Thrombocytopenia-Absent Radius Syndrome

Mendelian MONDO:0010121 Pathograph 22 Show in embeddings browser hereditary disease

Thrombocytopenia-absent radius (TAR) syndrome is a congenital malformation syndrome that couples bilateral radial aplasia with a hypomegakaryocytic thrombocytopenia, and is defined clinically by the preservation of both thumbs. That last feature is the discriminator from the other syndromes pairing a radial ray defect with marrow failure, notably Fanconi anemia and radioulnar synostosis with amegakaryocytic thrombocytopenia, in which the thumbs are absent or hypoplastic. The cause is insufficiency of Y14, the RBM8A-encoded subunit of the exon junction complex. Nearly all patients are compound heterozygous for a rare null allele - usually a recurrent 200-kb microdeletion at 1q21.1, occasionally a truncating RBM8A variant - in trans with one of two common low-frequency non-coding SNPs in the RBM8A 5'UTR or first intron that reduce its transcription. Neither allele is sufficient alone: deletion carriers and individuals homozygous for the regulatory allele are healthy, so the disorder is a dosage threshold effect rather than simple haploinsufficiency. Thrombocytopenia is typically most severe in infancy and remits with age, while the skeletal defect is fixed at birth.

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1
Inheritance
5
Pathophys.
14
Phenotypes
2
Hypotheses
3
Gaps
22
Pathograph
1
Genes
2
Variants
5
Medical Actions
2
Differentials
2
Datasets
2
Trials
1
Models
1
References
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Formally autosomal recessive, but with a two-allele structure that makes the observed pedigrees look unlike a classic recessive disorder. Affected individuals carry a rare null allele in trans with a common low-frequency hypomorphic regulatory allele of RBM8A. Because null alleles are rare and often de novo while the hypomorphic allele is common in the population, the pedigree pattern shows few affected sibs, apparent parent-to-child transmission, and affected second- and third-degree relatives. Carriers of either allele alone, including individuals homozygous for the hypomorphic allele, are asymptomatic. Recurrence risk therefore depends on which alleles the parents carry rather than on a single figure: a quarter when one parent carries the null allele and the other a single hypomorphic allele, and a half when the hypomorph-carrying parent is homozygous for it. The naive "25% autosomal recessive" answer is right only in the first of those cases.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:20301781 SUPPORT Human Clinical
"TAR syndrome is caused by compound heterozygosity for a null allele and an RBM8A hypomorphic allele and is inherited in an autosomal recessive manner."
States the compound null-plus-hypomorph structure and its formal recessive classification.
PMID:20301781 SUPPORT Human Clinical
"a paucity of affected sibs, apparent parent-to-child transmission, and affected second- and third-degree relatives"
Records the pedigree features that depart from a textbook autosomal recessive disorder, which follow from the differing allele frequencies.
PMID:20301781 SUPPORT Human Clinical
"If one parent is known to be heterozygous for a null allele and the other parent is heterozygous for an RBM8A hypomorphic allele, each sib of an affected individual has at conception a 25% chance of being affected."
Gives the recurrence risk for the commonest parental genotype combination, which is the case where the textbook figure applies.
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Mechanistic Hypotheses

2
Quantitative dose effect on a shared Y14 threshold
y14_dose_effect ALTERNATIVE
Evidence balance 1 support
Total Y14 falls below one critical level, and the megakaryocytic and radial ray compartments are simply the tissues with the highest requirement, so they fail first. On this model the selectivity is a consequence of differing demand, not of differing regulation, and nothing about those tissues is special beyond needing more Y14.
Pathograph links
Exon Junction Complex Insufficiency -> Megakaryocyte Maturation Failure DIRECT The megakaryocytic lineage is among the compartments least able to tolerate the reduced complex activity, and patient marrow is depleted of megakaryocytes.
Exon Junction Complex Insufficiency -> Radial Ray Developmental Failure INDIRECT KNOWN INTERMEDIATES The forelimb skeletal programme is the second compartment affected, producing the radial defect that is fixed at birth. A developmental stage-dependent effect has been proposed, since Evi1, the repressor predicted to bind the 5'UTR minor allele, is transiently expressed in emerging limb buds.
Show evidence (1 reference)
PMID:22366785 SUPPORT Human Clinical
"This suggests that compound inheritance of a null allele together with the minor allele of one of the two regulatory SNPs brings Y14 levels below a critical threshold in certain tissues."
States the threshold formulation that this hypothesis group represents.
Lineage-dependent Y14 requirement
y14_lineage_dependence ALTERNATIVE
Evidence balance 1 support
The deficit is not uniform. The regulatory alleles lower expression only in particular lineages and developmental windows, so the affected tissues are the ones where the variant actually acts, not merely the ones that need most protein. Reporter activity fell in megakaryocytic and osteoblast lines but not in endothelial or HEK293 cells, and Evi1, the repressor predicted to bind the 5'UTR minor allele, is transiently expressed in emerging limb buds. This is the model the rs139428292 mLOE classification presupposes.
The two groups are recorded as ALTERNATIVE rather than one CANONICAL and one ALTERNATIVE because the source explicitly declines to choose between them, and they are not mutually exclusive: a lineage-restricted reduction could still act by crossing a shared threshold in the tissues where it applies.
Pathograph links
Exon Junction Complex Insufficiency -> Megakaryocyte Maturation Failure DIRECT The megakaryocytic lineage is among the compartments least able to tolerate the reduced complex activity, and patient marrow is depleted of megakaryocytes.
Exon Junction Complex Insufficiency -> Radial Ray Developmental Failure INDIRECT KNOWN INTERMEDIATES The forelimb skeletal programme is the second compartment affected, producing the radial defect that is fixed at birth. A developmental stage-dependent effect has been proposed, since Evi1, the repressor predicted to bind the 5'UTR minor allele, is transiently expressed in emerging limb buds.
Show evidence (1 reference)
PMID:22366785 SUPPORT In Vitro
"The minor alleles were associated with significantly lower luciferase activity in human megakaryocytic CHRF and DAMI cell lines and the murine osteoblast cell line MC3T3."
Cell-type-restricted reduction is what distinguishes this model from a uniform dose effect.
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Discussions and Knowledge Gaps

3
By what molecular mechanism do the RBM8A 5'UTR and first-intron minor alleles reduce Y14 protein abundance in patients?
KNOWLEDGE GAP OPEN rbm8a_regulatory_snp_mechanism
Attached to
pathophysiology#Reduced RBM8A Gene Dosage
The genetic association is settled and the protein deficit is measured in patient platelets, but the step between them is not established. Reporter assays show both minor alleles lower promoter activity in megakaryocytic and osteoblast lines, yet allele-specific expression in platelet RNA from healthy heterozygotes showed no difference between transcripts, so reduced transcription alone does not account for the observed protein reduction. The authors state the mechanism remains open and may differ between the two SNPs. This matters for curation because the causal edge from genotype to Y14 insufficiency is currently supported by correlation plus a partially contradicted transcriptional model.
Show evidence (1 reference)
PMID:22366785 SUPPORT In Vitro
"It therefore still leaves open the question of the exact mechanism by which the non-coding SNPs lead to the decreased protein expression observed in TAR cases."
The authors state the gap directly, immediately after reporting the negative allele-specific expression result.
Would thrombopoietin receptor agonists raise the platelet count in TAR syndrome, and is there any reason to expect them to?
KNOWLEDGE GAP OPEN tpo_receptor_agonists_untested_in_tar
Attached to
treatments# pathophysiology#Megakaryocyte Maturation Failure
TPO-receptor agonists have accumulated real experience across the inherited thrombocytopenias, but the reported diagnoses are Wiskott-Aldrich, MYH9- and ANKRD26-related disease; TAR is not among them. The question is not purely empirical, because TAR patients have been reported to have elevated endogenous TPO with impaired responsiveness rather than TPO deficiency, so agonist therapy is not obviously indicated by the mechanism. Recorded as a gap rather than as a treatment: nothing here supports offering a TPO-RA in TAR, and nothing rules it out.
Show evidence (1 reference)
PMID:33919295 SUPPORT Human Clinical
"The main diagnoses were Wiskott-Aldrich syndrome, MYH9-related disorder and ANKRD26-related thrombocytopenia."
A systematic review of TPO-RA use across inherited thrombocytopenias whose reported diagnoses do not include TAR, which is what establishes the gap.
Should TAR be treated as an inherited bone marrow failure syndrome, and does it carry a leukemia predisposition?
INTERPRETATION OPEN ibmfs_classification_and_malignancy_risk
Attached to
clinical_burden# phenotypes#Thrombocytopenia
TAR is conventionally listed among the inherited bone marrow failure syndromes and is enrolled as one by the NCI natural-history cohort recorded under clinical_trials, but the haematological behaviour fits that label poorly and the literature says so directly. The thrombocytopenia is lineage-restricted and remits with age rather than progressing to pancytopenia, which is the opposite of the course in Fanconi anemia or dyskeratosis congenita. Leukemia in TAR is at case-report level: a 2017 review counted four reported cases in the entire literature, and further single cases have appeared since, including Philadelphia-positive AML and juvenile myelomonocytic leukemia. Recorded as an interpretation rather than as a phenotype because the honest statement is a reported near-absence, and a handful of cases across a rare disease does not establish a predisposition. Curators should not infer a Fanconi-like surveillance requirement from the IBMFS label alone.
One of the two later case reports (PMID:41925074) describes its patient as having a homozygous RBM8A c.-21G>A variant rather than the compound null-plus-hypomorph genotype this entry models, and GeneReviews states that individuals with biallelic hypomorphic alleles are asymptomatic. Flagged rather than acted on: a single case report is not enough to revise the inheritance model, and the discrepancy could equally be a reporting simplification. Worth checking against the primary genotype data if anyone revisits the allelic spectrum, which PMID:37611607 says is still open.
Show evidence (4 references)
PMID:28259746 SUPPORT Human Clinical
"TAR syndrome is not generally associated with bone marrow failure or malignancy."
States directly that neither marrow failure nor malignancy is a general feature, which is the claim this interpretation rests on.
PMID:28259746 SUPPORT Human Clinical
"Only four cases of leukemia were reported in TAR patients in the literature: three acute myeloid leukemia (AML) and one acute lymphoblastic leukemia."
Quantifies the reported malignancy experience, which is what makes this case-report level rather than an established predisposition.
PMID:39393038 SUPPORT Human Clinical
"One BMFS that is rarely associated with leukemic transformation is the autosomal recessive thrombocytopenia-absent radius (TAR) syndrome."
A later single case, whose own framing is that leukemic transformation is rare in this disorder.
+ 1 more reference
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Pathophysiology

5
Reduced RBM8A Gene Dosage
A rare null allele on one chromosome - most often the recurrent 200-kb interstitial microdeletion of 1q21.1, less often a frameshift or nonsense variant in RBM8A - is inherited in trans with a low-frequency non-coding SNP in the RBM8A 5'UTR or first intron. The regulatory minor alleles sit in active regulatory elements and lower transcription from the remaining copy, so total RBM8A output falls below what either lesion produces on its own. Two such regulatory SNPs accounted for nearly all cases in the original series, but the allelic spectrum is not closed: further TAR-associated SNPs continue to be identified.
RBM8A hgnc:9905 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RBM8A (hgnc:9905). hgnc:9905 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Y14 Protein Insufficiency Lowered transcription from the non-deleted allele, with no output from the null allele, reduces the amount of Y14 protein produced.
Show evidence (4 references)
PMID:22366785 SUPPORT Human Clinical
"Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR."
Establishes the two-allele genetic architecture that sets the reduced dosage.
PMID:17236129 SUPPORT Human Clinical
"we describe a common interstitial microdeletion of 200 kb on chromosome 1q21.1 in all 30 investigated patients with TAR syndrome"
Identifies the recurrent null allele carried by the large majority of patients.
PMID:17236129 SUPPORT Human Clinical
"Our results indicate that TAR syndrome is associated with a microdeletion on 1q21.1 that is necessary but not sufficient to cause the phenotype."
Shows the deletion alone does not produce disease, which is what requires the second, regulatory allele.
+ 1 more reference
Y14 Protein Insufficiency
Y14 abundance falls below the level the most sensitive tissues require. What is settled is the negative claim: this is not plain haploinsufficiency. Carriers of the 1q21.1 deletion alone are healthy and the regulatory SNPs alone have no measurable effect on platelet count, so only the combination produces disease. Why that combination is pathogenic while either allele alone is tolerated is not settled, and the source describes its data as compatible with two models. Both are recorded under mechanistic_hypotheses rather than asserted here.
Animal models
Zebrafish rbm8a morpholino knockdown Zebrafish fails to recapitulate Demonstrates that Y14 is developmentally essential, but does not model the disease state. TAR is caused by a partial reduction in Y14 that leaves viable, largely healthy tissue outside the megakaryocytic and radial ray compartments; the morphant is a near-complete knockdown that is lethal within two days, producing global malformation rather than the selective TAR phenotype.
Downstream
Exon Junction Complex Insufficiency Y14 is an obligate core subunit of the exon junction complex, so reduced Y14 limits how much functional complex can be assembled.
Show evidence (2 references)
PMID:22366785 SUPPORT Human Clinical
"Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR syndrome."
States Y14 insufficiency as the proximate cause of the syndrome.
PMID:22366785 SUPPORT Human Clinical
"simple haploinsufficiency is not sufficient to create an aberrant phenotype as evidenced by the apparently healthy carriers of the 1q21.1 deletion"
Supports treating this node as a dosage threshold rather than haploinsufficiency, since one null allele alone is tolerated.
Exon Junction Complex Insufficiency
The exon junction complex is deposited on spliced mRNA and governs nuclear export, subcellular transcript localization, translational enhancement and nonsense-mediated decay. Reduced complex availability perturbs these post-transcriptional steps. TAR is the first human disorder attributed to deficiency of an EJC subunit, and the consequences are selective rather than global, falling hardest on megakaryopoiesis and on radial ray patterning.
Lineage-dependent Y14 requirement Quantitative dose effect on a shared Y14 threshold
nonsense-mediated mRNA decay GO:0000184 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased nonsense-mediated mRNA decay, annotated with nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:0000184). GO:0000184 is a biological process from the Gene Ontology. ↓ DECREASED
exon-exon junction complex GO:0035145 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves decreased exon-exon junction complex (GO:0035145). GO:0035145 is a cellular component from the Gene Ontology.
Downstream
Megakaryocyte Maturation Failure The megakaryocytic lineage is among the compartments least able to tolerate the reduced complex activity, and patient marrow is depleted of megakaryocytes. Quantitative dose effect on a shared Y14 threshold Lineage-dependent Y14 requirement
Radial Ray Developmental Failure The forelimb skeletal programme is the second compartment affected, producing the radial defect that is fixed at birth. A developmental stage-dependent effect has been proposed, since Evi1, the repressor predicted to bind the 5'UTR minor allele, is transiently expressed in emerging limb buds. Quantitative dose effect on a shared Y14 threshold Lineage-dependent Y14 requirement
Show evidence (1 reference)
PMID:22366785 SUPPORT Human Clinical
"Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR syndrome."
Attributes the disorder to an exon junction complex defect downstream of the Y14 deficit.
Megakaryocyte Maturation Failure
Bone marrow shows reduced or absent megakaryocytes, so platelet production is curtailed at its source. The defect is not fixed for life: platelet counts characteristically improve through childhood, which distinguishes the haematological course from the static skeletal defect.
megakaryocyte CL:0000556 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves megakaryocyte (CL:0000556). CL:0000556 is a cell type from the Cell Ontology.
megakaryocyte differentiation GO:0030219 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased megakaryocyte differentiation (GO:0030219). GO:0030219 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Megakaryocytopenia The maturation failure is visible on marrow examination as a reduced or absent megakaryocyte population, which is how the defect is identified as one of production rather than peripheral destruction.
Thrombocytopenia Fewer maturing megakaryocytes yield fewer circulating platelets, giving the hypomegakaryocytic thrombocytopenia that defines the disorder.
Show evidence (1 reference)
PMID:22366785 SUPPORT Human Clinical
"TAR cases have low numbers of megakaryocytes, the platelet precursor cells that reside in the bone-marrow"
Documents the reduced megakaryocyte population underlying this node.
Radial Ray Developmental Failure
Patterning of the radial ray fails bilaterally during limb development, giving absent radii. The failure is confined to the radius and spares the thumb, which is the anatomical signature separating TAR from the other radial ray syndromes with marrow involvement. Severity varies from isolated radial absence to near-total absence of the upper limbs, and lower limb, rib and vertebral anomalies may accompany it.
forelimb morphogenesis GO:0035136 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased forelimb morphogenesis (GO:0035136). GO:0035136 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Abnormality of the upper limb The same patterning failure extends beyond the radius, so severity runs from isolated radial absence to near-total absence of the upper limbs.
Bilateral radial aplasia Failure of radial ray patterning presents at birth as bilaterally absent radii.
Show evidence (1 reference)
PMID:22366785 SUPPORT Human Clinical
"with preservation of the thumb, which distinguishes TAR from other syndromes that combine blood abnormalities with absence of the radius, such as Fanconi anemia"
Establishes that the developmental failure spares the thumb, the feature that separates this node from the radial ray defect of Fanconi anemia.
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Pathograph

