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Classifications

Harrison's Part

IUIS Category

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Inheritance

1

Autosomal dominant HP:0000006

Every reported allele in both genes is germline and heterozygous. Most MECOM cases are de novo, but dominant transmission through several generations is documented, and in those families expressivity is wide enough that a parent may be asymptomatic or have only a mild single cytopenia while a child needs a transplant. In both HOXA11 families the allele came from a father who had the arm malformation and no blood disease at all, which is the cleanest published demonstration that the skeletal and haematological arms of this syndrome can be uncoupled within one genotype.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:29519864 SUPPORT Human Clinical

"Based on genetic studies and clinical presentation, an autosomal dominant inheritance pattern was observed in families 1 and 5."

Direct statement of dominant inheritance in two MECOM families.

PMID:29519864 SUPPORT Human Clinical

"In both families the variant was inherited from the father. Interestingly, both fathers showed skeletal abnormalities of the arm but neither had any hematological disease."

Establishes germline transmission of the HOXA11 allele and, in the same sentence, the within-genotype uncoupling of the skeletal and haematological features.

PMID:37230770 SUPPORT Human Clinical

"disease-causing variants in MECOM, which are transmitted in an autosomal dominant pattern, are associated with a phenotypic spectrum encompassing RUSAT2 in addition to variable degrees of bone marrow failure without radioulnar synostosis"

States the inheritance pattern and, in the same clause, that the synostosis is not required for the diagnosis.

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Subtypes

2

RUSAT1 (HOXA11-related) MONDO:0024558

HOXA11 hgnc:5101

The founding form, and effectively a historical one. A single heterozygous frameshift allele, HOXA11 c.872delA p.Asn291ThrfsX3, was found in six individuals across two families; in both families it came from the father, and both fathers had the arm malformation without any haematological disease. No further HOXA11 family has been reported since, and a later cohort that screened HOXA11 in seven RUS families with blood disease found no coding variants. A curator should not read RUSAT1 as "the other half of RUSAT" - on current counts it is two families against approximately 66 MECOM cases, and ClinGen grades HOXA11-RUSAT1 Limited against MECOM's Definitive.

Show evidence (2 references)

PMID:29519864 SUPPORT Human Clinical

"The heterozygous variant c.872delA, p.Asn291ThrfsX3 was identified in six individuals from two families"

Gives the single HOXA11 allele and the number of individuals carrying it.

PMID:29519864 SUPPORT Human Clinical

"No coding variants were identified inHOXA11."

A seven-family RUS cohort screened HOXA11 and found nothing, which is why RUSAT1 remains at its original two families. The quoted text runs the gene symbol into the preceding word; that is an artefact of the cached full text, not a transcription error here.

RUSAT2 (MECOM-related) MONDO:0014758

MECOM hgnc:3498

Essentially all of RUSAT as it is now diagnosed. Heterozygous MECOM variants, de novo in most sporadic cases and dominantly transmitted in some families. The variants that produce the synostosis cluster in zinc fingers 8 and 9 of EVI1; MECOM variants elsewhere in the locus, including truncating alleles and whole-gene deletions, give marrow failure without it. Approximately 66 cases had been reported by 2025.

Show evidence (2 references)

PMID:26581901 SUPPORT Human Clinical

"These three mutations were clustered within the 8(th) zinc finger motif of the C-terminal zinc finger domain of EVI1."

The founding MECOM series, and the localisation that defines this subtype.

PMID:41635268 SUPPORT Other

"As of 2025, there were approximately 66 reported cases of RUSAT-2 reported in the literature, with clinical severity ranging from isolated thrombocytopenia to early-onset bone marrow failure requiring hematopoietic stem cell transplantation."

Case count and the breadth of severity within this subtype.

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Mechanistic Hypotheses

2

The RUSAT missense alleles act purely by reducing EVI1 dose

mecom_pure_haploinsufficiency ALTERNATIVE

Evidence balance 3 support

On this model there is one lesion - not enough functional EVI1 - and everything else is dosage and tissue sensitivity. It predicts that a zinc-finger 8/9 missense allele should behave like a null, that the knock-in mouse should phenocopy the exonic-deletion mice, and that the difference between patients with and without synostosis should come from modifiers or residual activity rather than from the variant doing anything a null does not. The knock-in mouse is the strongest evidence for it: its authors conclude the missense allele has a similar effect to loss-of-function alleles in haematopoiesis. Reviews of the disease describe it as haploinsufficiency without qualification.

Pathograph links

Loss of EVI1 Sequence-Specific DNA Binding -> Dysregulation of the EVI1 HSC Maintenance Network DIRECT Opted into `mecom_pure_haploinsufficiency` because this is the step the dose model explains well and the knock-in mouse supports: less functional EVI1 at its target sites, less of the network it maintains. Both hypotheses accept this edge; they diverge downstream, at the limb.

Show evidence (3 references)

PMID:37099686 SUPPORT Model Organism

"These findings suggest that Evi1KI/+ mice recapitulate the bone marrow dysfunction in RUSAT, similar to that caused by loss-of-function Mecom alleles."

The strongest single piece of evidence for the pure-dose model: in vivo, the missense allele behaves like a null in haematopoiesis.

PMID:37407873 SUPPORT Other

"MECOM deficiency is a recently identified inborn error of immunity and inherited bone marrow failure syndrome caused by haploinsufficiency of the hematopoietic transcription factor MECOM."

A review naming haploinsufficiency as the mechanism without qualification, which is this hypothesis stated as settled.

PMID:29519864 SUPPORT INDIRECT In Vitro

"Preliminary data suggest levels of MECOM appear to be reduced in lymphoblastoid cell lines heterozygous for p.Glu758Lys"

The only human datum bearing on the question that separates these two hypotheses: whether a zinc-finger missense allele actually lowers EVI1 dose, as a null would, or leaves a full complement of binding-incompetent protein. Reduced protein in a patient cell line is what the pure-dose model predicts. Held at INDIRECT and flagged as weak for the reasons the source itself gives - the authors call it "preliminary" and say levels "appear to be" reduced, it is one allele in a lymphoblastoid line rather than in a haematopoietic stem cell, and it appears in supplementary data rather than as a headline result.

The zinc finger 8/9 missense alleles do something a null allele does not

mecom_domain_specific_effect ALTERNATIVE

Evidence balance 2 support

On this model dose is not the whole story, and the evidence for it is a pattern in the human genetics that pure haploinsufficiency does not predict. Radioulnar synostosis and B-cell deficiency appear only with variants in one short C-terminal zinc-finger region; nonsense, frameshift, splice and whole-gene-deletion alleles - which remove more EVI1 than a missense change does - give marrow failure without the synostosis. If less protein were the whole mechanism, the alleles that remove the most protein should give the most complete syndrome, and they do not. The prediction that separates the models is a tissue-level one: a limb-bud requirement that a missense zinc-finger protein disrupts and a null allele does not, for instance by leaving a binding-incompetent protein in place at a developmental target.

Pathograph links

Loss of EVI1 Sequence-Specific DNA Binding -> B-Cell Developmental Arrest INDIRECT UNKNOWN INTERMEDIATES The primary route to the B-cell defect, drawn from the domain-specific lesion rather than from generic stem-cell failure, because that is where the human genetics puts it. B-cell deficiency and radioulnar synostosis appear only with variants in one short C-terminal zinc-finger region; truncating alleles and whole-gene deletions cause severe marrow failure without either. Two features with no obvious relationship to one another appearing and disappearing together with variant position is the strongest genotype-phenotype signal in this disease, and it places the B-cell arm beside the synostosis on this branch. The intervening steps are unknown, which is what the link type records.

Loss of EVI1 Sequence-Specific DNA Binding -> Failure of Proximal Radioulnar Joint Separation INDIRECT UNKNOWN INTERMEDIATES Recorded as INDIRECT because no source traces target genes from EVI1 to the limb bud. Opted into `mecom_domain_specific_effect` because this is the edge the two hypotheses disagree about: on a pure-dose model the limb phenotype should track total EVI1 loss and therefore appear with truncating alleles, which it does not. What supports the edge is that EVI1 is expressed in the developing limb and that the human genetics assign the synostosis to MECOM; the intervening developmental steps are unknown.

Hematopoietic Stem Cell Maintenance Failure -> B-Cell Developmental Arrest INDIRECT UNKNOWN INTERMEDIATES Retained as a weak second route, and deliberately not the primary one. B-cell output does depend on a functioning stem-cell compartment, so this edge is not wrong - but it does not explain the observation that matters, which is that truncating alleles cause severe marrow failure *without* B-cell deficiency. If the defect were simply downstream of generic HSC failure it would track marrow-failure severity, and it does not; it tracks variant region. The primary route is therefore drawn from the domain-specific lesion, and this edge opts into the same hypothesis group so the two can be filtered together.

Show evidence (2 references)

PMID:29540340 SUPPORT Human Clinical

"Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1."

The regional exclusivity that a pure-dose model does not predict.

PMID:37099686 SUPPORT Other

"RUSAT-associated mutations are located in the eighth and ninth zinc finger motifs, suggesting that RUSAT-associated mutations may have particular intravital effects"

The hypothesis stated in the literature, by the same authors whose mouse data support the competing model - which is why both are ALTERNATIVE here.

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Discussions and Knowledge Gaps

6

Does the name "radioulnar synostosis with amegakaryocytic thrombocytopenia" describe the disease this entry curates?

INTERPRETATION OPEN rusat_name_understates_disease

Attached to

disease#Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia pathophysiology#Progressive Multilineage Marrow Failure

Both halves of the name are wrong for a large share of patients, and the literature says so in two different directions. The haematological half is too narrow: a seven-family cohort concluded the blood disease is frequently global and variable rather than limited to thrombocytopenia, and proposed RUS-associated haematological disease (RUSHD) instead. The skeletal half is not required at all: the largest series found no single manifestation present in every patient, described a spectrum running from isolated synostosis with no blood disease to severe marrow failure with no skeletal abnormality, and proposed MECOM-associated syndrome as the covering term. The perinatal-lethal hydrops cases had neither synostosis nor a suspected diagnosis before sequencing. This entry keeps MONDO:0011555 and its label because that is the concept the knowledge base is curating against, and records both proposed renamings as synonyms. The practical consequence for a reader is a negative one worth stating plainly: a normal forearm does not exclude this disease, and finding an intact radius and ulna is not a reason to stop before sequencing MECOM.

Show evidence (4 references)

PMID:29519864 SUPPORT Human Clinical

"it has become clear that RUS-associated hematological abnormalities are frequently more global and variable, rather than being limited to thrombocytopenia"

The argument that the "amegakaryocytic thrombocytopenia" half understates the marrow phenotype.

PMID:29519864 SUPPORT Human Clinical

"The description RUS-associated hematological disease (RUSHD) is therefore perhaps more appropriate than RUS-associated amegakaryocytic thrombocytopenia (RUSAT)"

The proposed replacement name, quoted so the dispute is on the record rather than paraphrased.

PMID:29540340 SUPPORT Human Clinical

"No single clinical manifestation was detected in all patients affected by MECOM mutations."

Establishes that no feature in the name is obligate.

+ 1 more reference

Why do missense variants in zinc fingers 8 and 9 cause radioulnar synostosis while truncating and deletion alleles of the same gene do not?

INTERPRETATION OPEN rusat_variant_class_determines_synostosis

Attached to

pathophysiology#Germline Heterozygous MECOM Zinc Finger Variant pathophysiology#Failure of Proximal Radioulnar Joint Separation mechanistic_hypotheses#mecom_domain_specific_effect

The observation is consistent across three independent series. Variants co-presenting with synostosis cluster in a roughly ten-amino-acid span of the C-terminal zinc finger domain; B-cell deficiency segregates with the same region; congenital marrow failure without synostosis is caused by nonsense, indel and splice variants producing premature termination, and by whole-gene deletions. A literature-wide tally puts the same pattern in aggregate terms - missense variants frequently show synostosis, while the other four variant classes more commonly give marrow failure. Simple haploinsufficiency does not obviously predict this ordering, since the alleles that remove the most protein give the less complete syndrome. The alternative is that the limb requirement is specifically disrupted by a binding-incompetent zinc-finger protein. The two readings are curated as competing `mechanistic_hypotheses`, and this discussion is what stands between them. It matters practically as well: a MECOM truncating variant found in an infant with pancytopenia and normal forearms is not a different disease from RUSAT, and should not be reported as one.

Show evidence (4 references)

PMID:29540340 SUPPORT Human Clinical

"Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1."

The regional restriction, stated as an exclusive.

PMID:37099686 SUPPORT Other

"Individuals with congenital bone marrow failure without RUS exhibit nonsense, insertion/deletion, or splicing variants that result in a premature termination codon in MECOM"

The complementary half: the non-synostosis presentations carry protein-truncating alleles.

PMID:40170114 SUPPORT Other

"Patients with missense mutations frequently exhibited radioulnar synostosis, while bone marrow failure was more commonly associated with the other four types of mutations."

A literature-wide tally reproducing the same split by variant class.

+ 1 more reference

Why does a mouse carrying the exact human RUSAT allele have no radioulnar synostosis, and does that invalidate the mouse for the limb arm of this disease?

HUMAN MODEL MISMATCH OPEN rusat_mouse_no_synostosis

Attached to

pathophysiology#Failure of Proximal Radioulnar Joint Separation animal_models#Evi1 H752R knock-in mouse

The knock-in mouse carries the murine equivalent of a human RUSAT variant at the orthologous residue, so this is not a species-mismatched allele. It reproduces the haematopoietic side - reduced stem and progenitor cells, delayed recovery after myelosuppression, low platelet counts in older males - and reproduces none of the skeletal side. The forelimbs are normal. That is a substantive negative result rather than a failed experiment, and it cuts both ways. If the synostosis needs a developmental context the mouse forelimb does not provide, the mouse is simply the wrong system for the limb arm and its silence says nothing about the human mechanism. But if the same allele is sufficient for the marrow phenotype and insufficient for the limb phenotype in one animal, the two arms of the syndrome may have genuinely different dose or timing requirements - which is the same question the variant-class discussion raises from the human side. The haematological timing is also mismatched: the human disease is congenital and the mouse platelet defect appears only in older males, so the mouse is a model of the marrow deficit and not of its onset.

Proposed experiments

Limb-bud-restricted expression of the RUSAT allele during forelimb patterning

rusat_limb_bud_conditional_knockin

Express the knock-in allele under limb-bud control across the window of zeugopod segmentation, and separately test a limb-restricted null allele in parallel, scoring proximal radioulnar separation in both.

Would support

pathophysiology#Failure of Proximal Radioulnar Joint Separation mechanistic_hypotheses#mecom_domain_specific_effect

Supporting outcome

Proximal radioulnar fusion in the missense arm but not the null arm would support a domain-specific limb requirement and explain both the mouse's normal forelimbs (a dose or timing threshold not reached in the germline heterozygote) and the human variant-class split.

Refuting outcome

Normal forearms in both arms, or fusion in both, would argue that the mouse forelimb cannot report this phenotype at all, and that the limb arm of RUSAT needs a different system rather than a different allele.

Show evidence (2 references)

PMID:37099686 SUPPORT Model Organism

"Heterozygous mutant mice (Evi1KI/+ mice) grew normally without radioulnar synostosis."

The negative skeletal result in the patient-allele knock-in.

PMID:37099686 SUPPORT Model Organism

"These findings suggest that Evi1KI/+ mice recapitulate the bone marrow dysfunction in RUSAT, similar to that caused by loss-of-function Mecom alleles."

The positive haematopoietic result in the same animal, which is what makes the skeletal silence informative rather than merely a null model.

Is the overlap between RUSAT and congenital amegakaryocytic thrombocytopenia a coincidence of presentation, or a shared mechanism?

INTERPRETATION OPEN rusat_camt_convergence

Attached to

pathophysiology#Loss of EVI1 Transcriptional Control of MPL differential_diagnoses#Congenital Amegakaryocytic Thrombocytopenia

The two diseases are hard to separate in a neonate: both give congenital thrombocytopenia with an amegakaryocytic marrow, both progress to pancytopenia, and both are cured only by transplant. The finding that EVI1 transcriptionally regulates MPL - the receptor whose biallelic loss causes CAMT - offers a mechanistic account of that overlap rather than a coincidental one, and the paper reporting it says so explicitly. The claim should be held at the strength its evidence supports. What was shown is that EVI1 controls MPL transcription in vitro; what was not shown is reduced MPL message or thrombopoietin-receptor signalling in RUSAT patient megakaryocytes. The same paper states that the link between EVI1 dysfunction and thrombocytopenia is poorly understood. So this is a plausible and testable convergence, not an established shared pathway, and the `Loss of EVI1 Transcriptional Control of MPL` node is written to say so.

Show evidence (2 references)

PMID:37610030 SUPPORT In Vitro

"we demonstrated that EVI1 controls the transcriptional regulation of MPL, a gene whose mutations are responsible for congenital amegakaryocytic thrombocytopenia (CAMT), potentially explaining the partial overlap between MECOM-AS and CAMT"

The proposed mechanistic account of the RUSAT/CAMT overlap, including its own hedge ("potentially explaining").

PMID:37610030 SUPPORT In Vitro

"The mechanism linking the alteration of EVI1 function and thrombocytopenia is poorly understood."

The limit on the claim, from the paper that makes it.

How much of the apparent non-penetrance and spontaneous recovery in MECOM-associated syndrome is somatic reversion rather than mild disease?

INTERPRETATION OPEN rusat_somatic_rescue_and_penetrance

Attached to

pathophysiology#Clonal Selection of Revertant Hematopoietic Stem Cells diagnosis#Germline Testing on Non-Hematopoietic Tissue

Enough to change practice, and not enough to be the whole answer. In a 15-person cohort, 7 individuals showed spontaneous resolution, alleviation, or late onset; of 6 evaluable, 4 carried copy neutral loss of heterozygosity across 3q that duplicates the residual wild-type allele. The other 2 showed no allelic imbalance on longitudinal testing, so their mild course is unexplained. Reversion is therefore a major contributor to variable expressivity in this disease but not a complete account of it, and this entry does not present it as one. Two consequences follow. Diagnostically, blood is an unreliable germline sample in a recovered carrier and testing should use skin fibroblasts or hair follicles. Therapeutically, the source argues the existence of naturally selected corrected clones gives a rationale for gene-corrected autologous transplantation - which is a rationale, not a treatment, and no trial exists.

Show evidence (3 references)

PMID:38662475 SUPPORT Human Clinical

"Herein, we show that part of the variability in hematological presentation may be attributable to spontaneous reversion of germ line variants observed in some affected individuals."

The claim, at the strength the authors make it - "part of the variability", "may be attributable".

PMID:38662475 SUPPORT Human Clinical

"For 2 of 6 individuals, an explanation for mild presentation or symptom resolution remains enigmatic"

The limit on the claim, from the same paper: reversion does not explain every mild case.

PMID:38662475 SUPPORT Human Clinical

"The prevalence of somatic genetic rescue provides a rationale for gene-corrected autologous transplantation or direct gene editing approaches as potential treatments for the hematopoietic phenotype of MECOM-associated syndrome in the absence of matched donors."

The therapeutic argument, quoted with its own conditional framing so it is not read as an available option.

Is the high rate of pregnancy loss in MECOM families caused by the variant, and if so is the fetal or the maternal genotype responsible?

KNOWLEDGE GAP OPEN rusat_pregnancy_loss

Attached to

treatments#Genetic Counseling and Cascade Testing inheritance#Autosomal dominant

The observation is striking and the interpretation is not settled. Twelve of 16 pregnancies in five mothers with detailed histories ended in loss - 75%, against a quoted 15-25% in the general population and 12-20% in other inherited marrow failure syndromes. But fetal genotypes were unavailable, so nobody knows whether the lost pregnancies carried the variant; and losses also occurred in MECOM wild-type women in these families, including a stillbirth at 8.5 months in a mother who tested negative while her husband was affected. That last case is the one that keeps both hypotheses alive: it is consistent with a fetal-genotype effect, and equally with the losses being unrelated to MECOM. Until fetal genotyping is done this cannot become a recurrence-risk figure, and it should not be quoted to families as one. It is recorded here because the source's own recommendation - discuss it in reproductive counselling - depends on stating the uncertainty alongside the number.

Proposed experiments

Genotyping of products of conception in MECOM-variant families

rusat_fetal_genotyping_of_losses

Prospectively genotype MECOM in products of conception from pregnancies in known carrier families, and compare loss rates between variant-carrying and wild-type conceptuses within the same families.

Would support

phenotypes#Nonimmune hydrops fetalis

Supporting outcome

Enrichment of the variant among lost conceptuses, relative to liveborn siblings from the same families, would establish a fetal-genotype effect and connect the pregnancy losses to the severe prenatal end of the phenotype already curated here as hydrops.

Refuting outcome

No enrichment, with losses distributed independently of fetal genotype, would argue the excess is a maternal or family-level effect and should be removed from variant-specific counselling.

Show evidence (4 references)

PMID:38662475 SUPPORT Human Clinical

"Strikingly, there were 12 pregnancy losses of a total of 16 pregnancies in 5 mothers for whom detailed information regarding pregnancies was available"

The observation and its denominator.

PMID:38662475 SUPPORT Human Clinical

"This is a higher rate of loss (75%) than expected pregnancy outcomes in the general population (15%-25%) as well as other inherited BMF syndromes (12%-20%)."

The comparison, including the disease-class comparator that makes it more than a general-population contrast.

PMID:38662475 SUPPORT Human Clinical

"However, we were unable to ascertain the MECOM status for the fetus."

The specific missing datum that stops this becoming a risk estimate.

+ 1 more reference

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Pathophysiology

15

Germline Heterozygous MECOM Zinc Finger Variant

A single altered MECOM allele, almost always de novo, encoding the zinc-finger transcription factor EVI1. The variants that give the full RUSAT picture are missense changes in the region spanning zinc fingers 8 and 9 of the C-terminal zinc finger domain - about ten amino acids, comprising zinc finger 8 and the adjacent linker. That is not the only missense hotspot, and this node should not be read as saying it is. A 2026 series reports every missense variant mapping to "the zinc finger 6 or zinc finger 8/9 region", so there is a second cluster in the N-terminal zinc finger domain - the domain through which EVI1 binds the GATA2 promoter. A further reported variant, p.P634L, lies between the two domains altogether. Whether the ZF6 cluster produces synostosis is not established in anything cited here. Variants elsewhere in the locus, including nonsense, frameshift, splice and whole-gene deletion alleles, cause bone marrow failure without the synostosis. That the two variant classes give different syndromes from the same gene is the central genotype-phenotype observation in this disease, and it is why this node is specified by domain rather than simply as "loss of one MECOM allele".

Downstream

Loss of EVI1 Sequence-Specific DNA Binding The variant residues sit inside a Cys2His2 zinc finger, the DNA-contact module itself, so the immediate consequence is loss of binding rather than loss of protein.

Show evidence (2 references)

PMID:26581901 SUPPORT Human Clinical

"we performed whole exome sequencing in an individual with RUSAT and her healthy parents and identified a de novo missense mutation in MECOM, encoding EVI1, in the individual with RUSAT"

The founding observation: a de novo heterozygous MECOM missense variant in RUSAT.

PMID:29519864 SUPPORT Human Clinical

"It is noteworthy that all variants associated with the co-presentation of RUS and hematological disease cluster in region spanning zinc fingers 8 and 9."

Localises the RUSAT-producing variants to the region spanning zinc fingers 8 and 9, which is what makes this node domain-specific rather than gene-level. The source's ten-amino-acid span (aa750-760) is zinc finger 8 plus the adjacent linker rather than two whole motifs.

Germline Heterozygous HOXA11 Frameshift Variant

The RUSAT1 lesion: HOXA11 c.872delA, p.Asn291ThrfsX3, a single-nucleotide deletion falling in the third helix of the homeodomain and truncating the protein. It is the only HOXA11 allele ever reported in this disease, found in six individuals from two families. HOXA11 is a posterior HOX transcription factor with roles in both early forelimb patterning and haematopoiesis, which is the same dual requirement that makes MECOM a RUSAT gene.

Downstream

Loss of HOXA11 Sequence-Specific DNA Binding The truncation removes the third helix of the homeodomain, which is the DNA-recognition helix.

Show evidence (1 reference)

PMID:16765069 SUPPORT Human Clinical

"Previously, we identified an inherited syndrome of congenital amegakaryocytic thrombocytopenia and radio-ulnar synostosis that is associated with a point mutation in the third helix of HOXA11 homeodomain (HOXA11-DeltaH3)."

Restates the 2000 discovery in quotable form and localises the variant to the homeodomain third helix. This 2006 follow-up is cited in place of the 2000 discovery paper, PMID:11101832, whose cache is `content_type: unavailable` and so carries nothing quotable. The defect claim is about PMID:11101832, not about this reference, which has a normal abstract.

Loss of EVI1 Sequence-Specific DNA Binding

The zinc-finger 8/9 variants reduce EVI1 occupancy at its recognition sites. Protein modelling of the two mutational hotspots, zinc finger 6 and zinc fingers 8/9, predicts both are DNA-binding regions, so the variants are read as disabling contact with DNA rather than destabilising the protein as a whole. The functional consequence is measured on both sides of EVI1's dual role: it is a repressor at some targets and a permissive factor at others, and the variants shift both.

The RUSAT missense alleles act purely by reducing EVI1 dose The zinc finger 8/9 missense alleles do something a null allele does not

EVI1 DNA-binding transcription factor activity GO:0003700 ⇓ LOSS OF FUNCTION

Downstream

B-Cell Developmental Arrest The primary route to the B-cell defect, drawn from the domain-specific lesion rather than from generic stem-cell failure, because that is where the human genetics puts it. B-cell deficiency and radioulnar synostosis appear only with variants in one short C-terminal zinc-finger region; truncating alleles and whole-gene deletions cause severe marrow failure without either. Two features with no obvious relationship to one another appearing and disappearing together with variant position is the strongest genotype-phenotype signal in this disease, and it places the B-cell arm beside the synostosis on this branch. The intervening steps are unknown, which is what the link type records.

Multi-Organ Developmental MECOM Requirement The extra-haematopoietic malformations are grouped behind one node rather than hung individually off the network node, because what connects them is a single fact - MECOM is required in several developing organs - and not four separate demonstrated mechanisms.

Pulmonary Arterial Endothelial MECOM Deficiency Provisional, and the weakest branch in the entry. Modelling places the variant hotspots at a VEGFR2/KDR enhancer, which would make this an endothelial consequence of the same binding defect; nothing measures it.

Failure of Proximal Radioulnar Joint Separation Recorded as INDIRECT because no source traces target genes from EVI1 to the limb bud. Opted into `mecom_domain_specific_effect` because this is the edge the two hypotheses disagree about: on a pure-dose model the limb phenotype should track total EVI1 loss and therefore appear with truncating alleles, which it does not. What supports the edge is that EVI1 is expressed in the developing limb and that the human genetics assign the synostosis to MECOM; the intervening developmental steps are unknown.

Dysregulation of the EVI1 HSC Maintenance Network Opted into `mecom_pure_haploinsufficiency` because this is the step the dose model explains well and the knock-in mouse supports: less functional EVI1 at its target sites, less of the network it maintains. Both hypotheses accept this edge; they diverge downstream, at the limb.

Show evidence (2 references)

PMID:41617498 SUPPORT Computational

"Protein modelling predicted that both regions are DNA-binding, and that the variants may interfere with binding to a VEGFR2/KDR enhancer."

Structural prediction that the variant hotspots are DNA-contact regions. Graded COMPUTATIONAL because it is protein modelling, not an assay.

PMID:37610030 SUPPORT In Vitro

"whose effect was tested on pAP-1 enhancer element and promoters of targeted genes showing that the mutation impairs the repressive activity of the transcription factor"

A second, independent variant shown to impair EVI1's transcriptional activity at its target promoters. Read as a bound on this node rather than straightforward support: the variant tested, p.P634L, lies between the two zinc-finger domains, so impaired repression by it is not evidence that sequence-specific DNA binding is lost. It shows that transcriptional dysregulation can arise from outside the DNA-contact residues.

Loss of HOXA11 Sequence-Specific DNA Binding

The truncated HOXA11 protein cannot bind its consensus site, and the defect is not rescued by its cofactor. Wild-type HOXA11 binds DNA most efficiently in the presence of the TALE factor Meis1b; the truncated protein still associates with Meis1b but binding to DNA is abolished even so. The protein-protein interaction is therefore intact while the DNA contact is not, which localises the lesion to the homeodomain.

HOXA11 DNA-binding transcription factor activity GO:0003700 ⇓ LOSS OF FUNCTION

Downstream

Failure of Proximal Radioulnar Joint Separation RUSAT1's defining bone lesion. The edge is drawn on the human genetics - six individuals in two families carrying this allele with the synostosis - plus HOXA11's established role in forelimb zeugopod patterning. No source traces the intervening developmental steps, and the mouse data below differ from the human lesion in two ways set out in the target node's description.

Megakaryocyte Differentiation Arrest This is the weakest edge in the entry and is marked as such. Expressing the mutant in a megakaryocyte-competent cell line suppresses megakaryocytic differentiation - but so does expressing the wild-type protein, to almost the same degree, and the authors conclude the effect runs through sequences outside the homeodomain. So the edge from a homeodomain DNA-binding defect to a megakaryocyte arrest is drawn on the human genetics rather than on this assay, and both readings of the assay are recorded below.

Show evidence (1 reference)

PMID:16765069 SUPPORT In Vitro

"the binding between HOXA11-DeltaH3 and DNA is abrogated even in the presence of Meis1b, suggesting the point mutant causes a disruption in the DNA-binding capacity"

Abolished DNA binding that the cofactor cannot rescue. This node's own claim is well supported; what is contested is whether the binding defect is what produces the megakaryocyte phenotype, and that dispute is recorded on the downstream edge rather than here.

Dysregulation of the EVI1 HSC Maintenance Network

The central node of the MECOM arm, and the point at which one molecular lesion becomes several tissue phenotypes. EVI1 does not maintain haematopoietic stem cells through a single target: it binds regulatory enhancers controlling a network of hundreds of genes, and modelling MECOM haploinsufficiency in primary human haematopoietic stem cells shows that network is required for stem-cell maintenance. Among its targets are GATA2, whose promoter EVI1 binds through the N-terminal zinc fingers, and MPL, the thrombopoietin receptor. EVI1 also prevents the CTCF-dependent genome reorganisation that normally accompanies differentiation, so the consequence of losing it is not simply reduced output of one factor. Read the magnitude carefully, because the phenotype is severe and the transcriptional change is not. The primary-human-HSC study describes a "high degree of similarity" in the single-cell transcriptome after MECOM perturbation and, on random permutation analysis, detected no differentially expressed genes at all. This node therefore asserts coordinated dysregulation of a defined network, not a wholesale collapse of transcription. That a small, coordinated shift produces an absence of stem cells is the interesting part, not an argument for a larger shift.

TGF-beta-mediated transcriptional response GO:0007179 ↕ DYSREGULATED

EVI1 binding at haematopoietic stem cell enhancers GO:0000976 ↓ DECREASED

Experimental models

MECOM-haploinsufficient primary human hematopoietic stem cells PRIMARY CELL CULTURE Reproduces the human haploinsufficient state in human stem cells and reads out the transcriptional network directly.

Downstream

Loss of EVI1 Transcriptional Control of MPL

Hematopoietic Stem Cell Maintenance Failure

Show evidence (5 references)

PMID:37407873 SUPPORT Other

"MECOM binds to regulatory enhancers that control the expression of a network of genes essential for HSC maintenance and self-renewal."

States the network-level mechanism this node represents.

PMID:36522544 SUPPORT In Vitro

"we nominate cooperating transcriptional regulators and identify how MECOM prevents the CTCF-dependent genome reorganization that occurs as HSCs differentiate"

Gives the chromatin-level action by which EVI1 holds the self-renewal state, which is why its loss releases differentiation rather than merely reducing one target's output.

PMID:37099686 SUPPORT Other

"EVI1 binds to the promoter of GATA2, which encodes a transcription factor required for the proliferation and survival of early hematopoietic progenitor cells, through the N-terminal zinc finger domain."

