Roberts Syndrome

Mendelian MONDO:0100253 Pathograph 70 Show in embeddings browser cohesinopathy limb reduction defect autosomal recessive disease

Roberts syndrome, now also called ESCO2 spectrum disorder, is an autosomal recessive cohesinopathy caused by biallelic loss-of-function variants in ESCO2, the acetyltransferase that acetylates the SMC3 subunit of cohesin during S phase so that sister chromatids stay paired until anaphase. The clinical picture is prenatal-onset growth restriction, symmetric limb reduction in which the upper limbs are more often and more severely affected than the lower (from bilateral tetraphocomelia to mesomelic shortening, oligodactyly and thumb aplasia), flexion contractures, and a characteristic face with microcephaly, bilateral cleft lip and palate, micrognathia, widely spaced prominent eyes, malar flattening and underdeveloped nasal alae. Microphthalmia and corneal opacities, intellectual disability, cardiac and renal malformations, and in survivors cerebrovascular disease, are also reported. Severity is a continuum. The severe end (historically Roberts syndrome, OMIM 268300) includes stillbirth and neonatal death; the mild end (historically SC phocomelia, OMIM 269000) has lesser limb reduction and survival into adulthood. Both ends carry the same cytogenetic sign, premature centromere separation (heterochromatin repulsion, or "railroad track" chromosomes), and the same class of truncating ESCO2 alleles, so genotype does not predict severity and the two are curated here as one disease. The cellular lesion is failure to establish cohesion at pericentric heterochromatin. In patient cells and in fish and mouse models this is followed by prolonged mitosis, chromosome missegregation and aneuploidy, p53 activation and death or reduced proliferation of rapidly dividing embryonic progenitors, which is the most widely held explanation for the limb and craniofacial reduction. Impaired ribosome biogenesis with mTORC1 repression, cohesin-dependent transcriptional dysregulation, and, in the developing mouse limb, p53-dependent vascular disruption and hemorrhage are documented additional mechanisms whose relative weight is unresolved.

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1
Inheritance
18
Pathophys.
44
Phenotypes
5
Hypotheses
4
Gaps
70
Pathograph
1
Genes
10
Medical Actions
7
Differentials
8
Models
1
References
1
Deep Research
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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
ISDS Skeletal Nosology
limb hypoplasia reduction defects
👪

Inheritance

1
Autosomal recessive HP:0000007
Biallelic ESCO2 variants, homozygous (often with parental consanguinity) or compound heterozygous. Parents of an affected child are asymptomatic heterozygotes and each sib has a 25% risk of being affected. Carrier, prenatal and preimplantation testing are possible once both variants are known; prenatal diagnosis is also possible by cytogenetic detection of premature centromere separation in amniocytes or chorionic villi with ultrasound for limb reduction.
Autosomal recessive inheritance
Show evidence (5 references)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"ESCO2 spectrum disorder is inherited in an autosomal recessive manner."
GeneReviews genetic counseling statement of the mode of inheritance.
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"If both parents are known to be heterozygous for an ESCO2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a..."
GeneReviews recurrence-risk figures for sibs.
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"Prenatal testing for pregnancies at increased risk is also possible by cytogenetic testing of fetal cells obtained by amniocentesis or chorionic villus sampling in conjunction with ultrasound examination."
GeneReviews on cytogenetic prenatal diagnosis.
+ 2 more references
◈