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

14
Blood 7
Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
clinical_course is deliberately absent. ClinicalCourseEnum offers only PROGRESSIVE and STABLE, and this thrombocytopenia is neither: it is typically worst in infancy and remits with age. Recording either value would misstate the natural history, so the course is described in prose and carried by the cited evidence instead.
Sequelae: Abnormal bleeding Petechiae
Show evidence (1 reference)
PMID:20301781 SUPPORT Human Clinical
"Thrombocytopenia may be congenital or may develop within the first few weeks to months of life; in general, thrombocytopenic episodes decrease with age."
Documents both the timing of onset and the tendency to remit, which is why the course is not modelled as static.
Megakaryocytopenia HP:0005548 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Megakaryocytopenia (HP:0005548). HP:0005548 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17236129 SUPPORT Human Clinical
"Thrombocytopenia-absent radius (TAR) syndrome is characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia in the presence of both thumbs."
Characterises the thrombocytopenia as hypomegakaryocytic.
Petechiae HP:0000967 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Petechiae (HP:0000967). HP:0000967 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301781 SUPPORT Human Clinical
"Platelet count when evidence of increased bleeding tendency (bruising, petechiae) occurs."
Identifies bruising and petechiae as the bleeding signs prompting platelet monitoring.
Abnormal bleeding HP:0001892 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal bleeding (HP:0001892). HP:0001892 is a phenotype from the Human Phenotype Ontology.
Sequelae: Gastrointestinal hemorrhage
Show evidence (2 references)
PMID:17236129 SUPPORT Human Clinical
"Patients with TAR syndrome typically present with petechiae and severe bleeding during the first years of life."
Establishes severe bleeding, beyond petechiae, as a typical presenting feature.
PMID:41925074 SUPPORT Human Clinical
"Mortality in TAR syndrome, mainly due to hemorrhage, is generally confined to the first year of life"
Identifies haemorrhage as the main cause of death and confines that risk to the first year, which is what makes this phenotype the driver of early management.
Increased total leukocyte count HP:0001974 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Periodic leukemoid reaction, annotated with Increased total leukocyte count (HP:0001974). HP:0001974 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:3056062 SUPPORT Human Clinical
"the characteristic hematological findings are hypomegakaryocytic thrombocytopenia, periodic leukemoid reactions, and eosinophilia"
A 100-case review listing periodic leukemoid reactions among the characteristic haematological findings.
Increased total eosinophil count HP:0001880 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased total eosinophil count (HP:0001880). HP:0001880 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:3056062 SUPPORT Human Clinical
"the characteristic hematological findings are hypomegakaryocytic thrombocytopenia, periodic leukemoid reactions, and eosinophilia"
The same review lists eosinophilia among the characteristic haematological findings.
Gastrointestinal hemorrhage HP:0002239 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastrointestinal hemorrhage (HP:0002239). HP:0002239 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36872795 SUPPORT Human Clinical
"An eight-day-old male infant born at 36 weeks gestation with a diagnosis of TAR, presented with bright red blood in his stool."
A TAR neonate presenting with frank gastrointestinal bleeding.
Cardiovascular 1
Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:12471199 SUPPORT Human Clinical
"All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies."
Reports cardiac anomalies in 15% of the cohort.
PMID:17236129 SUPPORT Human Clinical
"Other frequent associations are congenital heart disease and a high incidence of cow's milk intolerance."
Independently lists congenital heart disease among the frequent associations.
Genitourinary 2
Aplasia of the uterus HP:0000151 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplasia of the uterus (HP:0000151). HP:0000151 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301781 SUPPORT Human Clinical
"Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur."
Names agenesis of the uterus, cervix and upper vagina among the genitourinary features.
Abnormal renal morphology HP:0012210 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal renal morphology (HP:0012210). HP:0012210 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12471199 SUPPORT Human Clinical
"All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies."
Reports renal anomalies in 23% of the cohort.
Immune 1
Cow milk allergy FREQUENT HP:0100327 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cow milk allergy (HP:0100327). HP:0100327 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:12471199 SUPPORT Human Clinical
"All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies."
Quantifies cow's milk intolerance at 47% of a 34-patient cohort.
PMID:20301781 SUPPORT Human Clinical
"Cow's milk allergy is common and can be associated with exacerbation of thrombocytopenia."
Establishes the link between milk exposure and worsening of the platelet count.
Limbs 3
Bilateral radial aplasia HP:0004977 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral radial aplasia (HP:0004977). HP:0004977 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12471199 SUPPORT Human Clinical
"All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies."
All 34 patients in the cohort had bilateral radial aplasia, establishing it as an obligate feature.
Abnormality of the upper limb HP:0002817 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the upper limb (HP:0002817). HP:0002817 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301781 SUPPORT Human Clinical
"Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur."
Lists upper-limb skeletal anomalies among the additional features of the syndrome.
Abnormality of the lower limb FREQUENT HP:0002814 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the lower limb (HP:0002814). HP:0002814 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12471199 SUPPORT Human Clinical
"All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies."
Reports lower limb anomalies in 47% of the cohort.
🧬

Genetic Associations

1
RBM8A
Gene: RBM8A hgnc:9905 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RBM8A (hgnc:9905). hgnc:9905 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:22366785 SUPPORT Human Clinical
"Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR."
Identifies RBM8A as the causal gene and states the required allele combination.
🔬

Variants

2
RBM8A rs139428292
Gene: RBM8A hgnc:9905 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in RBM8A (hgnc:9905). hgnc:9905 is a gene from the HUGO Gene Nomenclature Committee. mLOE
The recurrent low-frequency non-coding RBM8A regulatory allele, reported in trans with the 1q21.1 microdeletion in molecularly characterized patients. Named here because the entry otherwise refers to the regulatory alleles only by their position in the 5'UTR or first intron. Classified mLOE rather than LOE because the expression loss is modular, not global: reporter activity fell in megakaryocytic and osteoblast lines but not in endothelial or HEK293 cells. That cell-type restriction is the same observation the entry uses to model the phenotype as tissue-selective. The caveat is that the evidence is reporter activity in cell lines rather than expression measured in primary megakaryocytes and limb bud, so "modular" is inferred from which lines responded. RBM8A itself is widely expressed, so a reviewer who judged the reduction to be global rather than cell-type restricted would classify this LOE instead.
Show evidence (2 references)
PMID:22366785 SUPPORT In Vitro
"The minor alleles were associated with significantly lower luciferase activity in human megakaryocytic CHRF and DAMI cell lines and the murine osteoblast cell line MC3T3."
Shows reduced expression confined to megakaryocytic and osteoblast contexts, which is what makes this modular rather than global.
PMID:24053387 SUPPORT Human Clinical
"Molecular studies demonstrated compound heterozygosity for the 1q21.1 microdeletion and the RBM8A rs139428292 variant at the hemizygous state, inherited from the mother and father, respectively"
Names the specific hypomorphic allele and confirms biparental inheritance of the two lesions.
RBM8A rs201779890
Gene: RBM8A hgnc:9905 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in RBM8A (hgnc:9905). hgnc:9905 is a gene from the HUGO Gene Nomenclature Committee. mLOE
The second recurrent hypomorphic regulatory allele, in intron 1 of RBM8A. Together with the 5'UTR allele rs139428292 it accounted for nearly all cases in the founding series, though the allelic spectrum is not closed.
Show evidence (1 reference)
PMID:24053387 SUPPORT Human Clinical
"Genotyping of rs139428292 (G>A) and rs201779890"
Names both recurrent hypomorphic alleles and their nucleotide changes.
🗃️

External Assertions

2
OMIM thrombocytopenia-absent radius syndrome record
OMIM disease record OMIM:274000
OMIM entry for TAR syndrome, cross-referenced by MONDO:0010121.
Orphanet thrombocytopenia-absent radius syndrome record
Orphanet disease record ORPHA:3320
Orphanet entry for TAR syndrome, cross-referenced by MONDO:0010121. Not quoted as evidence here because this disorder is not among the Orphanet records currently present in references_cache/.
💊

Medical Actions

5
Platelet Transfusion
Action: Platelet TransfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Platelet Transfusion (NCIT:C15366). NCIT:C15366 is a clinical intervention from the NCI Thesaurus. NCIT:C15366
Platform: Other
Platelet transfusion supports the thrombocytopenia during the high-risk infant period and around procedures. Because counts improve with age, transfusion is deliberately restricted in older individuals once the count exceeds a threshold, to limit alloimmunization and transfusion-transmitted infection.
Mechanism Target:
Thrombocytopenia — Replaces circulating platelets that the marrow cannot produce, without correcting the underlying megakaryocyte defect.
Show evidence (1 reference)
PMID:20301781 SUPPORT Human Clinical
"Platelet transfusion for thrombocytopenia as needed"
Supports transfusion acting on the thrombocytopenia itself rather than on its cause.
Show evidence (1 reference)
PMID:20301781 SUPPORT Human Clinical
"Platelet transfusion for thrombocytopenia as needed"
Names platelet transfusion as the management of the thrombocytopenia.
In Utero Platelet Transfusion
Action: Platelet TransfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Platelet Transfusion (NCIT:C15366). NCIT:C15366 is a clinical intervention from the NCI Thesaurus. NCIT:C15366
Platform: Other
Where TAR is recognised antenatally and severe fetal thrombocytopenia is confirmed by cordocentesis, platelets can be transfused into the umbilical vein before delivery. The aim is peripartum haemostasis at the point of greatest bleeding risk, not correction of the underlying defect. This is reported experience from case management rather than trial evidence.
Mechanism Target:
Thrombocytopenia — Raises the fetal platelet count across delivery, when intracranial and other internal bleeding risk is highest.
Show evidence (1 reference)
PMID:7845901 SUPPORT Human Clinical
"Apheresis platelets were transfused into the umbilical vein to correct the thrombocytopenia and was followed by an uncomplicated delivery."
Describes the intervention acting directly on the fetal platelet count.
Show evidence (1 reference)
PMID:7845901 SUPPORT Human Clinical
"We conclude that TAR syndrome can be readily identified prenatally on sonogram, and if severe thrombocytopenia is confirmed by cordocentesis, platelets should be transfused to diminish the risk of serious internal bleeding during and immediately after delivery."
States the antenatal pathway and the recommendation to transfuse before delivery when severe thrombocytopenia is confirmed.
Cow's Milk Avoidance
Action: Dietary InterventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Dietary Intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. NCIT:C15447
Platform: Behavioral / lifestyle
Dietary exclusion of cow's milk. In this disorder it serves two purposes at once: it reduces the severity of the gastroenteritis, and it avoids exacerbations of the thrombocytopenia that milk exposure can precipitate.
Mechanism Target:
Cow milk allergy — Removes the antigenic exposure driving the gastrointestinal manifestations.
Show evidence (1 reference)
PMID:20301781 SUPPORT Human Clinical
"Avoidance of cow's milk to reduce the severity of gastroenteritis and to avoid exacerbations of thrombocytopenia."
States that avoidance acts on the gastrointestinal manifestation, and additionally on the thrombocytopenia it can exacerbate.
Show evidence (1 reference)
PMID:20301781 SUPPORT Human Clinical
"Avoidance of cow's milk to reduce the severity of gastroenteritis and to avoid exacerbations of thrombocytopenia."
States both the gastrointestinal and the haematological rationale for avoidance.
Avoidance of Antiplatelet Drugs
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Behavioral / lifestyle
NSAIDs and aspirin are avoided or used with caution. The rationale is not only the low platelet count: platelet function is itself somewhat impaired in this disorder, so an antiplatelet agent compounds a qualitative defect on top of a quantitative one. This matters most in infancy, when bleeding risk is highest, but the platelet functional defect does not resolve with the count.
Mechanism Target:
Abnormal bleeding — Removes an iatrogenic contribution to bleeding risk in a patient whose platelets are both few and functionally impaired.
Show evidence (1 reference)
PMID:20301781 SUPPORT Human Clinical
"Platelet function is somewhat impaired, suggesting that drugs such as nonsteroidal anti-inflammatory drugs or aspirin should be avoided or used with caution."
States both the impaired platelet function and the avoidance recommendation that follows from it.
Show evidence (1 reference)
PMID:20301781 SUPPORT Human Clinical
"Platelet function is somewhat impaired, suggesting that drugs such as nonsteroidal anti-inflammatory drugs or aspirin should be avoided or used with caution."
The management recommendation to avoid or limit NSAIDs and aspirin.
Orthopedic Intervention
Action: Orthopedic Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Orthopedic Surgical Procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. NCIT:C16186
Platform: Surgery
Orthopedic and reconstructive management of the upper limb deformity, directed at maximizing function rather than at correcting the underlying developmental defect. The preserved thumbs are functionally important and inform surgical planning.
Mechanism Target:
Bilateral radial aplasia — Addresses the functional consequences of the fixed skeletal defect.
Show evidence (1 reference)
PMID:20301781 SUPPORT Human Clinical
"Orthopedic intervention as needed to maximize limb function."
Supports the intervention targeting limb function rather than correcting the developmental defect.
Show evidence (1 reference)
PMID:20301781 SUPPORT Human Clinical
"Orthopedic intervention as needed to maximize limb function."
States the goal of orthopedic management in this disorder.
🔬

Diagnosis

4
Prenatal ultrasound detection of bilateral radial aplasia
Bilateral absence of the radii is visible on routine second-trimester ultrasound, and with the thumbs intact it is suggestive enough to prompt targeted work-up. Recognition antenatally is what opens the door to cordocentesis and, where indicated, in utero transfusion.
Show evidence (1 reference)
PMID:24053387 SUPPORT Human Clinical
"The fetus had bilateral radial agenesis and humeral hypo/aplasia with intact thumbs, micrognathia and urinary anomalies"
Records the sonographic presentation, including the intact thumbs that point to TAR rather than to a thumb-absent radial ray syndrome.
Preserved thumbs on examination of the hand
Both thumbs are present despite bilateral radial aplasia. This dissociation is the key bedside discriminator from the other radial ray syndromes with haematological involvement, in which the thumb is absent or hypoplastic, and it is part of the clinical diagnostic triad. Recorded here as a diagnostic criterion rather than as a phenotype: a present, normally formed thumb is a normal finding, and HPO, being an ontology of phenotypic abnormalities, has no term for one. Its significance in TAR is entirely differential.
Show evidence (2 references)
PMID:22366785 SUPPORT Human Clinical
"with preservation of the thumb, which distinguishes TAR from other syndromes that combine blood abnormalities with absence of the radius, such as Fanconi anemia"
States the finding and its discriminating value against Fanconi anemia.
PMID:20301781 SUPPORT Human Clinical
"The diagnosis of TAR syndrome is established in a proband with bilateral absent radii, present thumbs, and thrombocytopenia."
Places present thumbs in the clinical triad that establishes the diagnosis.
Cordocentesis platelet count
Fetal blood sampling confirms the thrombocytopenia and establishes whether it is severe enough to justify transfusion before delivery.
Show evidence (1 reference)
PMID:7845901 SUPPORT Human Clinical
"At 37 weeks of pregnancy, a CBC obtained by cordocentesis under ultrasound guidance confirmed the diagnosis of thrombocytopenia absent radii (TAR) syndrome."
Describes cordocentesis as the step that confirmed the diagnosis antenatally.
Molecular confirmation of the two RBM8A alleles
Diagnosis is confirmed by finding a null allele, usually the 1q21.1 microdeletion, together with an RBM8A hypomorphic allele in trans. Testing for only one of the two is not sufficient, because carriers of either alone are healthy.
Show evidence (1 reference)
PMID:20301781 SUPPORT Human Clinical
"Identification of a heterozygous null allele (most often a minimally deleted 200-kb region including RBM8A at chromosome band 1q21.1) in a compound heterozygous state with a heterozygous RBM8A hypomorphic allele on molecular genetic testing confirms the diagnosis."
States the two-allele finding that constitutes molecular confirmation.
📊

Prevalence

1
Worldwide
Birth Prevalence 0.5 per 100,000 1–9 per 1,000,000 (births)
Reported as approximately one in 200,000 live births, normalized here to 0.5 per 100,000.
Show evidence (1 reference)
PMID:36872795 SUPPORT Human Clinical
"Thrombocytopenia absent radius (TAR) syndrome is a rare disease with an estimated prevalence of one in 200,000 live births."
Source of the birth prevalence estimate recorded here.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Thrombocytopenia-Absent Radius Syndrome:

Fanconi anemia MONDO:0019391
Overlapping Features The principal differential, since both combine a radial ray defect with marrow failure.
Distinguishing Features
  • The thumbs are the discriminator. In TAR the radii are absent but both thumbs are present; in Fanconi anemia a radial defect is accompanied by an absent or hypoplastic thumb.
  • The haematology also diverges: TAR causes an isolated thrombocytopenia that improves with age, whereas Fanconi anemia causes progressive pancytopenia with a substantial risk of clonal evolution.
Show evidence (1 reference)
PMID:22366785 SUPPORT Human Clinical
"with preservation of the thumb, which distinguishes TAR from other syndromes that combine blood abnormalities with absence of the radius, such as Fanconi anemia"
Explicitly names Fanconi anemia as the syndrome that thumb preservation distinguishes TAR from.
Radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome MONDO:0011555
Overlapping Features A second forearm-plus-thrombocytopenia syndrome that enters the neonatal differential.
Distinguishing Features
  • The forearm lesion is a proximal radio-ulnar synostosis rather than radial aplasia.
  • The thrombocytopenia is amegakaryocytic and progresses toward marrow failure rather than remitting with age.
Show evidence (1 reference)
PMID:26581901 SUPPORT Human Clinical
"Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) is an inherited bone marrow failure syndrome, characterized by thrombocytopenia and congenital fusion of the radius and ulna."
Establishes the forearm lesion and marrow phenotype that distinguish RUSAT from the radial aplasia of TAR.
📊

Related Datasets

2
Array CGH in TAR syndrome geo:GSE5781
human MICROARRAY n=4
PMID:17236129
The array CGH series deposited by the study that identified the recurrent 200-kb 1q21.1 microdeletion, and therefore the primary data behind the null allele modelled in this entry. Triaged as DIRECT: the disease is named in the series title and the material is human patient DNA.
Prenatal phenotypes and pregnancy outcomes of fetuses with recurrent 1q21.1 microdeletions and microduplications geo:GSE240611
human MICROARRAY n=26
PMID:37692779
Prenatal cohort of recurrent 1q21.1 copy-number changes, which names TAR among the associated phenotypes. Relevant to the null allele rather than to TAR specifically, since the cohort is ascertained on the CNV and includes duplications and unaffected outcomes; use for deletion-level context, not as a TAR case series.
🔬

Clinical Trials

2
NCT00027274 NOT_APPLICABLE RECRUITING
NCI natural-history cohort of inherited bone marrow failure syndromes, studying cancer rates and types. TAR is one of the enrolled IBMFS, so this is the main organized source of long-term malignancy-risk data for the disorder. Enrollment reflects the conventional nosological grouping and should not be read as evidence of a leukemia predisposition; see the ibmfs_classification_and_malignancy_risk discussion.
Show evidence (1 reference)
clinicaltrials:NCT00027274 SUPPORT Human Clinical
"Thrombocytopenia absent radii: absent radii; early onset thrombocytopenia"
The trial record lists thrombocytopenia absent radii among the inherited bone marrow failure syndromes it enrolls.
NCT00086476 NOT_APPLICABLE COMPLETED
NHGRI study culturing megakaryocytes from CD34+ marrow cells of patients with platelet granule and vesicle disorders, TAR among them, to characterize megakaryocytopoiesis directly.
Target Phenotypes: Megakaryocytopenia HP:0005548 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Megakaryocytopenia (HP:0005548). HP:0005548 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT00086476 SUPPORT Human Clinical
"Other diseases associated with variable defects in platelet gamma-granules include Chediak-Higashi, Griscelli, Wiskott-Aldrich, and Thrombocytopenia Absent Radius syndromes."
Names TAR among the disorders whose megakaryocytes this protocol cultures and characterizes.
🐁