Names a specific, mechanistically informative target within the network. Graded OTHER rather than IN_VITRO because the sentence is this mouse paper's introduction citing prior work, not a result it reports.

+ 2 more references

Loss of EVI1 Transcriptional Control of MPL

EVI1 transcriptionally regulates MPL, the thrombopoietin receptor. Biallelic MPL loss is the cause of congenital amegakaryocytic thrombocytopenia, so this branch is the proposed mechanistic reason RUSAT and CAMT are hard to tell apart in a newborn with an amegakaryocytic marrow: they converge on the same receptor. The node is deliberately named for a loss of control rather than for a direction, because the direction is not established and the obvious guess is probably backwards. What the assay shows is that the variant "impairs the repressive activity of the transcription factor" - and impaired repression would, on its face, raise MPL rather than lower it. No measurement of MPL message or thrombopoietin-receptor signalling in RUSAT patient megakaryocytes is cited here. `DYSREGULATED` is the honest tag until someone measures it; naming this node for a direction would export an assertion no source supports into the graph.

thrombopoietin-mediated signaling pathway GO:0038163 ↕ DYSREGULATED

Downstream

Megakaryocyte Differentiation Arrest Drawn because MPL loss is an established cause of amegakaryocytic thrombocytopenia and MPL is under EVI1 control, not because the step has been demonstrated in RUSAT megakaryocytes. The second evidence item below is the source's own statement that it has not been.

Show evidence (1 reference)

PMID:37610030 SUPPORT In Vitro

"we demonstrated that EVI1 controls the transcriptional regulation of MPL, a gene whose mutations are responsible for congenital amegakaryocytic thrombocytopenia (CAMT), potentially explaining the partial overlap between MECOM-AS and CAMT"

The only published demonstration that MPL is under EVI1 transcriptional control, and the source of the CAMT convergence claim.

Hematopoietic Stem Cell Maintenance Failure

Haematopoietic stem cells are not maintained. The human phenotype modelled in primary HSCs is described as an early-onset absence of stem cells in vivo, which is what distinguishes this disease from the inherited marrow failure syndromes that declare themselves in later childhood or adolescence. The severity tracks gene dosage, and the consequence is multilineage rather than lineage-restricted - which is the main reason the "amegakaryocytic thrombocytopenia" half of the disease name understates what is happening.

The zinc finger 8/9 missense alleles do something a null allele does not

hematopoietic stem cell CL:0000037

stem cell population maintenance GO:0019827 ↓ DECREASED

Animal models

Evi1 H752R knock-in mouse Mouse recapitulates Heterozygotes lose haematopoietic stem and progenitor cells and recover poorly from myelosuppression, which is the stem-cell deficit this node asserts.

Downstream

Progressive Multilineage Marrow Failure

B-Cell Developmental Arrest Retained as a weak second route, and deliberately not the primary one. B-cell output does depend on a functioning stem-cell compartment, so this edge is not wrong - but it does not explain the observation that matters, which is that truncating alleles cause severe marrow failure *without* B-cell deficiency. If the defect were simply downstream of generic HSC failure it would track marrow-failure severity, and it does not; it tracks variant region. The primary route is therefore drawn from the domain-specific lesion, and this edge opts into the same hypothesis group so the two can be filtered together.

Age-Related Clonal Hematopoiesis The second of the two roads a marrow under selective pressure can take. Drawn from the failing marrow rather than from the revertant node, because the source's model is that reversion and clonal evolution are sibling outcomes of one selective pressure - not that one causes the other.

Clonal Selection of Revertant Hematopoietic Stem Cells The failing marrow is itself the selective pressure. A stem cell that loses the mutant allele has a fitness advantage over its neighbours precisely because its neighbours are failing, so the marrow deficit creates the conditions for its own partial reversal.

Megakaryocyte Differentiation Arrest A second route into the megakaryocyte node, independent of MPL: if stem cells are absent, no lineage is produced, the megakaryocyte lineage included.

Show evidence (1 reference)

PMID:37407873 SUPPORT Other

"It is unique among inherited bone marrow failure syndromes, many of which present during later childhood or adolescence, because of the early age of onset and severity of the pancytopenia, emphasizing the importance and gene dose dependency of MECOM during hematopoiesis."

Places the disease against its class and states the dose dependency that makes a heterozygous variant sufficient.

Megakaryocyte Differentiation Arrest

Megakaryocytes are absent or severely reduced in the marrow, which is what the "amegakaryocytic" in the disease name refers to and what separates RUSAT from a peripheral destructive thrombocytopenia at the bedside. Two upstream routes converge here in the MECOM arm - loss of stem cells, and loss of MPL transcriptional control - and one in the HOXA11 arm. Some cohorts describe the marrow as hypomegakaryocytic rather than amegakaryocytic; the distinction is one of degree.

megakaryocyte CL:0000556

megakaryocyte differentiation GO:0030219 ↓ DECREASED

Downstream

Megakaryocytopenia

Thrombocytopenia

Show evidence (1 reference)

PMID:37610030 SUPPORT Human Clinical

"MECOM-associated syndrome (MECOM-AS) is a rare disease characterized by amegakaryocytic thrombocytopenia, progressive bone marrow failure, pancytopenia and radioulnar synostosis with high penetrance."

Names the amegakaryocytic marrow as a defining feature.

Progressive Multilineage Marrow Failure

The thrombocytopenia does not stay isolated. Marrow output falls across lineages, producing anaemia and neutropenia on top of the platelet defect and, in a substantial fraction, frank pancytopenia requiring transplant. The rate is very variable: some infants are transfusion-dependent in the first weeks of life and some adults reach a modest single cytopenia only in later life, within the same family and sometimes with the same allele. At the most severe end the failure begins before birth and presents as non-immune hydrops with severe anaemia.

hematopoietic stem cell differentiation GO:0060218 ↓ DECREASED

Downstream

Pancytopenia

Bone marrow hypocellularity

Nonimmune hydrops fetalis

Anemia

Aplastic Anemia

Myelodysplasia

Show evidence (2 references)

PMID:29519864 SUPPORT Human Clinical

"some individuals had severe BMF in childhood whilst others only a modest single cytopenia well into adulthood"

The range of severity and tempo across one seven-family cohort.

PMID:29519864 SUPPORT Human Clinical

"we are able to demonstrate that even with the same variant the age of onset and the severity of BMF is highly variable"

Establishes that the variability is not explained by allele identity, which is what makes prognostication from genotype unreliable here.

B-Cell Developmental Arrest

A subset of MECOM patients have B-cell lymphopenia with hypogammaglobulinaemia, which has led to MECOM deficiency being classified as an inborn error of immunity as well as a marrow failure syndrome. The mechanism is unknown. What is notable is the co-segregation: in the largest series, B-cell deficiency and radioulnar synostosis were seen only in patients whose variants hit the same short C-terminal zinc-finger region - two features with no obvious relationship to one another, appearing and disappearing together with variant position.

B cell CL:0000236

B cell differentiation GO:0030183 ↓ DECREASED

Downstream

Decreased total B cell count

Decreased circulating immunoglobulin concentration

Show evidence (2 references)

PMID:29540340 SUPPORT Human Clinical

"Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1."

The co-segregation of the B-cell and skeletal features with one variant region, which is the strongest genotype-phenotype signal in the disease.

PMID:37407873 SUPPORT Other

"MECOM deficiency is a recently identified inborn error of immunity and inherited bone marrow failure syndrome caused by haploinsufficiency of the hematopoietic transcription factor MECOM."

The immunological reclassification that this node underwrites.

Clonal Selection of Revertant Hematopoietic Stem Cells

Somatic genetic rescue. In a failing marrow, a stem cell that has lost the mutant MECOM allele outgrows the rest, and the usual mechanism is copy neutral loss of heterozygosity across chromosome 3q, which duplicates the residual wild-type allele. In a 15-person cohort, 7 individuals showed spontaneous resolution, alleviation, or late onset of haematological disease, and in 4 of 6 evaluable such cases this reversion was found. This node is the reason several things about the disease look strange from outside. Apparent non-penetrance in an adult carrier may be a rescued marrow rather than a mild allele. Neonatal thrombocytopenia that resolves on its own is a documented course, not a misdiagnosis. And it is the one node in this entry with a direct, immediate consequence for how the disease is diagnosed: blood is an unreliable germline sample in a carrier whose counts have recovered. The same demand-adapted clonal dynamics run the other way as well. Clonal haematopoiesis is curated as a sibling of this node rather than as its consequence - both descend from the same selective pressure in a failing marrow, which is what the source's "two roads" model says and as far as it goes.

hematopoietic stem cell CL:0000037

Show evidence (2 references)

PMID:38662475 SUPPORT Human Clinical

"For 4 of 6 individuals (3-II-4, 4-II-4, 5-II-1, and patient 11), amelioration of symptoms appears associated with somatic genetic rescue, in the form of copy neutral loss of heterozygosity of chromosome 3q encompassing MECOM"

The mechanism and the count. Note the source's own hedge - "appears associated with" - and that 2 of 6 rescued-looking individuals had no allelic imbalance at all, so reversion is not the whole explanation for mild disease.

PMID:38662475 SUPPORT Human Clinical

"Our study identifies 7 of 15 affected individuals who show spontaneous resolution, alleviation of hematological symptoms, or late onset of hematological manifestation of MECOM-associated syndrome."

How common the phenomenon is in the one cohort that looked for it.

Age-Related Clonal Hematopoiesis

All three older individuals in the 15-person cohort of Venugopal et al. (PMID:38662475) carried somatic variants in age-related clonal haematopoiesis genes - ASXL1, DNMT3A, TET2 - and two also carried ETV6 variants, which is not a typical age-related finding. Transient 20q loss was seen in two individuals in the cohort, though not the same two - one of them is a younger carrier, so it is not a feature of the older group specifically. These clones likely improve haematopoietic output, which is the source's own hedged phrasing and the reason they expand; the cost is that the same alterations carry myeloid malignancy risk. Curated at the strength the source states and no further. Four myeloid malignancies had been reported among 80 MECOM-associated individuals - three adult myelodysplastic syndromes and one paediatric acute myeloid leukaemia, about 5% - and the source attributes that low frequency to most patients being transplanted young, which implies an underestimate without saying so outright. This entry therefore records myelodysplasia and clonal haematopoiesis as curated findings, and does not assert a quantified germline leukaemia predisposition, which no cited source supports.

hematopoietic stem cell CL:0000037

Downstream

Myelodysplasia

Show evidence (2 references)

PMID:38662475 SUPPORT Human Clinical

"Notably, all 3 older individuals within our cohort (4-II-1, 4-II-4, and 5-II-1) displayed somatic variants in known age–related clonal hematopoiesis genes"

The observation, with its small denominator visible in the quote itself.

PMID:38662475 SUPPORT Human Clinical

"which could explain relatively low frequency of progression to myeloid malignancy in 5% of patients (3 adult MDS cases and 1 pediatric acute myeloid leukemia of 80 individuals"

The published malignancy count and denominator, and the confounder - early transplant - that the source says makes it an underestimate.

Failure of Proximal Radioulnar Joint Separation

The radius and ulna fail to separate proximally during limb development and remain fused as bone. This is a developmental non-event rather than a destructive lesion: the joint interzone that should cavitate does not, so the forearm is fixed - usually in pronation - from birth and never supinates. The developmental biology is better established for one of the two genes than the other, and the entry keeps that asymmetry visible. For HOXA11 there is directly relevant joint data. Limb joint formation begins with the interzone, a band of flat, tightly packed mesenchymal cells marking the boundary between adjacent cartilage anlagen, and those cells give rise to the joint tissues; failure at that step is what leaves two elements fused. Mouse embryos lacking all Hox11 paralogues do not merely mispattern the zeugopod - their elbow joints are specifically remodelled, and the proximal ends of the mutant radius and ulna become morphologically similar and form an anatomically distinct joint. That is the same joint, at the same end of the same two bones, as the human lesion. The authors conclude Hox11 genes dictate joint identity and morphogenesis in the zeugopod. Two caveats keep this indirect: it is a triple-paralogue mutant rather than a single heterozygous allele, and remodelled joint identity is not the same event as failed separation. For MECOM there is no comparable data. What exists is expression - EVI1 in the developing limb - and the human genetics. The knock-in mouse carrying the patient allele has normal forelimbs, so the one experiment that could have supplied a MECOM limb mechanism returned a negative.

embryonic skeletal limb joint morphogenesis GO:0036023 ↓ DECREASED forelimb morphogenesis GO:0035136 ↓ DECREASED

Animal models

Evi1 H752R knock-in mouse Mouse fails to recapitulate The mouse has normal forelimbs. Carrying the orthologous patient allele is not sufficient to produce radioulnar synostosis in a mouse, so this model cannot be used to study the skeletal arm of the disease and its silence is not evidence that the human variant does not cause the synostosis.

Downstream

Radioulnar Synostosis

Show evidence (4 references)

PMID:26581901 SUPPORT Human Clinical

"We report missense mutations in MECOM resulting in a Mendelian disorder that provide compelling evidence for the critical role of EVI1 in normal hematopoiesis and in the development of forelimbs and fingers in humans."

Assigns forelimb development to EVI1 in humans on genetic grounds.

PMID:20978074 SUPPORT Model Organism

"joint formation initiates with the appearance of the so-called interzone that comprises flat and tightly packed mesenchymal cells and demarcates the boundary between adjacent cartilaginous skeletal anlaga"

The developmental event this node names. Cited because the node describes interzone failure, and a description that asserts a mechanism should not rest on general knowledge.

PMID:20978074 SUPPORT INDIRECT Model Organism

"The proximal ends of developing mutant ulna and radius elements became morphologically similar and formed an anatomically distinct elbow joint."

The closest experimental analogue of the human lesion in the literature: loss of Hox11 function reorganises the joint at the proximal ends of the radius and ulna, which is where RUSAT fuses them. INDIRECT because the mouse is a triple-paralogue mutant and its joint is remodelled rather than absent.

+ 1 more reference

Multi-Organ Developmental MECOM Requirement

A deliberately coarse node collecting the extra-haematopoietic malformations - digital, ungual, patellar, cardiac, renal and auditory - that recur across MECOM cohorts without any of them being obligate. The justification for grouping rather than splitting is that the only thing tying them together in the cited literature is one fact: MECOM is expressed at high levels in the embryonic heart, lungs, limb buds, nasal cavity and urinary tract, and those are the organs that turn out to be malformed. No source traces a pathway from EVI1 target genes to any individual lesion. Two honest limits. The expression data behind the grouping are murine, while the malformations are human. And a node at this resolution earns little: it says these findings are developmental rather than consequences of the marrow disease, which matters clinically - they are present at birth and are not corrected by transplant - but it does not explain any of them. Splitting it is the right move as soon as a source supports a specific route. The radioulnar synostosis is deliberately NOT routed through this node. It has its own node because it is the defining feature, because it segregates with a specific variant region, and because it has its own model-organism literature; folding it in here would lose all three.

embryonic organ development GO:0048568 ↓ DECREASED

Downstream

Global Developmental Delay Grouped with the other extra-haematopoietic findings on the same basis this node states: MECOM is broadly expressed in embryonic tissues and no source traces a pathway to any individual outcome. The caveat in the node description applies with extra force here, since developmental delay is the least anatomically localised of the findings collected under it.

Failure to Thrive Attached here rather than to the marrow failure. It is reported as a constitutional feature alongside the malformations rather than as a consequence of the cytopenias, but the two are not separable in the cited cohorts and this placement should not be read as excluding a haematologic contribution.

Clinodactyly

Ventricular Septal Defect

Renal Malformation

Sensorineural Hearing Impairment

Patellar Aplasia or Hypoplasia

Digital Phalangeal Hypoplasia

Nail Abnormality

Aortic Root Dilatation Grouped with the other developmental lesions on expression grounds, but note it behaves differently from them: the septal defects are static and congenital while the aortic dilatation is progressive, so this edge should not be read as implying a single shared lesion.

Show evidence (2 references)

PMID:37407873 SUPPORT Other

"Extra-hematopoietic manifestations of MECOM deficiency, including renal and cardiac anomalies, radioulnar synostosis, clinodactyly, and hearing loss, have been reported."

Names the set of malformations this node collects. Graded OTHER because the source is a review summarising prior reports rather than presenting primary data.

PMID:29540340 SUPPORT Human Clinical

"No single clinical manifestation was detected in all patients affected by MECOM mutations."

The reason this node has four optional downstream branches rather than an obligate syndrome definition: none of these findings is present in every patient.

Pulmonary Arterial Endothelial MECOM Deficiency

A branch reported only in 2026 and curated as provisional. MECOM is expressed principally in pulmonary arterial endothelial cells, and in a 15-person series assembled through GeneMatcher, 6 had pulmonary arterial hypertension. Protein modelling suggests the variant hotspots interfere with binding to a VEGFR2/KDR enhancer, which would give an endothelial route independent of the marrow. This is an ascertainment-prone series - it was assembled by querying for a phenotype the authors had already nominated MECOM for - and the mechanism is modelled rather than measured. It is attached downstream of the DNA-binding node rather than left free-floating, because its evidential shape is the same as the limb branch this entry does connect: expression data plus human genetics, with no intervening steps established, and variants in the same zinc-finger hotspot.

pulmonary arterial endothelial cell CL:1001568

Downstream

Pulmonary arterial hypertension

Show evidence (1 reference)

PMID:41617498 SUPPORT Human Clinical

"We identified 15 individuals with MECOM variants, including 11 unrelated probands and 8 de novo variants. 11 individuals had severe or mild thrombocytopenia, 9 had skeletal issues, 8 had cardiac anomalies, 6 had PAH and 10 had additional conditions."

The series and the PAH count within it.

⬡

Pathograph

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

●

Phenotypes

27

Blood 12

Thrombocytopenia HP:0001873

Temporal: CHRONIC

Sequelae: Petechiae Abnormal bleeding

Show evidence (2 references)

PMID:41635268 SUPPORT Other

"Radioulnar synostosis with amegakaryocytic thrombocytopenia type 2 (RUSAT-2) is a rare inherited bone marrow failure syndrome characterized by congenital or progressive thrombocytopenia, frequent radioulnar synostosis, and variable multisystem involvement."

Names congenital or progressive thrombocytopenia as the defining haematological feature.

PMID:29519864 SUPPORT Human Clinical

"All the affected children presented with thrombocytopenia from birth, with three out of the four undergoing BMT."

Congenital onset in the HOXA11 families, and the transplant rate among them.

Megakaryocytopenia HP:0005548

Show evidence (1 reference)

PMID:29540340 SUPPORT Human Clinical

"Here we report on 12 patients with congenital hypomegakaryocytic thrombocytopenia caused by MECOM mutations (including 10 novel mutations)."

The marrow phenotype in the series that defined MECOM-associated syndrome.

Pancytopenia HP:0001876

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:37610030 SUPPORT Human Clinical

"MECOM-associated syndrome (MECOM-AS) is a rare disease characterized by amegakaryocytic thrombocytopenia, progressive bone marrow failure, pancytopenia and radioulnar synostosis with high penetrance."

Lists pancytopenia as part of the core phenotype.

Bone marrow hypocellularity HP:0005528

Show evidence (1 reference)

PMID:29540340 SUPPORT Human Clinical

"the clinical spectrum ranged from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormality"

Marrow failure as the severe end of the described range.

Aplastic Anemia HP:0001915

Sequelae: Myelodysplasia

Show evidence (1 reference)

PMID:29519864 SUPPORT Human Clinical

"the hematological involvement progressed from aplastic anemia to myelodysplastic syndrome (MDS); this presentation of RUS and development of MDS in adulthood is similar to the family reported by Ripperger"

Documents aplastic anaemia and its progression in an adult carrier.

Myelodysplasia HP:0002863

Onset: ADULT

Show evidence (1 reference)

PMID:29519864 SUPPORT Human Clinical

"there is a subgroup of patients with RUS who also present with hematological abnormalities ranging from thrombocytopenia to myelodysplastic syndrome (MDS)"

Places MDS at the far end of the haematological range in this disease.

Anemia HP:0001903

Show evidence (1 reference)

PMID:37230770 SUPPORT Human Clinical

"We report two cases of infants born preterm who presented at birth with symptoms of bone marrow failure including severe anemia, hydrops, and petechial hemorrhages"

Severe anaemia at the most severe end of the spectrum.

Petechiae HP:0000967

Show evidence (1 reference)

PMID:37230770 SUPPORT Human Clinical

"We report two cases of infants born preterm who presented at birth with symptoms of bone marrow failure including severe anemia, hydrops, and petechial hemorrhages"

Petechial haemorrhage as a presenting sign at birth.

Abnormal bleeding HP:0001892

Sequelae: Intracranial hemorrhage

Show evidence (1 reference)

PMID:40170114 SUPPORT Human Clinical

"We report a 0-day-old female Han Chinese neonate who presented with severe thrombocytopenia and intracranial hemorrhage, ultimately succumbing to multiple organ failure and intracranial hemorrhage on the third day after birth."

Documents bleeding severe enough to be fatal in the neonatal period.

Intracranial hemorrhage HP:0002170

Show evidence (1 reference)

PMID:40170114 SUPPORT Human Clinical

"We report a 0-day-old female Han Chinese neonate who presented with severe thrombocytopenia and intracranial hemorrhage, ultimately succumbing to multiple organ failure and intracranial hemorrhage on the third day after birth."

A reported intracranial haemorrhage with a fatal outcome.

Decreased total B cell count HP:0010976

Sequelae: Recurrent infections

Show evidence (1 reference)

PMID:37407873 SUPPORT Other

"B-cell lymphopenia and hypogammaglobulinemia have been described in a subset of patients with MECOM deficiency."

Direct statement of the B-cell phenotype and its partial penetrance.

Decreased circulating immunoglobulin concentration HP:0004313

Show evidence (1 reference)

PMID:37407873 SUPPORT Other

"B-cell lymphopenia and hypogammaglobulinemia have been described in a subset of patients with MECOM deficiency."

Names hypogammaglobulinaemia in the same subset as the B-cell lymphopenia.

Cardiovascular 3

Ventricular Septal Defect HP:0001629

Show evidence (3 references)

PMID:29540340 SUPPORT Human Clinical

"The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss."

Cardiac malformation as a recognised feature of the syndrome.

PMID:41617498 SUPPORT Human Clinical

"11 individuals had severe or mild thrombocytopenia, 9 had skeletal issues, 8 had cardiac anomalies, 6 had PAH and 10 had additional conditions."

Quantifies cardiac anomalies in a 15-person series.

PMID:37067177 SUPPORT Human Clinical

"cardiac/vascular [patent ductus arteriosus (n=2), patent foramen ovale (n=2), ventricular septal defect, aortic root dilation, interrupted aortic arch, truncus arteriosus, single umbilical artery, (n=1 each)]"

Names the ventricular septal defect specifically, alongside the other cardiac lesions seen in the same cohort. This is the source for the lesion list in the description above.

Pulmonary arterial hypertension HP:0002092

Show evidence (1 reference)

PMID:41617498 SUPPORT Human Clinical

"11 individuals had severe or mild thrombocytopenia, 9 had skeletal issues, 8 had cardiac anomalies, 6 had PAH and 10 had additional conditions."

The count of pulmonary arterial hypertension within the series that reported the association.

Aortic Root Dilatation Aortic root aneurysm HP:0002616

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:38662475 SUPPORT Human Clinical

"We have observed 3 cases of aortic dilatation, with 1 progressing to an aortic aneurysm reaching the threshold for surgical correction in our cohort of 15 cases."

The count, the progression, and the denominator in one sentence.

Ear 1

Sensorineural Hearing Impairment HP:0000407

Show evidence (2 references)

PMID:29540340 SUPPORT Human Clinical

"The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss."

Names presenile hearing loss among the syndrome's features.

PMID:37407873 SUPPORT Other

"Extra-hematopoietic manifestations of MECOM deficiency, including renal and cardiac anomalies, radioulnar synostosis, clinodactyly, and hearing loss, have been reported."

Independent confirmation, grouped with the other extra-haematopoietic features.

Genitourinary 1

Renal Malformation Abnormality of the kidney HP:0000077

Show evidence (3 references)

PMID:37407873 SUPPORT Other

"Extra-hematopoietic manifestations of MECOM deficiency, including renal and cardiac anomalies, radioulnar synostosis, clinodactyly, and hearing loss, have been reported."

Names renal anomalies among the extra-haematopoietic features.

PMID:29540340 SUPPORT Human Clinical

"The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss."

Independent confirmation in the twelve-patient series.

PMID:37067177 SUPPORT Human Clinical

"renal insufficiency (n=1), malrotated and hypoplastic kidney (n=1)"

The specific renal lesions behind the general binding: they differ between patients, which is why the general urinary-system term is used.

Immune 1

Recurrent infections HP:0002719

Show evidence (1 reference)

PMID:37610030 SUPPORT Human Clinical

"The clinical phenotype may also include finger malformations, cardiac and renal alterations, hearing loss, B-cell deficiency and predisposition to infections."

Lists predisposition to infection among the recognised features.

Integument 1

Nail Abnormality Abnormal nail morphology HP:0001597

Show evidence (1 reference)

PMID:38245683 SUPPORT Human Clinical

"Additionally, other malformations such as cardiac malformations (27/64, 26.6%), hearing impairment (9/64, 14.1%), nail, or facial abnormalities (15/64, 23.4%)"

Gives the nail/facial figure, 15 of 64. Quoted in full rather than clipped to the nail clause because the surrounding counts are the useful context - but note one of them is arithmetically wrong in the source: it prints cardiac malformations as "27/64, 26.6%", and 27/64 is 42.2% while 26.6% is 17/64, so either the numerator or the percentage is a typo. This entry does not curate a cardiac frequency from this sentence for that reason; the cardiac phenotype here is cited to other sources. The nail figure, 15/64, checks out at 23.4%.

Limbs 5

Radioulnar Synostosis HP:0002974

Temporal: CHRONIC

Sequelae: Limited pronation and supination of the forearm

Show evidence (2 references)

PMID:38245683 SUPPORT Human Clinical

"characterized by varying presentation of congenital thrombocytopenia (progressing to pancytopenia), bilateral proximal radioulnar synostosis, and other skeletal abnormalities"

Gives the anatomical detail this entry curates: proximal and bilateral.

PMID:37067177 SUPPORT Human Clinical

"Within our full MECOM-associated syndrome cohort, skeletal abnormalities included radioulnar synostosis (n=5), clinodactyly (n=3), and radial hypoplasia (n=1)"

Counts the skeletal findings in an eight-patient cohort, giving both this phenotype and the digital ones.

Limited pronation and supination of the forearm Limited pronation/supination of forearm HP:0006394

Course: STABLE

Show evidence (1 reference)

PMID:29519864 SUPPORT Human Clinical

"Congenital radioulnar synostosis (RUS) is a rare developmental abnormality involving fusion of the bones of the forearms (radius and ulna) preventing normal supination of the affected forearm"

States the loss of supination as the direct consequence of the fusion.

Clinodactyly HP:0030084

Show evidence (2 references)

PMID:37067177 SUPPORT Human Clinical

"Within our full MECOM-associated syndrome cohort, skeletal abnormalities included radioulnar synostosis (n=5), clinodactyly (n=3), and radial hypoplasia (n=1)"

Counts clinodactyly in an eight-patient cohort.

PMID:29540340 SUPPORT Human Clinical

"The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss."

Independent confirmation in the twelve-patient series.

Patellar Aplasia or Hypoplasia Aplasia/Hypoplasia of the patella HP:0006498

Show evidence (2 references)

PMID:38662475 SUPPORT Human Clinical

"Proximal RUS, hypoplastic thumbs, short, broad fingers, short fifth digits, and coalition of right capitate and hamate, and bilateral absent patellae"

The aplastic end of the finding, in the individual whose forearm radiograph the same paper reproduces. Quoted in full rather than clipped to the patellar clause, because the surrounding list is the point: the patellar finding sits inside a broader skeletal phenotype in the same person, alongside the proximal synostosis this entry is named for.

PMID:38662475 SUPPORT Human Clinical

"Club foot and small patellae"

The hypoplastic end of the finding in a second individual, which is why the binding covers both severities.

Digital Phalangeal Hypoplasia Short middle phalanx of the 5th finger HP:0004220

Show evidence (1 reference)

PMID:38245683 SUPPORT Human Clinical

"The other relatively prevalent features, as observed in 42.2% of reported RUSAT-2 cases, were other skeletal malformation, including hypoplasia of middle and end phalanx D5, Toe malposition D2, Thumb under D2."

The finding and its share of a 64-patient literature review. No `frequency` band is set from it, consistently with every other phenotype in this entry - see `notes` for why this entry declines frequency bands across incommensurable cohorts.

Metabolism 1

Nonimmune hydrops fetalis HP:0001790

Show evidence (2 references)

PMID:37230770 SUPPORT Human Clinical

"These cases add to the growing body of literature that describe MECOM-associated disease, particularly MECOM as a cause of fetal hydrops due to bone marrow failure in utero."

Establishes MECOM-related marrow failure as a cause of non-immune fetal hydrops.

PMID:41617498 SUPPORT INDIRECT Human Clinical

"Three were diagnosed in utero and died in the neonatal period."

INDIRECT, and kept for what it does establish rather than what it says: the sentence reports prenatal diagnosis and neonatal death, not hydrops. It supports the claim that the severe prenatal pole of this disease is not confined to the two hydrops case reports, which is why the phenotype is not curated as a two-patient curiosity.

Nervous System 1

Global Developmental Delay HP:0001263

Show evidence (1 reference)

PMID:37067177 SUPPORT Human Clinical

"impaired growth or development [failure to thrive (n=2), developmental delay (n=4), hypotonia (n=1), hearing loss (n=2)]"

Names developmental delay and counts it, 4 of 8 - the commonest non-haematological finding in this cohort. No `frequency` is set from a single eight-patient series.

Growth 1

Failure to Thrive HP:0001508

Show evidence (1 reference)

PMID:37067177 SUPPORT Human Clinical

"impaired growth or development [failure to thrive (n=2), developmental delay (n=4), hypotonia (n=1), hearing loss (n=2)]"

Names failure to thrive and counts it, 2 of 8, in this cohort. No `frequency` is set from a denominator of eight in one series.

🧬

Genetic Associations

2

MECOM

Gene: MECOM hgnc:3498 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

CGGV:assertion_d1d25a48-f664-49c6-8ea4-dfddd0651209-2021-11-08T170000.000Z SUPPORT Other

Expert-panel grading at the highest tier, and the contrast that makes the HOXA11 Limited grading meaningful rather than a generic caveat.

PMID:26581901 SUPPORT Human Clinical

"Subsequent analysis of MECOM in two other individuals with RUSAT revealed two additional missense mutations."

Independent replication beyond the index trio in the founding report.

PMID:40170114 SUPPORT Other

"A comprehensive review of literature indicated that MECOM gene mutations included missense (68.3%), deletion (8.5%), splice site (8.5%), frameshift (7.3%), and nonsense (7.3%) mutations."

The variant-class distribution across the published literature.

+ 1 more reference

HOXA11

Gene: HOXA11 hgnc:5101 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

CGGV:assertion_48ef111f-28fc-4970-a0ca-8387e9ec2d0e-2024-09-04T160000.000Z SUPPORT Other

The expert-panel grading, and the most important single fact about this gene-disease relationship. Limited is ClinGen's lowest non-disputed tier and carries an explicit caution against treating the relationship as established for clinical use.

PMID:26581901 SUPPORT Human Clinical

"A heterozygous HOXA11 mutation has been identified in two unrelated families as a cause of RUSAT."

States the gene-disease relationship and its evidential base of two families.

PMID:26581901 SUPPORT Human Clinical

"However, HOXA11 mutations are absent in a number of individuals with RUSAT, which suggests that other genetic loci contribute to RUSAT."

The limit on HOXA11's share of the disease, from the paper that found the second gene.