Mechanistic Hypotheses

5
Mitotic failure and p53-dependent loss of embryonic progenitors
mitotic_failure_progenitor_apoptosis CANONICAL
Evidence balance 2 support 1 refute
Loss of pericentric cohesion prolongs mitosis and causes missegregation and aneuploidy; the resulting stress activates p53, and rapidly dividing progenitors in the limb buds, face and cortex die or proliferate too little, so the structures they build are reduced. Supported by patient cytogenetics and by fish and mouse models. It is qualified by the finding that patient lymphoblastoid lines show cell death without lengthened cell cycles, and by the Esco2 limb mouse, where p53 inhibition reduced apoptosis without restoring chondrogenesis.
Pathograph links
Prolonged Mitosis and Chromosome Missegregation -> p53 Pathway Activation INDIRECT KNOWN INTERMEDIATES
p53 Pathway Activation -> Apoptosis of Proliferating Embryonic Progenitors DIRECT
Apoptosis of Proliferating Embryonic Progenitors -> Limb Bud Outgrowth Failure INDIRECT KNOWN INTERMEDIATES
Apoptosis of Proliferating Embryonic Progenitors -> Cortical Progenitor Loss DIRECT
Apoptosis of Proliferating Embryonic Progenitors -> Deficient Craniofacial Primordium Growth INDIRECT UNKNOWN INTERMEDIATES
Reduced Proliferative Capacity of Embryonic Progenitors -> Limb Bud Outgrowth Failure INDIRECT UNKNOWN INTERMEDIATES
Reduced Proliferative Capacity of Embryonic Progenitors -> Deficient Craniofacial Primordium Growth INDIRECT UNKNOWN INTERMEDIATES
Show evidence (3 references)
PMID:8291532 SUPPORT REVIEW SYNTHESIS Human Clinical
"Therefore, RS has been interpreted as a human mitotic mutation syndrome which leads to secondary developmental defects."
The classical formulation of the mitotic model.
PMID:21637801 SUPPORT Model Organism
"We propose that cell proliferation defects and apoptosis could be the primary cause of the features of RBS."
Zebrafish support for the proliferation-and-apoptosis model.
PMID:39168984 REFUTE Model Organism
"We had presumed that the extensive cell death in the mesenchyme was the underlying cause of the limb deficiency, but pifithrin-α treatment only recovered the hemorrhage in mutant limbs and not the chondrogenesis."
Limits the apoptosis model as a complete explanation of limb reduction.
Nucleolar dysfunction and mTORC1-dependent translational deficit
ribosome_biogenesis_translation_defect ALTERNATIVE
Evidence balance 2 support
Reduced cohesin acetylation impairs nucleolar organization and rRNA production; the resulting translational deficit and mTORC1 repression reduce cell division and survival. L-leucine stimulation of mTORC1 partially rescues patient cells and esco2 mutant fish. Not tested in a mammalian embryo. Not mutually exclusive with the mitotic model.
Pathograph links
Failed Pericentric Sister Chromatid Cohesion Establishment -> Nucleolar Fragmentation and Impaired Ribosome Biogenesis INDIRECT UNKNOWN INTERMEDIATES Proposed to follow from reduced cohesin acetylation at the rDNA rather than from the mitotic defect; the intermediate steps are not established.
Nucleolar Fragmentation and Impaired Ribosome Biogenesis -> mTORC1 Repression and Reduced Protein Translation INDIRECT UNKNOWN INTERMEDIATES
Nucleolar Fragmentation and Impaired Ribosome Biogenesis -> p53 Pathway Activation INDIRECT UNKNOWN INTERMEDIATES
mTORC1 Repression and Reduced Protein Translation -> Reduced Proliferative Capacity of Embryonic Progenitors INDIRECT KNOWN INTERMEDIATES
Show evidence (2 references)
PMID:24098154 SUPPORT Model Organism
"Our data support the idea that RBS can be attributed in part to defects in ribosome biogenesis, and stimulation of the TOR pathway has therapeutic potential."
The authors' conclusion from patient cells and zebrafish.