Animal Models

1
Zebrafish rbm8a morpholino knockdown
Antisense morpholino knockdown of the zebrafish rbm8a orthologue, used to establish that Y14 is essential in vertebrate development.
Species
Zebrafish
Genotype
rbm8a antisense morpholino knockdown
Publication
PMID:22366785
Pathograph links
Y14 Protein Insufficiency fails to recapitulate fidelity: low Demonstrates that Y14 is developmentally essential, but does not model the disease state. TAR is caused by a partial reduction in Y14 that leaves viable, largely healthy tissue outside the megakaryocytic and radial ray compartments; the morphant is a near-complete knockdown that is lethal within two days, producing global malformation rather than the selective TAR phenotype.
Limitations: Morpholino knockdown is transient and its severity is not titrated to the partial dosage reduction seen in patients, so the model cannot reproduce the tissue-selective, threshold-dependent nature of the human disorder. Lethality at two days post fertilization also precludes assessment of the limb and haematopoietic phenotypes of interest.
Show evidence (1 reference)
PMID:22366785 SUPPORT Model Organism
"knock-down of the orthologous rbm8a transcript in Danio rerio by antisense morpholinos resulted in extreme malformations and death two days post fertilization"
Reports the lethal, globally malformed phenotype that departs from the selective human presentation.
Show evidence (1 reference)
PMID:22366785 SUPPORT Model Organism
"knock-down of the orthologous rbm8a transcript in Danio rerio by antisense morpholinos resulted in extreme malformations and death two days post fertilization"
Attests that the model exists and was used in the defining study, a separate claim from whether it is informative for any given node.
{ }