🔬

Variants

2

MECOM p.Arg750Trp

Gene: MECOM hgnc:3498 SNV

Numbering note before anything else, because this is a live source of confusion. p.Arg750Trp is EVI1 numbering (NP_001098548.2, transcript NM_001105078). The MDS1-EVI1 isoform adds 188 residues at the N-terminus, so this same allele is p.Arg938Trp in MDS1-EVI1 coordinates - the position shifts, the substituted residue does not. The trap is concrete: a different reported allele, c.2813G>A, appears in one cohort as p.(Arg938Gln), which is p.Arg750Gln in EVI1 numbering. Arg938Trp and Arg938Gln are different variants at the same codon, and an earlier version of this note conflated them. The recurrent RUSAT allele, and the most informative one for expressivity. It was the index variant in the founding MECOM report and recurred in three further families in a later cohort. Across six families carrying it, five were de novo with very early presentation and all required transplant, while the sixth showed dominant inheritance and progressed from aplastic anaemia to myelodysplastic syndrome in adulthood. Same allele, two very different clinical courses.

Show evidence (1 reference)

PMID:29519864 SUPPORT Human Clinical

"We observe that theMECOMvariant p.Arg750Trp is a recurrent change that can present with a variety of hematological defects in association with RUS."

Names the recurrent allele and its variable presentation. The gene symbol runs into the surrounding words in the cached full text; that is a formatting artefact of the source, not a transcription error.

HOXA11 p.Asn291ThrfsX3

Gene: HOXA11 hgnc:5101 DELETION

The single RUSAT1 allele, c.872delA, causing a frameshift and premature truncation of HOXA11. Found in six individuals from two families and never reported again. Functional work shows the truncated protein loses DNA binding while retaining its interaction with Meis1b.

Show evidence (1 reference)

PMID:29519864 SUPPORT Human Clinical

"The heterozygous variant c.872delA, p.Asn291ThrfsX3 was identified in six individuals from two families"

The allele, its consequence, and the number of carriers.

💊

Medical Actions

4

Allogeneic Hematopoietic Stem Cell Transplantation

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

Platform: Cell therapy

The only established curative treatment for the marrow failure, and the treatment most reported RUSAT patients receive. A retrospective series of six infants transplanted between 4 and 18 months of age with reduced-intensity conditioning - fludarabine, cyclophosphamide or melphalan, and rabbit anti-thymocyte globulin, with or without low-dose irradiation - reported that all survived with stable engraftment and full donor chimerism, no severe regimen-related toxicity, and only low-grade acute graft-versus-host disease. Related donors must be genotyped before they are used, and this disease makes that sharper than usual. Inheritance is dominant and transmission through a minimally affected or asymptomatic parent is documented, so an HLA-matched sibling can carry the variant; and because somatic reversion can normalise a carrier's counts, a donor can be under-called on a blood sample exactly as a proband can. The same non-haematopoietic-tissue caution recorded under `diagnosis` applies to donor screening. Note that all six infants in the reduced-intensity series were transplanted from unrelated donors. Targeted sibling testing is worth considering even when the proband's variant is de novo, because germline mosaicism is possible. Two further limits a reader should carry. Transplant replaces the haematopoietic compartment and does nothing for the synostosis, the hearing loss, the renal or cardiac anomalies, or the aortic dilatation, all of which are outside the graft and need their own follow-up - though the B-cell and immunological arm is haematopoietic and is corrected. And within the series itself, the three children given low-dose irradiation were relatively short compared with the three who were not - a small, uncontrolled comparison, but the authors raise it as a reason to question routine irradiation rather than as an established late effect.

Mechanism Target:

Hematopoietic Stem Cell Maintenance Failure — Replaces the MECOM-deficient stem cell compartment with donor cells that carry two functional alleles. It corrects the node rather than compensating for it, which is why it is curative for the marrow arm and irrelevant to every other arm.

Show evidence (1 reference)

PMID:36515795 SUPPORT Human Clinical

"All patients survived and achieved stable engraftment and complete chimerization with the donor type."

Full donor chimerism is the demonstration that the deficient compartment has been replaced.

Show evidence (6 references)

PMID:36515795 SUPPORT Human Clinical

"Therefore, allogeneic HSCT with RIC is an effective and feasible treatment for infants with MECOM-associated syndrome."

The series conclusion, in a cohort of six infants.

PMID:36515795 SUPPORT Human Clinical

"All patients received a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, cyclophosphamide or melphalan, and rabbit anti-thymocyte globulin and/or low-dose total body/thoracic-abdominal/total lymphoid irradiation, followed by allogeneic bone marrow or cord blood..."

The regimen and the age window, which is the operationally useful detail.

PMID:36515795 SUPPORT Human Clinical

"Three patients treated with low-dose irradiation had relatively short stature compared to three patients not treated with irradiation."

The late-effect signal, recorded with its three-against-three denominator visible so nobody reads it as an established outcome.

+ 3 more references

Platelet Transfusion

Action: platelet transfusion Ontology label: Platelet Transfusion NCIT:C15366

Platform: Other

Supportive management of the thrombocytopenia, and the mainstay before transplant. In one reported neonate, multiple platelet transfusions carried the child through the neonatal period until spontaneous recovery - which is a real course in this disease and a reason not to treat early transfusion dependence as proof that transplant is inevitable.

Mechanism Target:

Thrombocytopenia — Replaces the missing platelets. Purely compensatory: it does nothing to the megakaryocyte arrest upstream of it.

Show evidence (1 reference)

PMID:38662475 SUPPORT Human Clinical

"Neonatal thrombocytopenia managed with multiple platelet transfusions followed by spontaneous recovery"

Documents transfusion support of the thrombocytopenia in a reported patient.

Show evidence (1 reference)

PMID:38662475 SUPPORT Human Clinical

"Neonatal thrombocytopenia managed with multiple platelet transfusions followed by spontaneous recovery"

The one quotable account of transfusion management in this disease, and of the spontaneous recovery that followed it.

Surgical Correction of Radioulnar Synostosis

Action: surgical correction of radioulnar synostosis Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Reported in a single carrier, corrected at age four. Curated because the functional deficit is permanent otherwise and because it establishes that the orthopaedic arm of the disease is managed separately from the haematological arm - this child had bilateral synostosis and no haematological abnormality at all. The evidence base is one patient in a genotype-phenotype table, not an outcome series, so this entry states no indication, no technique and no result - including no claim about whether the proximal joint is restored, which nothing cited here supports. Congenital radioulnar synostosis has its own general orthopaedic literature; nothing in it is RUSAT-specific and none of it is cited here.

Mechanism Target:

Limited pronation and supination of the forearm — Targets the functional consequence rather than the malformation. This entry does not state what the operation achieves: the single cited case records only that correction was performed at age four, with no technique and no outcome, and the general congenital-radioulnar-synostosis surgical literature is not cited here.

Show evidence (1 reference)

PMID:38662475 SUPPORT Human Clinical

"Bilateral RUS-surgically corrected at age 4"

The one reported instance of surgical correction in a MECOM carrier.

Show evidence (1 reference)

PMID:38662475 SUPPORT Human Clinical

"Bilateral RUS-surgically corrected at age 4"

Establishes that surgical correction is done in this population. A single tabulated case; no outcome is claimed.

Genetic Counseling and Cascade Testing

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Autosomal dominant transmission gives a 50% recurrence risk per pregnancy, but the counselling problem in this disease is that the risk figure is the easy part. Expressivity within a family runs from a fixed forearm with normal counts to transfusion dependence in infancy, and somatic reversion can hide the phenotype in a carrier parent, so a genotype does not predict a course. Two points that are easy to miss. First, a de novo variant in the proband does not reduce sibling recurrence risk to zero: germline mosaicism is possible, and targeted sibling testing is recommended - which matters twice over, because those siblings are also the potential transplant donors. Cord blood banking from a molecularly unaffected, HLA-matched sibling is worth raising early, before it is needed. Second, a finding flagged as preliminary in its own source: in one cohort, 12 of 16 pregnancies in five mothers with detailed histories ended in loss, against a quoted general-population rate of 15-25%. See the `rusat_pregnancy_loss` discussion for why this is not yet a risk figure.

Show evidence (3 references)

PMID:38662475 SUPPORT Human Clinical

"Given the high rate of pregnancy losses in these families, they should be considered for counseling for reproductive planning and the use of preimplantation genetic diagnosis to reduce the risk of future pregnancy losses."

The source's own counselling recommendation, including the reproductive option it names.

PMID:37067177 SUPPORT Human Clinical

"Given HSCT is often a therapeutic option for this cohort, it may be beneficial to consider cord blood collection and banking of molecularly unaffected, HLA-matched siblings."

The forward-planning recommendation that links counselling to the transplant pathway.

PMID:37067177 SUPPORT Human Clinical

"Recognition of the expanded hematologic and non-hematologic clinical features allows for rapid molecular diagnosis, early identification of life-threatening complications, and improved genetic counseling for families."

Links the expanded phenotype directly to the counselling task.

🔬

Diagnosis

5

Complete Blood Count and Bone Marrow Examination

The blood count finds the thrombocytopenia; the marrow tells you what kind it is. Absent or severely reduced megakaryocytes with a hypocellular marrow is what separates a production failure from immune or alloimmune destruction in a neonate, and it is the finding that should stop immunoglobulin and steroids being given for an inherited marrow failure. Serial counts matter, because lineage involvement evolves in both directions - towards pancytopenia in most, and towards spontaneous recovery in some.

Show evidence (1 reference)

PMID:38662475 SUPPORT Human Clinical

"Hypocellular bone marrow with complete absence of megakaryocytes, dyserythropoiesis and left shifted granulopoiesis with abnormal granulation"

The marrow picture, described in a reported patient.

Bilateral Forearm Radiography

Radiographs of both forearms to look for proximal radioulnar fusion. Worth doing even when there is no visible deformity, because the external appearance can be unremarkable and the restriction subtle enough that an affected adult has never noticed it - one reported patient's synostosis was inferred from limited bilateral pronation rather than diagnosed radiographically. The test is worth doing for what it rules in, not for what it rules out: a normal forearm does not exclude the disease.

Show evidence (1 reference)

PMID:29519864 SUPPORT Human Clinical

"Radiographs of the radius and ulna fusions from families 4–6 (Figure 1), show all cases have a very similar radiological appearance."

Establishes that the radiographic appearance is consistent enough to be recognised across families.

Germline Molecular Genetic Testing of MECOM and HOXA11

Confirmatory, and in practice the only way the diagnosis is made - essentially every reported RUSAT2 case was identified by next-generation sequencing. Test both genes, and include copy-number analysis: whole-gene and partial MECOM deletions cause disease and are missed by sequencing alone. Trio exome or genome sequencing is what has actually found these patients, including the perinatal cases in whom the syndrome was never suspected clinically.

Show evidence (3 references)

PMID:38245683 SUPPORT Human Clinical

"To our knowledge, all reported RUSAT-2 cases were diagnosed through next generation sequencing and most of them received HSCT."

States that sequencing is how this diagnosis is made in practice.

PMID:29519864 SUPPORT Human Clinical

"including two deletions that either remove the MDS1 part of the complex or the entire gene region"

Documents partial and whole-gene MECOM deletions as disease-causing, which is why copy-number analysis belongs alongside sequencing rather than as an afterthought.

PMID:37230770 SUPPORT Human Clinical

"Furthermore, they support the use of a broad sequencing approach for perinatal diagnosis, as MECOM is absent from available targeted gene panels for hydrops, and highlight the importance of postmortem genomic investigation."

The specific reason to prefer broad sequencing over a targeted panel in the perinatal presentation.

Germline Testing on Non-Hematopoietic Tissue

The one diagnostic step in this entry that follows from a mechanism rather than from convention, and the one most easily skipped. Somatic reversion by 3q copy-neutral loss of heterozygosity expands a clone that has lost the mutant allele, so in a carrier whose counts have recovered, blood can be a misleading germline sample and the causative variant can be under-called or missed. Use cultured skin fibroblasts or hair follicles instead. The same caution applies after transplant, when circulating cells are the donor's.

Show evidence (1 reference)

PMID:38662475 SUPPORT Human Clinical

"the notable prevalence of somatic genetic rescue reiterates the importance of using DNA from nonhematopoietic tissue such as hair follicles or skin fibroblasts for genetic testing"

States both the reason and the recommended tissue sources.

Immunological Evaluation

B-cell count and immunoglobulins, because B-cell deficiency is part of the syndrome, is actionable on its own, and would otherwise be found only after an infection. It also carries diagnostic weight: B-cell deficiency segregates with the same zinc-finger region as the synostosis, so finding it alongside a fixed forearm strengthens the case for a variant in that region.

Show evidence (1 reference)

PMID:29540340 SUPPORT Human Clinical

"Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1."

The co-segregation that gives the immunological workup diagnostic value beyond its own management implications.

📈

Progression

4

Prenatal and perinatal

Age: In utero to the first days of life

The severe pole. Marrow failure beginning before birth presents as non-immune hydrops with severe anaemia, and both reported cases died in the neonatal period; a separate series records three individuals diagnosed in utero who died as neonates. Neither hydrops case had radioulnar synostosis and neither was suspected clinically before sequencing. A neonate presenting on day zero with severe thrombocytopenia and intracranial haemorrhage died on day three.

Show evidence (1 reference)

PMID:37230770 SUPPORT Human Clinical

"We report two cases of infants born preterm who presented at birth with symptoms of bone marrow failure including severe anemia, hydrops, and petechial hemorrhages; radioulnar synostosis was not observed in either patient, and, unfortunately, neither infant survived."

The perinatal-lethal presentation, including the absence of the skeletal feature that would have suggested the diagnosis.

Neonatal presentation

Age: Birth to the first months

The usual presentation. Thrombocytopenia is present from birth, often found on a blood count taken for petechiae or bleeding, with an amegakaryocytic or hypomegakaryocytic marrow. The synostosis is present at birth but is frequently not what brings the child to attention. Most reported RUSAT2 cases have been diagnosed by next-generation sequencing rather than recognised clinically.

Show evidence (1 reference)

PMID:29519864 SUPPORT Human Clinical

"All the affected children presented with thrombocytopenia from birth, with three out of the four undergoing BMT."

Congenital onset and the early transplant rate in the HOXA11 families.

Infancy and early childhood

Age: First months to early childhood

The branch point. In many, the single-lineage cytopenia becomes multilineage and progresses to pancytopenia, and transplant follows - reported infants were transplanted between 4 and 18 months of age. In others the course is the opposite: neonatal thrombocytopenia managed with transfusions resolves spontaneously, in at least some cases through somatic reversion. Which course a given child takes is not predictable from genotype.

Show evidence (2 references)

PMID:36515795 SUPPORT Human Clinical

"followed by allogeneic bone marrow or cord blood transplantation from unrelated donors"

The transplant arm of this phase, in a six-infant series.

PMID:38662475 SUPPORT Human Clinical

"Neonatal thrombocytopenia managed with multiple platelet transfusions followed by spontaneous recovery"

The opposite arm of the same phase, and the reason this entry does not describe the course as uniformly progressive.

Adulthood

Age: Adolescence to the seventh decade

Untransplanted carriers reaching adulthood follow two further courses. Some remain mildly affected, with a modest single cytopenia found incidentally, and at least one individual was in relatively good health into their sixties. Others accumulate clonal haematopoiesis - all three older individuals in one cohort carried somatic variants in ASXL1, DNMT3A or TET2 - and progress from aplastic anaemia to myelodysplastic syndrome. This is the phase that argues for long-term surveillance rather than discharge after a stable childhood.

Show evidence (2 references)

PMID:29519864 SUPPORT Human Clinical

"some individuals had severe BMF in childhood whilst others only a modest single cytopenia well into adulthood"

The mild adult course, alongside the severe childhood one, in one cohort.

PMID:38662475 SUPPORT Human Clinical

"The presence of clonal hematopoiesis of indeterminate potential in the older individuals, and the finding of additional cases of myeloid dysplasia in our cohort warrant consideration of surveillance particularly in older carriers."

The source's own surveillance recommendation, and the reason this phase is curated separately rather than folded into the childhood course.

📊

Prevalence

2

Worldwide, published cases (RUSAT2 / MECOM)

Cases In Literature Ultra Rare

Approximately 66 reported RUSAT-2 cases as of 2025. No population prevalence or incidence estimate has been published for either subtype, so no rate is computed here. This count is also an undercount of MECOM-related disease rather than an overcount: the perinatal-lethal presentations were diagnosed only on postmortem or rapid trio sequencing, and MECOM is absent from targeted hydrops gene panels.

Show evidence (1 reference)

PMID:41635268 SUPPORT Other

"As of 2025, there were approximately 66 reported cases of RUSAT-2 reported in the literature, with clinical severity ranging from isolated thrombocytopenia to early-onset bone marrow failure requiring hematopoietic stem cell transplantation."

The published case count for the MECOM subtype.

Worldwide, published cases (all RUSAT, families)

Cases In Literature Ultra Rare

A family-level rather than individual-level count, recorded separately because it uses a different denominator and a 2023 cut-off. It is not comparable with the 66-case figure above and the two must not be pooled.

Show evidence (1 reference)

PMID:37099686 SUPPORT Other

"Approximately 22 families have been reported to have individuals affected with RUSAT."

Family count across both subtypes as of 2023.

🔀

Differential Diagnoses

7

Conditions with similar clinical presentations that must be differentiated from Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia:

Congenital Amegakaryocytic Thrombocytopenia

Overlapping Features The closest mimic, and mechanistically the most interesting one. CAMT presents identically in a neonate: congenital thrombocytopenia, an amegakaryocytic marrow, progression to pancytopenia. Most cases are biallelic MPL, but CAMT is genetically heterogeneous and the exception changes management. Biallelic THPO variants - the ligand rather than the receptor - produce the same picture and respond to the thrombopoietin mimetic romiplostim, with trilineage responses and transfusion independence sustained for years. "Curable only by transplant" is therefore false for a real subset of the closest mimic, and it is precisely the subset in which going straight to transplant is the wrong move. The MPL overlap with RUSAT may not be coincidental - EVI1 transcriptionally regulates MPL, so the two diseases may converge on the same receptor from opposite ends of the same regulatory relationship.

Distinguishing Features

Inheritance separates them cleanly: CAMT is autosomal recessive, RUSAT autosomal dominant, so a de novo heterozygous variant or an affected parent points away from CAMT. Radioulnar synostosis, when present, is decisive - but it is present in only some RUSAT patients, so its absence separates nothing. Before the panel returns, two things are available. Family history, as above. And serum thrombopoietin, which is markedly elevated in MPL-CAMT because MPL is the clearance receptor for its own ligand - and is low in THPO-CAMT, which is the distinction that identifies the subset that responds to romiplostim. Note this entry cannot say what thrombopoietin does in RUSAT: the one report of patient-level TPO data could not be verified, and that gap is recorded in `notes`. In practice a panel containing MPL, THPO and MECOM settles it, which is why all three belong on the same test.

Show evidence (3 references)

PMID:37610030 SUPPORT In Vitro

"we demonstrated that EVI1 controls the transcriptional regulation of MPL, a gene whose mutations are responsible for congenital amegakaryocytic thrombocytopenia (CAMT), potentially explaining the partial overlap between MECOM-AS and CAMT"

Names both the clinical overlap and the proposed mechanistic basis for it.

PMID:29191945 SUPPORT Human Clinical

"In all the three affected children, treatment with the THPO-mimetic romiplostim induced trilineage hematological responses, remission of bleeding and infections, and transfusion independence, which were maintained after up to 6.5 years of observation."

The treatable CAMT subset, and the reason this differential is therapeutically consequential rather than merely taxonomic.

PMID:29191945 SUPPORT Human Clinical

"Recognizing patients with THPO mutations among those with juvenile bone marrow failure is essential to provide them with appropriate substitutive therapy and prevent the use of invasive and unnecessary treatments, such as hematopoietic stem cell transplantation or immunosuppression."

States the clinical stake directly: missing this subset sends a treatable child to transplant.

Thrombocytopenia-Absent Radius Syndrome

Overlapping Features The other congenital thrombocytopenia with a forearm malformation, and the one RUSAT is most likely to be confused with on a description rather than an image. TAR is caused by a rare RBM8A null allele in trans with a common hypomorphic regulatory variant.

Distinguishing Features

The bone lesion is different in kind, not degree. TAR is a bilateral absence of the radius with the thumbs preserved - a reduction defect. RUSAT is a fusion of two present bones at the proximal joint, with the radius intact. A single forearm radiograph separates them. The genetics diverge too: TAR requires a rare null allele together with a low-frequency regulatory variant on the other chromosome, so it does not segregate as a simple dominant the way RUSAT does. HOXA11 is not the TAR gene, and was excluded as such directly. This entry makes no claim about the comparative natural history of the two thrombocytopenias - no source cited here compares them.

Show evidence (3 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."

The TAR genotype this differential asserts, and the contrast with RUSAT's simple heterozygous dominant inheritance.

PMID:11841440 SUPPORT Human Clinical

"mutations in the coding sequence of the Hox genes known to affect radial development are not a common cause of TAR syndrome"

Excludes the RUSAT1 gene as a cause of TAR, which is what makes these two genuinely separate entities rather than one spectrum.

PMID:29519864 SUPPORT Human Clinical

"Congenital radioulnar synostosis (RUS) is a rare developmental abnormality involving fusion of the bones of the forearms (radius and ulna) preventing normal supination of the affected forearm"

The RUSAT lesion is a fusion of present bones, which is the contrast with TAR's absent radius.

Syndromic and Isolated Congenital Radioulnar Synostosis

Overlapping Features Radioulnar synostosis occurs on its own and as a feature of other syndromes, including aneuploidies and skeletal dysplasias, without any haematological disease. Someone presenting to orthopaedics with a fixed forearm and a normal blood count is much more likely to have one of these than RUSAT.

Distinguishing Features

A blood count is the discriminator, and it should be repeated rather than taken once: the haematological onset in MECOM disease ranges from in utero to late adulthood, so a normal count in childhood does not exclude it. Conversely a RUSAT variant can present as isolated synostosis with no haematological abnormality at all, so the two groups genuinely overlap and sequencing is what separates them.

Show evidence (2 references)

PMID:29519864 SUPPORT Human Clinical

"RUS can occur with other abnormalities in the skeleton, heart, urinary tract, as well as aneuploid syndromes."

Establishes the non-haematological causes of the same bone lesion.

PMID:29540340 SUPPORT Human Clinical

"the clinical spectrum ranged from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormality"

The reason the two groups overlap: a MECOM variant can give synostosis with no blood disease.

Dyskeratosis Congenita and the Telomere Biology Disorders

Overlapping Features An inherited marrow failure syndrome that is regularly misdiagnosed as congenital amegakaryocytic thrombocytopenia when the classic mucocutaneous triad is absent - which it often is. It shares with RUSAT a congenital cytopenia progressing to marrow failure, a dominant form, and a cancer predisposition, and it is caused by defects in telomere maintenance rather than in a haematopoietic transcription factor. This is on the list for one reason above the others, and it is not taxonomic: getting it wrong before transplant can kill the patient.

Distinguishing Features

Telomere length measurement is the discriminator, and it is the one test on this differential list that must be done *before* conditioning rather than at leisure. Telomere biology disorder patients do not tolerate standard alkylator and irradiation-based conditioning, and require fludarabine-based reduced-intensity protocols; a patient sent to standard conditioning on a RUSAT label they do not have is a foreseeable catastrophe. Nothing about the RUSAT phenotype excludes it on inspection. Radioulnar synostosis is not a DC feature, so its presence points away - but it is absent in a large share of MECOM patients, so its absence discriminates nothing, which is the same asymmetry this entry records for Fanconi anaemia. Note also that MECOM has itself been placed inside the telomere biology disorders by association in at least one related gene's literature; this entry makes no such claim for RUSAT, and no source cited here measures telomeres in a MECOM patient.

Show evidence (2 references)

PMID:35929966 SUPPORT Other

"Dyskeratosis congenita (DC) is a multisystem syndrome characterized by mucocutaneous abnormalities, bone marrow failure, and predisposition to cancer."

The overlapping features - marrow failure and cancer predisposition - that put this on the differential, and the mucocutaneous findings whose absence is what causes the misdiagnosis.

PMID:35929966 SUPPORT Other

"the only current curative treatment for these is hematopoietic stem cell transplantation (HSCT) using fludarabine-based conditioning protocols"

The conditioning requirement that makes this differential decision-changing rather than academic.

Neonatal Alloimmune and Immune Thrombocytopenia

Overlapping Features The commonest cause of severe thrombocytopenia in an otherwise well newborn, and of neonatal intracranial haemorrhage - which is precisely the presentation this entry curates at its severe pole. Maternal antibodies against fetal platelet antigens, or transplacental antibody in maternal ITP, destroy platelets peripherally. It is on the list because it is common, because it is the default assumption in a bleeding neonate, and because treating a production failure as an immune one wastes the window in which the real diagnosis matters.

Distinguishing Features

The marrow separates them decisively and immediately: alloimmune thrombocytopenia is peripheral destruction with normal or increased megakaryocytes, while RUSAT is a production failure with megakaryocytes absent or severely reduced. That single finding is why marrow examination sits first in this entry's diagnostic section. Two further pointers. Alloimmune thrombocytopenia is isolated and self-limiting as maternal antibody clears, whereas RUSAT thrombocytopenia persists and in many progresses to multilineage failure. And immunoglobulin and corticosteroids, which are reasonable empirical therapy for suspected immune disease, do nothing for an inherited marrow failure - so a non-response is itself informative rather than merely disappointing.

Show evidence (1 reference)

PMID:29540340 SUPPORT Human Clinical

"Here we report on 12 patients with congenital hypomegakaryocytic thrombocytopenia caused by MECOM mutations"

The marrow finding that distinguishes RUSAT from peripheral destruction. A hypomegakaryocytic marrow is not what alloimmune thrombocytopenia produces.

GATA2 Deficiency and the Dominant Thrombocytopenia-Myeloid Predisposition Syndromes

Overlapping Features The differential for the adult and adolescent pole of this disease rather than the neonatal one, and the group most likely to be reached for when a RUSAT carrier presents late. GATA2 deficiency, RUNX1-familial platelet disorder, ANKRD26- and ETV6-related thrombocytopenia all give dominantly inherited cytopenias with a predisposition to myelodysplastic syndrome and acute myeloid leukaemia, and relatives with mild or absent findings - which is exactly the pedigree pattern this entry documents for MECOM families. GATA2 is doubly relevant here. It is not only a differential: it is a direct EVI1 target in this entry's own mechanism, bound at its promoter through the N-terminal zinc fingers. And ETV6, one of this group's genes, appears in this entry's own clonal-haematopoiesis node as a somatic event in older MECOM carriers. The boundary between "differential" and "downstream" is genuinely blurred here.

Distinguishing Features

Radioulnar synostosis is the discriminator when present, since none of this group causes it - but the usual caveat applies with more force at this age, because a late-presenting MECOM carrier may have no skeletal finding at all and no known childhood cytopenia. A sequencing panel covering all of them is what separates them, and MECOM belongs on any panel used for suspected familial MDS. The practical point is the same one that drives donor screening in this entry: the whole group shares a requirement to identify the germline lesion before transplant, because it determines both donor selection and conditioning intensity.

Show evidence (2 references)

PMID:32571604 SUPPORT Other

"Familial clustering was first observed in patients with leukemia, which led to the identification of several germline variants, such as RUNX1, CEBPA, GATA2, ANKRD26, DDX41, and ETV6, among others, now established as HPS, with tendency to develop myeloid neoplasms."

Names the group this differential covers and its shared myeloid-neoplasm predisposition.

PMID:32571604 SUPPORT Other

"Timely recognition of HPS is critical to ensure safe choice of donors and/or conditioning-regimen intensity for allogeneic hematopoietic stem-cell transplantation"

The reason this differential is worth resolving before transplant rather than after, and independent support for the donor-screening and conditioning points recorded elsewhere in this entry.

Fanconi Anemia

Overlapping Features The inherited marrow failure syndrome that also puts a radial-ray abnormality next to a failing marrow, and the one most likely to be tested for first in a child with both. It is a DNA interstrand crosslink repair disorder, mechanistically unrelated to a transcription-factor haploinsufficiency.

Distinguishing Features

Chromosome breakage testing separates them: it is positive in Fanconi anaemia and normal in RUSAT. Two operational points. It must be done before conditioning, since the result changes regimen intensity. And blood-based testing can be falsely negative where haematopoietic mosaicism has corrected the lymphocyte compartment, requiring fibroblasts - the same non-haematopoietic-tissue logic this entry applies to its own somatic reversion. Note the asymmetry - a normal breakage test argues against Fanconi anaemia but establishes nothing about RUSAT, which has no functional confirmatory assay of its own and rests entirely on sequencing. The bone lesions also differ: Fanconi anaemia gives radial ray reduction defects, often with an absent or hypoplastic thumb, while RUSAT gives a proximal fusion with both bones present.

Show evidence (2 references)

PMID:20301575 SUPPORT Human Clinical

"increased chromosome breakage and radial forms on cytogenetic testing of"

The chromosome-breakage test this differential turns on, from the GeneReviews chapter for the comparator disease. It establishes what a positive result means for Fanconi anaemia and says nothing about RUSAT, which is exactly the asymmetry the distinguishing features record.

PMID:38662475 SUPPORT Human Clinical

"Somatic genetic rescue has been reported in several genetic diseases including skin disorders (eg, ichthyosis with confetti9 and epidermolysis bullosa10) and BMF syndromes (eg, Fanconi anemia,11 Diamond Blackfan anemia,12 Wiskott-Aldrich syndrome,13 and dyskeratosis congenita14), with only 1..."

Places RUSAT among the inherited marrow failure syndromes that Fanconi anaemia belongs to, and records that somatic reversion - the phenomenon curated in this entry's pathograph - is shared across that class rather than unique here.

🔬

Clinical Trials

1

NCT00027274 NOT_APPLICABLE RECRUITING

The NCI natural history study of cancer susceptibility in inherited bone marrow failure syndromes. RUSAT is not named among its listed conditions, which are Diamond-Blackfan anaemia, dyskeratosis congenita, Fanconi anaemia, Shwachman-Diamond syndrome and a generic "Inherited Bone Marrow Failure Syndrome, Aplastic Anemia" category; RUSAT is curated here as eligible under that generic category, since every source in this entry classes it as an IBMFS. That is an inference about eligibility, not a statement that RUSAT patients are enrolled. It is recorded because the question it studies - cancer rates in the IBMFS class - is precisely the question this entry declines to answer for RUSAT. Four myeloid malignancies among 80 reported individuals is the only figure available, and the source calls it likely low because most patients are transplanted young. A prospective cohort is the study design that would settle it.

Show evidence (1 reference)

clinicaltrials:NCT00027274 SUPPORT Other

"A prospective cohort of Inherited Bone Marrow Failure Syndrome (IBMFS) will provide new information regarding cancer rates and types in these disorders."

The study's own statement of what it is for, which is the open question this entry records for RUSAT.

🧫

Experimental Models

1

MECOM-haploinsufficient primary human hematopoietic stem cells PRIMARY_CELL_CULTURE

Primary human haematopoietic stem cells engineered to model MECOM haploinsufficiency, combined with single-cell genomics. This is the system that turned the disease from a gene assignment into a mechanism: it is where the EVI1-dependent maintenance network was defined, and it works in the species that has the disease, which the knock-in mouse does not.

Pathograph links

Dysregulation of the EVI1 HSC Maintenance Network recapitulates fidelity: high Reproduces the human haploinsufficient state in human stem cells and reads out the transcriptional network directly.

Limitations: An engineered haploinsufficiency rather than the patient allelic spectrum, so it models dose reduction and cannot address whether the zinc-finger 8/9 missense alleles do anything a null does not - which is exactly the question the two competing hypotheses in this entry turn on. It is also a cell-autonomous system with no marrow niche and no limb.

Readouts

HSC maintenance transcriptional network expression

Direction: ALTERED

Interpretation: Single-cell genomic definition of the gene network EVI1 maintains.

Show evidence (1 reference)

PMID:36522544 SUPPORT In Vitro

"By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC maintenance."