PMID:24098154 SUPPORT Model Organism
"Stimulation of the TOR pathway with L-leucine rescued many developmental defects of ESCO2-mutant embryos."
In vivo rescue in fish.
Cohesin-dependent transcriptional dysregulation of developmental genes
cohesin_transcriptional_dysregulation EMERGING
Evidence balance 2 support
As in Cornelia de Lange syndrome, part of the phenotype may come from altered transcription of developmental genes rather than from cell loss; candidate targets include cx43 in regenerating bone and ddb1 in the thalidomide-sensitive CRL4 pathway. Evidence is from zebrafish knockdowns and patient cell lines.
Pathograph links
Failed Pericentric Sister Chromatid Cohesion Establishment -> Cohesin-Dependent Transcriptional Dysregulation INDIRECT UNKNOWN INTERMEDIATES
Cohesin-Dependent Transcriptional Dysregulation -> Limb Bud Outgrowth Failure INDIRECT UNKNOWN INTERMEDIATES
Show evidence (2 references)
PMID:29084713 SUPPORT Model Organism
"A popular model states that RBS arises due to mitotic failure and loss of progenitor stem cells through apoptosis. Previous findings in the zebrafish regenerating fin, however, suggest that Esco2-knockdown results in transcription dysregulation, independent of apoptosis, similar to that observed..."
States the transcriptional model as an alternative to the apoptosis model.
PMID:26434741 SUPPORT Model Organism
"These results conceptually link ODDD to cohesinopathies and provide evidence that ESCO2 may play a transcriptional role critical for human development."
Transcriptional role of Esco2 in skeletal growth.
p53-dependent vascular disruption in the developing limb
limb_vascular_disruption EMERGING
Evidence balance 1 support
In the Esco2 limb mouse, p53-dependent disorganization of the limb bud vasculature and hemorrhage accompany the reduction, and genes linked to thalidomide embryopathy are dysregulated, suggesting a shared vascular component with the teratogenic phocomelia. Single study; human tissue not examined.
Pathograph links
p53 Pathway Activation -> Limb Bud Vascular Disruption and Hemorrhage DIRECT
Limb Bud Vascular Disruption and Hemorrhage -> Limb Bud Outgrowth Failure INDIRECT UNKNOWN INTERMEDIATES
Show evidence (1 reference)
PMID:39168984 SUPPORT Model Organism
"Our data show how loss of ESCO2 causes limb reduction phenotypes, through p53 induction, cell death, and vascular disruption."
The vascular arm as proposed by the authors.
Accumulated DNA and macromolecular damage
macromolecular_damage EMERGING
Evidence balance 3 support
ESCO2-deficient cells are hypersensitive to DNA-damaging agents and show impaired double-strand break repair; a review proposes that DNA and other macromolecular damage contribute to the developmental phenotype, feeding into p53 activation. Evidence is from patient cell lines and yeast models.
Pathograph links
Genotoxin Hypersensitivity and Defective DNA Damage Response -> p53 Pathway Activation INDIRECT UNKNOWN INTERMEDIATES
Show evidence (3 references)
PMID:33382686 SUPPORT REVIEW SYNTHESIS Other
"In this review, we highlight current models of RBS and reflect on data that suggests a novel role for macromolecular damage in the molecular etiology of RBS."
Review proposing the macromolecular-damage model.
PMID:30508616 SUPPORT In Vitro
"In addition to its developmental features, RBS can be, like ataxia telangiectasia, considered a DDR-defective syndrome, which contributes to its cellular, molecular, and clinical phenotype."
DNA damage response defect proposed to contribute to the phenotype.
PMID:34897432 SUPPORT Model Organism
"Here, we report evidence that supports an emerging model rooted in defective DNA damage responses."
Yeast support for the damage-response model.
?