Source YAML

click to show 
name: Thrombocytopenia-Absent Radius Syndrome
creation_date: "2026-09-01T00:00:00Z"
category: Mendelian
description: >-
  Thrombocytopenia-absent radius (TAR) syndrome is a congenital malformation
  syndrome that couples bilateral radial aplasia with a hypomegakaryocytic
  thrombocytopenia, and is defined clinically by the preservation of both
  thumbs. That last feature is the discriminator from the other syndromes
  pairing a radial ray defect with marrow failure, notably Fanconi anemia and
  radioulnar synostosis with amegakaryocytic thrombocytopenia, in which the
  thumbs are absent or hypoplastic. The cause is insufficiency of Y14, the
  RBM8A-encoded subunit of the exon junction complex. Nearly all patients are
  compound heterozygous for a rare null allele - usually a recurrent 200-kb
  microdeletion at 1q21.1, occasionally a truncating RBM8A variant - in trans
  with one of two common low-frequency non-coding SNPs in the RBM8A 5'UTR or
  first intron that reduce its transcription. Neither allele is sufficient
  alone: deletion carriers and individuals homozygous for the regulatory allele
  are healthy, so the disorder is a dosage threshold effect rather than simple
  haploinsufficiency. Thrombocytopenia is typically most severe in infancy and
  remits with age, while the skeletal defect is fixed at birth.
disease_term:
  preferred_term: thrombocytopenia-absent radius syndrome
  term:
    id: MONDO:0010121
    label: thrombocytopenia-absent radius syndrome
parents:
- hereditary disease
references:
- reference: PMID:20301781
  title: Thrombocytopenia Absent Radius Syndrome.
  tags:
  - GeneReviews
synonyms:
- TAR syndrome
- TAR
- thrombocytopenia with absent radii syndrome
- radial aplasia-thrombocytopenia syndrome
- absent radii and thrombocytopenia
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Formally autosomal recessive, but with a two-allele structure that makes the
    observed pedigrees look unlike a classic recessive disorder. Affected
    individuals carry a rare null allele in trans with a common low-frequency
    hypomorphic regulatory allele of RBM8A. Because null alleles are rare and
    often de novo while the hypomorphic allele is common in the population, the
    pedigree pattern shows few affected sibs, apparent parent-to-child
    transmission, and affected second- and third-degree relatives. Carriers of
    either allele alone, including individuals homozygous for the hypomorphic
    allele, are asymptomatic. Recurrence risk therefore depends on which alleles
    the parents carry rather than on a single figure: a quarter when one parent
    carries the null allele and the other a single hypomorphic allele, and a half
    when the hypomorph-carrying parent is homozygous for it. The naive "25%
    autosomal recessive" answer is right only in the first of those cases.
  evidence:
  - reference: PMID:20301781
    reference_title: Thrombocytopenia Absent Radius Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TAR syndrome is caused by compound heterozygosity for a null allele and an RBM8A hypomorphic allele and is inherited in an autosomal recessive manner.
    explanation: >-
      States the compound null-plus-hypomorph structure and its formal recessive
      classification.
  - reference: PMID:20301781
    reference_title: Thrombocytopenia Absent Radius Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a paucity of affected sibs, apparent parent-to-child transmission, and affected second- and third-degree relatives
    explanation: >-
      Records the pedigree features that depart from a textbook autosomal
      recessive disorder, which follow from the differing allele frequencies.
  - reference: PMID:20301781
    reference_title: Thrombocytopenia Absent Radius Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      If one parent is known to be heterozygous for a null allele and the other parent is heterozygous for an RBM8A hypomorphic allele, each sib of an affected individual has at conception a 25% chance of being affected.
    explanation: >-
      Gives the recurrence risk for the commonest parental genotype
      combination, which is the case where the textbook figure applies.
pathophysiology:
- name: Reduced RBM8A Gene Dosage
  biological_scale: MOLECULAR
  description: >-
    A rare null allele on one chromosome - most often the recurrent 200-kb
    interstitial microdeletion of 1q21.1, less often a frameshift or nonsense
    variant in RBM8A - is inherited in trans with a low-frequency non-coding
    SNP in the RBM8A 5'UTR or first intron. The regulatory minor alleles sit in
    active regulatory elements and lower transcription from the remaining copy,
    so total RBM8A output falls below what either lesion produces on its own.
    Two such regulatory SNPs accounted for nearly all cases in the original
    series, but the allelic spectrum is not closed: further TAR-associated SNPs
    continue to be identified.
  genes:
  - preferred_term: RBM8A
    term:
      id: hgnc:9905
      label: RBM8A
  evidence:
  - reference: PMID:22366785
    reference_title: >-
      Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR.
    explanation: >-
      Establishes the two-allele genetic architecture that sets the reduced
      dosage.
  - reference: PMID:17236129
    reference_title: >-
      Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we describe a common interstitial microdeletion of 200 kb on chromosome 1q21.1 in all 30 investigated patients with TAR syndrome
    explanation: >-
      Identifies the recurrent null allele carried by the large majority of
      patients.
  - reference: PMID:17236129
    reference_title: >-
      Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results indicate that TAR syndrome is associated with a microdeletion on 1q21.1 that is necessary but not sufficient to cause the phenotype.
    explanation: >-
      Shows the deletion alone does not produce disease, which is what requires
      the second, regulatory allele.
  - reference: PMID:37611607
    reference_title: >-
      Thrombocytopenia Absent Radius (TAR)-Syndrome: From Current Genetics to Patient Self-Empowerment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      further SNPs associated with TAR syndrome are still being identified
    explanation: >-
      Establishes that the regulatory allelic spectrum is still open, which is
      why this node is not written as a closed two-SNP model.
  downstream:
  - target: Y14 Protein Insufficiency
    description: >-
      Lowered transcription from the non-deleted allele, with no output from the
      null allele, reduces the amount of Y14 protein produced.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22366785
      reference_title: >-
        Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the two regulatory SNPs result in diminished RBM8A transcription in vitro
      explanation: >-
        Reporter work linking the regulatory alleles to reduced transcription.
    - reference: PMID:22366785
      reference_title: >-
        Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Y14 expression is reduced in platelets from individuals with TAR
      explanation: >-
        The corresponding protein deficit measured in material from patients, a
        separate observation from the reporter work above.
- name: Y14 Protein Insufficiency
  biological_scale: MOLECULAR
  description: >-
    Y14 abundance falls below the level the most sensitive tissues require.
    What is settled is the negative claim: this is not plain haploinsufficiency.
    Carriers of the 1q21.1 deletion alone are healthy and the regulatory SNPs
    alone have no measurable effect on platelet count, so only the combination
    produces disease. Why that combination is pathogenic while either allele
    alone is tolerated is not settled, and the source describes its data as
    compatible with two models. Both are recorded under mechanistic_hypotheses
    rather than asserted here.
  evidence:
  - reference: PMID:22366785
    reference_title: >-
      Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR syndrome.
    explanation: >-
      States Y14 insufficiency as the proximate cause of the syndrome.
  - reference: PMID:22366785
    reference_title: >-
      Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      simple haploinsufficiency is not sufficient to create an aberrant phenotype as evidenced by the apparently healthy carriers of the 1q21.1 deletion
    explanation: >-
      Supports treating this node as a dosage threshold rather than
      haploinsufficiency, since one null allele alone is tolerated.
  downstream:
  - target: Exon Junction Complex Insufficiency
    description: >-
      Y14 is an obligate core subunit of the exon junction complex, so reduced
      Y14 limits how much functional complex can be assembled.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22366785
      reference_title: >-
        Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Y14 is one of the four components of the exon junction splicing complex (EJC), which is involved in basic cellular functions such as nuclear export and subcellular localization of specific transcripts
      explanation: >-
        Identifies Y14 as one of the four core EJC subunits, which is why its
        insufficiency constrains complex function.
- name: Exon Junction Complex Insufficiency
  biological_scale: MOLECULAR
  description: >-
    The exon junction complex is deposited on spliced mRNA and governs nuclear
    export, subcellular transcript localization, translational enhancement and
    nonsense-mediated decay. Reduced complex availability perturbs these
    post-transcriptional steps. TAR is the first human disorder attributed to
    deficiency of an EJC subunit, and the consequences are selective rather than
    global, falling hardest on megakaryopoiesis and on radial ray patterning.
  biological_processes:
  - preferred_term: nonsense-mediated mRNA decay
    term:
      id: GO:0000184
      label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    modifier: DECREASED
  cellular_components:
  - preferred_term: exon-exon junction complex
    term:
      id: GO:0035145
      label: exon-exon junction complex
    modifier: DECREASED
  evidence:
  - reference: PMID:22366785
    reference_title: >-
      Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR syndrome.
    explanation: >-
      Attributes the disorder to an exon junction complex defect downstream of
      the Y14 deficit.
  downstream:
  - target: Megakaryocyte Maturation Failure
    hypothesis_groups:
    - y14_dose_effect
    - y14_lineage_dependence
    description: >-
      The megakaryocytic lineage is among the compartments least able to
      tolerate the reduced complex activity, and patient marrow is depleted of
      megakaryocytes.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22366785
      reference_title: >-
        Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        TAR cases have low numbers of megakaryocytes, the platelet precursor cells that reside in the bone-marrow
      explanation: >-
        Establishes the megakaryocyte deficit in patients as the cellular
        consequence in the haematopoietic arm.
  - target: Radial Ray Developmental Failure
    hypothesis_groups:
    - y14_dose_effect
    - y14_lineage_dependence
    description: >-
      The forelimb skeletal programme is the second compartment affected,
      producing the radial defect that is fixed at birth. A developmental
      stage-dependent effect has been proposed, since Evi1, the repressor
      predicted to bind the 5'UTR minor allele, is transiently expressed in
      emerging limb buds.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17236129
      reference_title: >-
        Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thrombocytopenia-absent radius (TAR) syndrome is characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia in the presence of both thumbs.
      explanation: >-
        Establishes the radial aplasia as a defining consequence alongside the
        marrow phenotype.
- name: Megakaryocyte Maturation Failure
  biological_scale: CELLULAR
  description: >-
    Bone marrow shows reduced or absent megakaryocytes, so platelet production
    is curtailed at its source. The defect is not fixed for life: platelet
    counts characteristically improve through childhood, which distinguishes the
    haematological course from the static skeletal defect.
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  biological_processes:
  - preferred_term: megakaryocyte differentiation
    term:
      id: GO:0030219
      label: megakaryocyte differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:22366785
    reference_title: >-
      Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TAR cases have low numbers of megakaryocytes, the platelet precursor cells that reside in the bone-marrow
    explanation: >-
      Documents the reduced megakaryocyte population underlying this node.
  downstream:
  - target: Megakaryocytopenia
    description: >-
      The maturation failure is visible on marrow examination as a reduced or
      absent megakaryocyte population, which is how the defect is identified as
      one of production rather than peripheral destruction.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22366785
      reference_title: >-
        Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        TAR cases have low numbers of megakaryocytes, the platelet precursor cells that reside in the bone-marrow
      explanation: >-
        Reports the reduced marrow megakaryocyte population that this node
        manifests as.
  - target: Thrombocytopenia
    description: >-
      Fewer maturing megakaryocytes yield fewer circulating platelets, giving
      the hypomegakaryocytic thrombocytopenia that defines the disorder.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17236129
      reference_title: >-
        Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thrombocytopenia-absent radius (TAR) syndrome is characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia in the presence of both thumbs.
      explanation: >-
        Names the thrombocytopenia as hypomegakaryocytic, tying the platelet
        deficit to the marrow precursor deficit.
- name: Radial Ray Developmental Failure
  biological_scale: TISSUE
  description: >-
    Patterning of the radial ray fails bilaterally during limb development,
    giving absent radii. The failure is confined to the radius and spares the
    thumb, which is the anatomical signature separating TAR from the other
    radial ray syndromes with marrow involvement. Severity varies from isolated
    radial absence to near-total absence of the upper limbs, and lower limb,
    rib and vertebral anomalies may accompany it.
  biological_processes:
  - preferred_term: forelimb morphogenesis
    term:
      id: GO:0035136
      label: forelimb morphogenesis
    modifier: DECREASED
  evidence:
  - reference: PMID:22366785
    reference_title: >-
      Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with preservation of the thumb, which distinguishes TAR from other syndromes that combine blood abnormalities with absence of the radius, such as Fanconi anemia
    explanation: >-
      Establishes that the developmental failure spares the thumb, the feature
      that separates this node from the radial ray defect of Fanconi anemia.
  downstream:
  - target: Abnormality of the upper limb
    description: >-
      The same patterning failure extends beyond the radius, so severity runs
      from isolated radial absence to near-total absence of the upper limbs.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22366785
      reference_title: >-
        Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The severity of skeletal abnormalities varies from absence of radii to virtual absence of upper limbs with or without lower limb defects, such as malformations of the hip and knee
      explanation: >-
        Places the wider upper-limb involvement on the same severity spectrum as
        the radial defect.
  - target: Bilateral radial aplasia
    description: >-
      Failure of radial ray patterning presents at birth as bilaterally absent
      radii.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301781
      reference_title: Thrombocytopenia Absent Radius Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs, and thrombocytopenia that is generally transient.
      explanation: >-
        Confirms bilateral radial absence as the presenting skeletal
        manifestation.
mechanistic_hypotheses:
- hypothesis_group_id: y14_dose_effect
  hypothesis_label: Quantitative dose effect on a shared Y14 threshold
  status: ALTERNATIVE
  description: >-
    Total Y14 falls below one critical level, and the megakaryocytic and radial
    ray compartments are simply the tissues with the highest requirement, so they
    fail first. On this model the selectivity is a consequence of differing
    demand, not of differing regulation, and nothing about those tissues is
    special beyond needing more Y14.
  evidence:
  - reference: PMID:22366785
    reference_title: >-
      Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This suggests that compound inheritance of a null allele together with the minor allele of one of the two regulatory SNPs brings Y14 levels below a critical threshold in certain tissues.
    explanation: >-
      States the threshold formulation that this hypothesis group represents.
- hypothesis_group_id: y14_lineage_dependence
  hypothesis_label: Lineage-dependent Y14 requirement
  status: ALTERNATIVE
  description: >-
    The deficit is not uniform. The regulatory alleles lower expression only in
    particular lineages and developmental windows, so the affected tissues are
    the ones where the variant actually acts, not merely the ones that need most
    protein. Reporter activity fell in megakaryocytic and osteoblast lines but
    not in endothelial or HEK293 cells, and Evi1, the repressor predicted to bind
    the 5'UTR minor allele, is transiently expressed in emerging limb buds. This
    is the model the rs139428292 mLOE classification presupposes.
  evidence:
  - reference: PMID:22366785
    reference_title: >-
      Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The minor alleles were associated with significantly lower luciferase activity in human megakaryocytic CHRF and DAMI cell lines and the murine osteoblast cell line MC3T3.
    explanation: >-
      Cell-type-restricted reduction is what distinguishes this model from a
      uniform dose effect.
  notes: >-
    The two groups are recorded as ALTERNATIVE rather than one CANONICAL and one
    ALTERNATIVE because the source explicitly declines to choose between them,
    and they are not mutually exclusive: a lineage-restricted reduction could
    still act by crossing a shared threshold in the tissues where it applies.
phenotypes:
- category: Hematologic
  name: Thrombocytopenia
  description: >-
    Hypomegakaryocytic thrombocytopenia, present at birth or developing within
    the first weeks to months of life. Counts are generally lowest in infancy
    and improve with age, so the haematological course is largely
    self-limiting, in contrast to the progressive marrow failure of Fanconi
    anemia. Cow's milk exposure and intercurrent illness can precipitate
    exacerbations.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  diagnostic: true
  notes: >-
    clinical_course is deliberately absent. ClinicalCourseEnum offers only
    PROGRESSIVE and STABLE, and this thrombocytopenia is neither: it is
    typically worst in infancy and remits with age. Recording either value
    would misstate the natural history, so the course is described in prose and
    carried by the cited evidence instead.
  evidence:
  - reference: PMID:20301781
    reference_title: Thrombocytopenia Absent Radius Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thrombocytopenia may be congenital or may develop within the first few weeks to months of life; in general, thrombocytopenic episodes decrease with age.
    explanation: >-
      Documents both the timing of onset and the tendency to remit, which is
      why the course is not modelled as static.
  sequelae:
  - target: Abnormal bleeding
    description: >-
      The platelet deficit produces bleeding beyond the cutaneous signs, and the
      risk persists as counts recover because it never fully normalises.
    evidence:
    - reference: PMID:17236129
      reference_title: >-
        Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Although platelet counts ameliorate over time, patients remain thrombocytopenic with continued risk of bleeding.
      explanation: >-
        Ties the continuing bleeding risk directly to the persisting
        thrombocytopenia.
  - target: Petechiae
    description: >-
      Reduced platelet counts produce the cutaneous bleeding that commonly
      brings infants to attention.
    evidence:
    - reference: PMID:20301781
      reference_title: Thrombocytopenia Absent Radius Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Platelet count when evidence of increased bleeding tendency (bruising, petechiae) occurs.
      explanation: >-
        Names bruising and petechiae as the bleeding manifestations monitored in
        this disorder.
- category: Skeletal
  name: Bilateral radial aplasia
  description: >-
    Bilateral absence of the radii, present in every reported patient and
    required for the clinical diagnosis. Severity of the wider skeletal
    involvement varies from isolated radial absence to near-total absence of the
    upper limbs.
  phenotype_term:
    preferred_term: Bilateral radial aplasia
    term:
      id: HP:0004977
      label: Bilateral radial aplasia
  diagnostic: true
  evidence:
  - reference: PMID:12471199
    reference_title: "Thrombocytopenia-absent radius syndrome: a clinical genetic study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies.
    explanation: >-
      All 34 patients in the cohort had bilateral radial aplasia, establishing
      it as an obligate feature.
- category: Hematologic
  name: Megakaryocytopenia
  description: >-
    Bone marrow examination shows reduced or absent megakaryocytes, identifying
    the thrombocytopenia as a production defect rather than peripheral
    destruction.
  phenotype_term:
    preferred_term: Megakaryocytopenia
    term:
      id: HP:0005548
      label: Megakaryocytopenia
  evidence:
  - reference: PMID:17236129
    reference_title: >-
      Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thrombocytopenia-absent radius (TAR) syndrome is characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia in the presence of both thumbs.
    explanation: >-
      Characterises the thrombocytopenia as hypomegakaryocytic.
- category: Hematologic
  name: Petechiae
  description: >-
    Cutaneous petechiae and bruising reflecting the platelet deficit; bleeding
    episodes are most frequent in the first year of life.
  phenotype_term:
    preferred_term: Petechiae
    term:
      id: HP:0000967
      label: Petechiae
  evidence:
  - reference: PMID:20301781
    reference_title: Thrombocytopenia Absent Radius Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Platelet count when evidence of increased bleeding tendency (bruising, petechiae) occurs.
    explanation: >-
      Identifies bruising and petechiae as the bleeding signs prompting platelet
      monitoring.
- category: Hematologic
  name: Abnormal bleeding
  description: >-
    Severe bleeding, not only cutaneous petechiae, is the dominant early threat.
    Haemorrhage is the main cause of the mortality that is concentrated in the
    first year of life, after which survivors generally have a normal life
    expectancy. This is the clinical reason the thrombocytopenia is managed
    aggressively in infancy and then relaxed as counts recover.
  phenotype_term:
    preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  sequelae:
  - target: Gastrointestinal hemorrhage
    description: >-
      The gut is one of the sites where the bleeding tendency manifests. Note
      that not every gastrointestinal bleed in this disorder is thrombocytopenic
      in origin: cow's milk protein allergy also causes bloody stool and
      resolves on withdrawing the feed, so the two causes have to be told apart
      at the bedside. This edge is for the thrombocytopenic route.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41925074
      reference_title: >-
        Successful Haplo-Hematopoietic Stem Cell Transplantation for Juvenile Myelomonocytic Leukemia in a Child With Underlying Thrombocytopenia-Absent Radius Syndrome: A Unique Case.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Investigations confirmed hematochezia and persistent thrombocytopenia, necessitating ongoing platelet transfusions
      explanation: >-
        Recurrent gastrointestinal bleeding tracking with persistent
        thrombocytopenia and requiring platelet support, which is the
        thrombocytopenic route this edge asserts.
  evidence:
  - reference: PMID:17236129
    reference_title: >-
      Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with TAR syndrome typically present with petechiae and severe bleeding during the first years of life.
    explanation: >-
      Establishes severe bleeding, beyond petechiae, as a typical presenting
      feature.
  - reference: PMID:41925074
    reference_title: >-
      Successful Haplo-Hematopoietic Stem Cell Transplantation for Juvenile Myelomonocytic Leukemia in a Child With Underlying Thrombocytopenia-Absent Radius Syndrome: A Unique Case.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mortality in TAR syndrome, mainly due to hemorrhage, is generally confined to the first year of life
    explanation: >-
      Identifies haemorrhage as the main cause of death and confines that risk
      to the first year, which is what makes this phenotype the driver of early
      management.
- category: Hematologic
  name: Increased total leukocyte count
  description: >-
    Periodic leukemoid reactions, transient marked leukocytosis without
    leukaemia, are a recognised part of the haematological picture and can
    prompt an unnecessary malignancy work-up if not anticipated. Bound to the
    general leukocytosis term because HPO has no term for a leukemoid reaction.
  phenotype_term:
    preferred_term: Periodic leukemoid reaction
    term:
      id: HP:0001974
      label: Increased total leukocyte count
  evidence:
  - reference: PMID:3056062
    reference_title: Thrombocytopenia with absent radii. A review of 100 cases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the characteristic hematological findings are hypomegakaryocytic thrombocytopenia, periodic leukemoid reactions, and eosinophilia
    explanation: >-
      A 100-case review listing periodic leukemoid reactions among the
      characteristic haematological findings.
- category: Hematologic
  name: Increased total eosinophil count
  description: >-
    Eosinophilia accompanies the thrombocytopenia and leukemoid reactions. It
    may relate to the cow's milk allergy that is common in this disorder, though
    the cited review lists it as a characteristic finding in its own right.
  phenotype_term:
    preferred_term: Increased total eosinophil count
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  evidence:
  - reference: PMID:3056062
    reference_title: Thrombocytopenia with absent radii. A review of 100 cases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the characteristic hematological findings are hypomegakaryocytic thrombocytopenia, periodic leukemoid reactions, and eosinophilia
    explanation: >-
      The same review lists eosinophilia among the characteristic haematological
      findings.
- category: Gastrointestinal
  name: Gastrointestinal hemorrhage
  description: >-
    Gastrointestinal bleeding occurs in infancy and can be the presenting
    complaint. It may be compounded by the cow's milk allergy, which is itself
    common in this disorder and can inflame the gut and worsen the
    thrombocytopenia at the same time.
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  evidence:
  - reference: PMID:36872795
    reference_title: "Case report: Pneumatosis in a neonate with thrombocytopenia absent radius syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An eight-day-old male infant born at 36 weeks gestation with a diagnosis of TAR, presented with bright red blood in his stool.
    explanation: >-
      A TAR neonate presenting with frank gastrointestinal bleeding.
- category: Skeletal
  name: Abnormality of the upper limb
  description: >-
    Skeletal involvement of the upper limb extends well beyond the radius.
    Ulnar, hand and humeral anomalies are common, and severity ranges from
    isolated radial absence to near-total absence of the upper limbs. Recorded
    at this general level because the cited source covers upper-limb anomalies
    collectively rather than itemising them.
  phenotype_term:
    preferred_term: Abnormality of the upper limb
    term:
      id: HP:0002817
      label: Abnormality of the upper limb
  evidence:
  - reference: PMID:20301781
    reference_title: Thrombocytopenia Absent Radius Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur.
    explanation: >-
      Lists upper-limb skeletal anomalies among the additional features of the
      syndrome.
- category: Genitourinary
  name: Aplasia of the uterus
  description: >-
    Mullerian agenesis, reported as absence of the uterus, cervix and the upper
    vagina, occurs alongside the renal anomalies. It matters for counselling
    adolescent and adult patients, and is distinct from the renal involvement
    already modelled.
  phenotype_term:
    preferred_term: Aplasia of the uterus
    term:
      id: HP:0000151
      label: Aplasia of the uterus
  evidence:
  - reference: PMID:20301781
    reference_title: Thrombocytopenia Absent Radius Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur.
    explanation: >-
      Names agenesis of the uterus, cervix and upper vagina among the
      genitourinary features.
- category: Gastrointestinal
  name: Cow milk allergy
  description: >-
    Cow's milk allergy or intolerance affects roughly half of patients and is
    clinically important beyond the gastrointestinal symptoms themselves,
    because exposure can exacerbate the thrombocytopenia. Avoidance is therefore
    a haematological intervention as well as a dietary one.
  phenotype_term:
    preferred_term: Cow milk allergy
    term:
      id: HP:0100327
      label: Cow milk allergy
  frequency: FREQUENT
  evidence:
  - reference: PMID:12471199
    reference_title: "Thrombocytopenia-absent radius syndrome: a clinical genetic study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies.
    explanation: >-
      Quantifies cow's milk intolerance at 47% of a 34-patient cohort.
  - reference: PMID:20301781
    reference_title: Thrombocytopenia Absent Radius Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cow's milk allergy is common and can be associated with exacerbation of thrombocytopenia.
    explanation: >-
      Establishes the link between milk exposure and worsening of the platelet
      count.
- category: Skeletal
  name: Abnormality of the lower limb
  description: >-
    Lower limb anomalies, including malformations of the hip and knee, occur in
    roughly half of patients.
  phenotype_term:
    preferred_term: Abnormality of the lower limb
    term:
      id: HP:0002814
      label: Abnormality of the lower limb
  frequency: FREQUENT
  evidence:
  - reference: PMID:12471199
    reference_title: "Thrombocytopenia-absent radius syndrome: a clinical genetic study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies.
    explanation: >-
      Reports lower limb anomalies in 47% of the cohort.
- category: Renal
  name: Abnormal renal morphology
  description: >-
    Renal anomalies occur in around a quarter of patients, and kidney function
    is monitored as part of routine surveillance.
  phenotype_term:
    preferred_term: Abnormal renal morphology