The network readout that this model exists to produce.

Show evidence (1 reference)

PMID:36522544 SUPPORT In Vitro

"Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo."

Establishes that the system models this disorder specifically.

Show evidence (1 reference)

PMID:36522544 SUPPORT In Vitro

"Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo."

Establishes that this system was built to model this disorder.

🐁

Animal Models

1

Evi1 H752R knock-in mouse

The only RUSAT animal model. It carries the mouse equivalent of a human RUSAT variant at the orthologous residue, which is what makes it worth taking seriously as a model of this disease rather than of MECOM loss in general - the previous mice were exonic deletions. Homozygotes die at embryonic day 10.5 to 11.5, so the model is necessarily heterozygous, which matches the human genotype.

Species

Mouse

Genotype

Mecom c.2255A>G knock-in, translating to EVI1 p.H752R / MDS1-EVI1 p.H942R (the mouse orthologue of a human RUSAT allele)

Publication

PMID:37099686

Pathograph links

Hematopoietic Stem Cell Maintenance Failure recapitulates fidelity: moderate Heterozygotes lose haematopoietic stem and progenitor cells and recover poorly from myelosuppression, which is the stem-cell deficit this node asserts.

Limitations: Fidelity is held at MODERATE on timing rather than direction. The human disease is congenital; the mouse HSPC decrease is detected at 8 to 12 weeks and its platelet defect only after 16 weeks, and only in males. The model therefore reproduces the deficit but not its onset, and cannot speak to the neonatal presentation that defines the human disease.

Readouts

Bone marrow HSPC frequency

Direction: DECREASED

Interpretation: Direct flow-cytometric measurement of the stem and progenitor compartment.

Show evidence (1 reference)

PMID:37099686 SUPPORT Model Organism

"Flow cytometric analysis of bone marrow cells revealed a decrease in HSPCs in Evi1KI"

Reports the measured decrease in the stem and progenitor compartment.

Haematopoietic recovery after 5-fluorouracil myelosuppression

Direction: DECREASED

Interpretation: A stress test of stem-cell reserve. Delayed recovery is the functional counterpart of the reduced HSPC count and is the more informative of the two, since it measures capacity rather than frequency.

Show evidence (1 reference)

PMID:37099686 SUPPORT Model Organism

"Moreover, Evi1KI/+ mice showed delayed leukocyte and platelet recovery after 5-fluorouracil-induced myelosuppression."

Functional demonstration of reduced regenerative capacity.

Show evidence (1 reference)

PMID:37099686 SUPPORT Model Organism

"These findings suggest that Evi1KI/+ mice recapitulate the bone marrow dysfunction in RUSAT, similar to that caused by loss-of-function Mecom alleles."

The authors' own assessment that the model is informative for the marrow arm of the disease.

Failure of Proximal Radioulnar Joint Separation fails to recapitulate fidelity: low The mouse has normal forelimbs. Carrying the orthologous patient allele is not sufficient to produce radioulnar synostosis in a mouse, so this model cannot be used to study the skeletal arm of the disease and its silence is not evidence that the human variant does not cause the synostosis.

Limitations: Two readings are open and this model cannot distinguish them: either the mouse forelimb does not require Evi1 the way the human forearm requires MECOM, or the germline heterozygote does not reach a dose or timing threshold that the human embryo does. Mouse and human zeugopod segmentation differ in tempo and in the relative timing of joint cavitation, so a negative skeletal result in a viable heterozygote is weak evidence either way. See the `rusat_mouse_no_synostosis` discussion.

Readouts

Presence of radioulnar synostosis

Direction: UNCHANGED

Interpretation: A real negative result, recorded as UNCHANGED rather than omitted: the forelimbs were examined and were normal.

Show evidence (1 reference)

PMID:37099686 SUPPORT Model Organism

"Heterozygous mutant mice (Evi1KI/+ mice) grew normally without radioulnar synostosis."

SUPPORT, because the claim being evidenced is the readout that the forelimbs were normal. The negative result is the finding; the evidence agrees with it.

Show evidence (1 reference)

PMID:37099686 SUPPORT Model Organism

"Heterozygous mutant mice (Evi1KI/+ mice) grew normally without radioulnar synostosis."

SUPPORT for the FAILS_TO_RECAPITULATE claim this link makes. The direction is easy to get backwards: the claim is that the model does not reproduce the lesion, and normal forelimbs is evidence for that claim, not against it.

Show evidence (1 reference)

PMID:37099686 SUPPORT Model Organism

"Homozygous mutant mice died at embryonic day 10.5 to 11.5."

Establishes the constraint that makes this a heterozygous model, which is also the human genotype.

{ }

Source YAML

click to show

name: Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia
creation_date: "2026-09-02T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome
  term:
    id: MONDO:0011555
    label: radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome
description: >
  Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) is an
  inherited bone marrow failure syndrome in which a congenital bony fusion of
  the proximal radius and ulna sits beside a marrow that makes no
  megakaryocytes. The forearm is fixed, usually in pronation, and the platelet
  count is low from birth. In many reported individuals the thrombocytopenia
  does not stay confined to one lineage: it progresses to pancytopenia, and
  allogeneic haematopoietic stem cell transplantation is the only curative
  treatment.

  Two genes are implicated, and they are not equally established. ClinGen's
  Hemostasis/Thrombosis expert panel grades MECOM Definitive for
  MECOM-associated syndrome and HOXA11 only Limited for RUSAT1 - its lowest
  non-disputed tier. Read the HOXA11 arm of this entry with that in mind
  throughout. HOXA11
  (RUSAT1) accounts for a single frameshift allele found in six individuals
  from two families in 2000, and no further HOXA11 family has been reported
  since. MECOM (RUSAT2), encoding the zinc-finger transcription factor EVI1,
  accounts for essentially every case identified since 2015 - approximately 66
  by 2025. Both proteins are transcription factors required in two places at
  once: in haematopoietic stem cells and in the developing forearm. That dual
  requirement, rather than any shared downstream pathway, is what puts a bone
  malformation and a marrow failure in the same syndrome.

  The mechanism has one central step and several branches. A heterozygous
  variant clustered in the eighth and ninth zinc fingers of EVI1 reduces
  sequence-specific DNA binding at its target sites, and the transcriptional
  network EVI1 maintains is dysregulated. One branch of that network holds
  haematopoietic stem cells in a self-renewing state, and losing it produces
  the progressive multilineage marrow failure. A second branch runs through
  MPL, the thrombopoietin receptor whose biallelic loss causes congenital
  amegakaryocytic thrombocytopenia - which is why RUSAT and CAMT can look
  identical in a neonate. A third branch is developmental, in the limb bud,
  where the proximal radioulnar joint fails to separate.

  The name is the least reliable thing about the disease. A large fraction of
  people carrying pathogenic MECOM variants have marrow failure with no
  synostosis at all, and some have synostosis with almost no haematological
  disease. The synostosis tracks the variant class rather than the diagnosis:
  it is a missense feature, and specifically a zinc-finger-8/9 missense
  feature, while truncating alleles and whole-gene deletions give bone marrow
  failure without it. A second missense hotspot at zinc finger 6 is reported
  and complicates that picture; the entry records it rather than tidying it
  away. Two competing
  renamings are in the literature - MECOM-associated syndrome, and
  RUS-associated haematological disease (RUSHD) - and this entry records that
  dispute rather than resolving it.
synonyms:
  - RUSAT
  - Radioulnar synostosis with amegakaryocytic thrombocytopenia
  - Amegakaryocytic thrombocytopenia with radio-ulnar synostosis
  - MECOM-associated syndrome
  - RUS-associated hematological disease
  - RUSHD
parents:
  - Inherited bone marrow failure syndrome
  - Congenital thrombocytopenia

classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
    evidence:
    - reference: PMID:41635268
      reference_title: "Syndrome of the Month: Radioulnar Synostosis With Amegakaryocytic Thrombocytopenia Type 2."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Radioulnar synostosis with amegakaryocytic thrombocytopenia type 2 (RUSAT-2) is a rare inherited bone marrow failure syndrome characterized by congenital or progressive thrombocytopenia, frequent radioulnar synostosis, and variable multisystem involvement."
      explanation: >
        A bone marrow failure syndrome presenting as cytopenia and progressing
        to pancytopenia, which places it in Harrison's haematology Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    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: "We report missense mutations in MECOM resulting in a Mendelian disorder that provide compelling evidence for the critical role of EVI1 in normal hematopoiesis and in the development of forelimbs and fingers in humans."
      explanation: >
        The source names the disorder Mendelian, which is the Harrison's
        genetics Part.
  iuis_category:
    classification_value: bone marrow failure
    evidence:
    - reference: PMID:37407873
      reference_title: "MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "MECOM deficiency is a recently identified inborn error of immunity and inherited bone marrow failure syndrome caused by haploinsufficiency of the hematopoietic transcription factor MECOM."
      explanation: >
        Names both halves of this assignment in one sentence: an inborn error
        of immunity, and a bone marrow failure syndrome. Graded OTHER because
        the source is a review with no primary data.
    notes: >
      IUIS Table 9 is the bone marrow failure table, whose members are the
      class this disease belongs to - Fanconi anaemia (twenty-two rows, Types A
      to W), dyskeratosis congenita (fourteen gene rows), MIRAGE, ataxia
      pancytopenia syndrome, Coats plus syndrome, BMFS1/2/5, and MECOM
      deficiency itself, which is the row this entry is. The table's own
      footnote records MECOM as the single new inborn error of immunity added
      to Table 9 in the 2022 update. Corrected 2026-09-13: this note previously
      named Shwachman-Diamond and Diamond-Blackfan anaemia as Table 9 members.
      Neither is. Shwachman-Diamond is in Table 5 (congenital defects of
      phagocyte number or function), and Diamond-Blackfan anaemia does not
      appear anywhere in the IUIS 2022 classification. The error came from an
      earlier version of the iuis_category enum description, fixed upstream in
      dismech#10107. Assigned there rather than to
      Table 3 (predominantly antibody deficiency) because the marrow failure is
      the obligate and defining feature while the B-cell deficiency is partial
      and variant-restricted, and because the source frames the disease as
      marrow failure with B-cell involvement rather than the reverse. Note the
      B-cell defect is *not* simply downstream of the marrow failure - it
      segregates by variant region, not by marrow-failure severity, which is
      how the pathograph draws it. That choice is curator inference from the cited sentence,
      not something the sentence states, which is why it sits here.

has_subtypes:
- name: RUSAT1
  subtype_term:
    preferred_term: radioulnar synostosis with amegakaryocytic thrombocytopenia 1
    term:
      id: MONDO:0024558
      label: radioulnar synostosis with amegakaryocytic thrombocytopenia 1
  display_name: RUSAT1 (HOXA11-related)
  description: >-
    The founding form, and effectively a historical one. A single heterozygous
    frameshift allele, HOXA11 c.872delA p.Asn291ThrfsX3, was found in six
    individuals across two families; in both families it came from the father,
    and both fathers had the arm malformation without any haematological
    disease. No further HOXA11 family has been reported since, and a later
    cohort that screened HOXA11 in seven RUS families with blood disease found
    no coding variants. A curator should not read RUSAT1 as "the other half of
    RUSAT" - on current counts it is two families against approximately 66
    MECOM cases, and ClinGen grades HOXA11-RUSAT1 Limited against MECOM's
    Definitive.
  genes:
  - preferred_term: HOXA11
    term:
      id: hgnc:5101
      label: HOXA11
  evidence:
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The heterozygous variant c.872delA, p.Asn291ThrfsX3 was identified in six individuals from two families"
    explanation: >-
      Gives the single HOXA11 allele and the number of individuals carrying it.
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No coding variants were identified inHOXA11."
    explanation: >-
      A seven-family RUS cohort screened HOXA11 and found nothing, which is why
      RUSAT1 remains at its original two families. The quoted text runs the gene
      symbol into the preceding word; that is an artefact of the cached full
      text, not a transcription error here.

- name: RUSAT2
  subtype_term:
    preferred_term: radioulnar synostosis with amegakaryocytic thrombocytopenia 2
    term:
      id: MONDO:0014758
      label: radioulnar synostosis with amegakaryocytic thrombocytopenia 2
  display_name: RUSAT2 (MECOM-related)
  description: >-
    Essentially all of RUSAT as it is now diagnosed. Heterozygous MECOM
    variants, de novo in most sporadic cases and dominantly transmitted in
    some families. The variants that produce the synostosis cluster in zinc
    fingers 8 and 9 of EVI1; MECOM variants elsewhere in the locus, including
    truncating alleles and whole-gene deletions, give marrow failure without
    it. Approximately 66 cases had been reported by 2025.
  genes:
  - preferred_term: MECOM
    term:
      id: hgnc:3498
      label: MECOM
  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: "These three mutations were clustered within the 8(th) zinc finger motif of the C-terminal zinc finger domain of EVI1."
    explanation: >-
      The founding MECOM series, and the localisation that defines this subtype.
  - reference: PMID:41635268
    reference_title: "Syndrome of the Month: Radioulnar Synostosis With Amegakaryocytic Thrombocytopenia Type 2."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "As of 2025, there were approximately 66 reported cases of RUSAT-2 reported in the literature, with clinical severity ranging from isolated thrombocytopenia to early-onset bone marrow failure requiring hematopoietic stem cell transplantation."
    explanation: >-
      Case count and the breadth of severity within this subtype.

inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    Every reported allele in both genes is germline and heterozygous. Most
    MECOM cases are de novo, but dominant transmission through several
    generations is documented, and in those families expressivity is wide
    enough that a parent may be asymptomatic or have only a mild single
    cytopenia while a child needs a transplant. In both HOXA11 families the
    allele came from a father who had the arm malformation and no blood
    disease at all, which is the cleanest published demonstration that the
    skeletal and haematological arms of this syndrome can be uncoupled within
    one genotype.
  evidence:
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on genetic studies and clinical presentation, an autosomal dominant inheritance pattern was observed in families 1 and 5."
    explanation: >
      Direct statement of dominant inheritance in two MECOM families.
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both families the variant was inherited from the father. Interestingly, both fathers showed skeletal abnormalities of the arm but neither had any hematological disease."
    explanation: >
      Establishes germline transmission of the HOXA11 allele and, in the same
      sentence, the within-genotype uncoupling of the skeletal and
      haematological features.
  - reference: PMID:37230770
    reference_title: "Perinatal-lethal nonimmune fetal hydrops attributed to MECOM-associated bone marrow failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "disease-causing variants in MECOM, which are transmitted in an autosomal dominant pattern, are associated with a phenotypic spectrum encompassing RUSAT2 in addition to variable degrees of bone marrow failure without radioulnar synostosis"
    explanation: >
      States the inheritance pattern and, in the same clause, that the
      synostosis is not required for the diagnosis.

prevalence:
- population: Worldwide, published cases (RUSAT2 / MECOM)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Approximately 66 reported RUSAT-2 cases as of 2025. No population
    prevalence or incidence estimate has been published for either subtype, so
    no rate is computed here. This count is also an undercount of MECOM-related
    disease rather than an overcount: the perinatal-lethal presentations were
    diagnosed only on postmortem or rapid trio sequencing, and MECOM is absent
    from targeted hydrops gene panels.
  evidence:
  - reference: PMID:41635268
    reference_title: "Syndrome of the Month: Radioulnar Synostosis With Amegakaryocytic Thrombocytopenia Type 2."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "As of 2025, there were approximately 66 reported cases of RUSAT-2 reported in the literature, with clinical severity ranging from isolated thrombocytopenia to early-onset bone marrow failure requiring hematopoietic stem cell transplantation."
    explanation: >-
      The published case count for the MECOM subtype.
- population: Worldwide, published cases (all RUSAT, families)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A family-level rather than individual-level count, recorded separately
    because it uses a different denominator and a 2023 cut-off. It is not
    comparable with the 66-case figure above and the two must not be pooled.
  evidence:
  - reference: PMID:37099686
    reference_title: "Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Approximately 22 families have been reported to have individuals affected with RUSAT."
    explanation: >-
      Family count across both subtypes as of 2023.

notes: >
  Two genes, two very different evidence bases, and the entry keeps them
  separate. The MECOM arm is supported by human genetics, a knock-in mouse,
  primary-human-HSPC modelling and reporter assays. The HOXA11 arm rests on two
  families reported in 2000 plus one in vitro follow-up in 2006, and nothing
  since. Where a mechanism node applies to only one gene, its description says
  so; no node silently generalises MECOM data to HOXA11 or the reverse.

  Counts in this entry name their denominator. The 66-case figure is RUSAT2
  only and is dated 2025; the 22-family figure covers both subtypes and is
  dated 2023; the eight-patient and twelve-patient series are separate
  ascertainments. No `frequency:` value is set on any phenotype. A band
  computed across these overlapping, differently ascertained series would be a
  scope error, and the largest cohorts explicitly report that no single
  manifestation is present in all patients.

  The pathograph deliberately carries no leukaemia node, and the reason is a
  direction-of-effect one. MECOM is a well-known oncogene whose somatic
  overexpression marks high-risk acute myeloid leukaemia, and the stem-cell
  network it maintains is co-opted by those leukaemias - but that is the
  opposite direction of effect from the germline loss modelled here, and
  importing it would be putting the somatic oncology literature into a
  haploinsufficiency entry. What is curated instead is what the germline
  literature actually reports: myelodysplasia as a phenotype, and age-related
  clonal haematopoiesis as a mechanism node. The published malignancy count is
  four myeloid malignancies among 80 reported individuals - three adult MDS,
  one paediatric AML - and the source attributes that low frequency to most
  patients being transplanted young, which implies the count understates lifetime
  risk without the source saying so outright. That is recorded in the clonal
  haematopoiesis node with its denominator, and is not restated as a
  quantified germline leukaemia predisposition, which no source cited here
  supports.

  No `conforms_to` declaration, and that is a decision rather than an
  oversight. `stem_cell_exhaustion` is the obvious candidate - this disease is
  a haematopoietic stem-cell maintenance failure, and that module's central
  node is a decline in stem-cell self-renewal and function. It is not declared
  because the module is explicitly the Lopez-Otin aging hallmark: it is
  categorised `AGING`, its chain runs accumulated damage to functional decline
  to regenerative failure, and its worked conformers are age-related diseases.
  RUSAT has no accumulated damage. The deficit is constitutive from conception,
  present at birth, and driven by a germline transcriptional lesion rather than
  by anything that accrues. Declaring conformance would assert a shared
  aetiology that does not exist, on the strength of a shared endpoint.

  The one place the two genuinely meet is `Age-Related Clonal Hematopoiesis`,
  which is age-related in this disease as it is in the general population - but
  that module's CHIP content is not a pathophysiology node, so there is no
  valid conformance target for it. If a CHIP node is ever added there, this
  entry is a candidate conformer at that node and nowhere else.

  One lead was chased and could not be closed, recorded so it is not re-chased.
  The falcon report attributes to Germeshausen 2018 (PMID:29540340) a set of
  patient-sample findings - reduced CD34-high/CD38-low progenitors, retained low
  MPL expression, elevated thrombopoietin - that would bear directly on the
  `Loss of EVI1 Transcriptional Control of MPL` node, since they would be the
  only human measurement of MPL and thrombopoietin in this disease. That
  paper's cache is `content_type: abstract_only`, and its PubMed Central record
  (PMC5873238) returns metadata only with no article body, so the sentences
  cannot be verified or quoted. If someone obtains the full text and those data
  are there, they settle the direction question that node is currently agnostic
  about, and a `biochemical:` block with a thrombopoietin readout becomes
  possible.

  No `datasets:` block. `just discover-datasets` returned 12 candidates and
  zero of them were DIRECT: every one was a gene-only hit, and the genes lead
  somewhere else entirely - MECOM to castration-resistant prostate cancer and
  to AML, HOXA11 to keloid fibroblasts and transcription-factor binding panels.
  That is the Named Entity Confusion pattern the dataset SOP warns about,
  reached through gene search rather than through disease name. There is no
  RUSAT expression dataset to curate, which is unsurprising for a disease with
  roughly 66 published cases.

  Two phenotypes are deliberately left as pathograph leaves: failure to thrive
  and global developmental delay. Both are real and counted (2 of 8 and 4 of 8
  in one cohort), but no cited source establishes a route from MECOM
  haploinsufficiency to either, and every other edge in this entry carries
  cited evidence. Grouping them under the multi-organ developmental node would
  be an unsupported guess, since developmental delay in a transfusion-dependent
  infant with multiple malformations has several plausible causes that have
  nothing to do with a direct MECOM requirement in brain. They are recorded as
  a decision rather than a gap.

  Three references were fetched and are deliberately not cited: PMID:30536840,
  PMID:35484980 and PMID:29200407 are all novel-variant case reports whose
  cache is `content_type: unavailable`, so nothing in them can be quoted. They
  are real and on topic; they simply cannot carry evidence in this repository's
  model. PMID:11101832, the 2000 Nature Genetics paper that founded RUSAT1, is
  in the same position - its cache has no abstract - so the HOXA11 discovery
  claim is cited to the 2006 follow-up and the 2018 cohort, both of which
  restate it in quotable form.

  The bone lesion itself is curated at low mechanistic resolution and that is
  honest rather than lazy. No source cited here traces a path from EVI1 or
  HOXA11 target genes to the failure of the proximal radioulnar joint to
  separate in a human embryo. What exists is expression data placing both
  factors in the developing limb, and mouse limb genetics for Hoxa11 that does
  not model the human synostosis. The node records that gap in its own
  description rather than inventing intermediate steps.

progression:
- phase: Prenatal and perinatal
  age_range: In utero to the first days of life
  notes: >-
    The severe pole. Marrow failure beginning before birth presents as
    non-immune hydrops with severe anaemia, and both reported cases died in the
    neonatal period; a separate series records three individuals diagnosed in
    utero who died as neonates. Neither hydrops case had radioulnar synostosis
    and neither was suspected clinically before sequencing. A neonate
    presenting on day zero with severe thrombocytopenia and intracranial
    haemorrhage died on day three.
  evidence:
  - reference: PMID:37230770
    reference_title: "Perinatal-lethal nonimmune fetal hydrops attributed to MECOM-associated bone marrow failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two cases of infants born preterm who presented at birth with symptoms of bone marrow failure including severe anemia, hydrops, and petechial hemorrhages; radioulnar synostosis was not observed in either patient, and, unfortunately, neither infant survived."
    explanation: >-
      The perinatal-lethal presentation, including the absence of the skeletal
      feature that would have suggested the diagnosis.
- phase: Neonatal presentation
  age_range: Birth to the first months
  notes: >-
    The usual presentation. Thrombocytopenia is present from birth, often found
    on a blood count taken for petechiae or bleeding, with an amegakaryocytic
    or hypomegakaryocytic marrow. The synostosis is present at birth but is
    frequently not what brings the child to attention. Most reported RUSAT2
    cases have been diagnosed by next-generation sequencing rather than
    recognised clinically.
  evidence:
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All the affected children presented with thrombocytopenia from birth, with three out of the four undergoing BMT."
    explanation: >-
      Congenital onset and the early transplant rate in the HOXA11 families.
- phase: Infancy and early childhood
  age_range: First months to early childhood
  notes: >-
    The branch point. In many, the single-lineage cytopenia becomes
    multilineage and progresses to pancytopenia, and transplant follows -
    reported infants were transplanted between 4 and 18 months of age. In
    others the course is the opposite: neonatal thrombocytopenia managed with
    transfusions resolves spontaneously, in at least some cases through somatic
    reversion. Which course a given child takes is not predictable from
    genotype.
  evidence:
  - reference: PMID:36515795
    reference_title: "Reduced-intensity conditioning is effective for allogeneic hematopoietic stem cell transplantation in infants with MECOM-associated syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "followed by allogeneic bone marrow or cord blood transplantation from unrelated donors"
    explanation: >-
      The transplant arm of this phase, in a six-infant series.
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonatal thrombocytopenia managed with multiple platelet transfusions followed by spontaneous recovery"
    explanation: >-
      The opposite arm of the same phase, and the reason this entry does not
      describe the course as uniformly progressive.
- phase: Adulthood
  age_range: Adolescence to the seventh decade
  notes: >-
    Untransplanted carriers reaching adulthood follow two further courses. Some
    remain mildly affected, with a modest single cytopenia found incidentally,
    and at least one individual was in relatively good health into their
    sixties. Others accumulate clonal haematopoiesis - all three older
    individuals in one cohort carried somatic variants in ASXL1, DNMT3A or TET2
    - and progress from aplastic anaemia to myelodysplastic syndrome. This is
    the phase that argues for long-term surveillance rather than discharge
    after a stable childhood.
  evidence:
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "some individuals had severe BMF in childhood whilst others only a modest single cytopenia well into adulthood"
    explanation: >-
      The mild adult course, alongside the severe childhood one, in one cohort.
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of clonal hematopoiesis of indeterminate potential in the older individuals, and the finding of additional cases of myeloid dysplasia in our cohort warrant consideration of surveillance particularly in older carriers."
    explanation: >-
      The source's own surveillance recommendation, and the reason this phase is
      curated separately rather than folded into the childhood course.

pathophysiology:
- name: Germline Heterozygous MECOM Zinc Finger Variant
  biological_scale: MOLECULAR
  description: >
    A single altered MECOM allele, almost always de novo, encoding the
    zinc-finger transcription factor EVI1. The variants that give the full
    RUSAT picture are missense changes in the region spanning zinc fingers 8
    and 9 of the C-terminal zinc finger domain - about ten amino acids,
    comprising zinc finger 8 and the adjacent linker.

    That is not the only missense hotspot, and this node should not be read as
    saying it is. A 2026 series reports every missense variant mapping to "the
    zinc finger 6 or zinc finger 8/9 region", so there is a second cluster in
    the N-terminal zinc finger domain - the domain through which EVI1 binds the
    GATA2 promoter. A further reported variant, p.P634L, lies between the two
    domains altogether. Whether the ZF6 cluster produces synostosis is not
    established in anything cited here. Variants elsewhere in the locus, including nonsense,
    frameshift, splice and whole-gene deletion alleles, cause bone marrow
    failure without the synostosis. That the two variant classes give
    different syndromes from the same gene is the central genotype-phenotype
    observation in this disease, and it is why this node is specified by
    domain rather than simply as "loss of one MECOM allele".
  downstream:
  - target: Loss of EVI1 Sequence-Specific DNA Binding
    causal_link_type: DIRECT
    description: >-
      The variant residues sit inside a Cys2His2 zinc finger, the DNA-contact
      module itself, so the immediate consequence is loss of binding rather
      than loss of protein.
    evidence:
    - reference: PMID:26581901
      reference_title: "Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Chromatin immunoprecipitation and qPCR assays of the regions harboring the ETS-like motif that is known as an EVI1 binding site showed a reduction in immunoprecipitated DNA for two EVI1 mutants compared with wild-type EVI1."
      explanation: >-
        Measures the variant's effect on occupancy at a known EVI1 site, which
        is the step this edge asserts.
  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: "we performed whole exome sequencing in an individual with RUSAT and her healthy parents and identified a de novo missense mutation in MECOM, encoding EVI1, in the individual with RUSAT"
    explanation: >
      The founding observation: a de novo heterozygous MECOM missense variant
      in RUSAT.
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is noteworthy that all variants associated with the co-presentation of RUS and hematological disease cluster in region spanning zinc fingers 8 and 9."
    explanation: >
      Localises the RUSAT-producing variants to the region spanning zinc
      fingers 8 and 9, which is what makes this node domain-specific rather
      than gene-level. The source's ten-amino-acid span (aa750-760) is zinc
      finger 8 plus the adjacent linker rather than two whole motifs.

- name: Germline Heterozygous HOXA11 Frameshift Variant
  biological_scale: MOLECULAR
  description: >
    The RUSAT1 lesion: HOXA11 c.872delA, p.Asn291ThrfsX3, a single-nucleotide
    deletion falling in the third helix of the homeodomain and truncating the
    protein. It is the only HOXA11 allele ever reported in this disease, found
    in six individuals from two families. HOXA11 is a posterior HOX
    transcription factor with roles in both early forelimb patterning and
    haematopoiesis, which is the same dual requirement that makes MECOM a
    RUSAT gene.
  downstream:
  - target: Loss of HOXA11 Sequence-Specific DNA Binding
    causal_link_type: DIRECT
    description: >-
      The truncation removes the third helix of the homeodomain, which is the
      DNA-recognition helix.
    evidence:
    - reference: PMID:16765069
      reference_title: "HOXA11 mutation in amegakaryocytic thrombocytopenia with radio-ulnar synostosis syndrome inhibits megakaryocytic differentiation in vitro."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Here, we demonstrate that this mutation results in a significantly truncated protein with impaired DNA-binding efficiency."
      explanation: >-
        States the truncation and the binding defect together, which is exactly
        this edge.
  evidence:
  - reference: PMID:16765069
    reference_title: "HOXA11 mutation in amegakaryocytic thrombocytopenia with radio-ulnar synostosis syndrome inhibits megakaryocytic differentiation in vitro."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously, we identified an inherited syndrome of congenital amegakaryocytic thrombocytopenia and radio-ulnar synostosis that is associated with a point mutation in the third helix of HOXA11 homeodomain (HOXA11-DeltaH3)."
    explanation: >
      Restates the 2000 discovery in quotable form and localises the variant to
      the homeodomain third helix. This 2006 follow-up is cited in place of the
      2000 discovery paper, PMID:11101832, whose cache is
      `content_type: unavailable` and so carries nothing quotable. The defect
      claim is about PMID:11101832, not about this reference, which has a
      normal abstract.