Discussions and Knowledge Gaps

4
Why do the same truncating ESCO2 alleles give tetraphocomelia and perinatal death in one patient and mild limb shortening with survival to adulthood in another, sometimes within one family?
KNOWLEDGE GAP OPEN rbs_genotype_severity_gap
Attached to
genetic#ESCO2 phenotypes#Tetraphocomelia
Nearly all alleles are loss of function, yet severity spans the whole Roberts-to-SC phocomelia range with no genotype correlation. Proposed modifiers include tissue and individual variation in nonsense-mediated decay and residual cohesion in a subset of cells, but none has been tested against clinical severity.
Show evidence (2 references)
PMID:16380922 SUPPORT Human Clinical
"Since only protein-truncating mutations were identified, regardless of clinical severity, we conclude that genotype does not predict phenotype."
States the gap.
PMID:26044958 SUPPORT Model Organism
"Surprisingly, although many cells required Esco2 to establish cohesion, 10-20% of cells had only weakened cohesion in the absence of Esco2, suggesting that compensatory cohesion mechanisms exist in these cells that undergo a normal mitotic division."
Compensatory cohesion as a candidate modifier.
Constitutive Esco2 loss is lethal in early mouse embryos, while humans with biallelic truncating ESCO2 variants are born and some reach adulthood. What supplies the residual function in human embryos, and how faithfully do tissue-restricted mouse knockouts model the human systemic-but-partial deficiency?
HUMAN MODEL MISMATCH OPEN rbs_mouse_lethality_mismatch
Attached to
animal_models#Mouse pathophysiology#Reduced SMC3 Acetylation of Chromatin-Bound Cohesin
The mismatch concerns the Esco2 constitutive knockout mouse; the animal_models#Mouse anchor resolves by species and so also matches the two conditional knockouts listed in this entry. The mouse data argue that Esco2 is not redundant with Esco1, whereas human survival implies partial redundancy or residual activity. The limb and cortex conclusions in this entry rest on conditional knockouts that delete Esco2 completely in one lineage, which is a different state from the human deficiency.
Proposed experiments
Patient-allele Esco2 knock-in mouse
rbs_patient_allele_knockin_mouse
Introduce a recurrent human truncating allele constitutively and test whether embryos survive to show limb, craniofacial and cortical phenotypes, and whether Esco1 dosage modifies severity.
Supporting outcome
  • Viable homozygous embryos with symmetric limb reduction, clefting and microcephaly whose severity varies with Esco1 dosage.
Refuting outcome
  • Early embryonic lethality as in the null, indicating that the human allele retains no function in the mouse.
Show evidence (1 reference)
PMID:22101327 SUPPORT BACKGROUND Model Organism
"Partial redundancy between ESCO1 and ESCO2 may also occur in Roberts syndrome (RBS), an ESCO2 deficiency in humans that does not lead to the loss of viability"
The authors frame the species difference.
Is limb reduction caused mainly by death of limb mesenchyme, by a proliferation shortfall, by p53-dependent vascular disruption, or by transcriptional dysregulation of limb genes?
CONTROVERSY OPEN rbs_limb_reduction_mechanism
Attached to
pathophysiology#Limb Bud Outgrowth Failure mechanistic_hypotheses#mitotic_failure_progenitor_apoptosis mechanistic_hypotheses#limb_vascular_disruption
In the Esco2 limb mouse, p53 inhibition reduced apoptosis and rescued hemorrhage but not chondrogenesis, so apoptosis alone does not explain the reduction; the fin-regeneration and translation studies propose apoptosis-independent routes. No study has compared these arms in one mammalian system.
Show evidence (1 reference)
PMID:39168984 SUPPORT Model Organism
"We had presumed that the extensive cell death in the mesenchyme was the underlying cause of the limb deficiency, but pifithrin-α treatment only recovered the hemorrhage in mutant limbs and not the chondrogenesis."
The observation that leaves the question open.
How often do ischemic stroke, aneurysm and small-vessel disease occur in surviving patients, and how does ESCO2 loss damage cerebral vessels?
KNOWLEDGE GAP OPEN rbs_cerebrovascular_gap
Attached to
pathophysiology#Cerebral Small-Vessel Vasculopathy phenotypes#Intracranial aneurysm
The cerebrovascular phenotype rests on case reports, yet GeneReviews now recommends neurovascular surveillance. The vasculopathy node has no upstream mechanism in this entry; the p53-dependent vascular disruption seen in the embryonic mouse limb is a possible lead but has not been examined in cerebral vessels.
Show evidence (1 reference)
PMID:37002187 SUPPORT Human Clinical
"This case expands not only the cerebral involvement in Roberts syndrome but also the disease spectrum of the neuroimaging triad with leukoencephalopathy, calcifications, and cysts."
The phenotype is newly described.
⚙