    term:
      id: HP:0012210
      label: Abnormal renal morphology
  evidence:
  - reference: PMID:12471199
    reference_title: "Thrombocytopenia-absent radius syndrome: a clinical genetic study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies.
    explanation: >-
      Reports renal anomalies in 23% of the cohort.
- category: Cardiovascular
  name: Abnormal heart morphology
  description: >-
    Congenital heart disease is a recognised association, reported in about 15%
    of patients in a 34-patient cohort.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:12471199
    reference_title: "Thrombocytopenia-absent radius syndrome: a clinical genetic study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies.
    explanation: >-
      Reports cardiac anomalies in 15% of the cohort.
  - reference: PMID:17236129
    reference_title: >-
      Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other frequent associations are congenital heart disease and a high incidence of cow's milk intolerance.
    explanation: >-
      Independently lists congenital heart disease among the frequent
      associations.
genetic:
- name: RBM8A
  gene_term:
    preferred_term: RBM8A
    term:
      id: hgnc:9905
      label: RBM8A
  relationship_type: CAUSATIVE
  notes: >-
    Encodes Y14, one of four core subunits of the exon junction complex. Disease
    requires a null allele in trans with a low-frequency hypomorphic regulatory
    allele; the null allele is usually the recurrent 200-kb 1q21.1 microdeletion
    that removes RBM8A, and less often a frameshift or nonsense variant.
  evidence:
  - reference: PMID:22366785
    reference_title: >-
      Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR.
    explanation: >-
      Identifies RBM8A as the causal gene and states the required allele
      combination.
prevalence:
- population: Worldwide
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.5
  notes: >-
    Reported as approximately one in 200,000 live births, normalized here to
    0.5 per 100,000.
  evidence:
  - reference: PMID:36872795
    reference_title: "Case report: Pneumatosis in a neonate with thrombocytopenia absent radius syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thrombocytopenia absent radius (TAR) syndrome is a rare disease with an estimated prevalence of one in 200,000 live births.
    explanation: >-
      Source of the birth prevalence estimate recorded here.
treatments:
- name: Platelet Transfusion
  description: >-
    Platelet transfusion supports the thrombocytopenia during the high-risk
    infant period and around procedures. Because counts improve with age,
    transfusion is deliberately restricted in older individuals once the count
    exceeds a threshold, to limit alloimmunization and transfusion-transmitted
    infection.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Platelet Transfusion
    term:
      id: NCIT:C15366
      label: Platelet Transfusion
  target_mechanisms:
  - target: Thrombocytopenia
    description: >-
      Replaces circulating platelets that the marrow cannot produce, without
      correcting the underlying megakaryocyte defect.
    evidence:
    - reference: PMID:20301781
      reference_title: Thrombocytopenia Absent Radius Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Platelet transfusion for thrombocytopenia as needed
      explanation: >-
        Supports transfusion acting on the thrombocytopenia itself rather than
        on its cause.
  evidence:
  - reference: PMID:20301781
    reference_title: Thrombocytopenia Absent Radius Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Platelet transfusion for thrombocytopenia as needed
    explanation: >-
      Names platelet transfusion as the management of the thrombocytopenia.
- name: In Utero Platelet Transfusion
  description: >-
    Where TAR is recognised antenatally and severe fetal thrombocytopenia is
    confirmed by cordocentesis, platelets can be transfused into the umbilical
    vein before delivery. The aim is peripartum haemostasis at the point of
    greatest bleeding risk, not correction of the underlying defect. This is
    reported experience from case management rather than trial evidence.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Platelet Transfusion
    term:
      id: NCIT:C15366
      label: Platelet Transfusion
  target_mechanisms:
  - target: Thrombocytopenia
    description: >-
      Raises the fetal platelet count across delivery, when intracranial and
      other internal bleeding risk is highest.
    evidence:
    - reference: PMID:7845901
      reference_title: >-
        Prenatal evaluation and in utero platelet transfusion for thrombocytopenia absent radii syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Apheresis platelets were transfused into the umbilical vein to correct the thrombocytopenia and was followed by an uncomplicated delivery.
      explanation: >-
        Describes the intervention acting directly on the fetal platelet count.
  evidence:
  - reference: PMID:7845901
    reference_title: >-
      Prenatal evaluation and in utero platelet transfusion for thrombocytopenia absent radii syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that TAR syndrome can be readily identified prenatally on sonogram, and if severe thrombocytopenia is confirmed by cordocentesis, platelets should be transfused to diminish the risk of serious internal bleeding during and immediately after delivery.
    explanation: >-
      States the antenatal pathway and the recommendation to transfuse before
      delivery when severe thrombocytopenia is confirmed.
- name: Cow's Milk Avoidance
  description: >-
    Dietary exclusion of cow's milk. In this disorder it serves two purposes at
    once: it reduces the severity of the gastroenteritis, and it avoids
    exacerbations of the thrombocytopenia that milk exposure can precipitate.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Cow milk allergy
    description: >-
      Removes the antigenic exposure driving the gastrointestinal
      manifestations.
    evidence:
    - reference: PMID:20301781
      reference_title: Thrombocytopenia Absent Radius Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Avoidance of cow's milk to reduce the severity of gastroenteritis and to avoid exacerbations of thrombocytopenia.
      explanation: >-
        States that avoidance acts on the gastrointestinal manifestation, and
        additionally on the thrombocytopenia it can exacerbate.
  evidence:
  - reference: PMID:20301781
    reference_title: Thrombocytopenia Absent Radius Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Avoidance of cow's milk to reduce the severity of gastroenteritis and to avoid exacerbations of thrombocytopenia.
    explanation: >-
      States both the gastrointestinal and the haematological rationale for
      avoidance.
- name: Avoidance of Antiplatelet Drugs
  description: >-
    NSAIDs and aspirin are avoided or used with caution. The rationale is not
    only the low platelet count: platelet function is itself somewhat impaired
    in this disorder, so an antiplatelet agent compounds a qualitative defect on
    top of a quantitative one. This matters most in infancy, when bleeding risk
    is highest, but the platelet functional defect does not resolve with the
    count.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Abnormal bleeding
    description: >-
      Removes an iatrogenic contribution to bleeding risk in a patient whose
      platelets are both few and functionally impaired.
    evidence:
    - reference: PMID:20301781
      reference_title: Thrombocytopenia Absent Radius Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Platelet function is somewhat impaired, suggesting that drugs such as nonsteroidal anti-inflammatory drugs or aspirin should be avoided or used with caution.
      explanation: >-
        States both the impaired platelet function and the avoidance
        recommendation that follows from it.
  evidence:
  - reference: PMID:20301781
    reference_title: Thrombocytopenia Absent Radius Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Platelet function is somewhat impaired, suggesting that drugs such as nonsteroidal anti-inflammatory drugs or aspirin should be avoided or used with caution.
    explanation: >-
      The management recommendation to avoid or limit NSAIDs and aspirin.
- name: Orthopedic Intervention
  description: >-
    Orthopedic and reconstructive management of the upper limb deformity,
    directed at maximizing function rather than at correcting the underlying
    developmental defect. The preserved thumbs are functionally important and
    inform surgical planning.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Orthopedic Surgical Procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_mechanisms:
  - target: Bilateral radial aplasia
    description: >-
      Addresses the functional consequences of the fixed skeletal defect.
    evidence:
    - reference: PMID:20301781
      reference_title: Thrombocytopenia Absent Radius Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Orthopedic intervention as needed to maximize limb function.
      explanation: >-
        Supports the intervention targeting limb function rather than correcting
        the developmental defect.
  evidence:
  - reference: PMID:20301781
    reference_title: Thrombocytopenia Absent Radius Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Orthopedic intervention as needed to maximize limb function.
    explanation: >-
      States the goal of orthopedic management in this disorder.
differential_diagnoses:
- name: Fanconi anemia
  disease_term:
    preferred_term: Fanconi anemia
    term:
      id: MONDO:0019391
      label: Fanconi anemia
  description: >-
    The principal differential, since both combine a radial ray defect with
    marrow failure.
  distinguishing_features:
  - >-
      The thumbs are the discriminator. In TAR the radii are absent but both
      thumbs are present; in Fanconi anemia a radial defect is accompanied by an
      absent or hypoplastic thumb.
  - >-
      The haematology also diverges: TAR causes an isolated thrombocytopenia
      that improves with age, whereas Fanconi anemia causes progressive
      pancytopenia with a substantial risk of clonal evolution.
  evidence:
  - reference: PMID:22366785
    reference_title: >-
      Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with preservation of the thumb, which distinguishes TAR from other syndromes that combine blood abnormalities with absence of the radius, such as Fanconi anemia
    explanation: >-
      Explicitly names Fanconi anemia as the syndrome that thumb preservation
      distinguishes TAR from.
- name: Radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome
  disease_term:
    preferred_term: radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome
    term:
      id: MONDO:0011555
      label: radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome
  description: >-
    A second forearm-plus-thrombocytopenia syndrome that enters the neonatal
    differential.
  distinguishing_features:
  - >-
      The forearm lesion is a proximal radio-ulnar synostosis rather than radial
      aplasia.
  - >-
      The thrombocytopenia is amegakaryocytic and progresses toward marrow
      failure rather than remitting with age.
  evidence:
  - reference: PMID:26581901
    reference_title: >-
      Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) is an inherited bone marrow failure syndrome, characterized by thrombocytopenia and congenital fusion of the radius and ulna.
    explanation: >-
      Establishes the forearm lesion and marrow phenotype that distinguish RUSAT
      from the radial aplasia of TAR.
  notes: >-
    Distinguished on the described clinical features; no dismech entry exists
    for this disorder yet, so it is referenced by its MONDO term only. Worth
    noting that the two disorders converge on one transcription factor from
    opposite directions: RUSAT is caused by missense variants in MECOM, which
    encodes EVI1, and EVI1 is the repressor predicted to bind the minor allele
    of the TAR 5'UTR regulatory SNP. This is an observation about the
    literature, not a curated mechanistic claim in this entry.
animal_models:
- name: Zebrafish rbm8a morpholino knockdown
  species: Zebrafish
  genotype: rbm8a antisense morpholino knockdown
  publication: PMID:22366785
  description: >-
    Antisense morpholino knockdown of the zebrafish rbm8a orthologue, used to
    establish that Y14 is essential in vertebrate development.
  evidence:
  - reference: PMID:22366785
    reference_title: >-
      Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      knock-down of the orthologous rbm8a transcript in Danio rerio by antisense morpholinos resulted in extreme malformations and death two days post fertilization
    explanation: >-
      Attests that the model exists and was used in the defining study, a
      separate claim from whether it is informative for any given node.
  modeled_mechanisms:
  - target: Y14 Protein Insufficiency
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Demonstrates that Y14 is developmentally essential, but does not model the
      disease state. TAR is caused by a partial reduction in Y14 that leaves
      viable, largely healthy tissue outside the megakaryocytic and radial ray
      compartments; the morphant is a near-complete knockdown that is lethal
      within two days, producing global malformation rather than the selective
      TAR phenotype.
    limitations: >-
      Morpholino knockdown is transient and its severity is not titrated to the
      partial dosage reduction seen in patients, so the model cannot reproduce
      the tissue-selective, threshold-dependent nature of the human disorder.
      Lethality at two days post fertilization also precludes assessment of the
      limb and haematopoietic phenotypes of interest.
    evidence:
    - reference: PMID:22366785
      reference_title: >-
        Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        knock-down of the orthologous rbm8a transcript in Danio rerio by antisense morpholinos resulted in extreme malformations and death two days post fertilization
      explanation: >-
        Reports the lethal, globally malformed phenotype that departs from the
        selective human presentation.
discussions:
- discussion_id: rbm8a_regulatory_snp_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what molecular mechanism do the RBM8A 5'UTR and first-intron minor
    alleles reduce Y14 protein abundance in patients?
  attaches_to:
  - pathophysiology#Reduced RBM8A Gene Dosage
  rationale: >-
    The genetic association is settled and the protein deficit is measured in
    patient platelets, but the step between them is not established. Reporter
    assays show both minor alleles lower promoter activity in megakaryocytic and
    osteoblast lines, yet allele-specific expression in platelet RNA from
    healthy heterozygotes showed no difference between transcripts, so reduced
    transcription alone does not account for the observed protein reduction. The
    authors state the mechanism remains open and may differ between the two
    SNPs. This matters for curation because the causal edge from genotype to Y14
    insufficiency is currently supported by correlation plus a partially
    contradicted transcriptional model.
  evidence:
  - reference: PMID:22366785
    reference_title: >-
      Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      It therefore still leaves open the question of the exact mechanism by which the non-coding SNPs lead to the decreased protein expression observed in TAR cases.
    explanation: >-
      The authors state the gap directly, immediately after reporting the
      negative allele-specific expression result.
- discussion_id: tpo_receptor_agonists_untested_in_tar
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Would thrombopoietin receptor agonists raise the platelet count in TAR
    syndrome, and is there any reason to expect them to?
  attaches_to:
  - treatments#
  - pathophysiology#Megakaryocyte Maturation Failure
  rationale: >-
    TPO-receptor agonists have accumulated real experience across the inherited
    thrombocytopenias, but the reported diagnoses are Wiskott-Aldrich, MYH9- and
    ANKRD26-related disease; TAR is not among them. The question is not purely
    empirical, because TAR patients have been reported to have elevated
    endogenous TPO with impaired responsiveness rather than TPO deficiency, so
    agonist therapy is not obviously indicated by the mechanism. Recorded as a
    gap rather than as a treatment: nothing here supports offering a TPO-RA in
    TAR, and nothing rules it out.
  evidence:
  - reference: PMID:33919295
    reference_title: >-
      Role of Thrombopoietin Receptor Agonists in Inherited Thrombocytopenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main diagnoses were Wiskott-Aldrich syndrome, MYH9-related disorder and ANKRD26-related thrombocytopenia.
    explanation: >-
      A systematic review of TPO-RA use across inherited thrombocytopenias whose
      reported diagnoses do not include TAR, which is what establishes the gap.
- discussion_id: ibmfs_classification_and_malignancy_risk
  kind: INTERPRETATION
  status: OPEN
  prompt: >-
    Should TAR be treated as an inherited bone marrow failure syndrome, and does
    it carry a leukemia predisposition?
  attaches_to:
  - clinical_burden#
  - phenotypes#Thrombocytopenia
  notes: >-
    One of the two later case reports (PMID:41925074) describes its patient as
    having a homozygous RBM8A c.-21G>A variant rather than the compound
    null-plus-hypomorph genotype this entry models, and GeneReviews states that
    individuals with biallelic hypomorphic alleles are asymptomatic. Flagged
    rather than acted on: a single case report is not enough to revise the
    inheritance model, and the discrepancy could equally be a reporting
    simplification. Worth checking against the primary genotype data if anyone
    revisits the allelic spectrum, which PMID:37611607 says is still open.
  rationale: >-
    TAR is conventionally listed among the inherited bone marrow failure
    syndromes and is enrolled as one by the NCI natural-history cohort recorded
    under clinical_trials, but the haematological behaviour fits that label
    poorly and the literature says so directly. The thrombocytopenia is
    lineage-restricted and remits with age rather than progressing to
    pancytopenia, which is the opposite of the course in Fanconi anemia or
    dyskeratosis congenita. Leukemia in TAR is at case-report level: a 2017
    review counted four reported cases in the entire literature, and further
    single cases have appeared since, including Philadelphia-positive AML and
    juvenile myelomonocytic leukemia. Recorded as an interpretation rather than
    as a phenotype because the honest statement is a reported near-absence, and
    a handful of cases across a rare disease does not establish a predisposition.
    Curators should not infer a Fanconi-like surveillance requirement from the
    IBMFS label alone.
  evidence:
  - reference: PMID:28259746
    reference_title: >-
      Acute myeloid leukemia in a patient with thrombocytopenia with absent radii: A case report and review of the literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TAR syndrome is not generally associated with bone marrow failure or malignancy.
    explanation: >-
      States directly that neither marrow failure nor malignancy is a general
      feature, which is the claim this interpretation rests on.
  - reference: PMID:28259746
    reference_title: >-
      Acute myeloid leukemia in a patient with thrombocytopenia with absent radii: A case report and review of the literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only four cases of leukemia were reported in TAR patients in the literature: three acute myeloid leukemia (AML) and one acute lymphoblastic leukemia.
    explanation: >-
      Quantifies the reported malignancy experience, which is what makes this
      case-report level rather than an established predisposition.
  - reference: PMID:39393038
    reference_title: >-
      Characterization and Clinical Outcome of Philadelphia Chromosome-Positive AML in Thrombocytopenia-Absent Radius Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One BMFS that is rarely associated with leukemic transformation is the autosomal recessive thrombocytopenia-absent radius (TAR) syndrome.
    explanation: >-
      A later single case, whose own framing is that leukemic transformation is
      rare in this disorder.
  - reference: PMID:41925074
    reference_title: >-
      Successful Haplo-Hematopoietic Stem Cell Transplantation for Juvenile Myelomonocytic Leukemia in a Child With Underlying Thrombocytopenia-Absent Radius Syndrome: A Unique Case.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      its association with hematologic malignancies is extremely rare, with only a few reported cases of leukemia
    explanation: >-
      A further single case, again describing the malignancy association as
      extremely rare rather than established.
diagnosis:
- name: Prenatal ultrasound detection of bilateral radial aplasia
  description: >-
    Bilateral absence of the radii is visible on routine second-trimester
    ultrasound, and with the thumbs intact it is suggestive enough to prompt
    targeted work-up. Recognition antenatally is what opens the door to
    cordocentesis and, where indicated, in utero transfusion.
  evidence:
  - reference: PMID:24053387
    reference_title: >-
      Prenatal diagnosis and post-mortem examination in a fetus with thrombocytopenia-absent radius (TAR) syndrome due to compound heterozygosity for a 1q21.1 microdeletion and a RBM8A hypomorphic allele: a case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The fetus had bilateral radial agenesis and humeral hypo/aplasia with intact thumbs, micrognathia and urinary anomalies
    explanation: >-
      Records the sonographic presentation, including the intact thumbs that
      point to TAR rather than to a thumb-absent radial ray syndrome.
- name: Preserved thumbs on examination of the hand
  description: >-
    Both thumbs are present despite bilateral radial aplasia. This dissociation
    is the key bedside discriminator from the other radial ray syndromes with
    haematological involvement, in which the thumb is absent or hypoplastic, and
    it is part of the clinical diagnostic triad. Recorded here as a diagnostic
    criterion rather than as a phenotype: a present, normally formed thumb is a
    normal finding, and HPO, being an ontology of phenotypic abnormalities, has
    no term for one. Its significance in TAR is entirely differential.
  evidence:
  - reference: PMID:22366785
    reference_title: >-
      Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with preservation of the thumb, which distinguishes TAR from other syndromes that combine blood abnormalities with absence of the radius, such as Fanconi anemia
    explanation: >-
      States the finding and its discriminating value against Fanconi anemia.
  - reference: PMID:20301781
    reference_title: Thrombocytopenia Absent Radius Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of TAR syndrome is established in a proband with bilateral absent radii, present thumbs, and thrombocytopenia.
    explanation: >-
      Places present thumbs in the clinical triad that establishes the diagnosis.
- name: Cordocentesis platelet count
  description: >-
    Fetal blood sampling confirms the thrombocytopenia and establishes whether
    it is severe enough to justify transfusion before delivery.
  evidence:
  - reference: PMID:7845901
    reference_title: >-
      Prenatal evaluation and in utero platelet transfusion for thrombocytopenia absent radii syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 37 weeks of pregnancy, a CBC obtained by cordocentesis under ultrasound guidance confirmed the diagnosis of thrombocytopenia absent radii (TAR) syndrome.
    explanation: >-
      Describes cordocentesis as the step that confirmed the diagnosis
      antenatally.
- name: Molecular confirmation of the two RBM8A alleles
  description: >-
    Diagnosis is confirmed by finding a null allele, usually the 1q21.1
    microdeletion, together with an RBM8A hypomorphic allele in trans. Testing
    for only one of the two is not sufficient, because carriers of either alone
    are healthy.
  evidence:
  - reference: PMID:20301781
    reference_title: Thrombocytopenia Absent Radius Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Identification of a heterozygous null allele (most often a minimally deleted 200-kb region including RBM8A at chromosome band 1q21.1) in a compound heterozygous state with a heterozygous RBM8A hypomorphic allele on molecular genetic testing confirms the diagnosis.
    explanation: >-
      States the two-allele finding that constitutes molecular confirmation.
variants:
- name: RBM8A rs139428292
  description: >-
    The recurrent low-frequency non-coding RBM8A regulatory allele, reported in
    trans with the 1q21.1 microdeletion in molecularly characterized patients.
    Named here because the entry otherwise refers to the regulatory alleles only
    by their position in the 5'UTR or first intron. Classified mLOE rather than
    LOE because the expression loss is modular, not global: reporter activity
    fell in megakaryocytic and osteoblast lines but not in endothelial or HEK293
    cells. That cell-type restriction is the same observation the entry uses to
    model the phenotype as tissue-selective. The caveat is that the evidence is
    reporter activity in cell lines rather than expression measured in primary
    megakaryocytes and limb bud, so "modular" is inferred from which lines
    responded. RBM8A itself is widely expressed, so a reviewer who judged the
    reduction to be global rather than cell-type restricted would classify this
    LOE instead.
  gene:
    preferred_term: RBM8A
    term:
      id: hgnc:9905
      label: RBM8A
  regulatory_category: mLOE
  evidence:
  - reference: PMID:22366785
    reference_title: >-
      Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The minor alleles were associated with significantly lower luciferase activity in human megakaryocytic CHRF and DAMI cell lines and the murine osteoblast cell line MC3T3.
    explanation: >-
      Shows reduced expression confined to megakaryocytic and osteoblast
      contexts, which is what makes this modular rather than global.
  - reference: PMID:24053387
    reference_title: >-
      Prenatal diagnosis and post-mortem examination in a fetus with thrombocytopenia-absent radius (TAR) syndrome due to compound heterozygosity for a 1q21.1 microdeletion and a RBM8A hypomorphic allele: a case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Molecular studies demonstrated compound heterozygosity for the 1q21.1 microdeletion and the RBM8A rs139428292 variant at the hemizygous state, inherited from the mother and father, respectively
    explanation: >-
      Names the specific hypomorphic allele and confirms biparental inheritance
      of the two lesions.
- name: RBM8A rs201779890
  description: >-
    The second recurrent hypomorphic regulatory allele, in intron 1 of RBM8A.
    Together with the 5'UTR allele rs139428292 it accounted for nearly all cases
    in the founding series, though the allelic spectrum is not closed.
  gene:
    preferred_term: RBM8A
    term:
      id: hgnc:9905
      label: RBM8A
  regulatory_category: mLOE
  evidence:
  - reference: PMID:24053387
    reference_title: >-
      Prenatal diagnosis and post-mortem examination in a fetus with thrombocytopenia-absent radius (TAR) syndrome due to compound heterozygosity for a 1q21.1 microdeletion and a RBM8A hypomorphic allele: a case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genotyping of rs139428292 (G>A) and rs201779890
    explanation: >-
      Names both recurrent hypomorphic alleles and their nucleotide changes.
datasets:
- accession: geo:GSE5781
  title: Array CGH in TAR syndrome
  data_type: MICROARRAY
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 4
  publication: PMID:17236129
  genes:
  - preferred_term: RBM8A
    term:
      id: hgnc:9905
      label: RBM8A
  notes: >-
    The array CGH series deposited by the study that identified the recurrent
    200-kb 1q21.1 microdeletion, and therefore the primary data behind the null
    allele modelled in this entry. Triaged as DIRECT: the disease is named in
    the series title and the material is human patient DNA.
- accession: geo:GSE240611
  title: >-
    Prenatal phenotypes and pregnancy outcomes of fetuses with recurrent 1q21.1
    microdeletions and microduplications
  data_type: MICROARRAY
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 26
  publication: PMID:37692779
  notes: >-
    Prenatal cohort of recurrent 1q21.1 copy-number changes, which names TAR
    among the associated phenotypes. Relevant to the null allele rather than to
    TAR specifically, since the cohort is ascertained on the CNV and includes
    duplications and unaffected outcomes; use for deletion-level context, not as
    a TAR case series.
clinical_trials:
- name: NCT00027274
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    NCI natural-history cohort of inherited bone marrow failure syndromes,
    studying cancer rates and types. TAR is one of the enrolled IBMFS, so this
    is the main organized source of long-term malignancy-risk data for the
    disorder. Enrollment reflects the conventional nosological grouping and
    should not be read as evidence of a leukemia predisposition; see the
    ibmfs_classification_and_malignancy_risk discussion.
  evidence:
  - reference: clinicaltrials:NCT00027274
    reference_title: >-
      Etiologic Investigation of Cancer Susceptibility in Inherited Bone Marrow Failure Syndromes: A Natural History Study
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thrombocytopenia absent radii: absent radii; early onset thrombocytopenia
    explanation: >-
      The trial record lists thrombocytopenia absent radii among the inherited
      bone marrow failure syndromes it enrolls.
- name: NCT00086476
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    NHGRI study culturing megakaryocytes from CD34+ marrow cells of patients
    with platelet granule and vesicle disorders, TAR among them, to characterize
    megakaryocytopoiesis directly.
  target_phenotypes:
  - preferred_term: Megakaryocytopenia
    term:
      id: HP:0005548
      label: Megakaryocytopenia
  evidence:
  - reference: clinicaltrials:NCT00086476
    reference_title: >-
      Investigations of Megakaryocytes From Patients With Abnormal Platelet Vesicles
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other diseases associated with variable defects in platelet gamma-granules include Chediak-Higashi, Griscelli, Wiskott-Aldrich, and Thrombocytopenia Absent Radius syndromes.
    explanation: >-
      Names TAR among the disorders whose megakaryocytes this protocol cultures
      and characterizes.
external_assertions:
- name: OMIM thrombocytopenia-absent radius syndrome record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:274000
  url: https://omim.org/entry/274000
  description: >-
    OMIM entry for TAR syndrome, cross-referenced by MONDO:0010121.
- name: Orphanet thrombocytopenia-absent radius syndrome record
  source: Orphanet
  assertion_type: disease_record
  external_id: ORPHA:3320
  url: https://www.orpha.net/en/disease/detail/3320
  description: >-
    Orphanet entry for TAR syndrome, cross-referenced by MONDO:0010121. Not
    quoted as evidence here because this disorder is not among the Orphanet
    records currently present in references_cache/.
notes: >-
  Curated against MONDO:0010121 as the anchor. MONDO cross-references
  OMIM:274000, Orphanet:3320, NCIT:C99038, DECIPHER:64 and UMLS:C0175703 for
  this concept; the first two are recorded as external assertions, and the NCIT
  identifier is deliberately not placed in mappings.ncit_mappings, which the
  schema scopes to cancer entries.