- name: Loss of EVI1 Sequence-Specific DNA Binding
  biological_scale: MOLECULAR
  description: >
    The zinc-finger 8/9 variants reduce EVI1 occupancy at its recognition
    sites. Protein modelling of the two mutational hotspots, zinc finger 6 and
    zinc fingers 8/9, predicts both are DNA-binding regions, so the variants
    are read as disabling contact with DNA rather than destabilising the
    protein as a whole. The functional consequence is measured on both sides
    of EVI1's dual role: it is a repressor at some targets and a permissive
    factor at others, and the variants shift both.
  molecular_functions:
  - preferred_term: EVI1 DNA-binding transcription factor activity
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    modifier: LOSS_OF_FUNCTION
  downstream:
  - target: B-Cell Developmental Arrest
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - mecom_domain_specific_effect
    description: >-
      The primary route to the B-cell defect, drawn from the domain-specific
      lesion rather than from generic stem-cell failure, because that is where
      the human genetics puts it. B-cell deficiency and radioulnar synostosis
      appear only with variants in one short C-terminal zinc-finger region;
      truncating alleles and whole-gene deletions cause severe marrow failure
      without either. Two features with no obvious relationship to one another
      appearing and disappearing together with variant position is the
      strongest genotype-phenotype signal in this disease, and it places the
      B-cell arm beside the synostosis on this branch. The intervening steps
      are unknown, which is what the link type records.
    evidence:
    - reference: PMID:29540340
      reference_title: "MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1."
      explanation: >-
        The co-segregation, stated as an exclusive, and the reason this edge is
        parented here rather than under generic marrow failure.
  - target: Multi-Organ Developmental MECOM Requirement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The extra-haematopoietic malformations are grouped behind one node rather
      than hung individually off the network node, because what connects them
      is a single fact - MECOM is required in several developing organs - and
      not four separate demonstrated mechanisms.
    evidence:
    - reference: PMID:37067177
      reference_title: "Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "MECOM transcription factors are expressed at high levels in the embryonic heart, lungs, limb buds, nasal cavity, and urinary tract, suggesting an important role in multi-organ development"
      explanation: >-
        The expression basis for a shared developmental requirement across the
        organs that are malformed in this syndrome. Graded OTHER on the same
        rule used elsewhere here: the sentence is that cohort paper's
        introduction citing prior work. The underlying expression data are
        murine.
  - target: Pulmonary Arterial Endothelial MECOM Deficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Provisional, and the weakest branch in the entry. Modelling places the
      variant hotspots at a VEGFR2/KDR enhancer, which would make this an
      endothelial consequence of the same binding defect; nothing measures it.
    evidence:
    - reference: PMID:41617498
      reference_title: "Expanding the phenotypic spectrum of MECOM-associated syndrome: rare variants are associated with syndromic pulmonary arterial hypertension."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "All missense variants map to the zinc finger 6 or zinc finger 8/9 region, a known hotspot for MECOM-associated syndrome."
      explanation: >-
        Places the PAH-associated variants in this gene's missense hotspots,
        which licenses running the branch off the shared binding defect rather
        than treating it as unrelated. Note the quote says zinc finger 6 OR
        zinc finger 8/9, so it does not put them in the same region as the
        synostosis-associated variants - it names a second cluster.
  - target: Failure of Proximal Radioulnar Joint Separation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - mecom_domain_specific_effect
    description: >-
      Recorded as INDIRECT because no source traces target genes from EVI1 to
      the limb bud. Opted into `mecom_domain_specific_effect` because this is
      the edge the two hypotheses disagree about: on a pure-dose model the
      limb phenotype should track total EVI1 loss and therefore appear with
      truncating alleles, which it does not. What supports the edge is that EVI1 is expressed in the
      developing limb and that the human genetics assign the synostosis to
      MECOM; the intervening developmental steps are unknown.
    evidence:
    - reference: PMID:37099686
      reference_title: "Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Evi1 is highly expressed in the urinary system, lungs, heart, and developing limbs of mouse embryos."
      explanation: >-
        Places the factor in the developing limb, which is the necessary
        condition for this branch. Graded OTHER on the same rule applied
        elsewhere in this entry: the sentence is this mouse paper's
        introduction citing prior work, not a result it reports. The underlying
        expression data are murine.
  - target: Dysregulation of the EVI1 HSC Maintenance Network
    causal_link_type: DIRECT
    hypothesis_groups:
    - mecom_pure_haploinsufficiency
    description: >-
      Opted into `mecom_pure_haploinsufficiency` because this is the step the
      dose model explains well and the knock-in mouse supports: less functional
      EVI1 at its target sites, less of the network it maintains. Both
      hypotheses accept this edge; they diverge downstream, at the limb.
    evidence:
    - reference: PMID:26581901
      reference_title: "Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "reporter assays showed that MECOM mutations led to alterations in both AP-1- and TGF-β-mediated transcriptional responses"
      explanation: >-
        Loss of binding is followed by measurable change in downstream
        transcriptional output, which is the step this edge asserts.
  evidence:
  - reference: PMID:41617498
    reference_title: "Expanding the phenotypic spectrum of MECOM-associated syndrome: rare variants are associated with syndromic pulmonary arterial hypertension."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Protein modelling predicted that both regions are DNA-binding, and that the variants may interfere with binding to a VEGFR2/KDR enhancer."
    explanation: >
      Structural prediction that the variant hotspots are DNA-contact regions.
      Graded COMPUTATIONAL because it is protein modelling, not an assay.
  - reference: PMID:37610030
    reference_title: "A novel mutation in MECOM affects MPL regulation in vitro and results in thrombocytopenia and bone marrow failure."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "whose effect was tested on pAP-1 enhancer element and promoters of targeted genes showing that the mutation impairs the repressive activity of the transcription factor"
    explanation: >
      A second, independent variant shown to impair EVI1's transcriptional
      activity at its target promoters. Read as a bound on this node rather
      than straightforward support: the variant tested, p.P634L, lies between
      the two zinc-finger domains, so impaired repression by it is not evidence
      that sequence-specific DNA binding is lost. It shows that transcriptional
      dysregulation can arise from outside the DNA-contact residues.

- name: Loss of HOXA11 Sequence-Specific DNA Binding
  biological_scale: MOLECULAR
  description: >
    The truncated HOXA11 protein cannot bind its consensus site, and the defect
    is not rescued by its cofactor. Wild-type HOXA11 binds DNA most efficiently
    in the presence of the TALE factor Meis1b; the truncated protein still
    associates with Meis1b but binding to DNA is abolished even so. The
    protein-protein interaction is therefore intact while the DNA contact is
    not, which localises the lesion to the homeodomain.
  molecular_functions:
  - preferred_term: HOXA11 DNA-binding transcription factor activity
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    modifier: LOSS_OF_FUNCTION
  downstream:
  - target: Failure of Proximal Radioulnar Joint Separation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      RUSAT1's defining bone lesion. The edge is drawn on the human genetics -
      six individuals in two families carrying this allele with the synostosis -
      plus HOXA11's established role in forelimb zeugopod patterning. No source
      traces the intervening developmental steps, and the mouse data below
      differ from the human lesion in two ways set out in the target node's
      description.
    evidence:
    - reference: PMID:14668414
      reference_title: "Multiple roles of Hoxa11 and Hoxd11 in the formation of the mammalian forelimb zeugopod."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "malformation of the forelimb zeugopod in Hoxa11/Hoxd11 double mutants is a consequence of interruption at multiple steps during the formation of the radius and ulna"
      explanation: >-
        Places HOXA11 in radius and ulna formation. INDIRECT twice over: the
        murine lesion is a growth-plate and patterning defect rather than a
        failure of joint separation, and it requires loss of both Hoxa11 and
        Hoxd11 rather than the single heterozygous allele humans carry.
    - reference: PMID:20978074
      reference_title: "Hox11 genes establish synovial joint organization and phylogenetic characteristics in developing mouse zeugopod skeletal elements."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Hox11 genes co-regulate and coordinate the development of zeugopod skeletal elements and adjacent elbow and knee joints, and dictate joint identity, morphogenesis and anatomical and functional organization."
      explanation: >-
        The strongest available support for this edge, and the reason it is
        drawn from the HOXA11 arm rather than left to the human genetics alone:
        Hox11 function is established as determining joint identity and
        morphogenesis in exactly the skeletal segment and at exactly the joint
        that RUSAT fuses. INDIRECT because the demonstration is a
        triple-paralogue mouse mutant.
  - target: Megakaryocyte Differentiation Arrest
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      This is the weakest edge in the entry and is marked as such. Expressing
      the mutant in a megakaryocyte-competent cell line suppresses
      megakaryocytic differentiation - but so does expressing the wild-type
      protein, to almost the same degree, and the authors conclude the effect
      runs through sequences outside the homeodomain. So the edge from a
      homeodomain DNA-binding defect to a megakaryocyte arrest is drawn on the
      human genetics rather than on this assay, and both readings of the assay
      are recorded below.
    evidence:
    - reference: PMID:16765069
      reference_title: "HOXA11 mutation in amegakaryocytic thrombocytopenia with radio-ulnar synostosis syndrome inhibits megakaryocytic differentiation in vitro."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Stable expression of FLAG-HOXA11-WT or -DeltaH3 in K562 cells significantly impacts megakaryocytic differentiation."
      explanation: >-
        The only published functional link from HOXA11 to the megakaryocyte
        lineage. INDIRECT because the quoted sentence covers wild-type and
        mutant together, so it does not on its own establish a mutant-specific
        effect.
    - reference: PMID:16765069
      reference_title: "HOXA11 mutation in amegakaryocytic thrombocytopenia with radio-ulnar synostosis syndrome inhibits megakaryocytic differentiation in vitro."
      supports: REFUTE
      evidence_source: IN_VITRO
      snippet: "Interestingly, we found only a slight difference in CD61 expression between wild-type and mutant HOXA11 K562. These data suggest that HoxA11 inhibition of differentiation may involve nonhomeodomain sequences."
      explanation: >-
        REFUTE against this edge specifically - that loss of homeodomain DNA
        binding is what impairs megakaryocytic differentiation. Wild-type and
        mutant behaved almost identically in the readout, and the authors
        attribute the effect to sequences outside the homeodomain. An earlier
        draft of this entry attached this item to the parent node, where it
        read as contradicting the DNA-binding claim that the same paper in fact
        proves; the claim it actually contradicts is this edge.
  evidence:
  - reference: PMID:16765069
    reference_title: "HOXA11 mutation in amegakaryocytic thrombocytopenia with radio-ulnar synostosis syndrome inhibits megakaryocytic differentiation in vitro."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the binding between HOXA11-DeltaH3 and DNA is abrogated even in the presence of Meis1b, suggesting the point mutant causes a disruption in the DNA-binding capacity"
    explanation: >
      Abolished DNA binding that the cofactor cannot rescue. This node's own
      claim is well supported; what is contested is whether the binding defect
      is what produces the megakaryocyte phenotype, and that dispute is
      recorded on the downstream edge rather than here.

- name: Dysregulation of the EVI1 HSC Maintenance Network
  biological_scale: MOLECULAR
  description: >
    The central node of the MECOM arm, and the point at which one molecular
    lesion becomes several tissue phenotypes. EVI1 does not maintain
    haematopoietic stem cells through a single target: it binds regulatory
    enhancers controlling a network of hundreds of genes, and modelling
    MECOM haploinsufficiency in primary human haematopoietic stem cells shows
    that network is required for stem-cell maintenance. Among its targets are
    GATA2, whose promoter EVI1 binds through the N-terminal zinc fingers, and
    MPL, the thrombopoietin receptor. EVI1 also prevents the CTCF-dependent
    genome reorganisation that normally accompanies differentiation, so the
    consequence of losing it is not simply reduced output of one factor.

    Read the magnitude carefully, because the phenotype is severe and the
    transcriptional change is not. The primary-human-HSC study describes a
    "high degree of similarity" in the single-cell transcriptome after MECOM
    perturbation and, on random permutation analysis, detected no
    differentially expressed genes at all. This node therefore asserts
    coordinated dysregulation of a defined network, not a wholesale collapse
    of transcription. That a small, coordinated shift produces an absence of
    stem cells is the interesting part, not an argument for a larger shift.
  molecular_functions:
  - preferred_term: EVI1 binding at haematopoietic stem cell enhancers
    term:
      id: GO:0000976
      label: transcription cis-regulatory region binding
    modifier: DECREASED
  biological_processes:
  - preferred_term: TGF-beta-mediated transcriptional response
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: DYSREGULATED
  downstream:
  - target: Loss of EVI1 Transcriptional Control of MPL
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37610030
      reference_title: "A novel mutation in MECOM affects MPL regulation in vitro and results in thrombocytopenia and bone marrow failure."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we demonstrated that EVI1 controls the transcriptional regulation of MPL, a gene whose mutations are responsible for congenital amegakaryocytic thrombocytopenia (CAMT), potentially explaining the partial overlap between MECOM-AS and CAMT"
      explanation: >-
        Establishes MPL as an EVI1 target and names the clinical consequence
        this branch is curated to explain.
  - target: Hematopoietic Stem Cell Maintenance Failure
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36522544
      reference_title: "A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC maintenance."
      explanation: >-
        The network is shown to be required for HSC maintenance in primary
        human cells modelling this exact haploinsufficiency.
  evidence:
  - reference: PMID:37407873
    reference_title: "MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MECOM binds to regulatory enhancers that control the expression of a network of genes essential for HSC maintenance and self-renewal."
    explanation: >
      States the network-level mechanism this node represents.
  - reference: PMID:36522544
    reference_title: "A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we nominate cooperating transcriptional regulators and identify how MECOM prevents the CTCF-dependent genome reorganization that occurs as HSCs differentiate"
    explanation: >
      Gives the chromatin-level action by which EVI1 holds the self-renewal
      state, which is why its loss releases differentiation rather than merely
      reducing one target's output.
  - reference: PMID:37099686
    reference_title: "Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "EVI1 binds to the promoter of GATA2, which encodes a transcription factor required for the proliferation and survival of early hematopoietic progenitor cells, through the N-terminal zinc finger domain."
    explanation: >
      Names a specific, mechanistically informative target within the network.
      Graded OTHER rather than IN_VITRO because the sentence is this mouse
      paper's introduction citing prior work, not a result it reports.
  - reference: PMID:36522544
    reference_title: "A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "These results reveal a high degree of similarity in the high-dimensional transcriptomic analysis of LT-HSCs following MECOM perturbation"
    explanation: >
      The magnitude constraint on this node, and the reason it is named
      "dysregulation" rather than "collapse". INDIRECT because the sentence
      bounds the size of the transcriptional change rather than asserting the
      dysregulation itself; it is included precisely because it cuts against
      the stronger reading.
  - reference: PMID:36522544
    reference_title: "A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "we performed random permutation analysis and did not detect any differentially expressed genes"
    explanation: >
      REFUTE against any reading of this node as a global transcriptional
      failure. On the authors' own permutation test no gene reached
      significance individually. The network effect in this paper is
      established by aggregate and chromatin-level analysis, not by a
      differential-expression list, and the node must not be read as claiming
      one.

- name: Loss of EVI1 Transcriptional Control of MPL
  biological_scale: MOLECULAR
  description: >
    EVI1 transcriptionally regulates MPL, the thrombopoietin receptor.
    Biallelic MPL loss is the cause of congenital amegakaryocytic
    thrombocytopenia, so this branch is the proposed mechanistic reason RUSAT
    and CAMT are hard to tell apart in a newborn with an amegakaryocytic
    marrow: they converge on the same receptor.

    The node is deliberately named for a loss of control rather than for a
    direction, because the direction is not established and the obvious guess
    is probably backwards. What the assay shows is that the variant "impairs
    the repressive activity of the transcription factor" - and impaired
    repression would, on its face, raise MPL rather than lower it. No
    measurement of MPL message or thrombopoietin-receptor signalling in RUSAT
    patient megakaryocytes is cited here. `DYSREGULATED` is the honest tag
    until someone measures it; naming this node for a direction would export an
    assertion no source supports into the graph.
  biological_processes:
  - preferred_term: thrombopoietin-mediated signaling pathway
    term:
      id: GO:0038163
      label: thrombopoietin-mediated signaling pathway
    modifier: DYSREGULATED
  downstream:
  - target: Megakaryocyte Differentiation Arrest
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Drawn because MPL loss is an established cause of amegakaryocytic
      thrombocytopenia and MPL is under EVI1 control, not because the step has
      been demonstrated in RUSAT megakaryocytes. The second evidence item below
      is the source's own statement that it has not been.
    evidence:
    - reference: PMID:37610030
      reference_title: "A novel mutation in MECOM affects MPL regulation in vitro and results in thrombocytopenia and bone marrow failure."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "EVI1 controls the transcriptional regulation of MPL, a gene whose mutations are responsible for congenital amegakaryocytic thrombocytopenia (CAMT)"
      explanation: >-
        Supports the edge through one inference step: MPL is under EVI1 control,
        and losing MPL is a known cause of exactly this megakaryocyte
        phenotype. INDIRECT because the source establishes the regulatory
        relationship, not the consequence in RUSAT cells.
    - reference: PMID:37610030
      reference_title: "A novel mutation in MECOM affects MPL regulation in vitro and results in thrombocytopenia and bone marrow failure."
      supports: NO_EVIDENCE
      evidence_source: IN_VITRO
      snippet: "The mechanism linking the alteration of EVI1 function and thrombocytopenia is poorly understood."
      explanation: >-
        Recorded as NO_EVIDENCE, which is what it is: the source states that
        this link is not established. It is recorded rather than omitted
        because the limitation is worth carrying on the edge itself, where a
        reader meets the claim.
  evidence:
  - reference: PMID:37610030
    reference_title: "A novel mutation in MECOM affects MPL regulation in vitro and results in thrombocytopenia and bone marrow failure."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we demonstrated that EVI1 controls the transcriptional regulation of MPL, a gene whose mutations are responsible for congenital amegakaryocytic thrombocytopenia (CAMT), potentially explaining the partial overlap between MECOM-AS and CAMT"
    explanation: >
      The only published demonstration that MPL is under EVI1 transcriptional
      control, and the source of the CAMT convergence claim.

- name: Hematopoietic Stem Cell Maintenance Failure
  biological_scale: CELLULAR
  description: >
    Haematopoietic stem cells are not maintained. The human phenotype modelled
    in primary HSCs is described as an early-onset absence of stem cells in
    vivo, which is what distinguishes this disease from the inherited marrow
    failure syndromes that declare themselves in later childhood or
    adolescence. The severity tracks gene dosage, and the consequence is
    multilineage rather than lineage-restricted - which is the main reason the
    "amegakaryocytic thrombocytopenia" half of the disease name understates
    what is happening.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  biological_processes:
  - preferred_term: stem cell population maintenance
    term:
      id: GO:0019827
      label: stem cell population maintenance
    modifier: DECREASED
  downstream:
  - target: Progressive Multilineage Marrow Failure
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41635268
      reference_title: "Syndrome of the Month: Radioulnar Synostosis With Amegakaryocytic Thrombocytopenia Type 2."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Disruption of highly conserved zinc finger domains within MECOM impairs long-term hematopoietic stem cell maintenance, leading to amegakaryocytic thrombocytopenia and, in many cases, progression to pancytopenia."
      explanation: >-
        States the stem-cell-to-pancytopenia step directly.
  - target: B-Cell Developmental Arrest
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - mecom_domain_specific_effect
    description: >-
      Retained as a weak second route, and deliberately not the primary one.
      B-cell output does depend on a functioning stem-cell compartment, so this
      edge is not wrong - but it does not explain the observation that matters,
      which is that truncating alleles cause severe marrow failure *without*
      B-cell deficiency. If the defect were simply downstream of generic HSC
      failure it would track marrow-failure severity, and it does not; it
      tracks variant region. The primary route is therefore drawn from the
      domain-specific lesion, and this edge opts into the same hypothesis group
      so the two can be filtered together.
    evidence:
    - reference: PMID:37407873
      reference_title: "MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "While the mechanisms underlying the B-cell deficiency are currently unknown, recent work has provided mechanistic insights into the function of MECOM in hematopoietic stem cell (HSC) maintenance."
      explanation: >-
        INDIRECT, and doing less work than it looks: the sentence juxtaposes the
        B-cell defect with the HSC mechanism while explicitly saying the
        connection is unknown.
  - target: Age-Related Clonal Hematopoiesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The second of the two roads a marrow under selective pressure can take.
      Drawn from the failing marrow rather than from the revertant node, because
      the source's model is that reversion and clonal evolution are sibling
      outcomes of one selective pressure - not that one causes the other.
    evidence:
    - reference: PMID:38662475
      reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In the dynamic hematopoietic environment, demand-adapted hematopoiesis can drive mosaicism down 2 roads: clonal evolution through the acquisition of deleterious variants leading to cancer; or alternatively, revertant mosaicism resulting in partial/complete rescue of phenotype."
      explanation: >-
        The two-roads model: both outcomes descend from demand-adapted
        haematopoiesis in a stressed marrow, which is this edge's source node.
  - target: Clonal Selection of Revertant Hematopoietic Stem Cells
    causal_link_type: DIRECT
    description: >-
      The failing marrow is itself the selective pressure. A stem cell that
      loses the mutant allele has a fitness advantage over its neighbours
      precisely because its neighbours are failing, so the marrow deficit
      creates the conditions for its own partial reversal.
    evidence:
    - reference: PMID:38662475
      reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "thereby duplicating the residual wild-type allele in an expanding clone"
      explanation: >-
        Names the expansion of the revertant clone, which is the step this edge
        asserts.
  - target: Megakaryocyte Differentiation Arrest
    causal_link_type: DIRECT
    description: >-
      A second route into the megakaryocyte node, independent of MPL: if stem
      cells are absent, no lineage is produced, the megakaryocyte lineage
      included.
    evidence:
    - reference: PMID:36522544
      reference_title: "A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo."
      explanation: >-
        An absence of stem cells is upstream of every lineage output including
        megakaryopoiesis.
  evidence:
  - reference: PMID:37407873
    reference_title: "MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It is unique among inherited bone marrow failure syndromes, many of which present during later childhood or adolescence, because of the early age of onset and severity of the pancytopenia, emphasizing the importance and gene dose dependency of MECOM during hematopoiesis."
    explanation: >
      Places the disease against its class and states the dose dependency that
      makes a heterozygous variant sufficient.

- name: Megakaryocyte Differentiation Arrest
  biological_scale: CELLULAR
  description: >
    Megakaryocytes are absent or severely reduced in the marrow, which is what
    the "amegakaryocytic" in the disease name refers to and what separates
    RUSAT from a peripheral destructive thrombocytopenia at the bedside. Two
    upstream routes converge here in the MECOM arm - loss of stem cells, and
    loss of MPL transcriptional control - and one in the HOXA11 arm. Some
    cohorts describe the marrow as hypomegakaryocytic rather than
    amegakaryocytic; the distinction is one of degree.
  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
  downstream:
  - target: Megakaryocytopenia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29540340
      reference_title: "MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here we report on 12 patients with congenital hypomegakaryocytic thrombocytopenia caused by MECOM mutations (including 10 novel mutations)."
      explanation: >-
        The marrow finding named in the largest single MECOM series.
  - target: Thrombocytopenia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29540340
      reference_title: "MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here we report on 12 patients with congenital hypomegakaryocytic thrombocytopenia caused by MECOM mutations"
      explanation: >-
        Names the megakaryocyte deficit and the thrombocytopenia as one
        compound phenotype, which is what this edge asserts.
  evidence:
  - reference: PMID:37610030
    reference_title: "A novel mutation in MECOM affects MPL regulation in vitro and results in thrombocytopenia and bone marrow failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MECOM-associated syndrome (MECOM-AS) is a rare disease characterized by amegakaryocytic thrombocytopenia, progressive bone marrow failure, pancytopenia and radioulnar synostosis with high penetrance."
    explanation: >
      Names the amegakaryocytic marrow as a defining feature.

- name: Progressive Multilineage Marrow Failure
  biological_scale: TISSUE
  description: >
    The thrombocytopenia does not stay isolated. Marrow output falls across
    lineages, producing anaemia and neutropenia on top of the platelet defect
    and, in a substantial fraction, frank pancytopenia requiring transplant.
    The rate is very variable: some infants are transfusion-dependent in the
    first weeks of life and some adults reach a modest single cytopenia only
    in later life, within the same family and sometimes with the same allele.
    At the most severe end the failure begins before birth and presents as
    non-immune hydrops with severe anaemia.
  biological_processes:
  - preferred_term: hematopoietic stem cell differentiation
    term:
      id: GO:0060218
      label: hematopoietic stem cell differentiation
    modifier: DECREASED
  downstream:
  - target: Pancytopenia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38245683
      reference_title: "A novel missense mutation in the MECOM gene in a Chinese boy with radioulnar synostosis with amegakaryocytic thrombocytopenia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "characterized by varying presentation of congenital thrombocytopenia (progressing to pancytopenia), bilateral proximal radioulnar synostosis, and other skeletal abnormalities"
      explanation: >-
        Names the progression from single-lineage to multilineage cytopenia.
  - target: Bone marrow hypocellularity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38662475
      reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hypocellular bone marrow with complete absence of megakaryocytes, dyserythropoiesis and left shifted granulopoiesis with abnormal granulation"
      explanation: >-
        States the marrow cellularity directly, in a reported patient.
  - target: Nonimmune hydrops fetalis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37230770
      reference_title: "Perinatal-lethal nonimmune fetal hydrops attributed to MECOM-associated bone marrow failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These cases add to the growing body of literature that describe MECOM-associated disease, particularly MECOM as a cause of fetal hydrops due to bone marrow failure in utero."
      explanation: >-
        Names marrow failure in utero as the cause of the hydrops, which is the
        causal direction this edge asserts.
  - target: Anemia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37230770
      reference_title: "Perinatal-lethal nonimmune fetal hydrops attributed to MECOM-associated bone marrow failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "presented at birth with symptoms of bone marrow failure including severe anemia"
      explanation: >-
        Names the anaemia as a symptom of the marrow failure, which is the
        direction this edge asserts.
  - target: Aplastic Anemia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29519864
      reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "diverse hematological defects ranging from single cytopenias to global bone marrow failure (BMF); some individuals had severe BMF in childhood"
      explanation: >-
        Places global marrow failure at the end of the progression from single
        cytopenias, which is the aplastic pole this edge reaches.
  - target: Myelodysplasia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29519864
      reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the hematological involvement progressed from aplastic anemia to myelodysplastic syndrome (MDS); this presentation of RUS and development of MDS in adulthood is similar to the family reported by Ripperger"
      explanation: >-
        Documents progression from aplastic anaemia to MDS in an adult, in two
        independent families.
  evidence:
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "some individuals had severe BMF in childhood whilst others only a modest single cytopenia well into adulthood"
    explanation: >
      The range of severity and tempo across one seven-family cohort.
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we are able to demonstrate that even with the same variant the age of onset and the severity of BMF is highly variable"
    explanation: >
      Establishes that the variability is not explained by allele identity,
      which is what makes prognostication from genotype unreliable here.

- name: B-Cell Developmental Arrest
  biological_scale: CELLULAR
  description: >
    A subset of MECOM patients have B-cell lymphopenia with
    hypogammaglobulinaemia, which has led to MECOM deficiency being classified
    as an inborn error of immunity as well as a marrow failure syndrome. The
    mechanism is unknown. What is notable is the co-segregation: in the largest
    series, B-cell deficiency and radioulnar synostosis were seen only in
    patients whose variants hit the same short C-terminal zinc-finger region -
    two features with no obvious relationship to one another, appearing and
    disappearing together with variant position.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: B cell differentiation
    term:
      id: GO:0030183
      label: B cell differentiation
    modifier: DECREASED
  downstream:
  - target: Decreased total B cell count
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37407873
      reference_title: "MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "B-cell lymphopenia and hypogammaglobulinemia have been described in a subset of patients with MECOM deficiency."
      explanation: >-
        Names both the cellular and the humoral consequence.
  - target: Decreased circulating immunoglobulin concentration
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37407873
      reference_title: "MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "B-cell lymphopenia and hypogammaglobulinemia have been described in a subset of patients with MECOM deficiency."
      explanation: >-
        The hypogammaglobulinaemia follows the B-cell defect in the same
        sentence.
  evidence:
  - reference: PMID:29540340
    reference_title: "MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1."
    explanation: >
      The co-segregation of the B-cell and skeletal features with one variant
      region, which is the strongest genotype-phenotype signal in the disease.
  - reference: PMID:37407873
    reference_title: "MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MECOM deficiency is a recently identified inborn error of immunity and inherited bone marrow failure syndrome caused by haploinsufficiency of the hematopoietic transcription factor MECOM."
    explanation: >
      The immunological reclassification that this node underwrites.

- name: Clonal Selection of Revertant Hematopoietic Stem Cells
  biological_scale: CELLULAR
  description: >
    Somatic genetic rescue. In a failing marrow, a stem cell that has lost the
    mutant MECOM allele outgrows the rest, and the usual mechanism is copy
    neutral loss of heterozygosity across chromosome 3q, which duplicates the
    residual wild-type allele. In a 15-person cohort, 7 individuals showed
    spontaneous resolution, alleviation, or late onset of haematological
    disease, and in 4 of 6 evaluable such cases this reversion was found.

    This node is the reason several things about the disease look strange from
    outside. Apparent non-penetrance in an adult carrier may be a rescued
    marrow rather than a mild allele. Neonatal thrombocytopenia that resolves
    on its own is a documented course, not a misdiagnosis. And it is the one
    node in this entry with a direct, immediate consequence for how the disease
    is diagnosed: blood is an unreliable germline sample in a carrier whose
    counts have recovered.

    The same demand-adapted clonal dynamics run the other way as well. Clonal
    haematopoiesis is curated as a sibling of this node rather than as its
    consequence - both descend from the same selective pressure in a failing
    marrow, which is what the source's "two roads" model says and as far as it
    goes.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  downstream:
  evidence:
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For 4 of 6 individuals (3-II-4, 4-II-4, 5-II-1, and patient 11), amelioration of symptoms appears associated with somatic genetic rescue, in the form of copy neutral loss of heterozygosity of chromosome 3q encompassing MECOM"
    explanation: >
      The mechanism and the count. Note the source's own hedge - "appears
      associated with" - and that 2 of 6 rescued-looking individuals had no
      allelic imbalance at all, so reversion is not the whole explanation for
      mild disease.
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study identifies 7 of 15 affected individuals who show spontaneous resolution, alleviation of hematological symptoms, or late onset of hematological manifestation of MECOM-associated syndrome."
    explanation: >
      How common the phenomenon is in the one cohort that looked for it.

- name: Age-Related Clonal Hematopoiesis
  biological_scale: CELLULAR
  description: >
    All three older individuals in the 15-person cohort of Venugopal et al.
    (PMID:38662475) carried somatic
    variants in age-related clonal haematopoiesis genes - ASXL1, DNMT3A, TET2 -
    and two also carried ETV6 variants, which is not a typical age-related
    finding. Transient 20q loss was seen in two individuals in the cohort,
    though not the same two - one of them is a younger carrier, so it is not a
    feature of the older group specifically. These clones likely improve
    haematopoietic output, which is the source's own hedged phrasing and the
    reason they expand; the cost is that the same alterations carry myeloid
    malignancy risk.

    Curated at the strength the source states and no further. Four myeloid
    malignancies had been reported among 80 MECOM-associated individuals -
    three adult myelodysplastic syndromes and one paediatric acute myeloid
    leukaemia, about 5% - and the source attributes that low frequency to most
    patients being transplanted young, which implies an underestimate without
    saying so outright. This
    entry therefore records myelodysplasia and clonal haematopoiesis as
    curated findings, and does not assert a quantified germline leukaemia
    predisposition, which no cited source supports.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  downstream:
  - target: Myelodysplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38662475
      reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Although the presence of such somatic alterations likely improves hematopoietic output, it may also signify an elevated risk of myeloid malignancy development, particularly with advancing age."
      explanation: >-
        The source's own statement of the risk, hedged as it is; INDIRECT
        because it is an inference from the clonal genotypes rather than an
        observed progression within this cohort.
  evidence:
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, all 3 older individuals within our cohort (4-II-1, 4-II-4, and 5-II-1) displayed somatic variants in known age–related clonal hematopoiesis genes"
    explanation: >
      The observation, with its small denominator visible in the quote itself.
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which could explain relatively low frequency of progression to myeloid malignancy in 5% of patients (3 adult MDS cases and 1 pediatric acute myeloid leukemia of 80 individuals"
    explanation: >
      The published malignancy count and denominator, and the confounder -
      early transplant - that the source says makes it an underestimate.

- name: Failure of Proximal Radioulnar Joint Separation
  biological_scale: TISSUE
  description: >
    The radius and ulna fail to separate proximally during limb development and
    remain fused as bone. This is a developmental non-event rather than a
    destructive lesion: the joint interzone that should cavitate does not, so
    the forearm is fixed - usually in pronation - from birth and never
    supinates.

    The developmental biology is better established for one of the two genes
    than the other, and the entry keeps that asymmetry visible.

    For HOXA11 there is directly relevant joint data. Limb joint formation
    begins with the interzone, a band of flat, tightly packed mesenchymal cells
    marking the boundary between adjacent cartilage anlagen, and those cells
    give rise to the joint tissues; failure at that step is what leaves two
    elements fused. Mouse embryos lacking all Hox11 paralogues do not merely
    mispattern the zeugopod - their elbow joints are specifically remodelled,
    and the proximal ends of the mutant radius and ulna become morphologically
    similar and form an anatomically distinct joint. That is the same joint, at
    the same end of the same two bones, as the human lesion. The authors
    conclude Hox11 genes dictate joint identity and morphogenesis in the
    zeugopod. Two caveats keep this indirect: it is a triple-paralogue mutant
    rather than a single heterozygous allele, and remodelled joint identity is
    not the same event as failed separation.

