hemoglobin H" among its other names
GO:0000462 (1 mention) - the report calls it "maturation of SSU-rRNA from tricistronic rRNA transcript"; GO calls it maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)
GO:0006446 (1 mention) - the report calls it "regulation of translational initiation — secondary"; GO calls it regulation of translational initiation
GO:0036503 (1 mention) - the report calls it "ERAD pathway — not applicable"; GO calls it ERAD pathway
GO:0043066 (1 mention) - the report calls it "negative regulation of apoptotic process — for the p53/MDM2 axis, inverted as appropriate"; GO calls it negative regulation of apoptotic process
GO:0008565 (1 mention) - the report calls it "protein transporter activity — for the importin-disassembly role"; GO calls it obsolete protein transporter activity
CL:0002321 (1 mention) - the report calls it "embryonic cell, cranial neural crest lineage"; CL calls it embryonic cell (metazoa)
UBERON:0001846 (2 mentions) - the report calls it "external auditory meatus"; UBERON calls it internal ear
UBERON:0002190 (1 mention) - the report calls it "subcutaneous adipose — not relevant"; UBERON calls it subcutaneous adipose tissue
NCIT:C16186 (1 mention) - the report calls it "Orthopedic Surgical Procedure, if applicable to mandibular work"; NCIT calls it Orthopedic Surgical Procedure
NCIT:C15240 (1 mention) - the report calls it "Genetic counseling for the family"; NCIT calls it Genetic Counseling

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.

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Classifications

Mappings

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Diamond-Blackfan Anemia 14 with Mandibulofacial Dysostosis (DBA14) — Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain (numbered, from lesion to phenotype)

Molecular pathways

Cellular processes

Protein dysfunction

Tissue damage mechanisms

Suggested ontology terms

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Key Citations

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look

Prefixes with no resolver