  Two points a reviewer may want to check. First, the entry treats the
  genotype-to-phenotype relation as a dosage threshold rather than
  haploinsufficiency, which is what the healthy-carrier observation requires;
  the residual uncertainty about how the regulatory alleles lower Y14 is
  recorded as an open knowledge gap rather than smoothed over in the causal
  edge. Second, preserved thumbs are recorded under diagnosis rather than as a
  phenotype. A present, normally formed thumb is a normal finding, and HPO is an
  ontology of phenotypic abnormalities, so it has no term for one; the finding
  matters here only as a discriminator from the thumb-absent radial ray
  syndromes, which is a diagnostic role rather than a phenotypic one.

  Third, several phenotypes are deliberately left as pathograph leaves with no
  incoming causal edge: the leukocyte and eosinophil findings, uterine aplasia,
  and the lower-limb, renal and cardiac anomalies. The route from Y14
  insufficiency to each of these is not established, and the pathograph edges in
  this entry each carry their own cited evidence. Attaching them to the nearest
  plausible node would assert a mechanism no source states. The radial ray node
  covers forelimb patterning specifically, so it is not a defensible parent for
  the lower-limb anomalies even though one cited sentence mentions both.
📚

References & Deep Research

References

1
PMID:20301781
Thrombocytopenia Absent Radius Syndrome.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Thrombocytopenia-Absent Radius Syndrome (MONDO:0010121) · 2026-09-01T20:22:32Z · View source

De novo curation of TAR syndrome, claimed via issue #10431. Scope decision: entry_type DISEASE. MONDO:0010121 records no descendants, one causal gene (RBM8A), and one conserved pathograph, so it is a disease rather than a grouping or a subtype. Preflight against origin/main found no existing coverage by MONDO ID, by label, or by gene symbol, and no open PR. The nearest existing entries are Inherited_Aplastic_Anemia.yaml, which lists five IBMFS but not TAR, and Fanconi_Anemia.yaml. Note a naive grep for 'TAR syndrome' matches Scimitar_Syndrome.yaml as a substring; that hit is spurious. Pathograph: Reduced RBM8A Gene Dosage -> Y14 Protein Insufficiency -> Exon Junction Complex Insufficiency -> (Megakaryocyte Maturation Failure -> Thrombocytopenia; Radial Ray Developmental Failure -> Bilateral radial aplasia). Dosage framing revised after curator review. The Y14 Protein Insufficiency node previously asserted a threshold effect operating in a cell-type- and developmental-stage-dependent way, which blended two models the source explicitly declines to choose between: Albers states the results are "compatible with both a dose-effect phenomenon and a lineage dependent deficiency of Y14". The node now asserts only the settled negative claim, that this is not plain haploinsufficiency, and the two models are recorded as mechanistic_hypotheses y14_dose_effect and y14_lineage_dependence, both ALTERNATIVE. The two branch edges out of Exon Junction Complex Insufficiency opt into both groups, since that is where the models make different predictions. They are not mutually exclusive, which the hypothesis notes say. IBMFS classification researched at curator request rather than assumed. TAR is conventionally listed among the inherited bone marrow failure syndromes and the NCI cohort NCT00027274 enrolls it as one, but the literature states directly that "TAR syndrome is not generally associated with bone marrow failure or malignancy", and a 2017 review counted only four reported leukemia cases in the whole literature. Recorded as an INTERPRETATION discussion rather than as phenotype content, because the finding is a reported near-absence; the trial description was also qualified so enrollment is not read as evidence of a predisposition. This is another instance of the gap in #10190: the most useful statement here is a negative one. A stop-hook untracked-file warning surfaced a defect worth recording. Two case reports fetched while researching the IBMFS question were left uncommitted, and checking why showed the discussion rationale asserted that "further single cases have appeared since, including Philadelphia-positive AML and juvenile myelomonocytic leukemia" with no evidence item behind it. The fix was to cite them (PMID:39393038, PMID:41925074), not to delete the files, since deleting would have left the prose claim unsupported. A prose assertion inside a rationale is still an assertion and needs the same backing as one in a description. Flagged while doing so: PMID:41925074 reports its patient as homozygous for RBM8A c.-21G>A rather than carrying the compound null-plus-hypomorph genotype this entry models, and GeneReviews states biallelic hypomorph carriers are asymptomatic. Recorded in the discussion notes and deliberately not acted on; one case report does not revise an inheritance model, and it may be a reporting simplification. Automated review (ai4c-reviewer, CHANGES_REQUESTED on PR #10440) requested four changes, all addressed. Item 1: added a top-level references block tagging PMID:20301781 as GeneReviews, which a new Mendelian entry requires. Item 2: modelled the GeneReviews NSAID/aspirin avoidance recommendation as a supportive-care treatment; the quote was already in the cache and had been verified earlier in the session but never used. Item 3: added Abnormal bleeding (HP:0001892) and Gastrointestinal hemorrhage (HP:0002239). Item 4: added Abnormality of the upper limb (HP:0002817). Item 3 needed no new fetch in the end. The reviewer expected one because the deep-research report's hemorrhage statistics trace to a De Alarcon book chapter whose cache is content_type unavailable and therefore not quotable. PMID:41925074, already cited for the JMML case, carries "Mortality in TAR syndrome, mainly due to hemorrhage, is generally confined to the first year of life", which supports the claim directly. Intracranial hemorrhage specifically was NOT added: no cached source states it, and binding a term on the strength of an unquotable secondary figure would be the fabrication risk the evidence SOP exists to prevent. Gastrointestinal hemorrhage is added because PMID:36872795 documents a TAR neonate with frank rectal bleeding. Non-blocking suggestions also taken: Mullerian agenesis (HP:0000151), the GeneReviews recurrence-risk figures on the inheritance block, the intron-1 allele rs201779890 in variants, splitting the mixed in-vitro/patient-platelet snippet into two items with one evidence_source each, regrading the EJC-composition definitional statement from HUMAN_CLINICAL to OTHER, and deleting six orphaned DOI reference caches left over from the DOI-to-PMID conversion. The earlier rationale for keeping those caches (that the research report cites the DOIs) does not hold: the report carries its own citations sidecar and its validation section is already baked in, so nothing depends on them. Self-caught during the review response: two reference caches were staged and pushed without being cited, the same orphan-cache defect the reviewer had just flagged. PMID:3056062 (Hedberg, 100-case review) was then actually used, adding periodic leukemoid reaction and eosinophilia, which closes another non-blocking gap the review listed. PMID:33282142 (a dental implant case report) was not useful and was removed. Every reference cache this branch adds is now cited by the entry. Re-review approved the PR and left one non-blocking suggestion: several phenotypes were pathograph leaves with no incoming causal edge. Four edges were wired, each with its own cited evidence: Thrombocytopenia -> Abnormal bleeding, Abnormal bleeding -> Gastrointestinal hemorrhage, Megakaryocyte Maturation Failure -> Megakaryocytopenia, and Radial Ray Developmental Failure -> Abnormality of the upper limb. The remaining leaves are deliberate and now documented in the entry notes rather than left looking like an oversight: the leukocyte and eosinophil findings, uterine aplasia, and the lower-limb, renal and cardiac anomalies. The reviewer agreed the genitourinary and leukocyte features are mechanistically unresolved. The lower-limb anomaly was specifically not attached to Radial Ray Developmental Failure: that node covers forelimb patterning, so parenting a lower-limb phenotype to it would assert a mechanism no source states, even though one cited sentence happens to mention both. Note that this push dismisses the approval, since main runs dismiss_stale_reviews. That is the accepted cost of taking the suggestion rather than a reason to skip it. Third review caught a real evidence error in the pathograph-wiring commit. The Abnormal bleeding -> Gastrointestinal hemorrhage edge was cited to PMID:36872795 with a snippet about worsening blood counts. That sentence says nothing about bleeding, and worse, that paper attributes its patient's bloody stool to cow's milk protein allergy which resolved when enteral feeds were held. Citing it for a thrombocytopenia-driven GI bleed argued against the source's own conclusion. The entry already knew the distinction: the phenotype description says the bleeding may be compounded by the milk allergy, and the edge was the one place that nuance was dropped. Fixed by swapping the evidence to PMID:41925074, already cited elsewhere here, which reports recurrent hematochezia tracking with persistent thrombocytopenia and requiring ongoing platelet transfusions. That is the thrombocytopenic route the edge asserts. The edge description now also states explicitly that not every GI bleed in TAR is thrombocytopenic in origin, so the two causes are told apart rather than conflated. The phenotype's own evidence stays on PMID:36872795, where it is correct. Worth recording how this got past me: the snippet was an exact substring of a cached, on-topic paper, so every mechanical check passed. check-source-defect-claims passes both before and after. Only reading the cited paper's conclusion catches a quote that supports the wrong claim. Two curation judgments worth review. First, the genotype-phenotype relation is modelled as a dosage threshold rather than haploinsufficiency, because 1q21.1 deletion carriers and individuals homozygous for the hypomorphic regulatory allele are both healthy. Second, the mechanism linking the regulatory SNPs to reduced Y14 protein is recorded as an open KNOWLEDGE_GAP rather than asserted in the causal edge: reporter assays show reduced promoter activity, but allele-specific expression in platelet RNA from healthy heterozygotes showed no difference, and the source authors state the mechanism remains open. Ontology note: preserved thumbs were initially curated as an unbound phenotype and were later moved to the diagnosis section. Running the threshold-aware compliance analyzer against conf/qc_config.yaml showed this was the entry's only violation: phenotypes[].phenotype_term.term at 88.9% against a 90% floor, caused by that single unbindable slot. The fix was not to force a binding but to correct the modelling. HPO is an ontology of phenotypic abnormalities and a present, normally formed thumb is a normal finding, which is why exhaustive search returns only thumb-malformation terms and nothing for a preserved thumb. The finding's entire significance in TAR is as a discriminator from the thumb-absent radial ray syndromes, which is a diagnostic role. Moving it lost no information: the fact was already stated with evidence in seven other places, and nothing referenced it as an entity reference or pathograph target. Phenotype term coverage is now 100% (8/8) and the entry has no threshold violations. Superseded note: 'Preserved thumbs' was deliberately left unbound. HPO has no positive term for a thumb preserved in the presence of radial aplasia, and binding a thumb-malformation term would assert the opposite of the finding. GO:0035145 (exon-exon junction complex) was initially placed in molecular_functions and moved to cellular_components after term validation rejected it; the CURIE and label were correct but the term is a cellular component. References: five, all fetched and title-verified before use. PMID:20301781 (GeneReviews), PMID:22366785 (Albers 2012, mechanism), PMID:17236129 (Klopocki 2007, microdeletion), PMID:12471199 (Greenhalgh 2002, 34-patient cohort frequencies), PMID:36872795 (birth prevalence). Three PMIDs recalled from memory during drafting proved to name unrelated papers and were discarded before use; all citations here were resolved via PubMed E-utilities and confirmed against the fetched title. Correction during curation: clinical_course: PROGRESSIVE was initially set on the Thrombocytopenia phenotype and removed. It contradicted the cited sources and this entry's own description, both of which state the thrombocytopenia remits with age. ClinicalCourseEnum offers only PROGRESSIVE and STABLE, neither of which describes a remitting course, so the slot is left absent and the natural history is carried in prose and evidence. Post-curation deep-research cross-check (falcon / Edison Scientific Literature, template_sha 1e7ea4ee). Run after the entry was curated from primary sources, so it was used as a gap-finder, not a source. Its preflight raised a Named Entity Confusion WARN on rival gene TPO at 41% of RBM8A mentions; investigated and cleared, because the TPO material is genuine TAR megakaryocyte biology rather than drift into congenital amegakaryocytic thrombocytopenia. Several of the report's own references were unusable (Unknown journal, no PMID/DOI) and were not cited. Four things were taken from it and independently re-verified before use: PMID:37611607 (Strauss 2023), which prompted softening the closed "one of two SNPs" claim because further TAR-associated SNPs are still being identified; clinicaltrials:NCT00027274 and NCT00086476; and the observation that no published model recapitulates the full triad, which corroborates the FAILS_TO_RECAPITULATE grading already recorded. Additions in the same pass: datasets geo:GSE5781 (the array CGH series from the Klopocki study already cited) and geo:GSE240611, both accession-verified; nine GENE_ONLY dataset candidates were rejected on relevance triage as Named Entity Confusion via RBM8A. Evidence added to the animal model, the RUSAT differential (PMID:26581901) and all three treatment mechanism links. Compliance rose from 90.8% to 95.6%; every remaining gap is deliberate - the unbound Preserved thumbs phenotype, the two dataset records which by repository policy carry publication and notes rather than evidence, and the two registry external assertions. Second pass from the report's full BibTeX citation list, which carried DOIs for entries the report's numbered list had shown only as "Unknown journal". Three were usable and filled a section the entry lacked entirely, prenatal care: Weinblatt 1994 (DOI:10.1002/pd.1970140922) for sonographic detection, cordocentesis and in utero platelet transfusion; Bottillo 2013 (DOI:10.1186/1756-0500-6-376) for the prenatal presentation and for naming the recurrent hypomorphic allele rs139428292; and Bastida 2021 (DOI:10.3390/ijms22094330), used only to establish a knowledge gap, since its reported TPO-RA diagnoses do not include TAR and it therefore cannot support a treatment claim here. Two citation-list entries (sanchez2020, clemence2023) remain journal-less with no DOI and were not used; the OpenTargets entry is a tool query, not a publication. Added in this pass: a diagnosis section (prenatal ultrasound, cordocentesis, molecular confirmation of both alleles), an In Utero Platelet Transfusion treatment, a variants entry for rs139428292, and a second KNOWLEDGE_GAP on TPO-receptor agonists. The rs139428292 variant is classified regulatory_category mLOE rather than LOE on the schema's own distinction: mLOE is modular loss of expression affecting only a subset of cell types, and the Albers reporter assays showed reduced activity in megakaryocytic and osteoblast lines but not in endothelial or HEK293 cells. That is the same cell-type restriction the entry uses to model the phenotype as tissue-selective. The three DOI-cited references were subsequently replaced by their PMIDs, resolved via PubMed on the [AID] field and confirmed by fetching each and matching the title: 10.1002/pd.1970140922 -> PMID:7845901, 10.1186/1756-0500-6-376 -> PMID:24053387, 10.3390/ijms22094330 -> PMID:33919295. This was done because linkml-reference-validator skips DOI-prefixed snippets, so those six quotes were unchecked by tooling and verified only by hand; the entry now reports 52 of 52 verified with nothing skipped. Two of the PMID records also carry fuller text than the DOI records did. Swapping surfaced a real discrepancy: the DOI record renders "Wiskott-Aldrich" with an en dash and the PubMed record with a hyphen, so the snippet had to be corrected to stay an exact substring. The DOI cache files are retained because the deep-research report itself cites those DOIs; they are the report's references, not the entry's. Trial status correction: NCT00086476 was initially recorded as RECRUITING from assumption and corrected to COMPLETED against the ClinicalTrials.gov API, which the cached record does not carry. Validation: just validate passes schema and term validation with 36/36 snippets verified against cached references. check-causal-targets, check-entity-refs, check-duplicate-keys, check-qualifier-terms and check-enum-values all pass.

Falcon ▸
Thrombocytopenia–Absent Radius Syndrome (TAR): Disease-Characteristics Research Report
Edison Scientific Literature 26 citations 2026-09-01T20:44:36.787352

Thrombocytopenia–Absent Radius Syndrome (TAR): Disease-Characteristics Research Report

Executive summary

Thrombocytopenia–absent radius syndrome (TAR syndrome) is a rare congenital Mendelian disorder defined by bilateral radial aplasia with preserved thumbs and transient, sometimes profound, hypomegakaryocytic thrombocytopenia. The usual molecular cause is compound inheritance of one null RBM8A allele—most often a recurrent approximately 200-kb 1q21.1 deletion—and a hypomorphic regulatory allele on the other chromosome. The major early threat is intracranial, gastrointestinal, or other severe hemorrhage during infancy; platelet counts and bleeding tendency usually improve with age. Limb differences remain lifelong and may require occupational therapy and reconstructive surgery. Current care is supportive; no disease-modifying drug, gene therapy, or TAR-specific interventional trial has established efficacy.