    For MECOM there is no comparable data. What exists is expression - EVI1 in
    the developing limb - and the human genetics. The knock-in mouse carrying
    the patient allele has normal forelimbs, so the one experiment that could
    have supplied a MECOM limb mechanism returned a negative.
  biological_processes:
  - preferred_term: embryonic skeletal limb joint morphogenesis
    term:
      id: GO:0036023
      label: embryonic skeletal limb joint morphogenesis
    modifier: DECREASED
  - preferred_term: forelimb morphogenesis
    term:
      id: GO:0035136
      label: forelimb morphogenesis
    modifier: DECREASED
  downstream:
  - target: Radioulnar Synostosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29519864
      reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Congenital radioulnar synostosis (RUS) is a rare developmental abnormality involving fusion of the bones of the forearms (radius and ulna) preventing normal supination of the affected forearm"
      explanation: >-
        Names the malformation as developmental and gives its functional
        consequence.
  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: "We report missense mutations in MECOM resulting in a Mendelian disorder that provide compelling evidence for the critical role of EVI1 in normal hematopoiesis and in the development of forelimbs and fingers in humans."
    explanation: >
      Assigns forelimb development to EVI1 in humans on genetic grounds.
  - reference: PMID:20978074
    reference_title: "Hox11 genes establish synovial joint organization and phylogenetic characteristics in developing mouse zeugopod skeletal elements."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "joint formation initiates with the appearance of the so-called interzone that comprises flat and tightly packed mesenchymal cells and demarcates the boundary between adjacent cartilaginous skeletal anlaga"
    explanation: >
      The developmental event this node names. Cited because the node describes
      interzone failure, and a description that asserts a mechanism should not
      rest on general knowledge.
  - reference: PMID:20978074
    reference_title: "Hox11 genes establish synovial joint organization and phylogenetic characteristics in developing mouse zeugopod skeletal elements."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "The proximal ends of developing mutant ulna and radius elements became morphologically similar and formed an anatomically distinct elbow joint."
    explanation: >
      The closest experimental analogue of the human lesion in the literature:
      loss of Hox11 function reorganises the joint at the proximal ends of the
      radius and ulna, which is where RUSAT fuses them. INDIRECT because the
      mouse is a triple-paralogue mutant and its joint is remodelled rather
      than absent.
  - reference: PMID:14668414
    reference_title: "Multiple roles of Hoxa11 and Hoxd11 in the formation of the mammalian forelimb zeugopod."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "the most significant defect appears to be the failure to form normal growth plates at the proximal and distal ends of the zeugopod bones"
    explanation: >
      Developmental context for the HOXA11 arm, and INDIRECT for two reasons
      stated in the node description: the lesion is a growth-plate defect
      rather than a failure of joint separation, and it requires loss of both
      Hoxa11 and Hoxd11 rather than a single heterozygous allele.

- name: Multi-Organ Developmental MECOM Requirement
  biological_scale: TISSUE
  description: >
    A deliberately coarse node collecting the extra-haematopoietic
    malformations - digital, ungual, patellar, cardiac, renal and auditory - that recur across
    MECOM cohorts without any of them being obligate. The justification for
    grouping rather than splitting is that the only thing tying them together
    in the cited literature is one fact: MECOM is expressed at high levels in
    the embryonic heart, lungs, limb buds, nasal cavity and urinary tract, and
    those are the organs that turn out to be malformed. No source traces a
    pathway from EVI1 target genes to any individual lesion.

    Two honest limits. The expression data behind the grouping are murine,
    while the malformations are human. And a node at this resolution earns
    little: it says these findings are developmental rather than consequences
    of the marrow disease, which matters clinically - they are present at birth
    and are not corrected by transplant - but it does not explain any of them.
    Splitting it is the right move as soon as a source supports a specific
    route.

    The radioulnar synostosis is deliberately NOT routed through this node. It
    has its own node because it is the defining feature, because it segregates
    with a specific variant region, and because it has its own model-organism
    literature; folding it in here would lose all three.
  biological_processes:
  - preferred_term: embryonic organ development
    term:
      id: GO:0048568
      label: embryonic organ development
    modifier: DECREASED
  downstream:
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Grouped with the other extra-haematopoietic findings on the same basis
      this node states: MECOM is broadly expressed in embryonic tissues and no
      source traces a pathway to any individual outcome. The caveat in the node
      description applies with extra force here, since developmental delay is
      the least anatomically localised of the findings collected under it.
  - target: Failure to Thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Attached here rather than to the marrow failure. It is reported as a
      constitutional feature alongside the malformations rather than as a
      consequence of the cytopenias, but the two are not separable in the cited
      cohorts and this placement should not be read as excluding a
      haematologic contribution.
  - target: Clinodactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ventricular Septal Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Renal Malformation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Sensorineural Hearing Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Patellar Aplasia or Hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Digital Phalangeal Hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Nail Abnormality
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Aortic Root Dilatation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Grouped with the other developmental lesions on expression grounds, but
      note it behaves differently from them: the septal defects are static and
      congenital while the aortic dilatation is progressive, so this edge
      should not be read as implying a single shared lesion.
  evidence:
  - reference: PMID:37407873
    reference_title: "MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Extra-hematopoietic manifestations of MECOM deficiency, including renal and cardiac anomalies, radioulnar synostosis, clinodactyly, and hearing loss, have been reported."
    explanation: >
      Names the set of malformations this node collects. Graded OTHER because
      the source is a review summarising prior reports rather than presenting
      primary data.
  - reference: PMID:29540340
    reference_title: "MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No single clinical manifestation was detected in all patients affected by MECOM mutations."
    explanation: >
      The reason this node has four optional downstream branches rather than an
      obligate syndrome definition: none of these findings is present in every
      patient.

- name: Pulmonary Arterial Endothelial MECOM Deficiency
  biological_scale: CELLULAR
  description: >
    A branch reported only in 2026 and curated as provisional. MECOM is
    expressed principally in pulmonary arterial endothelial cells, and in a
    15-person series assembled through GeneMatcher, 6 had pulmonary arterial
    hypertension. Protein modelling suggests the variant hotspots interfere
    with binding to a VEGFR2/KDR enhancer, which would give an endothelial
    route independent of the marrow. This is an ascertainment-prone series -
    it was assembled by querying for a phenotype the authors had already
    nominated MECOM for - and the mechanism is modelled rather than measured.

    It is attached downstream of the DNA-binding node rather than left
    free-floating, because its evidential shape is the same as the limb branch
    this entry does connect: expression data plus human genetics, with no
    intervening steps established, and variants in the same zinc-finger
    hotspot.
  cell_types:
  - preferred_term: pulmonary arterial endothelial cell
    term:
      id: CL:1001568
      label: pulmonary artery endothelial cell
  downstream:
  - target: Pulmonary arterial hypertension
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41617498
      reference_title: "Expanding the phenotypic spectrum of MECOM-associated syndrome: rare variants are associated with syndromic pulmonary arterial hypertension."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Data from LungMAP showed that MECOM is primarily expressed in pulmonary arterial endothelial cells."
      explanation: >-
        The expression datum that makes an endothelial route plausible. INDIRECT
        as a link type because expression plus association is not a
        demonstrated causal path.
  evidence:
  - reference: PMID:41617498
    reference_title: "Expanding the phenotypic spectrum of MECOM-associated syndrome: rare variants are associated with syndromic pulmonary arterial hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 15 individuals with MECOM variants, including 11 unrelated probands and 8 de novo variants. 11 individuals had severe or mild thrombocytopenia, 9 had skeletal issues, 8 had cardiac anomalies, 6 had PAH and 10 had additional conditions."
    explanation: >
      The series and the PAH count within it.

mechanistic_hypotheses:
- hypothesis_group_id: mecom_pure_haploinsufficiency
  hypothesis_label: The RUSAT missense alleles act purely by reducing EVI1 dose
  status: ALTERNATIVE
  description: >
    On this model there is one lesion - not enough functional EVI1 - and
    everything else is dosage and tissue sensitivity. It predicts that a
    zinc-finger 8/9 missense allele should behave like a null, that the
    knock-in mouse should phenocopy the exonic-deletion mice, and that the
    difference between patients with and without synostosis should come from
    modifiers or residual activity rather than from the variant doing anything
    a null does not. The knock-in mouse is the strongest evidence for it: its
    authors conclude the missense allele has a similar effect to
    loss-of-function alleles in haematopoiesis. Reviews of the disease describe
    it as haploinsufficiency without qualification.
  evidence:
  - reference: PMID:37099686
    reference_title: "Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These findings suggest that Evi1KI/+ mice recapitulate the bone marrow dysfunction in RUSAT, similar to that caused by loss-of-function Mecom alleles."
    explanation: >-
      The strongest single piece of evidence for the pure-dose model: in vivo,
      the missense allele behaves like a null in haematopoiesis.
  - reference: PMID:37407873
    reference_title: "MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MECOM deficiency is a recently identified inborn error of immunity and inherited bone marrow failure syndrome caused by haploinsufficiency of the hematopoietic transcription factor MECOM."
    explanation: >-
      A review naming haploinsufficiency as the mechanism without qualification,
      which is this hypothesis stated as settled.
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Preliminary data suggest levels of MECOM appear to be reduced in lymphoblastoid cell lines heterozygous for p.Glu758Lys"
    explanation: >-
      The only human datum bearing on the question that separates these two
      hypotheses: whether a zinc-finger missense allele actually lowers EVI1
      dose, as a null would, or leaves a full complement of binding-incompetent
      protein. Reduced protein in a patient cell line is what the pure-dose
      model predicts. Held at INDIRECT and flagged as weak for the reasons the
      source itself gives - the authors call it "preliminary" and say levels
      "appear to be" reduced, it is one allele in a lymphoblastoid line rather
      than in a haematopoietic stem cell, and it appears in supplementary data
      rather than as a headline result.
- hypothesis_group_id: mecom_domain_specific_effect
  hypothesis_label: The zinc finger 8/9 missense alleles do something a null allele does not
  status: ALTERNATIVE
  description: >
    On this model dose is not the whole story, and the evidence for it is a
    pattern in the human genetics that pure haploinsufficiency does not
    predict. Radioulnar synostosis and B-cell deficiency appear only with
    variants in one short C-terminal zinc-finger region; nonsense, frameshift,
    splice and whole-gene-deletion alleles - which remove more EVI1 than a
    missense change does - give marrow failure without the synostosis. If less
    protein were the whole mechanism, the alleles that remove the most protein
    should give the most complete syndrome, and they do not. The prediction
    that separates the models is a tissue-level one: a limb-bud requirement
    that a missense zinc-finger protein disrupts and a null allele does not,
    for instance by leaving a binding-incompetent protein in place at a
    developmental target.
  evidence:
  - reference: PMID:29540340
    reference_title: "MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1."
    explanation: >-
      The regional exclusivity that a pure-dose model does not predict.
  - reference: PMID:37099686
    reference_title: "Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RUSAT-associated mutations are located in the eighth and ninth zinc finger motifs, suggesting that RUSAT-associated mutations may have particular intravital effects"
    explanation: >-
      The hypothesis stated in the literature, by the same authors whose mouse
      data support the competing model - which is why both are ALTERNATIVE here.

discussions:
- discussion_id: rusat_name_understates_disease
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - disease#Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia
  - pathophysiology#Progressive Multilineage Marrow Failure
  prompt: >-
    Does the name "radioulnar synostosis with amegakaryocytic thrombocytopenia"
    describe the disease this entry curates?
  rationale: >-
    Both halves of the name are wrong for a large share of patients, and the
    literature says so in two different directions. The haematological half is
    too narrow: a seven-family cohort concluded the blood disease is frequently
    global and variable rather than limited to thrombocytopenia, and proposed
    RUS-associated haematological disease (RUSHD) instead. The skeletal half is
    not required at all: the largest series found no single manifestation
    present in every patient, described a spectrum running from isolated
    synostosis with no blood disease to severe marrow failure with no skeletal
    abnormality, and proposed MECOM-associated syndrome as the covering term.
    The perinatal-lethal hydrops cases had neither synostosis nor a suspected
    diagnosis before sequencing.

    This entry keeps MONDO:0011555 and its label because that is the concept the
    knowledge base is curating against, and records both proposed renamings as
    synonyms. The practical consequence for a reader is a negative one worth
    stating plainly: a normal forearm does not exclude this disease, and
    finding an intact radius and ulna is not a reason to stop before sequencing
    MECOM.
  evidence:
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it has become clear that RUS-associated hematological abnormalities are frequently more global and variable, rather than being limited to thrombocytopenia"
    explanation: >-
      The argument that the "amegakaryocytic thrombocytopenia" half understates
      the marrow phenotype.
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The description RUS-associated hematological disease (RUSHD) is therefore perhaps more appropriate than RUS-associated amegakaryocytic thrombocytopenia (RUSAT)"
    explanation: >-
      The proposed replacement name, quoted so the dispute is on the record
      rather than paraphrased.
  - reference: PMID:29540340
    reference_title: "MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No single clinical manifestation was detected in all patients affected by MECOM mutations."
    explanation: >-
      Establishes that no feature in the name is obligate.
  - reference: PMID:37230770
    reference_title: "Perinatal-lethal nonimmune fetal hydrops attributed to MECOM-associated bone marrow failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, neither infant was reported to have radioulnar synostosis, nor was a MECOM-associated syndrome suspected clinically prior to the molecular diagnosis."
    explanation: >-
      The clinical cost of the name: two fatal cases in which the absent
      synostosis contributed to the diagnosis being missed until sequencing.

- discussion_id: rusat_variant_class_determines_synostosis
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - pathophysiology#Germline Heterozygous MECOM Zinc Finger Variant
  - pathophysiology#Failure of Proximal Radioulnar Joint Separation
  - mechanistic_hypotheses#mecom_domain_specific_effect
  prompt: >-
    Why do missense variants in zinc fingers 8 and 9 cause radioulnar
    synostosis while truncating and deletion alleles of the same gene do not?
  rationale: >-
    The observation is consistent across three independent series. Variants
    co-presenting with synostosis cluster in a roughly ten-amino-acid span of
    the C-terminal zinc finger domain; B-cell deficiency segregates with the
    same region; congenital marrow failure without synostosis is caused by
    nonsense, indel and splice variants producing premature termination, and by
    whole-gene deletions. A literature-wide tally puts the same pattern in
    aggregate terms - missense variants frequently show synostosis, while the
    other four variant classes more commonly give marrow failure.

    Simple haploinsufficiency does not obviously predict this ordering, since
    the alleles that remove the most protein give the less complete syndrome.
    The alternative is that the limb requirement is specifically disrupted by a
    binding-incompetent zinc-finger protein. The two readings are curated as
    competing `mechanistic_hypotheses`, and this discussion is what stands
    between them. It matters practically as well: a MECOM truncating variant
    found in an infant with pancytopenia and normal forearms is not a
    different disease from RUSAT, and should not be reported as one.
  evidence:
  - reference: PMID:29540340
    reference_title: "MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1."
    explanation: >-
      The regional restriction, stated as an exclusive.
  - reference: PMID:37099686
    reference_title: "Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Individuals with congenital bone marrow failure without RUS exhibit nonsense, insertion/deletion, or splicing variants that result in a premature termination codon in MECOM"
    explanation: >-
      The complementary half: the non-synostosis presentations carry
      protein-truncating alleles.
  - reference: PMID:40170114
    reference_title: "A novel MECOM gene variant causes severe thrombocytopenia in a neonate: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients with missense mutations frequently exhibited radioulnar synostosis, while bone marrow failure was more commonly associated with the other four types of mutations."
    explanation: >-
      A literature-wide tally reproducing the same split by variant class.
  - reference: PMID:37099686
    reference_title: "Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RUSAT-associated mutations are located in the eighth and ninth zinc finger motifs, suggesting that RUSAT-associated mutations may have particular intravital effects"
    explanation: >-
      The authors' own reading, that these alleles may do something beyond
      dose reduction, which is the domain-specific hypothesis.

- discussion_id: rusat_mouse_no_synostosis
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Failure of Proximal Radioulnar Joint Separation
  - animal_models#Evi1 H752R knock-in mouse
  prompt: >-
    Why does a mouse carrying the exact human RUSAT allele have no radioulnar
    synostosis, and does that invalidate the mouse for the limb arm of this
    disease?
  rationale: >-
    The knock-in mouse carries the murine equivalent of a human RUSAT variant
    at the orthologous residue, so this is not a species-mismatched allele. It
    reproduces the haematopoietic side - reduced stem and progenitor cells,
    delayed recovery after myelosuppression, low platelet counts in older
    males - and reproduces none of the skeletal side. The forelimbs are normal.

    That is a substantive negative result rather than a failed experiment, and
    it cuts both ways. If the synostosis needs a developmental context the
    mouse forelimb does not provide, the mouse is simply the wrong system for
    the limb arm and its silence says nothing about the human mechanism. But if
    the same allele is sufficient for the marrow phenotype and insufficient for
    the limb phenotype in one animal, the two arms of the syndrome may have
    genuinely different dose or timing requirements - which is the same
    question the variant-class discussion raises from the human side. The
    haematological timing is also mismatched: the human disease is congenital
    and the mouse platelet defect appears only in older males, so the mouse is
    a model of the marrow deficit and not of its onset.
  evidence:
  - reference: PMID:37099686
    reference_title: "Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Heterozygous mutant mice (Evi1KI/+ mice) grew normally without radioulnar synostosis."
    explanation: >-
      The negative skeletal result in the patient-allele knock-in.
  - reference: PMID:37099686
    reference_title: "Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These findings suggest that Evi1KI/+ mice recapitulate the bone marrow dysfunction in RUSAT, similar to that caused by loss-of-function Mecom alleles."
    explanation: >-
      The positive haematopoietic result in the same animal, which is what makes
      the skeletal silence informative rather than merely a null model.
  proposed_experiments:
  - experiment_id: rusat_limb_bud_conditional_knockin
    name: Limb-bud-restricted expression of the RUSAT allele during forelimb patterning
    description: >-
      Express the knock-in allele under limb-bud control across the window of
      zeugopod segmentation, and separately test a limb-restricted null allele
      in parallel, scoring proximal radioulnar separation in both.
    would_support:
    - pathophysiology#Failure of Proximal Radioulnar Joint Separation
    - mechanistic_hypotheses#mecom_domain_specific_effect
    supporting_outcome:
    - >-
      Proximal radioulnar fusion in the missense arm but not the null arm would
      support a domain-specific limb requirement and explain both the mouse's
      normal forelimbs (a dose or timing threshold not reached in the germline
      heterozygote) and the human variant-class split.
    refuting_outcome:
    - >-
      Normal forearms in both arms, or fusion in both, would argue that the
      mouse forelimb cannot report this phenotype at all, and that the limb arm
      of RUSAT needs a different system rather than a different allele.

- discussion_id: rusat_camt_convergence
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - pathophysiology#Loss of EVI1 Transcriptional Control of MPL
  - differential_diagnoses#Congenital Amegakaryocytic Thrombocytopenia
  prompt: >-
    Is the overlap between RUSAT and congenital amegakaryocytic
    thrombocytopenia a coincidence of presentation, or a shared mechanism?
  rationale: >-
    The two diseases are hard to separate in a neonate: both give congenital
    thrombocytopenia with an amegakaryocytic marrow, both progress to
    pancytopenia, and both are cured only by transplant. The finding that EVI1
    transcriptionally regulates MPL - the receptor whose biallelic loss causes
    CAMT - offers a mechanistic account of that overlap rather than a
    coincidental one, and the paper reporting it says so explicitly.

    The claim should be held at the strength its evidence supports. What was
    shown is that EVI1 controls MPL transcription in vitro; what was not shown
    is reduced MPL message or thrombopoietin-receptor signalling in RUSAT
    patient megakaryocytes. The same paper states that the link between EVI1
    dysfunction and thrombocytopenia is poorly understood. So this is a
    plausible and testable convergence, not an established shared pathway, and
    the `Loss of EVI1 Transcriptional Control of MPL` node is written to say so.
  evidence:
  - reference: PMID:37610030
    reference_title: "A novel mutation in MECOM affects MPL regulation in vitro and results in thrombocytopenia and bone marrow failure."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we demonstrated that EVI1 controls the transcriptional regulation of MPL, a gene whose mutations are responsible for congenital amegakaryocytic thrombocytopenia (CAMT), potentially explaining the partial overlap between MECOM-AS and CAMT"
    explanation: >-
      The proposed mechanistic account of the RUSAT/CAMT overlap, including its
      own hedge ("potentially explaining").
  - reference: PMID:37610030
    reference_title: "A novel mutation in MECOM affects MPL regulation in vitro and results in thrombocytopenia and bone marrow failure."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The mechanism linking the alteration of EVI1 function and thrombocytopenia is poorly understood."
    explanation: >-
      The limit on the claim, from the paper that makes it.

- discussion_id: rusat_somatic_rescue_and_penetrance
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - pathophysiology#Clonal Selection of Revertant Hematopoietic Stem Cells
  - diagnosis#Germline Testing on Non-Hematopoietic Tissue
  prompt: >-
    How much of the apparent non-penetrance and spontaneous recovery in
    MECOM-associated syndrome is somatic reversion rather than mild disease?
  rationale: >-
    Enough to change practice, and not enough to be the whole answer. In a
    15-person cohort, 7 individuals showed spontaneous resolution, alleviation,
    or late onset; of 6 evaluable, 4 carried copy neutral loss of heterozygosity
    across 3q that duplicates the residual wild-type allele. The other 2 showed
    no allelic imbalance on longitudinal testing, so their mild course is
    unexplained. Reversion is therefore a major contributor to variable
    expressivity in this disease but not a complete account of it, and this
    entry does not present it as one.

    Two consequences follow. Diagnostically, blood is an unreliable germline
    sample in a recovered carrier and testing should use skin fibroblasts or
    hair follicles. Therapeutically, the source argues the existence of
    naturally selected corrected clones gives a rationale for gene-corrected
    autologous transplantation - which is a rationale, not a treatment, and no
    trial exists.
  evidence:
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein, we show that part of the variability in hematological presentation may be attributable to spontaneous reversion of germ line variants observed in some affected individuals."
    explanation: >-
      The claim, at the strength the authors make it - "part of the
      variability", "may be attributable".
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For 2 of 6 individuals, an explanation for mild presentation or symptom resolution remains enigmatic"
    explanation: >-
      The limit on the claim, from the same paper: reversion does not explain
      every mild case.
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of somatic genetic rescue provides a rationale for gene-corrected autologous transplantation or direct gene editing approaches as potential treatments for the hematopoietic phenotype of MECOM-associated syndrome in the absence of matched donors."
    explanation: >-
      The therapeutic argument, quoted with its own conditional framing so it
      is not read as an available option.

- discussion_id: rusat_pregnancy_loss
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Genetic Counseling and Cascade Testing
  - inheritance#Autosomal dominant
  prompt: >-
    Is the high rate of pregnancy loss in MECOM families caused by the variant,
    and if so is the fetal or the maternal genotype responsible?
  rationale: >-
    The observation is striking and the interpretation is not settled. Twelve
    of 16 pregnancies in five mothers with detailed histories ended in loss -
    75%, against a quoted 15-25% in the general population and 12-20% in other
    inherited marrow failure syndromes. But fetal genotypes were unavailable,
    so nobody knows whether the lost pregnancies carried the variant; and
    losses also occurred in MECOM wild-type women in these families, including
    a stillbirth at 8.5 months in a mother who tested negative while her
    husband was affected. That last case is the one that keeps both hypotheses
    alive: it is consistent with a fetal-genotype effect, and equally with the
    losses being unrelated to MECOM.

    Until fetal genotyping is done this cannot become a recurrence-risk figure,
    and it should not be quoted to families as one. It is recorded here because
    the source's own recommendation - discuss it in reproductive counselling -
    depends on stating the uncertainty alongside the number.
  evidence:
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strikingly, there were 12 pregnancy losses of a total of 16 pregnancies in 5 mothers for whom detailed information regarding pregnancies was available"
    explanation: >-
      The observation and its denominator.
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a higher rate of loss (75%) than expected pregnancy outcomes in the general population (15%-25%) as well as other inherited BMF syndromes (12%-20%)."
    explanation: >-
      The comparison, including the disease-class comparator that makes it more
      than a general-population contrast.
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, we were unable to ascertain the MECOM status for the fetus."
    explanation: >-
      The specific missing datum that stops this becoming a risk estimate.
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is also worth noting that 2-I-2 and 3-I-2 (both wild-type for MECOM) have also experienced pregnancy losses."
    explanation: >-
      Losses in wild-type women in the same families, which is the observation
      that keeps a non-MECOM explanation open.
  proposed_experiments:
  - experiment_id: rusat_fetal_genotyping_of_losses
    name: Genotyping of products of conception in MECOM-variant families
    description: >-
      Prospectively genotype MECOM in products of conception from pregnancies in
      known carrier families, and compare loss rates between variant-carrying
      and wild-type conceptuses within the same families.
    would_support:
    - phenotypes#Nonimmune hydrops fetalis
    supporting_outcome:
    - >-
      Enrichment of the variant among lost conceptuses, relative to liveborn
      siblings from the same families, would establish a fetal-genotype effect
      and connect the pregnancy losses to the severe prenatal end of the
      phenotype already curated here as hydrops.
    refuting_outcome:
    - >-
      No enrichment, with losses distributed independently of fetal genotype,
      would argue the excess is a maternal or family-level effect and should be
      removed from variant-specific counselling.

phenotypes:
- category: Hematologic
  name: Thrombocytopenia
  description: >
    The presenting feature in almost every case, present from birth and often
    severe enough to be found on a neonatal blood count taken for bleeding or
    petechiae. It is the feature the disease is named for and, in the mildest
    dominantly transmitted families, may be the only one.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
    temporality: CHRONIC
  sequelae:
  - target: Petechiae
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37230770
      reference_title: "Perinatal-lethal nonimmune fetal hydrops attributed to MECOM-associated bone marrow failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "presented at birth with symptoms of bone marrow failure including severe anemia, hydrops, and petechial hemorrhages"
      explanation: >-
        Petechial haemorrhage reported as a presenting sign of the marrow
        failure at birth.
  - target: Abnormal bleeding
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40170114
      reference_title: "A novel MECOM gene variant causes severe thrombocytopenia in a neonate: a case report and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We report a 0-day-old female Han Chinese neonate who presented with severe thrombocytopenia and intracranial hemorrhage"
      explanation: >-
        Thrombocytopenia and haemorrhage reported together at presentation.
  evidence:
  - reference: PMID:41635268
    reference_title: "Syndrome of the Month: Radioulnar Synostosis With Amegakaryocytic Thrombocytopenia Type 2."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Radioulnar synostosis with amegakaryocytic thrombocytopenia type 2 (RUSAT-2) is a rare inherited bone marrow failure syndrome characterized by congenital or progressive thrombocytopenia, frequent radioulnar synostosis, and variable multisystem involvement."
    explanation: >
      Names congenital or progressive thrombocytopenia as the defining
      haematological feature.
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All the affected children presented with thrombocytopenia from birth, with three out of the four undergoing BMT."
    explanation: >
      Congenital onset in the HOXA11 families, and the transplant rate among
      them.

- category: Hematologic
  name: Megakaryocytopenia
  description: >
    Absent or severely reduced megakaryocytes on marrow examination. This is
    the finding that makes the thrombocytopenia a production failure rather
    than a destructive process, and it is the single most useful marrow result
    in separating RUSAT from immune thrombocytopenia in a neonate. Series
    variously describe the marrow as amegakaryocytic or hypomegakaryocytic.
  phenotype_term:
    preferred_term: Megakaryocytopenia
    term:
      id: HP:0005548
      label: Megakaryocytopenia
  evidence:
  - reference: PMID:29540340
    reference_title: "MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report on 12 patients with congenital hypomegakaryocytic thrombocytopenia caused by MECOM mutations (including 10 novel mutations)."
    explanation: >
      The marrow phenotype in the series that defined MECOM-associated
      syndrome.

- category: Skeletal
  name: Radioulnar Synostosis
  description: >
    Congenital bony fusion of the proximal radius and ulna, usually bilateral.
    It is present at birth, does not progress, and is frequently found only
    when someone looks for it - the functional deficit is limited enough that
    an affected parent may be unaware of it. Its diagnostic value is
    asymmetric: finding it in a child with congenital thrombocytopenia points
    hard at this disease, but not finding it excludes nothing.
  phenotype_term:
    preferred_term: Bilateral proximal radioulnar synostosis
    term:
      id: HP:0002974
      label: Radioulnar synostosis
    temporality: CHRONIC
  sequelae:
  - target: Limited pronation and supination of the forearm
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29519864
      reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "fusion of the bones of the forearms (radius and ulna) preventing normal supination of the affected forearm"
      explanation: >-
        States the fusion as the cause of the lost supination.
  evidence:
  - reference: PMID:38245683
    reference_title: "A novel missense mutation in the MECOM gene in a Chinese boy with radioulnar synostosis with amegakaryocytic thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by varying presentation of congenital thrombocytopenia (progressing to pancytopenia), bilateral proximal radioulnar synostosis, and other skeletal abnormalities"
    explanation: >
      Gives the anatomical detail this entry curates: proximal and bilateral.
  - reference: PMID:37067177
    reference_title: "Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Within our full MECOM-associated syndrome cohort, skeletal abnormalities included radioulnar synostosis (n=5), clinodactyly (n=3), and radial hypoplasia (n=1)"
    explanation: >
      Counts the skeletal findings in an eight-patient cohort, giving both this
      phenotype and the digital ones.

- category: Skeletal
  name: Limited pronation and supination of the forearm
  description: >
    The functional consequence of the fusion. The forearm is fixed, typically
    in pronation, and rotation at the proximal radioulnar joint is lost. This
    is what a patient actually notices; the synostosis itself is radiographic.
  phenotype_term:
    preferred_term: Limited pronation/supination of forearm
    term:
      id: HP:0006394
      label: Limited pronation/supination of forearm
    clinical_course: STABLE
  evidence:
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital radioulnar synostosis (RUS) is a rare developmental abnormality involving fusion of the bones of the forearms (radius and ulna) preventing normal supination of the affected forearm"
    explanation: >
      States the loss of supination as the direct consequence of the fusion.

- category: Hematologic
  name: Pancytopenia
  description: >
    Progression from isolated thrombocytopenia to a fall in all three lineages.
    The tempo is the most variable thing about this disease: some infants reach
    it within months and need a transplant before their first birthday, while
    some carriers of the same allele reach only a single mild cytopenia in
    adulthood.
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:37610030
    reference_title: "A novel mutation in MECOM affects MPL regulation in vitro and results in thrombocytopenia and bone marrow failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MECOM-associated syndrome (MECOM-AS) is a rare disease characterized by amegakaryocytic thrombocytopenia, progressive bone marrow failure, pancytopenia and radioulnar synostosis with high penetrance."
    explanation: >
      Lists pancytopenia as part of the core phenotype.

- category: Hematologic
  name: Bone marrow hypocellularity
  description: >
    A hypocellular marrow is the tissue-level correlate of the peripheral
    cytopenias and is what places this disease among the inherited bone marrow
    failure syndromes rather than among the isolated inherited
    thrombocytopenias. In the largest series it is the pole of a spectrum whose
    other end is an essentially normal blood count.
  phenotype_term:
    preferred_term: Bone marrow hypocellularity
    term:
      id: HP:0005528
      label: Bone marrow hypocellularity
  evidence:
  - reference: PMID:29540340
    reference_title: "MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the clinical spectrum ranged from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormality"
    explanation: >
      Marrow failure as the severe end of the described range.

- category: Hematologic
  name: Aplastic Anemia
  description: >
    Frank aplastic anaemia is documented in adults with MECOM variants, in at
    least one case as the stage preceding myelodysplastic syndrome. It is the
    late-onset counterpart of the neonatal presentation and is a reason RUSAT
    belongs on the differential for an adult with unexplained aplastic anaemia
    and a fixed forearm.
  phenotype_term:
    preferred_term: Aplastic anemia
    term:
      id: HP:0001915
      label: Aplastic anemia
  sequelae:
  - target: Myelodysplasia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29519864
      reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the hematological involvement progressed from aplastic anemia to myelodysplastic syndrome (MDS)"
      explanation: >-
        The progression itself, in one reported carrier.
  evidence:
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the hematological involvement progressed from aplastic anemia to myelodysplastic syndrome (MDS); this presentation of RUS and development of MDS in adulthood is similar to the family reported by Ripperger"
    explanation: >
      Documents aplastic anaemia and its progression in an adult carrier.

- category: Hematologic
  name: Myelodysplasia
  description: >
    Reported in adults in two independent families, following a period of
    aplastic anaemia. Note the scope limit deliberately kept here: this entry
    records myelodysplastic progression, and does not extend it to a germline
    leukaemia predisposition claim. MECOM's association with acute myeloid
    leukaemia is through somatic overexpression, which is the opposite
    direction of effect from the germline loss modelled in this entry.
  phenotype_term:
    preferred_term: Myelodysplasia
    term:
      id: HP:0002863
      label: Myelodysplasia
    onset:
      onset_category: ADULT
  evidence:
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there is a subgroup of patients with RUS who also present with hematological abnormalities ranging from thrombocytopenia to myelodysplastic syndrome (MDS)"
    explanation: >
      Places MDS at the far end of the haematological range in this disease.

- category: Hematologic
  name: Anemia
  description: >
    Part of the multilineage failure, and at the severe end it is the feature
    that kills: the two perinatal-lethal cases presented with severe anaemia
    and hydrops at birth.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:37230770
    reference_title: "Perinatal-lethal nonimmune fetal hydrops attributed to MECOM-associated bone marrow failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two cases of infants born preterm who presented at birth with symptoms of bone marrow failure including severe anemia, hydrops, and petechial hemorrhages"
    explanation: >
      Severe anaemia at the most severe end of the spectrum.

- category: Prenatal
  name: Nonimmune hydrops fetalis
  description: >
    The most severe presentation, and one that is systematically
    under-ascertained. Both reported cases died in the neonatal period, neither
    had radioulnar synostosis, and neither was suspected clinically before
    sequencing - in one case the diagnosis came from postmortem trio exome
    sequencing. MECOM is not on targeted hydrops gene panels, so a broad
    sequencing approach is what finds these cases.
  phenotype_term:
    preferred_term: Nonimmune hydrops fetalis
    term:
      id: HP:0001790
      label: Nonimmune hydrops fetalis
  evidence:
  - reference: PMID:37230770
    reference_title: "Perinatal-lethal nonimmune fetal hydrops attributed to MECOM-associated bone marrow failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These cases add to the growing body of literature that describe MECOM-associated disease, particularly MECOM as a cause of fetal hydrops due to bone marrow failure in utero."
    explanation: >
      Establishes MECOM-related marrow failure as a cause of non-immune fetal
      hydrops.
  - reference: PMID:41617498
    reference_title: "Expanding the phenotypic spectrum of MECOM-associated syndrome: rare variants are associated with syndromic pulmonary arterial hypertension."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three were diagnosed in utero and died in the neonatal period."
    explanation: >
      INDIRECT, and kept for what it does establish rather than what it says:
      the sentence reports prenatal diagnosis and neonatal death, not hydrops.
      It supports the claim that the severe prenatal pole of this disease is
      not confined to the two hydrops case reports, which is why the phenotype
      is not curated as a two-patient curiosity.

- category: Hematologic
  name: Petechiae
  description: >
    A common presenting sign of the neonatal thrombocytopenia, and often what
    prompts the blood count that finds the disease.
  phenotype_term:
    preferred_term: Petechiae
    term:
      id: HP:0000967
      label: Petechiae
  evidence:
  - reference: PMID:37230770
    reference_title: "Perinatal-lethal nonimmune fetal hydrops attributed to MECOM-associated bone marrow failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two cases of infants born preterm who presented at birth with symptoms of bone marrow failure including severe anemia, hydrops, and petechial hemorrhages"
    explanation: >
      Petechial haemorrhage as a presenting sign at birth.

- category: Hematologic
  name: Abnormal bleeding
  description: >
    The clinical risk that makes the platelet count urgent. In the severe
    neonatal presentation the bleeding can be intracranial and fatal within
    days of birth.
  phenotype_term:
    preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  sequelae:
  - target: Intracranial hemorrhage
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40170114
      reference_title: "A novel MECOM gene variant causes severe thrombocytopenia in a neonate: a case report and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "ultimately succumbing to multiple organ failure and intracranial hemorrhage on the third day after birth"
      explanation: >-
        The intracranial bleed as the fatal outcome of the bleeding tendency.
  evidence:
  - reference: PMID:40170114
    reference_title: "A novel MECOM gene variant causes severe thrombocytopenia in a neonate: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a 0-day-old female Han Chinese neonate who presented with severe thrombocytopenia and intracranial hemorrhage, ultimately succumbing to multiple organ failure and intracranial hemorrhage on the third day after birth."
    explanation: >
      Documents bleeding severe enough to be fatal in the neonatal period.

- category: Neurologic
  name: Intracranial hemorrhage
  description: >
    Reported as a cause of neonatal death in a MECOM-related case presenting on
    day zero with severe thrombocytopenia. Curated as a distinct phenotype
    because it is the specific catastrophic outcome that drives transfusion
    thresholds in the first weeks of life, rather than a generic bleeding
    tendency.
  phenotype_term:
    preferred_term: Intracranial hemorrhage
    term:
      id: HP:0002170
      label: Intracranial hemorrhage
  evidence:
  - reference: PMID:40170114
    reference_title: "A novel MECOM gene variant causes severe thrombocytopenia in a neonate: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a 0-day-old female Han Chinese neonate who presented with severe thrombocytopenia and intracranial hemorrhage, ultimately succumbing to multiple organ failure and intracranial hemorrhage on the third day after birth."
    explanation: >
      A reported intracranial haemorrhage with a fatal outcome.

- category: Immunologic
  name: Decreased total B cell count
  description: >
    B-cell lymphopenia, reported in a subset and sufficient for MECOM
    deficiency to be classified as an inborn error of immunity alongside its
    marrow phenotype. It co-segregates with radioulnar synostosis by variant
    region.
  phenotype_term:
    preferred_term: Decreased total B cell count
    term:
      id: HP:0010976
      label: Decreased total B cell count
  sequelae:
  - target: Recurrent infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37610030
      reference_title: "A novel mutation in MECOM affects MPL regulation in vitro and results in thrombocytopenia and bone marrow failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The clinical phenotype may also include finger malformations, cardiac and renal alterations, hearing loss, B-cell deficiency and predisposition to infections."
      explanation: >-
        Lists B-cell deficiency and infection susceptibility together. Graded
        INDIRECT_UNKNOWN_INTERMEDIATES because the source groups them rather
        than demonstrating that the B-cell defect is what drives the infections;
        neutropenia from the same marrow failure is a competing contributor.
  evidence:
  - reference: PMID:37407873
    reference_title: "MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "B-cell lymphopenia and hypogammaglobulinemia have been described in a subset of patients with MECOM deficiency."
    explanation: >
      Direct statement of the B-cell phenotype and its partial penetrance.

- category: Immunologic
  name: Decreased circulating immunoglobulin concentration
  description: >
    Hypogammaglobulinaemia accompanying the B-cell lymphopenia. Worth measuring
    in any RUSAT patient, since it is actionable independently of the marrow
    disease.
  phenotype_term:
    preferred_term: Decreased circulating immunoglobulin concentration
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:37407873
    reference_title: "MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "B-cell lymphopenia and hypogammaglobulinemia have been described in a subset of patients with MECOM deficiency."
    explanation: >
      Names hypogammaglobulinaemia in the same subset as the B-cell
      lymphopenia.

- category: Immunologic
  name: Recurrent infections
  description: >
    Predisposition to infection follows the B-cell deficiency, and is
    compounded by neutropenia once the marrow failure becomes multilineage.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:37610030
    reference_title: "A novel mutation in MECOM affects MPL regulation in vitro and results in thrombocytopenia and bone marrow failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical phenotype may also include finger malformations, cardiac and renal alterations, hearing loss, B-cell deficiency and predisposition to infections."
    explanation: >
      Lists predisposition to infection among the recognised features.

- category: Skeletal
  name: Clinodactyly
  description: >
    Curvature of a digit, most often the fifth finger, reported in a minority
    across several series. It belongs with the synostosis as part of a limb
    developmental phenotype rather than as an incidental finding: the founding
    MECOM paper attributes forelimb and finger development to EVI1 in the same
    sentence.
  phenotype_term:
    preferred_term: Clinodactyly
    term:
      id: HP:0030084
      label: Clinodactyly
  evidence:
  - reference: PMID:37067177
    reference_title: "Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Within our full MECOM-associated syndrome cohort, skeletal abnormalities included radioulnar synostosis (n=5), clinodactyly (n=3), and radial hypoplasia (n=1)"
    explanation: >
      Counts clinodactyly in an eight-patient cohort.
  - reference: PMID:29540340
    reference_title: "MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss."
    explanation: >
      Independent confirmation in the twelve-patient series.

- category: Auditory
  name: Sensorineural Hearing Impairment
  description: >
    Described as presenile hearing loss, and reported in independent cohorts.
    Because it can appear later than the haematological presentation, it is a
    reason to keep audiological follow-up in the care plan of a child whose
    marrow disease has been cured by transplant.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:29540340
    reference_title: "MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss."
    explanation: >
      Names presenile hearing loss among the syndrome's features.
  - reference: PMID:37407873
    reference_title: "MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Extra-hematopoietic manifestations of MECOM deficiency, including renal and cardiac anomalies, radioulnar synostosis, clinodactyly, and hearing loss, have been reported."
    explanation: >
      Independent confirmation, grouped with the other extra-haematopoietic
      features.

- category: Cardiovascular
  name: Ventricular Septal Defect
  description: >
    Cardiac malformations are recurrent in MECOM-associated syndrome and match
    the expression pattern - the factor is expressed at high levels in the
    embryonic heart. A ventricular septal defect is the specific lesion
    recorded in a North American cohort, alongside patent ductus arteriosus,
    patent foramen ovale and more complex outflow anomalies.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:29540340
    reference_title: "MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss."
    explanation: >
      Cardiac malformation as a recognised feature of the syndrome.
  - reference: PMID:41617498
    reference_title: "Expanding the phenotypic spectrum of MECOM-associated syndrome: rare variants are associated with syndromic pulmonary arterial hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "11 individuals had severe or mild thrombocytopenia, 9 had skeletal issues, 8 had cardiac anomalies, 6 had PAH and 10 had additional conditions."
    explanation: >
      Quantifies cardiac anomalies in a 15-person series.
  - reference: PMID:37067177
    reference_title: "Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac/vascular [patent ductus arteriosus (n=2), patent foramen ovale (n=2), ventricular septal defect, aortic root dilation, interrupted aortic arch, truncus arteriosus, single umbilical artery, (n=1 each)]"
    explanation: >
      Names the ventricular septal defect specifically, alongside the other
      cardiac lesions seen in the same cohort. This is the source for the
      lesion list in the description above.

- category: Cardiovascular
  name: Pulmonary arterial hypertension
  description: >
    A 2026 addition to the phenotype, reported in 6 of 15 individuals in a
    series assembled through GeneMatcher after MECOM had been nominated as a
    paediatric PAH candidate gene. That ascertainment route inflates the
    apparent frequency, so the 6-of-15 figure should not be read as a
    population estimate; what it establishes is that the association exists and
    that PAH is worth looking for. MECOM is expressed principally in pulmonary
    arterial endothelial cells, which gives it a plausible route independent of
    the marrow.
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: PMID:41617498
    reference_title: "Expanding the phenotypic spectrum of MECOM-associated syndrome: rare variants are associated with syndromic pulmonary arterial hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "11 individuals had severe or mild thrombocytopenia, 9 had skeletal issues, 8 had cardiac anomalies, 6 had PAH and 10 had additional conditions."
    explanation: >
      The count of pulmonary arterial hypertension within the series that
      reported the association.

- category: Renal
  name: Renal Malformation
  description: >
    Renal anomalies - hypoplastic, malrotated, or with renal insufficiency -
    recur across cohorts, again matching the expression pattern: MECOM is
    highly expressed in the developing urinary tract. Bound at kidney level
    rather than to a specific lesion because the reported lesions differ
    between patients - hypoplastic, malrotated, small, agenetic, plus renal
    insufficiency - and no single one is characteristic. The variability is
    within the kidney, so the broader urinary-system term would be a level too
    general.
  phenotype_term:
    preferred_term: Renal malformation
    term:
      id: HP:0000077
      label: Abnormality of the kidney
  evidence:
  - reference: PMID:37407873
    reference_title: "MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Extra-hematopoietic manifestations of MECOM deficiency, including renal and cardiac anomalies, radioulnar synostosis, clinodactyly, and hearing loss, have been reported."
    explanation: >
      Names renal anomalies among the extra-haematopoietic features.
  - reference: PMID:29540340
    reference_title: "MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss."
    explanation: >
      Independent confirmation in the twelve-patient series.
  - reference: PMID:37067177
    reference_title: "Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "renal insufficiency (n=1), malrotated and hypoplastic kidney (n=1)"
    explanation: >
      The specific renal lesions behind the general binding: they differ
      between patients, which is why the general urinary-system term is used.

- category: Growth
  name: Failure to Thrive
  description: >
    Reported in a minority alongside developmental delay in the cohort that
    most broadened the non-haematological phenotype. Recorded because it is
    part of what brings these infants to attention: most were identified under
    two years of age with multiple malformations rather than with an isolated
    blood count abnormality.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:37067177
    reference_title: "Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired growth or development [failure to thrive (n=2), developmental delay (n=4), hypotonia (n=1), hearing loss (n=2)]"
    explanation: >
      Names failure to thrive and counts it, 2 of 8, in this cohort. No
      `frequency` is set from a denominator of eight in one series.

- category: Neurologic
  name: Global Developmental Delay
  description: >
    Developmental delay was the commonest non-haematological, non-malformation
    finding in the eight-patient North American cohort. It is not a feature of
    the original RUSAT description and belongs to the broader
    MECOM-associated-syndrome phenotype.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:37067177
    reference_title: "Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired growth or development [failure to thrive (n=2), developmental delay (n=4), hypotonia (n=1), hearing loss (n=2)]"
    explanation: >
      Names developmental delay and counts it, 4 of 8 - the commonest
      non-haematological finding in this cohort. No `frequency` is set from a
      single eight-patient series.

- category: Skeletal
  name: Patellar Aplasia or Hypoplasia
  description: >
    Absent or small patellae, in 3 of the same 15-person cohort that supplies
    the aortic dilatation figure - bilateral absent patellae in one individual,
    documented radiographically in that paper's own figure, and small patellae
    in two more. Patellar hypoplasia and aplasia are a recognised and
    distinctive part of the MECOM skeletal phenotype, and they are worth
    looking for precisely because nothing draws attention to them: unlike the
    forearm, a small patella causes no obvious functional complaint in
    infancy.

    Bound to the combined aplasia/hypoplasia term because the cohort reports
    both severities and no single one is characteristic.
  phenotype_term:
    preferred_term: Patellar aplasia or hypoplasia
    term:
      id: HP:0006498
      label: Aplasia/Hypoplasia of the patella
  evidence:
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Proximal RUS, hypoplastic thumbs, short, broad fingers, short fifth digits, and coalition of right capitate and hamate, and bilateral absent patellae"
    explanation: >
      The aplastic end of the finding, in the individual whose forearm
      radiograph the same paper reproduces. Quoted in full rather than clipped
      to the patellar clause, because the surrounding list is the point: the
      patellar finding sits inside a broader skeletal phenotype in the same
      person, alongside the proximal synostosis this entry is named for.
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Club foot and small patellae"
    explanation: >
      The hypoplastic end of the finding in a second individual, which is why
      the binding covers both severities.

- category: Skeletal
  name: Digital Phalangeal Hypoplasia
  description: >
    Hypoplasia of the middle and distal phalanges of the fifth digit, reported
    together with toe malposition and thumb positioning anomalies as "other
    skeletal malformation" in 42.2% of a 64-patient literature review. In that
    series it is the second most common feature after the radioulnar synostosis
    itself, ahead of every other finding - which makes its absence from an
    earlier version of this entry a real gap rather than a rounding error.

    Two things about the binding. The source names both the middle and the end
    phalanx of D5; `HP:0004220` captures the middle-phalanx component
    specifically, which is the most precise term available for what is named,
    and the distal-phalanx and toe findings are described here rather than
    bound, because the source reports them as one composite percentage and they
    cannot be separated from it. And this is a different finding from the
    `Clinodactyly` already curated in this entry: clinodactyly is curvature,
    this is hypoplasia, and the source lists them as distinct.
  phenotype_term:
    preferred_term: Hypoplasia of the middle and distal phalanges of the fifth digit
    term:
      id: HP:0004220
      label: Short middle phalanx of the 5th finger
  evidence:
  - reference: PMID:38245683
    reference_title: "A novel missense mutation in the MECOM gene in a Chinese boy with radioulnar synostosis with amegakaryocytic thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The other relatively prevalent features, as observed in 42.2% of reported RUSAT-2 cases, were other skeletal malformation, including hypoplasia of middle and end phalanx D5, Toe malposition D2, Thumb under D2."
    explanation: >
      The finding and its share of a 64-patient literature review. No
      `frequency` band is set from it, consistently with every other phenotype
      in this entry - see `notes` for why this entry declines frequency bands
      across incommensurable cohorts.

- category: Integumentary
  name: Nail Abnormality
  description: >
    Nail abnormalities, reported in 23.4% of the same 64-patient review. The
    source counts nail and facial abnormalities together in one figure, so that
    percentage covers both and cannot be split; this phenotype records the nail
    component, which is the one with a usable HPO binding.
  phenotype_term:
    preferred_term: Nail abnormality
    term:
      id: HP:0001597
      label: Abnormal nail morphology
  evidence:
  - reference: PMID:38245683
    reference_title: "A novel missense mutation in the MECOM gene in a Chinese boy with radioulnar synostosis with amegakaryocytic thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, other malformations such as cardiac malformations (27/64, 26.6%), hearing impairment (9/64, 14.1%), nail, or facial abnormalities (15/64, 23.4%)"
    explanation: >
      Gives the nail/facial figure, 15 of 64. Quoted in full rather than
      clipped to the nail clause because the surrounding counts are the useful
      context - but note one of them is arithmetically wrong in the source: it
      prints cardiac malformations as "27/64, 26.6%", and 27/64 is 42.2% while
      26.6% is 17/64, so either the numerator or the percentage is a typo.
      This entry does not curate a cardiac frequency from this sentence for
      that reason; the cardiac phenotype here is cited to other sources. The
      nail figure, 15/64, checks out at 23.4%.

- category: Cardiovascular
  name: Aortic Root Dilatation
  description: >
    Reported in 3 of 15 individuals in one cohort, with one progressing to an
    aneurysm large enough to meet the threshold for surgical correction. Worth
    separating from the septal defects: those are static congenital lesions,
    while aortic dilatation is progressive and needs surveillance rather than a
    single echocardiogram. The same cohort notes that only one case each of
    aortic coarctation and aortic root dilatation had been reported before,
    so this is a recent addition to the phenotype and its frequency is not
    established.
  phenotype_term:
    preferred_term: Aortic root dilatation
    term:
      id: HP:0002616
      label: Aortic root aneurysm
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have observed 3 cases of aortic dilatation, with 1 progressing to an aortic aneurysm reaching the threshold for surgical correction in our cohort of 15 cases."
    explanation: >
      The count, the progression, and the denominator in one sentence.

animal_models:
- name: Evi1 H752R knock-in mouse
  species: Mouse
  genotype: Mecom c.2255A>G knock-in, translating to EVI1 p.H752R / MDS1-EVI1 p.H942R (the mouse orthologue of a human RUSAT allele)
  publication: PMID:37099686
  description: >
    The only RUSAT animal model. It carries the mouse equivalent of a human
    RUSAT variant at the orthologous residue, which is what makes it worth
    taking seriously as a model of this disease rather than of MECOM loss in
    general - the previous mice were exonic deletions. Homozygotes die at
    embryonic day 10.5 to 11.5, so the model is necessarily heterozygous, which
    matches the human genotype.
  evidence:
  - reference: PMID:37099686
    reference_title: "Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Homozygous mutant mice died at embryonic day 10.5 to 11.5."
    explanation: >-
      Establishes the constraint that makes this a heterozygous model, which is
      also the human genotype.
  modeled_mechanisms:
  - target: Hematopoietic Stem Cell Maintenance Failure
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >
      Heterozygotes lose haematopoietic stem and progenitor cells and recover
      poorly from myelosuppression, which is the stem-cell deficit this node
      asserts.
    limitations: >-
      Fidelity is held at MODERATE on timing rather than direction. The human
      disease is congenital; the mouse HSPC decrease is detected at 8 to 12
      weeks and its platelet defect only after 16 weeks, and only in males. The
      model therefore reproduces the deficit but not its onset, and cannot
      speak to the neonatal presentation that defines the human disease.
    readouts:
    - name: Bone marrow HSPC frequency
      target: Hematopoietic Stem Cell Maintenance Failure
      direction: DECREASED
      interpretation: Direct flow-cytometric measurement of the stem and progenitor compartment.
      evidence:
      - reference: PMID:37099686
        reference_title: "Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Flow cytometric analysis of bone marrow cells revealed a decrease in HSPCs in Evi1KI"
        explanation: Reports the measured decrease in the stem and progenitor compartment.
    - name: Haematopoietic recovery after 5-fluorouracil myelosuppression
      target: Hematopoietic Stem Cell Maintenance Failure
      direction: DECREASED
      interpretation: >-
        A stress test of stem-cell reserve. Delayed recovery is the functional
        counterpart of the reduced HSPC count and is the more informative of
        the two, since it measures capacity rather than frequency.
      evidence:
      - reference: PMID:37099686
        reference_title: "Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Moreover, Evi1KI/+ mice showed delayed leukocyte and platelet recovery after 5-fluorouracil-induced myelosuppression."
        explanation: Functional demonstration of reduced regenerative capacity.
    evidence:
    - reference: PMID:37099686
      reference_title: "Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These findings suggest that Evi1KI/+ mice recapitulate the bone marrow dysfunction in RUSAT, similar to that caused by loss-of-function Mecom alleles."
      explanation: >-
        The authors' own assessment that the model is informative for the marrow
        arm of the disease.
  - target: Failure of Proximal Radioulnar Joint Separation
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >
      The mouse has normal forelimbs. Carrying the orthologous patient allele
      is not sufficient to produce radioulnar synostosis in a mouse, so this
      model cannot be used to study the skeletal arm of the disease and its
      silence is not evidence that the human variant does not cause the
      synostosis.
    limitations: >-
      Two readings are open and this model cannot distinguish them: either the
      mouse forelimb does not require Evi1 the way the human forearm requires
      MECOM, or the germline heterozygote does not reach a dose or timing
      threshold that the human embryo does. Mouse and human zeugopod
      segmentation differ in tempo and in the relative timing of joint
      cavitation, so a negative skeletal result in a viable heterozygote is
      weak evidence either way. See the `rusat_mouse_no_synostosis` discussion.
    readouts:
    - name: Presence of radioulnar synostosis
      target: Failure of Proximal Radioulnar Joint Separation
      direction: UNCHANGED
      interpretation: >-
        A real negative result, recorded as UNCHANGED rather than omitted: the
        forelimbs were examined and were normal.
      evidence:
      - reference: PMID:37099686
        reference_title: "Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Heterozygous mutant mice (Evi1KI/+ mice) grew normally without radioulnar synostosis."
        explanation: >-
          SUPPORT, because the claim being evidenced is the readout that the
          forelimbs were normal. The negative result is the finding; the
          evidence agrees with it.
    evidence:
    - reference: PMID:37099686
      reference_title: "Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Heterozygous mutant mice (Evi1KI/+ mice) grew normally without radioulnar synostosis."
      explanation: >-
        SUPPORT for the FAILS_TO_RECAPITULATE claim this link makes. The
        direction is easy to get backwards: the claim is that the model does
        not reproduce the lesion, and normal forelimbs is evidence for that
        claim, not against it.

experimental_models:
- name: MECOM-haploinsufficient primary human hematopoietic stem cells
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >
    Primary human haematopoietic stem cells engineered to model MECOM
    haploinsufficiency, combined with single-cell genomics. This is the system
    that turned the disease from a gene assignment into a mechanism: it is
    where the EVI1-dependent maintenance network was defined, and it works in
    the species that has the disease, which the knock-in mouse does not.
  evidence:
  - reference: PMID:36522544
    reference_title: "A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo."
    explanation: >-
      Establishes that this system was built to model this disorder.
  modeled_mechanisms:
  - target: Dysregulation of the EVI1 HSC Maintenance Network
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >
      Reproduces the human haploinsufficient state in human stem cells and
      reads out the transcriptional network directly.
    limitations: >-
      An engineered haploinsufficiency rather than the patient allelic
      spectrum, so it models dose reduction and cannot address whether the
      zinc-finger 8/9 missense alleles do anything a null does not - which is
      exactly the question the two competing hypotheses in this entry turn on.
      It is also a cell-autonomous system with no marrow niche and no limb.
    readouts:
    - name: HSC maintenance transcriptional network expression
      target: Dysregulation of the EVI1 HSC Maintenance Network
      direction: ALTERED
      interpretation: >-
        Single-cell genomic definition of the gene network EVI1 maintains.
      evidence:
      - reference: PMID:36522544
        reference_title: "A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC maintenance."
        explanation: The network readout that this model exists to produce.
    evidence:
    - reference: PMID:36522544
      reference_title: "A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo."
      explanation: >-
        Establishes that the system models this disorder specifically.

genetic:
- name: MECOM
  gene_term:
    preferred_term: MECOM
    term:
      id: hgnc:3498
      label: MECOM
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >
    MECOM, the MDS1 and EVI1 complex locus, encodes several transcription
    factor isoforms of which EVI1 - a 1051-amino-acid protein with seven
    N-terminal and three C-terminal zinc fingers - is the best characterised.
    Germline heterozygous variants cause disease; the RUSAT-producing alleles
    are missense changes in zinc fingers 8 and 9, while nonsense, frameshift,
    splice and whole-gene-deletion alleles cause marrow failure without
    synostosis. Across the literature, missense changes account for roughly
    two-thirds of reported variants. The same gene is a well-known oncogene
    when somatically overexpressed, which is the opposite direction of effect
    from the germline mechanism here.
  review_notes: >-
    ClinGen grades this relationship **Definitive**, its highest tier, cited
    below. `relationship_type: CAUSATIVE` is well supported: de novo variants in
    trio-sequenced probands, dominant segregation in several families,
    recurrence of the same alleles across unrelated families, a knock-in mouse
    reproducing the haematopoietic phenotype, and a primary-human-HSC model
    defining the mechanism. No ClinGen gene-disease validity assertion for
    MECOM in RUSAT is cited here.
  evidence:
  - reference: CGGV:assertion_d1d25a48-f664-49c6-8ea4-dfddd0651209-2021-11-08T170000.000Z
    reference_title: "MECOM / MECOM-associated syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MECOM | HGNC:3498 | MECOM-associated syndrome | MONDO:0100458 | AD | Definitive"
    explanation: >
      Expert-panel grading at the highest tier, and the contrast that makes the
      HOXA11 Limited grading meaningful rather than a generic caveat.
  - reference: PMID:26581901
    reference_title: "Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subsequent analysis of MECOM in two other individuals with RUSAT revealed two additional missense mutations."
    explanation: >
      Independent replication beyond the index trio in the founding report.
  - reference: PMID:40170114
    reference_title: "A novel MECOM gene variant causes severe thrombocytopenia in a neonate: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A comprehensive review of literature indicated that MECOM gene mutations included missense (68.3%), deletion (8.5%), splice site (8.5%), frameshift (7.3%), and nonsense (7.3%) mutations."
    explanation: >
      The variant-class distribution across the published literature.
  - reference: PMID:37067177
    reference_title: "Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As each subject presented with unique MECOM variants, the series failed to demonstrate clear genotype-to-phenotype correlation but may suggest a role for additional modifiers that affect gene expression and subsequent phenotype."
    explanation: >
      A necessary counterweight to the variant-class pattern curated elsewhere
      in this entry. The domain-level split between synostosis and no
      synostosis is well supported, but within it, individual variants do not
      predict individual phenotypes, and this cohort says so.

- name: HOXA11
  gene_term:
    preferred_term: HOXA11
    term:
      id: hgnc:5101
      label: HOXA11
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >
    HOXA11 is a posterior HOX homeodomain transcription factor. Its role in
    forelimb zeugopod patterning is well established, including at the joint -
    Hox11 paralogues determine joint identity and morphogenesis at the proximal
    radius and ulna. Its haematopoietic role is not established to the same
    standard, and this entry previously overstated the symmetry with MECOM.
    MECOM's requirement in haematopoietic stem cells is demonstrated
    independently, in primary human HSCs; HOXA11's is inferred largely from
    this disease itself plus one in-vitro assay whose key readout was
    equivocal, and Hoxa11-null mice have limb, kidney and reproductive-tract
    phenotypes without reported marrow failure. The "dual requirement" framing
    is a clean story the evidence supports for one gene and not the other.

    Exactly one disease allele is known, a frameshift truncating the
    homeodomain, in six individuals from two families. The protein retains its
    interaction with the cofactor Meis1b but loses DNA binding.
  review_notes: >-
    ClinGen grades this relationship **Limited** - its lowest non-disputed tier
    - and that grading is cited below. `relationship_type: CAUSATIVE` is
    retained because the schema has no tier between CAUSATIVE and UNKNOWN, and
    UNKNOWN would understate real segregation and functional data; but
    CAUSATIVE here should be read as "asserted in the literature", not as
    "established". The evidence is two families, no new family in 25 years, a
    negative HOXA11 screen in a later seven-family cohort, and one in-vitro
    follow-up whose key readout was equivocal - which is precisely the profile
    that earns Limited.

    An earlier version of this note asked a reviewer to check whether a ClinGen
    assertion existed and said the field should be revisited rather than
    defended if it graded below Definitive. It does, and this is the revision.
  evidence:
  - reference: CGGV:assertion_48ef111f-28fc-4970-a0ca-8387e9ec2d0e-2024-09-04T160000.000Z
    reference_title: "HOXA11 / radioulnar synostosis with amegakaryocytic thrombocytopenia 1 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HOXA11 | HGNC:5101 | radioulnar synostosis with amegakaryocytic thrombocytopenia 1 | MONDO:0024558 | AD | Limited"
    explanation: >
      The expert-panel grading, and the most important single fact about this
      gene-disease relationship. Limited is ClinGen's lowest non-disputed tier
      and carries an explicit caution against treating the relationship as
      established for clinical use.
  - reference: PMID:26581901
    reference_title: "Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A heterozygous HOXA11 mutation has been identified in two unrelated families as a cause of RUSAT."
    explanation: >
      States the gene-disease relationship and its evidential base of two
      families.
  - reference: PMID:26581901
    reference_title: "Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, HOXA11 mutations are absent in a number of individuals with RUSAT, which suggests that other genetic loci contribute to RUSAT."
    explanation: >
      The limit on HOXA11's share of the disease, from the paper that found the
      second gene.

variants:
- name: MECOM p.Arg750Trp
  description: >-
    Numbering note before anything else, because this is a live source of
    confusion. p.Arg750Trp is EVI1 numbering (NP_001098548.2, transcript
    NM_001105078). The MDS1-EVI1 isoform adds 188 residues at the N-terminus,
    so this same allele is p.Arg938Trp in MDS1-EVI1 coordinates - the position
    shifts, the substituted residue does not.

    The trap is concrete: a different reported allele, c.2813G>A, appears in one
    cohort as p.(Arg938Gln), which is p.Arg750Gln in EVI1 numbering. Arg938Trp
    and Arg938Gln are different variants at the same codon, and an earlier
    version of this note conflated them.

    The recurrent RUSAT allele, and the most informative one for expressivity.
    It was the index variant in the founding MECOM report and recurred in three
    further families in a later cohort. Across six families carrying it, five
    were de novo with very early presentation and all required transplant,
    while the sixth showed dominant inheritance and progressed from aplastic
    anaemia to myelodysplastic syndrome in adulthood. Same allele, two very
    different clinical courses.
  gene:
    preferred_term: MECOM
    term:
      id: hgnc:3498
      label: MECOM
  type: SNV
  evidence:
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observe that theMECOMvariant p.Arg750Trp is a recurrent change that can present with a variety of hematological defects in association with RUS."
    explanation: >-
      Names the recurrent allele and its variable presentation. The gene symbol
      runs into the surrounding words in the cached full text; that is a
      formatting artefact of the source, not a transcription error.