Domain Knowledge-base statement Quantitative/variant detail Evidence type and key source
Disease identifiers Thrombocytopenia-absent radius (TAR) syndrome is a Mendelian disorder characterized by thrombocytopenia with bilateral absence of the radii and preserved thumbs. MONDO_0010121; OMIM 274000. Review text states TAR is characterized by platelet counts generally <50 × 10^9/L and bilateral absent radii with both thumbs present. Disease ontology association and review evidence (OpenTargets Search: thrombocytopenia-absent radius syndrome-RBM8A, sanchez2020moleculargeneticaspects pages 1-4)
Defining phenotype The hallmark clinical combination is bilateral radial aplasia/agenesis with normal thumbs plus neonatal/infant thrombocytopenia due to reduced megakaryocytes. Distinguishes TAR from Fanconi anemia, Holt-Oram syndrome, and Roberts syndrome, where thumbs are absent or hypoplastic. Megakaryocytes are absent or reduced in marrow. Clinical review/book chapter and review article (alarcon2005newbornplateletdisorders pages 33-35, sanchez2020moleculargeneticaspects pages 1-4)
Epidemiology TAR is rare. Approximate incidence reported as 1 in 240,000 live births and 0.42 per 100,000 individuals/live births. Slight female predominance reported. Clinical review/case-based summary (sanchez2020moleculargeneticaspects pages 1-4, bottillo2013prenataldiagnosisand pages 1-2, clemence2023aneonatewith pages 3-4)
Core genetics TAR syndrome is caused by compound inheritance involving one null RBM8A allele and one hypomorphic noncoding RBM8A allele. Null allele usually a ~200 kb 1q21.1 microdeletion; hypomorphic alleles include rs139428292 (5'UTR) and rs201779890 (intron 1). Molecular genetics review and disease-target evidence linking RBM8A to TAR (sanchez2020moleculargeneticaspects pages 4-7, bottillo2013prenataldiagnosisand pages 1-2, sanchez2020moleculargeneticaspects pages 1-4, OpenTargets Search: thrombocytopenia-absent radius syndrome-RBM8A)
Deletion statistics The 1q21.1 deletion is necessary but not sufficient on its own. In a 30-patient series, the heterozygous 1q21.1 ~200 kb deletion was found in 100% of TAR cases; 75% inherited, 25% de novo; present in 32% of unaffected relatives. Summarized primary human genetics evidence from review (sanchez2020moleculargeneticaspects pages 4-7)
Molecular mechanism RBM8A encodes Y14, a component of the exon-junction complex (EJC); reduced Y14 is the leading mechanistic explanation for hematopoietic defects in TAR. Y14 is a 174-aa protein in the 4-subunit EJC; functions include mRNA export, localization, translation efficiency, and nonsense-mediated decay. Y14 levels are reduced in patient platelets. Complete biallelic loss is thought incompatible with life. Molecular review/mechanistic synthesis (sanchez2020moleculargeneticaspects pages 4-7, sanchez2020moleculargeneticaspects pages 1-4)
Megakaryopoiesis/TPO signaling Thrombocytopenia reflects impaired megakaryopoiesis with abnormal thrombopoietin (TPO) signaling in at least a subset of patients. In reported series, marrow megakaryocytes were absent in 28/52 and decreased in 22/58 cases; studies showed abnormal TPO-induced tyrosine phosphorylation and one report of failed JAK2 phosphorylation. Clinical review summarizing primary functional studies (alarcon2005newbornplateletdisorders pages 33-35, alarcon2005newbornplateletdisorders pages 35-36)
Phenotype frequencies (34-patient series) TAR is multisystemic beyond the upper limbs. In a 34-patient series: 100% bilateral radial aplasia, 100% thrombocytopenia, 47% cow’s milk intolerance, 47% lower-limb involvement, 23% renal anomalies, 15% cardiac anomalies, 3% cleft palate. Another review text reports cardiac and renal anomalies in 47% and 23%, respectively. Clinical review/book chapter and review synthesis (alarcon2005newbornplateletdisorders pages 35-36, sanchez2020moleculargeneticaspects pages 1-4)
Temporal course and mortality The highest bleeding risk is in early infancy; platelet counts often improve with age. 50–60% of hemorrhagic episodes occur in the first week of life; 82% had platelet counts <50,000/mm^3 at birth in one series; mortality reported as 21/77 overall with 14 deaths within 4 months, all with platelets <30,000/mm^3. Neonatal mortality of about 25% from hemorrhage has also been reported. Clinical reviews and prenatal case report (weinblatt1994prenatalevaluationand pages 3-5, alarcon2005newbornplateletdisorders pages 33-35, clemence2023aneonatewith pages 3-4, sanchez2020moleculargeneticaspects pages 1-4)
Prenatal findings TAR can be suspected prenatally from limb findings and confirmed with targeted fetal/genetic testing. Prenatal ultrasound can identify bilateral radial defects with preserved thumbs; fetal platelet count of 40,000/mm^3 was documented by cordocentesis in one case. In a 2023 prenatal CNV cohort, 4 cases involved the TAR region among 26 1q21.1 CNV pregnancies from 8,252 tested pregnancies. Prenatal case report and 2023 prenatal cohort (weinblatt1994prenatalevaluationand pages 2-3, weinblatt1994prenatalevaluationand pages 3-5, yue2023prenatalphenotypesand pages 1-2, bottillo2013prenataldiagnosisand pages 1-2)
Diagnostic approach Diagnosis is clinical-radiologic plus molecular confirmation. Key tests: CBC/platelet count, bone marrow megakaryocyte assessment when needed, limb radiographs, and genetics with chromosomal microarray for 1q21.1 deletion plus RBM8A sequencing/genotyping for hypomorphic alleles. Differential diagnosis includes Fanconi anemia, Holt-Oram syndrome, Roberts syndrome, and other radial-ray disorders. Review and prenatal molecular case report (sanchez2020moleculargeneticaspects pages 1-4, bottillo2013prenataldiagnosisand pages 1-2, weinblatt1994prenatalevaluationand pages 2-3)
Standard treatment Management is largely supportive, focused on bleeding prevention and orthopedic function. Platelet transfusion is the main acute therapy, especially for severe thrombocytopenia, surgery, or infection-related drops; reconstructive hand surgery may benefit selected patients and is often delayed until bleeding risk falls. In utero platelet transfusion has been reported in severe prenatal thrombocytopenia. Clinical management reports and 2023 review snippet (weinblatt1994prenatalevaluationand pages 3-5, weinblatt1994prenatalevaluationand pages 2-3, strauss2023thrombocytopeniaabsentradius pages 1-1)
Current research and trials Current published progress is mainly in genetics, prenatal diagnosis, and patient-network/self-empowerment; there is little TAR-specific interventional evidence. Retrieved ClinicalTrials.gov records were observational, not TAR-specific drug trials: NCT00086476 (completed megakaryocyte study; actual enrollment 3) and NCT00027274 (recruiting IBMFS natural-history study; estimated enrollment 4000). No retrieved TAR-specific gene, RNA, cell therapy, HSCT standard-of-care, or TPO-receptor-agonist trial evidence. 2023 review and clinical-trial records (strauss2023thrombocytopeniaabsentradius pages 1-1, NCT00086476 chunk 1, NCT00027274 chunk 1, bastida2021roleofthrombopoietin pages 15-16)

Table: This table summarizes the most actionable disease-knowledge facts for thrombocytopenia-absent radius syndrome using only evidence already retrieved in the session. It highlights identifiers, defining features, epidemiology, RBM8A genetics, phenotype frequencies, natural history, diagnostic workup, standard care, and current evidence gaps.

Evidence conventions: “Human cohort/case” denotes direct clinical evidence; “functional” denotes patient-cell or in-vitro evidence; “review” denotes secondary synthesis. Frequencies derive mainly from small historical series and should not be treated as precise population penetrance estimates.

1. Disease information

Definition and classification

TAR syndrome is a congenital syndromic thrombocytopenia/radial-ray malformation disorder. Its defining combination is: (1) bilateral absence or severe hypoplasia of the radii, (2) bilateral preservation of the thumbs, and (3) thrombocytopenia, commonly below 50 × 10^9/L in infancy. Preserved thumbs are diagnostically important because thumbs are usually absent or hypoplastic in Fanconi anemia, Holt–Oram syndrome, and Roberts syndrome. The disorder was described in 1959 and delineated as a syndrome by Judith Hall in 1969. A useful exact summary from a 2020 review is: “characterized by bilateral absence of the radii with the presence of both thumbs and thrombocytopenia.” (Review; published 2020.) (sanchez2020moleculargeneticaspects pages 1-4)

Identifiers and synonyms

  • MONDO: MONDO:0010121.
  • OMIM: 274000.
  • Orphanet: commonly indexed as ORPHA:3320; this identifier should be validated against the current Orphanet release before database ingestion.
  • Gene–disease association: RBM8A, Ensembl ENSG00000265241; Open Targets reports five association-evidence records, all linked to PMID 22366785. (OpenTargets Search: thrombocytopenia-absent radius syndrome-RBM8A)
  • ICD-10/ICD-11: no adequately specific TAR code was established in the retrieved evidence; coding generally uses congenital limb-malformation and thrombocytopenia categories.
  • MeSH: no dedicated TAR descriptor was established here; broader concepts include inherited blood-platelet disorders, thrombocytopenia, and congenital limb deformities.
  • Synonyms: thrombocytopenia with absent radius/radii; thrombocytopenia–absent radii syndrome; radial aplasia–thrombocytopenia syndrome; TAR syndrome.

This report synthesizes aggregated disease-level literature, small cohorts, individual case reports, database records, and trial registries—not patient-specific EHR data.

2. Etiology, risk, protection, and gene–environment interaction

Causal genetic architecture

TAR is best described as autosomal-recessive compound inheritance with one null and one hypomorphic RBM8A allele, rather than classic inheritance of two rare coding variants. The null allele is usually a recurrent approximately 200-kb proximal 1q21.1 deletion containing RBM8A; rarer frameshift or nonsense null alleles occur. The trans allele generally carries a low-frequency regulatory variant, especially rs139428292 in the 5′ UTR or rs201779890 in intron 1, which reduces RBM8A expression. The landmark discovery is Albers et al., Nature Genetics 2012, PMID 22366785, DOI 10.1038/ng.1083. (OpenTargets Search: thrombocytopenia-absent radius syndrome-RBM8A, sanchez2020moleculargeneticaspects pages 4-7, bottillo2013prenataldiagnosisand pages 1-2)

In an early 30-patient series, the approximately 200-kb deletion occurred in 100% of affected patients, but also in 32% of unaffected relatives; 75% were inherited and 25% de novo. Thus, the deletion alone is neither sufficient nor equivalent to TAR. Among inherited deletions, approximately two-thirds were maternal and one-third paternal in the cited synthesis. (Human genetics summarized in review.) (sanchez2020moleculargeneticaspects pages 4-7, bottillo2013prenataldiagnosisand pages 1-2)

Risk and modifier factors

  • Established genetic risk: a null RBM8A allele in trans with a hypomorphic RBM8A regulatory allele.
  • Genotype–phenotype modifier: patients carrying the 5′-UTR hypomorphic allele have, on average, lower platelet counts than carriers of the intron-1 allele. (sanchez2020moleculargeneticaspects pages 4-7)
  • Possible clinical triggers: infection and cow’s-milk exposure/intolerance can coincide with thrombocytopenic episodes, but they do not cause the congenital syndrome. Cow’s-milk intolerance occurred in 47% of one 34-patient series. (alarcon2005newbornplateletdisorders pages 33-35, alarcon2005newbornplateletdisorders pages 35-36)
  • Environmental, occupational, infectious, lifestyle, sex, and age causes: none is established as an initiating cause. A slight female excess is reported, but this is not a proven biological risk factor. (clemence2023aneonatewith pages 3-4, sanchez2020moleculargeneticaspects pages 1-4)
  • Protective alleles: none validated.
  • Environmental protection: avoiding recognized individual triggers, especially cow’s-milk protein when clinically implicated, may reduce episodes but does not prevent the genotype or limb defect.
  • Gene–environment interaction: plausible for episodic platelet worsening during infection or food intolerance, but no quantified molecular G×E model was found.

There is no basis for attributing TAR to smoking, alcohol, pollution, radiation, or maternal infection. Such exposures instead belong in the differential diagnosis of acquired or teratogenic limb abnormalities.

3. Phenotypes

Major phenotype matrix

  • Thrombocytopenia—laboratory abnormality: congenital/early infancy; severe, fluctuating, and episodic early, usually improving after infancy. Suggested HPO: Thrombocytopenia (HP:0001873) and Amegakaryocytic/hypomegakaryocytic thrombocytopenia. In one series, 82% had platelets below 50,000/mm³ at birth; symptoms occur in up to 90%, with 50% presenting at birth and 95% within the first weeks. (alarcon2005newbornplateletdisorders pages 33-35, clemence2023aneonatewith pages 3-4)
  • Bleeding—sign/symptom: petechiae, ecchymoses, epistaxis, gastrointestinal bleeding, and potentially fatal intracranial hemorrhage or DIC. Suggested HPO: petechiae, ecchymosis, epistaxis, gastrointestinal hemorrhage, intracranial hemorrhage. Frequency and severity decline with age. (weinblatt1994prenatalevaluationand pages 3-5, clemence2023aneonatewith pages 3-4, sanchez2020moleculargeneticaspects pages 1-4)
  • Bilateral radial aplasia—physical manifestation: congenital, stable, 100% in the classic 34-patient series; thumbs are present. Suggested HPO: bilateral radial aplasia/absent radius and preserved thumb. (alarcon2005newbornplateletdisorders pages 35-36)
  • Other upper-limb anomalies: ulnar or hand abnormalities in 75–78%; humeral abnormalities in approximately 40%. Findings include ulnar/humeral hypoplasia or aplasia, radial deviation, limited finger extension, and carpal/phalangeal hypoplasia. (alarcon2005newbornplateletdisorders pages 33-35, sanchez2020moleculargeneticaspects pages 1-4)
  • Lower-limb anomalies: 47% in a 34-patient series; usually less severe than upper-limb defects. Hip dislocation, knee subluxation, tibial anomalies, genu varum, and absent patella are described. (alarcon2005newbornplateletdisorders pages 33-35, alarcon2005newbornplateletdisorders pages 35-36, sanchez2020moleculargeneticaspects pages 1-4)
  • Cow’s-milk intolerance/allergy: 47% in the 34-patient series; predominantly infancy/childhood and potentially associated with platelet exacerbations. Suggested HPO: food intolerance/cow’s-milk allergy. (alarcon2005newbornplateletdisorders pages 33-35, alarcon2005newbornplateletdisorders pages 35-36)
  • Renal/urogenital anomalies: 23% in the 34-patient series; renal malrotation, horseshoe kidney, duplicated ureter, renal-pelvic dilatation, cryptorchidism, Müllerian anomalies. Suggested HPO terms corresponding to each finding. (alarcon2005newbornplateletdisorders pages 33-35, sanchez2020moleculargeneticaspects pages 1-4)
  • Cardiac anomalies: estimates vary—15% in one tabulation and as high as approximately one-third or 47% in other summaries, indicating ascertainment/series heterogeneity. Septal defects, tetralogy of Fallot, coarctation, dextrocardia, and ventricular hypertrophy are reported. (alarcon2005newbornplateletdisorders pages 33-35, alarcon2005newbornplateletdisorders pages 35-36, sanchez2020moleculargeneticaspects pages 1-4)
  • Cleft palate: 3% in one 34-patient series. (alarcon2005newbornplateletdisorders pages 35-36)
  • Neurologic/cerebrovascular abnormalities: uncommon; corpus-callosum agenesis, cerebellar-vermis hypoplasia, and intracranial vascular malformations are reported. Neurodevelopmental disability is not considered intrinsic, although hemorrhagic brain injury can cause secondary disability. (clemence2023aneonatewith pages 3-4, sanchez2020moleculargeneticaspects pages 1-4)
  • Transient leukemoid reaction: leukocytes above 35,000/mm³ have been reported without leukemia. (bottillo2013prenataldiagnosisand pages 1-2, sanchez2020moleculargeneticaspects pages 1-4)

Quality of life

No TAR-specific EQ-5D, SF-36, PROMIS, or validated disease-specific quality-of-life study was retrieved. Anticipated burdens include infant hospitalizations and transfusions, bleeding anxiety, feeding restriction, reduced upper-limb reach/grip and self-care, orthopedic procedures, and psychosocial effects of visible limb difference. Occupational adaptation can yield substantial independence. These are clinically reasonable impacts, but quantitative utilities are unavailable.

4. Genetic and molecular information

Causal gene: RBM8A, RNA binding motif protein 8A, encoding Y14, a 174-amino-acid exon-junction-complex protein. The Open Targets association score was 0.779, supported by five evidence records tied to PMID 22366785. (OpenTargets Search: thrombocytopenia-absent radius syndrome-RBM8A, sanchez2020moleculargeneticaspects pages 4-7)

Variant classes and origin: germline structural deletion, frameshift, nonsense, and noncoding regulatory variants. The recurrent deletion is commonly de novo or inherited from an unaffected carrier; the regulatory alleles are inherited hypomorphic alleles. These are not somatic cancer mutations. Complete biallelic Y14 loss is presumed embryonic lethal because no surviving complete-loss genotype has been documented. (sanchez2020moleculargeneticaspects pages 4-7, bottillo2013prenataldiagnosisand pages 1-2)

Functional consequence: reduced RBM8A/Y14 dosage, not gain of function or dominant negativity. Y14 is part of the four-subunit exon-junction complex, contributing to mRNA export/localization, translational efficiency, and nonsense-mediated decay. Patient platelets have reduced Y14. A 2020 review stated that TAR was the first human disease associated with a defect in an exon-junction-complex subunit. (sanchez2020moleculargeneticaspects pages 4-7, sanchez2020moleculargeneticaspects pages 1-4)

Allele frequency and ACMG interpretation: exact gnomAD frequencies and current ClinVar classifications were not retrieved. The two common hypomorphic alleles should not be classified independently as fully penetrant pathogenic variants: pathogenicity is genotype/context dependent. The deletion/null allele plus a trans hypomorphic allele constitutes the disease-causing configuration.

Chromosomal abnormality: proximal 1q21.1 BP2–BP3/TAR-region deletion, approximately 0.2 Mb. This region is rich in low-copy repeats and susceptible to non-allelic homologous recombination. (bottillo2013prenataldiagnosisand pages 1-2, yue2023prenatalphenotypesand pages 1-2)

Modifier genes/epigenetics: no replicated modifier gene, disease-specific methylation signature, histone alteration, or chromatin biomarker was identified. Larger 1q21.1 CNVs can produce additional phenotypes, but should not be conflated with classic biallelic RBM8A insufficiency.

5. Environmental information

No toxin, radiation, pollution, occupation, lifestyle, or infectious agent causes inherited TAR syndrome. Infection may exacerbate thrombocytopenia; cow’s-milk protein may trigger gastrointestinal/allergic illness and platelet worsening in susceptible infants. These are downstream modifiers, not primary etiology. There is no zoonotic or transmissible component. (alarcon2005newbornplateletdisorders pages 33-35, strauss2023thrombocytopeniaabsentradius pages 1-1)

6. Mechanism and pathophysiology

Ordered causal chain

  1. A germline RBM8A null allele plus a trans hypomorphic regulatory allele leads to reduced RBM8A/Y14 dosage. (Demonstrated.)
  2. Reduced Y14 leads to impaired exon-junction-complex-dependent RNA processing, translation regulation, and nonsense-mediated decay. (Y14’s functions demonstrated; disease-relevant transcripts remain incompletely mapped.)
  3. Altered RNA handling leads to lineage-sensitive defects in megakaryocyte proliferation/maturation and thrombopoietin responsiveness. (Supported by patient marrow/cell studies; the precise transcript-to-cell causal bridge remains partly inferred.)
  4. Defective megakaryopoiesis leads to absent/decreased marrow megakaryocytes, low ploidy/small megakaryocytes, inadequate platelet production, and sometimes platelet functional defects. (Demonstrated.)
  5. Reduced platelet number/function leads to petechiae, mucosal bleeding, gastrointestinal hemorrhage, intracranial hemorrhage, and occasionally DIC, especially in early infancy. (Demonstrated clinically.)
  6. Branch A: developmental Y14 insufficiency leads to—by a mechanism not yet demonstrated— abnormal radial-ray and sometimes lower-limb, cardiac, and renal development.
  7. Branch B: infection or cow’s-milk-associated inflammatory/allergic stress may lead to episodic platelet decline and increased bleeding. (Clinical association; mechanism inferred.)
  8. Developmental maturation/compensation leads to rising platelet counts and fewer bleeding episodes with age. (Clinical natural history demonstrated; molecular basis uncertain.)

Marrow megakaryocytes were absent in 28/52 and decreased in 22/58 reported cases. Patient studies found heterogeneous TPO biology: elevated TPO in some patients, abnormal CFU-megakaryocyte formation, small low-ploidy megakaryocytes, failure of TPO-induced tyrosine phosphorylation despite receptor presence, and failed JAK2 phosphorylation in one case. These findings implicate the TPO/MPL–JAK2 signaling axis, but they do not establish an MPL mutation or a uniform signaling lesion in all TAR patients. (alarcon2005newbornplateletdisorders pages 33-35, alarcon2005newbornplateletdisorders pages 35-36)

Suggested annotations include GO: mRNA splicing via spliceosome; exon-junction complex assembly; nonsense-mediated mRNA decay; regulation of translation; megakaryocyte differentiation; platelet formation; cellular response to thrombopoietin. Cell Ontology: hematopoietic stem cell; megakaryocyte progenitor; megakaryocyte; platelet. GO cellular components: nucleus, nuclear speck, spliceosomal complex/exon-junction complex, cytoplasm.