- name: HOXA11 p.Asn291ThrfsX3
  description: >-
    The single RUSAT1 allele, c.872delA, causing a frameshift and premature
    truncation of HOXA11. Found in six individuals from two families and never
    reported again. Functional work shows the truncated protein loses DNA
    binding while retaining its interaction with Meis1b.
  gene:
    preferred_term: HOXA11
    term:
      id: hgnc:5101
      label: HOXA11
  type: DELETION
  evidence:
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The heterozygous variant c.872delA, p.Asn291ThrfsX3 was identified in six individuals from two families"
    explanation: >-
      The allele, its consequence, and the number of carriers.

clinical_trials:
- name: NCT00027274
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >
    The NCI natural history study of cancer susceptibility in inherited bone
    marrow failure syndromes. RUSAT is not named among its listed conditions,
    which are Diamond-Blackfan anaemia, dyskeratosis congenita, Fanconi
    anaemia, Shwachman-Diamond syndrome and a generic "Inherited Bone Marrow
    Failure Syndrome, Aplastic Anemia" category; RUSAT is curated here as
    eligible under that generic category, since every source in this entry
    classes it as an IBMFS. That is an inference about eligibility, not a
    statement that RUSAT patients are enrolled.

    It is recorded because the question it studies - cancer rates in the IBMFS
    class - is precisely the question this entry declines to answer for RUSAT.
    Four myeloid malignancies among 80 reported individuals is the only figure
    available, and the source calls it likely low because most patients are
    transplanted young. A prospective cohort is the study design that would
    settle it.
  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: OTHER
    snippet: "A prospective cohort of Inherited Bone Marrow Failure Syndrome (IBMFS) will provide new information regarding cancer rates and types in these disorders."
    explanation: >
      The study's own statement of what it is for, which is the open question
      this entry records for RUSAT.

treatments:
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >
    The only established curative treatment for the marrow failure, and the
    treatment most reported RUSAT patients receive. A retrospective series of
    six infants transplanted between 4 and 18 months of age with
    reduced-intensity conditioning - fludarabine, cyclophosphamide or
    melphalan, and rabbit anti-thymocyte globulin, with or without low-dose
    irradiation - reported that all survived with stable engraftment and full
    donor chimerism, no severe regimen-related toxicity, and only low-grade
    acute graft-versus-host disease.

    Related donors must be genotyped before they are used, and this disease
    makes that sharper than usual. Inheritance is dominant and transmission
    through a minimally affected or asymptomatic parent is documented, so an
    HLA-matched sibling can carry the variant; and because somatic reversion
    can normalise a carrier's counts, a donor can be under-called on a blood
    sample exactly as a proband can. The same non-haematopoietic-tissue
    caution recorded under `diagnosis` applies to donor screening. Note that
    all six infants in the reduced-intensity series were transplanted from
    unrelated donors. Targeted sibling testing is worth considering even when
    the proband's variant is de novo, because germline mosaicism is possible.

    Two further limits a reader should carry. Transplant replaces the
    haematopoietic compartment and does nothing for the synostosis, the hearing loss, the
    renal or cardiac anomalies, or the aortic dilatation, all of which are
    outside the graft and need their own follow-up - though the B-cell and
    immunological arm is haematopoietic and is corrected. And within the
    series
    itself, the three children given low-dose irradiation were relatively short
    compared with the three who were not - a small, uncontrolled comparison,
    but the authors raise it as a reason to question routine irradiation rather
    than as an established late effect.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: allogeneic hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Hematopoietic Stem Cell Maintenance Failure
    description: >-
      Replaces the MECOM-deficient stem cell compartment with donor cells that
      carry two functional alleles. It corrects the node rather than
      compensating for it, which is why it is curative for the marrow arm and
      irrelevant to every other arm.
    evidence:
    - reference: PMID:36515795
      reference_title: "Reduced-intensity conditioning is effective for allogeneic hematopoietic stem cell transplantation in infants with MECOM-associated syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All patients survived and achieved stable engraftment and complete chimerization with the donor type."
      explanation: >-
        Full donor chimerism is the demonstration that the deficient
        compartment has been replaced.
  evidence:
  - reference: PMID:36515795
    reference_title: "Reduced-intensity conditioning is effective for allogeneic hematopoietic stem cell transplantation in infants with MECOM-associated syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, allogeneic HSCT with RIC is an effective and feasible treatment for infants with MECOM-associated syndrome."
    explanation: >
      The series conclusion, in a cohort of six infants.
  - reference: PMID:36515795
    reference_title: "Reduced-intensity conditioning is effective for allogeneic hematopoietic stem cell transplantation in infants with MECOM-associated syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients received a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, cyclophosphamide or melphalan, and rabbit anti-thymocyte globulin and/or low-dose total body/thoracic-abdominal/total lymphoid irradiation, followed by allogeneic bone marrow or cord blood transplantation from unrelated donors"
    explanation: >
      The regimen and the age window, which is the operationally useful detail.
  - reference: PMID:36515795
    reference_title: "Reduced-intensity conditioning is effective for allogeneic hematopoietic stem cell transplantation in infants with MECOM-associated syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients treated with low-dose irradiation had relatively short stature compared to three patients not treated with irradiation."
    explanation: >
      The late-effect signal, recorded with its three-against-three denominator
      visible so nobody reads it as an established outcome.
  - reference: PMID:37067177
    reference_title: "Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "guide cascade testing of family members and related HSCT donor candidates"
    explanation: >
      The donor-screening recommendation, from a cohort paper this entry
      already cites throughout.
  - reference: PMID:37067177
    reference_title: "Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Even in cases of de novo MECOM alterations, targeted testing of siblings should be considered given rare possibility of germline mosaicism."
    explanation: >
      Why a de novo result in the proband does not exempt siblings from
      testing before they are used as donors.
  - reference: PMID:37407873
    reference_title: "MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Those infants with MECOM-associated bone marrow failure require HSC transplantation for survival."
    explanation: >
      Independent statement that transplant is required rather than optional at
      the severe end.

- name: Platelet Transfusion
  description: >
    Supportive management of the thrombocytopenia, and the mainstay before
    transplant. In one reported neonate, multiple platelet transfusions carried
    the child through the neonatal period until spontaneous recovery - which is
    a real course in this disease and a reason not to treat early transfusion
    dependence as proof that transplant is inevitable.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: platelet transfusion
    term:
      id: NCIT:C15366
      label: Platelet Transfusion
  target_mechanisms:
  - target: Thrombocytopenia
    description: >-
      Replaces the missing platelets. Purely compensatory: it does nothing to
      the megakaryocyte arrest upstream of it.
    evidence:
    - reference: PMID:38662475
      reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Neonatal thrombocytopenia managed with multiple platelet transfusions followed by spontaneous recovery"
      explanation: >-
        Documents transfusion support of the thrombocytopenia in a reported
        patient.
  evidence:
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonatal thrombocytopenia managed with multiple platelet transfusions followed by spontaneous recovery"
    explanation: >
      The one quotable account of transfusion management in this disease, and
      of the spontaneous recovery that followed it.

- name: Surgical Correction of Radioulnar Synostosis
  description: >
    Reported in a single carrier, corrected at age four. Curated because the
    functional deficit is permanent otherwise and because it establishes that
    the orthopaedic arm of the disease is managed separately from the
    haematological arm - this child had bilateral synostosis and no
    haematological abnormality at all.

    The evidence base is one patient in a genotype-phenotype table, not an
    outcome series, so this entry states no indication, no technique and no
    result - including no claim about whether the proximal joint is restored,
    which nothing cited here supports. Congenital radioulnar
    synostosis has its own general orthopaedic literature; nothing in it is
    RUSAT-specific and none of it is cited here.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical correction of radioulnar synostosis
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Limited pronation and supination of the forearm
    description: >-
      Targets the functional consequence rather than the malformation. This
      entry does not state what the operation achieves: the single cited case
      records only that correction was performed at age four, with no technique
      and no outcome, and the general congenital-radioulnar-synostosis surgical
      literature is not cited here.
    evidence:
    - reference: PMID:38662475
      reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Bilateral RUS-surgically corrected at age 4"
      explanation: >-
        The one reported instance of surgical correction in a MECOM carrier.
  evidence:
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bilateral RUS-surgically corrected at age 4"
    explanation: >
      Establishes that surgical correction is done in this population. A single
      tabulated case; no outcome is claimed.

- name: Genetic Counseling and Cascade Testing
  description: >
    Autosomal dominant transmission gives a 50% recurrence risk per pregnancy,
    but the counselling problem in this disease is that the risk figure is the
    easy part. Expressivity within a family runs from a fixed forearm with
    normal counts to transfusion dependence in infancy, and somatic reversion
    can hide the phenotype in a carrier parent, so a genotype does not predict
    a course.

    Two points that are easy to miss. First, a de novo variant in the proband
    does not reduce sibling recurrence risk to zero: germline mosaicism is
    possible, and targeted sibling testing is recommended - which matters twice
    over, because those siblings are also the potential transplant donors.
    Cord blood banking from a molecularly unaffected, HLA-matched sibling is
    worth raising early, before it is needed.

    Second, a finding flagged as preliminary in its own source: in one cohort, 12 of 16 pregnancies in
    five mothers with detailed histories ended in loss, against a quoted
    general-population rate of 15-25%. See the `rusat_pregnancy_loss`
    discussion for why this is not yet a risk figure.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Given the high rate of pregnancy losses in these families, they should be considered for counseling for reproductive planning and the use of preimplantation genetic diagnosis to reduce the risk of future pregnancy losses."
    explanation: >
      The source's own counselling recommendation, including the reproductive
      option it names.
  - reference: PMID:37067177
    reference_title: "Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Given HSCT is often a therapeutic option for this cohort, it may be beneficial to consider cord blood collection and banking of molecularly unaffected, HLA-matched siblings."
    explanation: >
      The forward-planning recommendation that links counselling to the
      transplant pathway.
  - reference: PMID:37067177
    reference_title: "Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recognition of the expanded hematologic and non-hematologic clinical features allows for rapid molecular diagnosis, early identification of life-threatening complications, and improved genetic counseling for families."
    explanation: >
      Links the expanded phenotype directly to the counselling task.

diagnosis:
- name: Complete Blood Count and Bone Marrow Examination
  description: >
    The blood count finds the thrombocytopenia; the marrow tells you what kind
    it is. Absent or severely reduced megakaryocytes with a hypocellular marrow
    is what separates a production failure from immune or alloimmune
    destruction in a neonate, and it is the finding that should stop
    immunoglobulin and steroids being given for an inherited marrow failure.
    Serial counts matter, because lineage involvement evolves in both
    directions - towards pancytopenia in most, and towards spontaneous recovery
    in some.
  evidence:
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypocellular bone marrow with complete absence of megakaryocytes, dyserythropoiesis and left shifted granulopoiesis with abnormal granulation"
    explanation: >
      The marrow picture, described in a reported patient.

- name: Bilateral Forearm Radiography
  description: >
    Radiographs of both forearms to look for proximal radioulnar fusion. Worth
    doing even when there is no visible deformity, because the external
    appearance can be unremarkable and the restriction subtle enough that an
    affected adult has never noticed it - one reported patient's synostosis was
    inferred from limited bilateral pronation rather than diagnosed
    radiographically. The test is worth doing for what it rules in, not for
    what it rules out: a normal forearm does not exclude the disease.
  evidence:
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographs of the radius and ulna fusions from families 4–6 (Figure 1), show all cases have a very similar radiological appearance."
    explanation: >
      Establishes that the radiographic appearance is consistent enough to be
      recognised across families.

- name: Germline Molecular Genetic Testing of MECOM and HOXA11
  description: >
    Confirmatory, and in practice the only way the diagnosis is made -
    essentially every reported RUSAT2 case was identified by next-generation
    sequencing. Test both genes, and include copy-number analysis: whole-gene
    and partial MECOM deletions cause disease and are missed by sequencing
    alone. Trio exome or genome sequencing is what has actually found these
    patients, including the perinatal cases in whom the syndrome was never
    suspected clinically.
  evidence:
  - reference: PMID:38245683
    reference_title: "A novel missense mutation in the MECOM gene in a Chinese boy with radioulnar synostosis with amegakaryocytic thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To our knowledge, all reported RUSAT-2 cases were diagnosed through next generation sequencing and most of them received HSCT."
    explanation: >
      States that sequencing is how this diagnosis is made in practice.
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including two deletions that either remove the MDS1 part of the complex or the entire gene region"
    explanation: >
      Documents partial and whole-gene MECOM deletions as disease-causing,
      which is why copy-number analysis belongs alongside sequencing rather
      than as an afterthought.
  - reference: PMID:37230770
    reference_title: "Perinatal-lethal nonimmune fetal hydrops attributed to MECOM-associated bone marrow failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, they support the use of a broad sequencing approach for perinatal diagnosis, as MECOM is absent from available targeted gene panels for hydrops, and highlight the importance of postmortem genomic investigation."
    explanation: >
      The specific reason to prefer broad sequencing over a targeted panel in
      the perinatal presentation.

- name: Germline Testing on Non-Hematopoietic Tissue
  description: >
    The one diagnostic step in this entry that follows from a mechanism rather
    than from convention, and the one most easily skipped. Somatic reversion by
    3q copy-neutral loss of heterozygosity expands a clone that has lost the
    mutant allele, so in a carrier whose counts have recovered, blood can be a
    misleading germline sample and the causative variant can be under-called or
    missed. Use cultured skin fibroblasts or hair follicles instead. The same
    caution applies after transplant, when circulating cells are the donor's.
  evidence:
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the notable prevalence of somatic genetic rescue reiterates the importance of using DNA from nonhematopoietic tissue such as hair follicles or skin fibroblasts for genetic testing"
    explanation: >
      States both the reason and the recommended tissue sources.

- name: Immunological Evaluation
  description: >
    B-cell count and immunoglobulins, because B-cell deficiency is part of the
    syndrome, is actionable on its own, and would otherwise be found only after
    an infection. It also carries diagnostic weight: B-cell deficiency
    segregates with the same zinc-finger region as the synostosis, so finding
    it alongside a fixed forearm strengthens the case for a variant in that
    region.
  evidence:
  - reference: PMID:29540340
    reference_title: "MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1."
    explanation: >
      The co-segregation that gives the immunological workup diagnostic value
      beyond its own management implications.

differential_diagnoses:
- name: Congenital Amegakaryocytic Thrombocytopenia
  description: >
    The closest mimic, and mechanistically the most interesting one. CAMT
    presents identically in a neonate: congenital thrombocytopenia, an
    amegakaryocytic marrow, progression to pancytopenia.

    Most cases are biallelic MPL, but CAMT is genetically heterogeneous and the
    exception changes management. Biallelic THPO variants - the ligand rather
    than the receptor - produce the same picture and respond to the
    thrombopoietin mimetic romiplostim, with trilineage responses and
    transfusion independence sustained for years. "Curable only by transplant"
    is therefore false for a real subset of the closest mimic, and it is
    precisely the subset in which going straight to transplant is the wrong
    move.

    The MPL overlap with RUSAT may not be coincidental - EVI1 transcriptionally
    regulates MPL, so the two diseases may converge on the same receptor from
    opposite ends of the same regulatory relationship.
  distinguishing_features:
  - >-
    Inheritance separates them cleanly: CAMT is autosomal recessive, RUSAT
    autosomal dominant, so a de novo heterozygous variant or an affected parent
    points away from CAMT. Radioulnar synostosis, when present, is decisive -
    but it is present in only some RUSAT patients, so its absence separates
    nothing.

    Before the panel returns, two things are available. Family history, as
    above. And serum thrombopoietin, which is markedly elevated in MPL-CAMT
    because MPL is the clearance receptor for its own ligand - and is low in
    THPO-CAMT, which is the distinction that identifies the subset that
    responds to romiplostim. Note this entry cannot say what thrombopoietin does in
    RUSAT: the one report of patient-level TPO data could not be verified, and
    that gap is recorded in `notes`.

    In practice a panel containing MPL, THPO and MECOM settles it, which is why
    all three belong on the same test.
  evidence:
  - reference: PMID:37610030
    reference_title: "A novel mutation in MECOM affects MPL regulation in vitro and results in thrombocytopenia and bone marrow failure."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we demonstrated that EVI1 controls the transcriptional regulation of MPL, a gene whose mutations are responsible for congenital amegakaryocytic thrombocytopenia (CAMT), potentially explaining the partial overlap between MECOM-AS and CAMT"
    explanation: >
      Names both the clinical overlap and the proposed mechanistic basis for
      it.
  - reference: PMID:29191945
    reference_title: "Thrombopoietin mutation in congenital amegakaryocytic thrombocytopenia treatable with romiplostim."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all the three affected children, treatment with the THPO-mimetic romiplostim induced trilineage hematological responses, remission of bleeding and infections, and transfusion independence, which were maintained after up to 6.5 years of observation."
    explanation: >
      The treatable CAMT subset, and the reason this differential is
      therapeutically consequential rather than merely taxonomic.
  - reference: PMID:29191945
    reference_title: "Thrombopoietin mutation in congenital amegakaryocytic thrombocytopenia treatable with romiplostim."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recognizing patients with THPO mutations among those with juvenile bone marrow failure is essential to provide them with appropriate substitutive therapy and prevent the use of invasive and unnecessary treatments, such as hematopoietic stem cell transplantation or immunosuppression."
    explanation: >
      States the clinical stake directly: missing this subset sends a treatable
      child to transplant.

- name: Thrombocytopenia-Absent Radius Syndrome
  description: >
    The other congenital thrombocytopenia with a forearm malformation, and the
    one RUSAT is most likely to be confused with on a description rather than
    an image. TAR is caused by a rare RBM8A null allele in trans with a common
    hypomorphic regulatory variant.
  distinguishing_features:
  - >-
    The bone lesion is different in kind, not degree. TAR is a bilateral
    absence of the radius with the thumbs preserved - a reduction defect. RUSAT
    is a fusion of two present bones at the proximal joint, with the radius
    intact. A single forearm radiograph separates them. The genetics diverge
    too: TAR requires a rare null allele together with a low-frequency
    regulatory variant on the other chromosome, so it does not segregate as a
    simple dominant the way RUSAT does. HOXA11 is not the TAR gene, and was
    excluded as such directly. This entry makes no claim about the comparative
    natural history of the two thrombocytopenias - no source cited here
    compares them.
  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: >
      The TAR genotype this differential asserts, and the contrast with RUSAT's
      simple heterozygous dominant inheritance.
  - reference: PMID:11841440
    reference_title: "Absence of mutations in the HoxA10, HoxA11 and HoxD11 nucleotide coding sequences in thrombocytopenia with absent radius syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mutations in the coding sequence of the Hox genes known to affect radial development are not a common cause of TAR syndrome"
    explanation: >
      Excludes the RUSAT1 gene as a cause of TAR, which is what makes these two
      genuinely separate entities rather than one spectrum.
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital radioulnar synostosis (RUS) is a rare developmental abnormality involving fusion of the bones of the forearms (radius and ulna) preventing normal supination of the affected forearm"
    explanation: >
      The RUSAT lesion is a fusion of present bones, which is the contrast with
      TAR's absent radius.

- name: Syndromic and Isolated Congenital Radioulnar Synostosis
  description: >
    Radioulnar synostosis occurs on its own and as a feature of other
    syndromes, including aneuploidies and skeletal dysplasias, without any
    haematological disease. Someone presenting to orthopaedics with a fixed
    forearm and a normal blood count is much more likely to have one of these
    than RUSAT.
  distinguishing_features:
  - >-
    A blood count is the discriminator, and it should be repeated rather than
    taken once: the haematological onset in MECOM disease ranges from in utero
    to late adulthood, so a normal count in childhood does not exclude it.
    Conversely a RUSAT variant can present as isolated synostosis with no
    haematological abnormality at all, so the two groups genuinely overlap and
    sequencing is what separates them.
  evidence:
  - reference: PMID:29519864
    reference_title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RUS can occur with other abnormalities in the skeleton, heart, urinary tract, as well as aneuploid syndromes."
    explanation: >
      Establishes the non-haematological causes of the same bone lesion.
  - reference: PMID:29540340
    reference_title: "MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the clinical spectrum ranged from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormality"
    explanation: >
      The reason the two groups overlap: a MECOM variant can give synostosis
      with no blood disease.

- name: Dyskeratosis Congenita and the Telomere Biology Disorders
  description: >
    An inherited marrow failure syndrome that is regularly misdiagnosed as
    congenital amegakaryocytic thrombocytopenia when the classic mucocutaneous
    triad is absent - which it often is. It shares with RUSAT a congenital
    cytopenia progressing to marrow failure, a dominant form, and a cancer
    predisposition, and it is caused by defects in telomere maintenance rather
    than in a haematopoietic transcription factor.

    This is on the list for one reason above the others, and it is not
    taxonomic: getting it wrong before transplant can kill the patient.
  distinguishing_features:
  - >-
    Telomere length measurement is the discriminator, and it is the one test on
    this differential list that must be done *before* conditioning rather than
    at leisure. Telomere biology disorder patients do not tolerate standard
    alkylator and irradiation-based conditioning, and require
    fludarabine-based reduced-intensity protocols; a patient sent to standard
    conditioning on a RUSAT label they do not have is a foreseeable
    catastrophe.

    Nothing about the RUSAT phenotype excludes it on inspection. Radioulnar
    synostosis is not a DC feature, so its presence points away - but it is
    absent in a large share of MECOM patients, so its absence discriminates
    nothing, which is the same asymmetry this entry records for Fanconi
    anaemia. Note also that MECOM has itself been placed inside the telomere
    biology disorders by association in at least one related gene's literature;
    this entry makes no such claim for RUSAT, and no source cited here measures
    telomeres in a MECOM patient.
  evidence:
  - reference: PMID:35929966
    reference_title: "The biology and management of dyskeratosis congenita and related disorders of telomeres."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Dyskeratosis congenita (DC) is a multisystem syndrome characterized by mucocutaneous abnormalities, bone marrow failure, and predisposition to cancer."
    explanation: >
      The overlapping features - marrow failure and cancer predisposition -
      that put this on the differential, and the mucocutaneous findings whose
      absence is what causes the misdiagnosis.
  - reference: PMID:35929966
    reference_title: "The biology and management of dyskeratosis congenita and related disorders of telomeres."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the only current curative treatment for these is hematopoietic stem cell transplantation (HSCT) using fludarabine-based conditioning protocols"
    explanation: >
      The conditioning requirement that makes this differential
      decision-changing rather than academic.

- name: Neonatal Alloimmune and Immune Thrombocytopenia
  description: >
    The commonest cause of severe thrombocytopenia in an otherwise well
    newborn, and of neonatal intracranial haemorrhage - which is precisely the
    presentation this entry curates at its severe pole. Maternal antibodies
    against fetal platelet antigens, or transplacental antibody in maternal
    ITP, destroy platelets peripherally.

    It is on the list because it is common, because it is the default
    assumption in a bleeding neonate, and because treating a production failure
    as an immune one wastes the window in which the real diagnosis matters.
  distinguishing_features:
  - >-
    The marrow separates them decisively and immediately: alloimmune
    thrombocytopenia is peripheral destruction with normal or increased
    megakaryocytes, while RUSAT is a production failure with megakaryocytes
    absent or severely reduced. That single finding is why marrow examination
    sits first in this entry's diagnostic section.

    Two further pointers. Alloimmune thrombocytopenia is isolated and
    self-limiting as maternal antibody clears, whereas RUSAT thrombocytopenia
    persists and in many progresses to multilineage failure. And immunoglobulin
    and corticosteroids, which are reasonable empirical therapy for suspected
    immune disease, do nothing for an inherited marrow failure - so a
    non-response is itself informative rather than merely disappointing.
  evidence:
  - reference: PMID:29540340
    reference_title: "MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report on 12 patients with congenital hypomegakaryocytic thrombocytopenia caused by MECOM mutations"
    explanation: >
      The marrow finding that distinguishes RUSAT from peripheral destruction.
      A hypomegakaryocytic marrow is not what alloimmune thrombocytopenia
      produces.

- name: GATA2 Deficiency and the Dominant Thrombocytopenia-Myeloid Predisposition Syndromes
  description: >
    The differential for the adult and adolescent pole of this disease rather
    than the neonatal one, and the group most likely to be reached for when a
    RUSAT carrier presents late. GATA2 deficiency, RUNX1-familial platelet
    disorder, ANKRD26- and ETV6-related thrombocytopenia all give dominantly
    inherited cytopenias with a predisposition to myelodysplastic syndrome and
    acute myeloid leukaemia, and relatives with mild or absent findings - which
    is exactly the pedigree pattern this entry documents for MECOM families.

    GATA2 is doubly relevant here. It is not only a differential: it is a
    direct EVI1 target in this entry's own mechanism, bound at its promoter
    through the N-terminal zinc fingers. And ETV6, one of this group's genes,
    appears in this entry's own clonal-haematopoiesis node as a somatic event in
    older MECOM carriers. The boundary between "differential" and "downstream"
    is genuinely blurred here.
  distinguishing_features:
  - >-
    Radioulnar synostosis is the discriminator when present, since none of this
    group causes it - but the usual caveat applies with more force at this age,
    because a late-presenting MECOM carrier may have no skeletal finding at all
    and no known childhood cytopenia. A sequencing panel covering all of them
    is what separates them, and MECOM belongs on any panel used for suspected
    familial MDS.

    The practical point is the same one that drives donor screening in this
    entry: the whole group shares a requirement to identify the germline lesion
    before transplant, because it determines both donor selection and
    conditioning intensity.
  evidence:
  - reference: PMID:32571604
    reference_title: "Hereditary Predisposition to Hematopoietic Neoplasms: When Bloodline Matters for Blood Cancers."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Familial clustering was first observed in patients with leukemia, which led to the identification of several germline variants, such as RUNX1, CEBPA, GATA2, ANKRD26, DDX41, and ETV6, among others, now established as HPS, with tendency to develop myeloid neoplasms."
    explanation: >
      Names the group this differential covers and its shared myeloid-neoplasm
      predisposition.
  - reference: PMID:32571604
    reference_title: "Hereditary Predisposition to Hematopoietic Neoplasms: When Bloodline Matters for Blood Cancers."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Timely recognition of HPS is critical to ensure safe choice of donors and/or conditioning-regimen intensity for allogeneic hematopoietic stem-cell transplantation"
    explanation: >
      The reason this differential is worth resolving before transplant rather
      than after, and independent support for the donor-screening and
      conditioning points recorded elsewhere in this entry.

- name: Fanconi Anemia
  description: >
    The inherited marrow failure syndrome that also puts a radial-ray
    abnormality next to a failing marrow, and the one most likely to be tested
    for first in a child with both. It is a DNA interstrand crosslink repair
    disorder, mechanistically unrelated to a transcription-factor
    haploinsufficiency.
  distinguishing_features:
  - >-
    Chromosome breakage testing separates them: it is positive in Fanconi
    anaemia and normal in RUSAT. Two operational points. It must be done before
    conditioning, since the result changes regimen intensity. And blood-based
    testing can be falsely negative where haematopoietic mosaicism has
    corrected the lymphocyte compartment, requiring fibroblasts - the same
    non-haematopoietic-tissue logic this entry applies to its own somatic
    reversion. Note the asymmetry - a normal breakage test
    argues against Fanconi anaemia but establishes nothing about RUSAT, which
    has no functional confirmatory assay of its own and rests entirely on
    sequencing. The bone lesions also differ: Fanconi anaemia gives radial ray
    reduction defects, often with an absent or hypoplastic thumb, while RUSAT
    gives a proximal fusion with both bones present.
  evidence:
  - reference: PMID:20301575
    reference_title: "Fanconi Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased chromosome breakage and radial forms on cytogenetic testing of"
    explanation: >
      The chromosome-breakage test this differential turns on, from the
      GeneReviews chapter for the comparator disease. It establishes what a
      positive result means for Fanconi anaemia and says nothing about RUSAT,
      which is exactly the asymmetry the distinguishing features record.
  - reference: PMID:38662475
    reference_title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Somatic genetic rescue has been reported in several genetic diseases including skin disorders (eg, ichthyosis with confetti9 and epidermolysis bullosa10) and BMF syndromes (eg, Fanconi anemia,11 Diamond Blackfan anemia,12 Wiskott-Aldrich syndrome,13 and dyskeratosis congenita14), with only 1 report in MECOM-associated syndrome."
    explanation: >
      Places RUSAT among the inherited marrow failure syndromes that Fanconi
      anaemia belongs to, and records that somatic reversion - the phenomenon
      curated in this entry's pathograph - is shared across that class rather
      than unique here.

references:
- reference: PMID:35929966
  title: "The biology and management of dyskeratosis congenita and related disorders of telomeres."
- reference: PMID:32571604
  title: "Hereditary Predisposition to Hematopoietic Neoplasms: When Bloodline Matters for Blood Cancers."
- reference: PMID:29191945
  title: "Thrombopoietin mutation in congenital amegakaryocytic thrombocytopenia treatable with romiplostim."
- reference: CGGV:assertion_48ef111f-28fc-4970-a0ca-8387e9ec2d0e-2024-09-04T160000.000Z
  title: "HOXA11 / radioulnar synostosis with amegakaryocytic thrombocytopenia 1 (Limited)"
- reference: CGGV:assertion_d1d25a48-f664-49c6-8ea4-dfddd0651209-2021-11-08T170000.000Z
  title: "MECOM / MECOM-associated syndrome (Definitive)"
- reference: PMID:26581901
  title: "Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia."
- reference: PMID:16765069
  title: "HOXA11 mutation in amegakaryocytic thrombocytopenia with radio-ulnar synostosis syndrome inhibits megakaryocytic differentiation in vitro."
- reference: PMID:29540340
  title: "MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia."
- reference: PMID:29519864
  title: "Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease."
- reference: PMID:36522544
  title: "A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia."
- reference: PMID:37099686
  title: "Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice."
- reference: PMID:37610030
  title: "A novel mutation in MECOM affects MPL regulation in vitro and results in thrombocytopenia and bone marrow failure."
- reference: PMID:37407873
  title: "MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development."
- reference: PMID:37067177
  title: "Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes."
- reference: PMID:38662475
  title: "Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion."
- reference: PMID:41635268
  title: "Syndrome of the Month: Radioulnar Synostosis With Amegakaryocytic Thrombocytopenia Type 2."
- reference: PMID:36515795
  title: "Reduced-intensity conditioning is effective for allogeneic hematopoietic stem cell transplantation in infants with MECOM-associated syndrome."
- reference: PMID:37230770
  title: "Perinatal-lethal nonimmune fetal hydrops attributed to MECOM-associated bone marrow failure."
- reference: PMID:41617498
  title: "Expanding the phenotypic spectrum of MECOM-associated syndrome: rare variants are associated with syndromic pulmonary arterial hypertension."
- reference: PMID:38245683
  title: "A novel missense mutation in the MECOM gene in a Chinese boy with radioulnar synostosis with amegakaryocytic thrombocytopenia."
- reference: PMID:40170114
  title: "A novel MECOM gene variant causes severe thrombocytopenia in a neonate: a case report and review of the literature."
- reference: PMID:14668414
  title: "Multiple roles of Hoxa11 and Hoxd11 in the formation of the mammalian forelimb zeugopod."
- reference: PMID:20978074
  title: "Hox11 genes establish synovial joint organization and phylogenetic characteristics in developing mouse zeugopod skeletal elements."
- reference: PMID:11841440
  title: "Absence of mutations in the HoxA10, HoxA11 and HoxD11 nucleotide coding sequences in thrombocytopenia with absent radius syndrome."
- reference: PMID:22366785
  title: "Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome."
- reference: PMID:20301575
  title: "Fanconi Anemia."
  tags:
  - GeneReviews
- reference: clinicaltrials:NCT00027274
  title: "Etiologic Investigation of Cancer Susceptibility in Inherited Bone Marrow Failure Syndromes: A Natural History Study"

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References & Deep Research