No robust TAR-specific metabolomic, lipidomic, proteomic, single-cell, spatial-transcriptomic, or multi-omic signature was found. The skeletal mechanism remains a major expert-identified knowledge gap; the 2020 review explicitly concluded that further research was needed to explain the relationship between RBM8A and skeletal manifestations. (sanchez2020moleculargeneticaspects pages 1-4)

7. Anatomical structures affected

  • Primary: bilateral radius (forearm; usually complete aplasia), bone marrow megakaryocytic lineage, circulating platelets.
  • Additional musculoskeletal: ulna, humerus, scapula, carpal bones, phalanges, hips, knees, tibiae, and patellae.
  • Secondary/variable: heart and great vessels; kidneys, ureters, uterus/vagina, testes; palate; gastrointestinal tract; brain/cerebrovasculature.
  • Lateralization: radial defect is characteristically bilateral; severity can be asymmetric. Thumbs are bilateral and preserved.
  • Suggested UBERON concepts: radius, ulna, humerus, hand, thumb, lower limb, bone marrow, heart, kidney, ureter, uterus, brain.
  • Tissues/cells: developing mesenchyme/skeletal connective tissue and hematopoietic tissue; megakaryocyte progenitors and megakaryocytes are the best-supported affected cells.
  • Subcellular: nuclear/cytoplasmic exon-junction complex and RNA-processing machinery; no primary mitochondrial, lysosomal, or ER defect has been established. (alarcon2005newbornplateletdisorders pages 33-35, sanchez2020moleculargeneticaspects pages 1-4)

8. Temporal development

The limb malformation is embryonic and congenital. Thrombocytopenia is usually neonatal or emerges within the first four months; approximately 50–60% of hemorrhagic manifestations occur in the first week. The first year, especially the first four months, is the critical mortality window. The first two years carry the greatest morbidity, after which platelet counts commonly become subnormal or normal and bleeding becomes less frequent. The skeletal phenotype is stable, although functional consequences evolve with growth. (weinblatt1994prenatalevaluationand pages 3-5, alarcon2005newbornplateletdisorders pages 33-35, clemence2023aneonatewith pages 3-4, sanchez2020moleculargeneticaspects pages 1-4)

There is no formal staging system. A practical course model is: prenatal structural phase → neonatal high-risk thrombocytopenic phase → fluctuating infant phase → improving childhood hematologic phase → lifelong orthopedic/functional phase. Remission is usually spontaneous hematologic improvement rather than cure of the genotype.

9. Inheritance and population

Reported incidence is approximately 1 in 240,000 live births, equivalent to about 0.42 per 100,000. No reliable prevalence, annual incidence, carrier frequency, or geographic/ethnic gradient was identified. TAR has been reported across populations. (bottillo2013prenataldiagnosisand pages 1-2, sanchez2020moleculargeneticaspects pages 1-4)

Inheritance is autosomal recessive in functional terms, but recurrence depends on the exact parental alleles. Penetrance of the isolated deletion is incomplete; variable expressivity is substantial. No anticipation, repeat expansion, mitochondrial inheritance, or established founder effect is known. Germline mosaicism is theoretically possible for a de novo deletion but was not quantified. Consanguinity is not required because one disease allele is often a low-frequency regulatory variant. A slight female predominance was reported, approximately 0.8 male:1 female, but small cohorts limit inference. (sanchez2020moleculargeneticaspects pages 4-7, sanchez2020moleculargeneticaspects pages 1-4)

Genetic counseling must phase the deletion/null allele and hypomorphic allele, test both parents, and calculate recurrence from the actual parental genotypes—not simply quote 25% without qualification.

10. Diagnostics

Clinical and laboratory diagnosis

The core work-up is CBC with serial platelet counts; examination for bleeding; bilateral limb radiography documenting radial aplasia and preserved thumbs; and assessment for cardiac, renal, lower-limb, and feeding/allergy involvement. Bone-marrow examination is not routinely required in a classic molecularly confirmed case, but when performed it shows absent/decreased megakaryocytes. Platelet function may also be abnormal. (alarcon2005newbornplateletdisorders pages 33-35, alarcon2005newbornplateletdisorders pages 35-36, weinblatt1994prenatalevaluationand pages 2-3)

Genetic testing algorithm

  1. Chromosomal microarray/CNV assay for the proximal 1q21.1 TAR-region deletion.
  2. Targeted RBM8A testing for rs139428292, rs201779890, and other regulatory/coding null variants.
  3. Parental testing and phasing to show variants in trans.
  4. If negative/atypical, use an inherited-thrombocytopenia/radial-ray panel or WES/WGS with validated CNV detection. Exome-only analysis can miss the deletion and regulatory alleles; WGS may resolve both but requires appropriate interpretation.
  5. Karyotyping is generally too low-resolution; FISH/MLPA/qPCR can confirm a known deletion. Mitochondrial and repeat-expansion testing are not indicated.

A prenatal case was molecularly confirmed by array-CGH plus RBM8A analysis. (bottillo2013prenataldiagnosisand pages 1-2)

Prenatal diagnosis and screening

Ultrasound can detect bilateral radial agenesis with preserved thumbs and associated humeral/lower-limb anomalies. For a known familial genotype, CVS or amniocentesis permits targeted molecular diagnosis. Invasive fetal platelet counting or transfusion carries risk and should be restricted to specialist fetal-medicine settings. A historical case used cordocentesis at 37 weeks, found 40,000 platelets/mm³, and performed in-utero transfusion. (weinblatt1994prenatalevaluationand pages 3-5, weinblatt1994prenatalevaluationand pages 2-3)

A 2023 prenatal study of 8,252 tested pregnancies found 26 1q21.1 CNVs—11 deletions (0.13%) and 15 duplications (0.18%); four involved only the TAR region and six covered all stated regions. These are ascertained invasive-testing frequencies, not population TAR incidence. The authors concluded that “variable expressivity and incomplete penetrance” justify long-term follow-up. Published 24 August 2023, DOI 10.3389/fmed.2023.1207891. (yue2023prenatalphenotypesand pages 1-2)

Differential diagnosis

Fanconi anemia, Holt–Oram syndrome, Roberts/SC phocomelia, thalidomide embryopathy, VACTERL with hydrocephalus, congenital amegakaryocytic thrombocytopenia, MECOM-related radioulnar synostosis with thrombocytopenia, and other radial longitudinal deficiencies should be considered. Preserved thumbs plus bilateral absent radii and early thrombocytopenia strongly favor TAR. Chromosome-breakage testing helps exclude Fanconi anemia where appropriate. (NCT00027274 chunk 1, sanchez2020moleculargeneticaspects pages 1-4)

No population newborn biochemical screen exists. Cascade testing, reproductive carrier testing in known families, prenatal diagnosis, and preimplantation genetic testing are feasible once familial alleles are defined.

11. Outcome and prognosis

Historical reports found 21 deaths among 77 cases, including 14 within four months; all fatal cases had platelet counts below 30,000/mm³. Another report estimated 25% neonatal mortality from intracranial or gastrointestinal hemorrhage. These figures predate modern neonatal and transfusion practice and probably overestimate current mortality. Prognosis improves greatly after survival through infancy; only one fatality after 14 months was reported in the historical synthesis. (weinblatt1994prenatalevaluationand pages 3-5, alarcon2005newbornplateletdisorders pages 33-35)

Poor prognostic factors are very low platelet count, severe early bleeding, intracranial hemorrhage, DIC, infection-associated count decline, and major cardiac or renal malformations. Long-term morbidity is chiefly orthopedic/functional or secondary to hemorrhagic brain injury. No validated prognostic biomarker beyond platelet count/bleeding phenotype exists, and no reliable five- or ten-year survival estimates or TAR-specific quality-of-life scores were found.

12. Treatment and current implementation

Practical strategy

  1. Coordinate pediatric hematology, neonatology, orthopedics/hand surgery, rehabilitation, genetics, cardiology/renal care as indicated.
  2. Monitor platelets and bleeding closely during infancy and during infection, procedures, or suspected food-triggered episodes.
  3. Use platelet transfusion for clinically important bleeding, profound thrombocytopenia with high risk, or peri-procedural coverage; minimize unnecessary exposure and alloimmunization.
  4. Avoid platelet-impairing drugs and traumatic procedures when counts are low.
  5. Evaluate cow’s-milk intolerance and use nutritionally supervised avoidance when clinically demonstrated.
  6. Begin physical/occupational therapy and adaptive-device assessment early.
  7. Consider reconstructive hand/upper-limb surgery after hematologic risk has improved; individual anatomy and function should drive timing.

Platelet transfusion remains the principal acute treatment because TAR reflects impaired production rather than accelerated immune destruction. Historical prenatal management used irradiated platelets and Cesarean delivery, but these case-based practices are not universal modern guidelines. (weinblatt1994prenatalevaluationand pages 3-5, weinblatt1994prenatalevaluationand pages 2-3, strauss2023thrombocytopeniaabsentradius pages 1-1)

Not established specifically for TAR: corticosteroids, IVIG, splenectomy, TPO-receptor agonists, hematopoietic stem-cell transplantation, CRISPR/gene replacement, RNA therapy, or cell therapy. A 2021 TPO-agonist review described 126 patients with inherited thrombocytopenias, but its documented diagnoses centered on Wiskott–Aldrich, MYH9, ANKRD26/Paris–Trousseau, and THPO-related disease—not TAR; extrapolation is inappropriate. (bastida2021roleofthrombopoietin pages 15-16)

Suggested NCIt intervention concepts: platelet transfusion; red-blood-cell transfusion when required; orthopedic surgery; reconstructive surgery; physical therapy; occupational therapy; genetic counseling; dietary intervention.

Trials

  • NCT00086476, NIH/NHGRI, “Study of Megakaryocytes From Patients With Abnormal Platelet Vesicles”: completed observational study, 29 June 2004–13 June 2011, actual enrollment 3; TAR was eligible, but it was not a TAR treatment trial. ClinicalTrials.gov. (NCT00086476 chunk 1)
  • NCT00027274, NIH/NCI inherited-bone-marrow-failure natural-history study: TAR is eligible; estimated enrollment 4,000, family-based observational design. ClinicalTrials.gov. The retrieved record reported recruiting status, although registry status should be rechecked at ingestion because records change. (NCT00027274 chunk 1)

No TAR-specific interventional trial or response-rate dataset was identified.

13. Prevention

Primary prevention through lifestyle or vaccination is not possible for a germline developmental disorder. Reproductive prevention options include genetic counseling, parental phasing, carrier/cascade testing, prenatal diagnosis, and preimplantation genetic testing. Secondary prevention consists of prenatal or early postnatal recognition, immediate platelet assessment, and surveillance during the high-risk infant period. Tertiary prevention includes bleeding precautions, rapid treatment of infection/bleeding, safe perioperative transfusion planning, nutritional management of milk intolerance, rehabilitation, and timely management of cardiac/renal anomalies. Routine immunization should follow standard schedules unless temporarily modified for bleeding risk; there is no TAR vaccine or anti-infective prophylaxis.

14. Other species and natural disease

No naturally occurring TAR-equivalent veterinary disorder, affected breed, zoonotic transmission, or cross-species infectious susceptibility was identified. RBM8A/Y14 and exon-junction-complex biology are evolutionarily conserved, but conservation alone does not establish a spontaneous animal disease. Relevant orthologues include mouse Rbm8a and zebrafish rbm8a; exact current NCBI Gene, Taxon, and VBO identifiers should be imported directly from their respective databases rather than inferred. Human TAR has no zoonotic potential.

15. Model organisms and experimental systems

The most directly relevant available experimental systems are patient platelets, marrow-derived CD34+ cultures, megakaryocyte colony assays, and potentially patient-derived iPSCs differentiated toward megakaryocytes. The completed NIH protocol cultured megakaryocytes from marrow CD34+ cells using recombinant human TPO and compared granule, RNA, and protein expression, although its actual enrollment was only three across several eligible disorders. (NCT00086476 chunk 1)

No retrieved mouse, rat, zebrafish, Drosophila, organoid, or CRISPR model was shown to recapitulate the complete human triad of RBM8A compound inheritance, thrombocytopenia, and preserved-thumb radial aplasia. Complete Rbm8a loss is expected to be developmentally severe/lethal, limiting conventional knockout models. Appropriate future models would include conditional or hypomorphic knockdown, humanized regulatory alleles, compound deletion/hypomorph models, and isogenic iPSC pairs. Their primary applications would be identifying Y14-sensitive transcripts in megakaryocytes and limb mesenchyme, resolving the unexplained skeletal branch, and testing whether altered RNA splicing or TPO signaling is therapeutically reversible.

Recent developments and evidence gaps

The most important recent synthesis is Strauss et al., August 2023, “Thrombocytopenia Absent Radius (TAR)-Syndrome: From Current Genetics to Patient Self-Empowerment,” Hämostaseologie 43:252–260, DOI 10.1055/a-2088-1801. Its abstract emphasizes continued discovery of regulatory RBM8A alleles and patient networking/self-empowerment. (strauss2023thrombocytopeniaabsentradius pages 1-1)

The 2023 prenatal 1q21.1 cohort extended real-world CMA experience but also reinforced that a TAR-region deletion is not itself diagnostic of TAR without the second RBM8A allele and phenotype. (yue2023prenatalphenotypesand pages 1-2)

Major unresolved questions are: which Y14-dependent transcripts drive megakaryocyte failure; why the radius is selectively affected while thumbs are spared; why platelet production improves with age; which factors explain clinical variability; and whether any TPO-pathway or RNA-processing intervention can safely restore thrombopoiesis. Current expert interpretation therefore favors precise molecular diagnosis and multidisciplinary supportive care, while treating disease-modifying therapy as investigational.

References

  1. (OpenTargets Search: thrombocytopenia-absent radius syndrome-RBM8A): Open Targets Query (thrombocytopenia-absent radius syndrome-RBM8A, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (sanchez2020moleculargeneticaspects pages 1-4): KL Sánchez and DCC González. Molecular genetic aspects of the thrombocytopenia syndrome with absent radii. Unknown journal, 2020.

  3. (alarcon2005newbornplateletdisorders pages 33-35): Pedro A. De Alarcón. Newborn platelet disorders, pages 187-253. Cambridge University Press, Aug 2005. URL: https://doi.org/10.1017/cbo9780511545306.012, doi:10.1017/cbo9780511545306.012. This article has 5 citations.

  4. (bottillo2013prenataldiagnosisand pages 1-2): Irene Bottillo, Marco Castori, Carmelilia De Bernardo, Romano Fabbri, Barbara Grammatico, Nicoletta Preziosi, Giovanna Sforzolini Scassellati, Evelina Silvestri, Antonella Spagnuolo, Luigi Laino, and Paola Grammatico. Prenatal diagnosis and post-mortem examination in a fetus with thrombocytopenia-absent radius (tar) syndrome due to compound heterozygosity for a 1q21.1 microdeletion and a rbm8a hypomorphic allele: a case report. BMC Research Notes, Sep 2013. URL: https://doi.org/10.1186/1756-0500-6-376, doi:10.1186/1756-0500-6-376. This article has 40 citations and is from a peer-reviewed journal.

  5. (clemence2023aneonatewith pages 3-4): P Clemence, N Mwamanenge, and KP Manji. A neonate with thrombocytopenia absent radius presenting with dic sydrome. Unknown journal, 2023.

  6. (sanchez2020moleculargeneticaspects pages 4-7): KL Sánchez and DCC González. Molecular genetic aspects of the thrombocytopenia syndrome with absent radii. Unknown journal, 2020.

  7. (alarcon2005newbornplateletdisorders pages 35-36): Pedro A. De Alarcón. Newborn platelet disorders, pages 187-253. Cambridge University Press, Aug 2005. URL: https://doi.org/10.1017/cbo9780511545306.012, doi:10.1017/cbo9780511545306.012. This article has 5 citations.

  8. (weinblatt1994prenatalevaluationand pages 3-5): Mark Weinblatt, Boris Petrikovsky, Martin Bialer, Joseph Kochen, and Rita Harper. Prenatal evaluation and in utero platelet transfusion for thrombocytopenia absent radii syndrome. Prenatal Diagnosis, 14:892-896, Sep 1994. URL: https://doi.org/10.1002/pd.1970140922, doi:10.1002/pd.1970140922. This article has 25 citations and is from a peer-reviewed journal.

  9. (weinblatt1994prenatalevaluationand pages 2-3): Mark Weinblatt, Boris Petrikovsky, Martin Bialer, Joseph Kochen, and Rita Harper. Prenatal evaluation and in utero platelet transfusion for thrombocytopenia absent radii syndrome. Prenatal Diagnosis, 14:892-896, Sep 1994. URL: https://doi.org/10.1002/pd.1970140922, doi:10.1002/pd.1970140922. This article has 25 citations and is from a peer-reviewed journal.

  10. (yue2023prenatalphenotypesand pages 1-2): Fagui Yue, Xiao Yang, Yuting Jiang, Shibo Li, Ruizhi Liu, and Hongguo Zhang. Prenatal phenotypes and pregnancy outcomes of fetuses with recurrent 1q21.1 microdeletions and microduplications. Frontiers in Medicine, Aug 2023. URL: https://doi.org/10.3389/fmed.2023.1207891, doi:10.3389/fmed.2023.1207891. This article has 5 citations.

  11. (strauss2023thrombocytopeniaabsentradius pages 1-1): Gabriele Strauss, Kristina Mott, Eva Klopocki, and Harald Schulze. Thrombocytopenia absent radius (tar)-syndrome: from current genetics to patient self-empowerment. Aug 2023. URL: https://doi.org/10.1055/a-2088-1801, doi:10.1055/a-2088-1801. This article has 12 citations.

  12. (NCT00086476 chunk 1): Study of Megakaryocytes From Patients With Abnormal Platelet Vesicles. National Human Genome Research Institute (NHGRI). 2004. ClinicalTrials.gov Identifier: NCT00086476

  13. (NCT00027274 chunk 1): Cancer in Inherited Bone Marrow Failure Syndromes. National Cancer Institute (NCI). 2001. ClinicalTrials.gov Identifier: NCT00027274

  14. (bastida2021roleofthrombopoietin pages 15-16): José María Bastida, José Ramón Gonzalez-Porras, José Rivera, and María Luisa Lozano. Role of thrombopoietin receptor agonists in inherited thrombocytopenia. International Journal of Molecular Sciences, 22:4330, Apr 2021. URL: https://doi.org/10.3390/ijms22094330, doi:10.3390/ijms22094330. This article has 38 citations.

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