Pathophysiology

18
ESCO2 Biallelic Loss of Function
Mechanism confidence: Established
Homozygous or compound heterozygous ESCO2 variants that remove all or part of the C-terminal acetyltransferase domain (frameshift, nonsense and splice-site alleles, often in exon 3), or, rarely, missense changes in that domain such as W539G that abolish autoacetylation. Truncating alleles lower mRNA through nonsense-mediated decay and no truncated protein is detected in patient cells.
ESCO2 hgnc:27230 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ESCO2 (hgnc:27230). hgnc:27230 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context ESCO2 hgnc:27230 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns ESCO2 (hgnc:27230). hgnc:27230 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Biallelic, homozygous or compound heterozygous; most alleles are protein-truncating.
cohesin acetyltransferase activity GO:0061733 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased cohesin acetyltransferase activity, annotated with protein-lysine-acetyltransferase activity (GO:0061733). GO:0061733 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Reduced SMC3 Acetylation of Chromatin-Bound Cohesin ESCO2 is an acetyltransferase whose substrate is the SMC3 subunit of cohesin.
Show evidence (5 references)
PMID:15821733 SUPPORT Human Clinical
"We identified mutations in a new human gene, ESCO2, associated with Roberts syndrome in 15 kindreds."
Gene discovery.
PMID:16380922 SUPPORT Human Clinical
"Since only protein-truncating mutations were identified, regardless of clinical severity, we conclude that genotype does not predict phenotype."
Truncating alleles across the whole severity range, including SC phocomelia.
PMID:18411254 SUPPORT In Vitro
"We found that ESCO2 W539G results in loss of autoacetyltransferase activity."
The one missense allele abolishes the enzymatic activity.
+ 2 more references
Reduced SMC3 Acetylation of Chromatin-Bound Cohesin
Mechanism confidence: Established
Without ESCO2, S-phase acetylation of SMC3 is reduced, particularly at pericentric heterochromatin where ESCO2 localizes, and less Sororin is recruited to chromatin-bound cohesin. ESCO1 provides partial redundancy, which is one explanation for why human cells and patients remain viable.
cohesin complex GO:0008278 Gene Ontology (GO) Relation: this pathophysiological event involves this protein complex This pathophysiological event involves cohesin complex (GO:0008278). GO:0008278 is a protein complex from the Gene Ontology.
pericentric heterochromatin GO:0005721 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves pericentric heterochromatin (GO:0005721). GO:0005721 is a cellular component from the Gene Ontology.
Downstream
Failed Pericentric Sister Chromatid Cohesion Establishment
Show evidence (2 references)
PMID:22101327 SUPPORT In Vitro
"In interphase, Esco2 depletion leads to a reduction in cohesin acetylation and Sororin recruitment to chromatin."
Reduced cohesin acetylation and Sororin loading in Esco2-deficient cells.
PMID:22101327 SUPPORT In Vitro
"Esco2 is transiently expressed during S-phase when it localizes to pericentric heterochromatin (PCH)."
Places the ESCO2 requirement at pericentric heterochromatin in S phase.
Failed Pericentric Sister Chromatid Cohesion Establishment
Mechanism confidence: Established
Sister chromatids are not held together at pericentric heterochromatin and the Yq heterochromatin. In metaphase spreads this is seen as premature centromere separation and heterochromatin repulsion (puffing), giving the "railroad track" chromosome, the diagnostic cytogenetic sign. 3D-FISH of fetal nuclei shows the separation already in interphase. Restoring wild-type, but not W539G, ESCO2 corrects the defect in patient cells.
Cohesin-dependent transcriptional dysregulation of developmental genes Nucleolar dysfunction and mTORC1-dependent translational deficit
establishment of mitotic sister chromatid cohesion GO:0034087 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased establishment of mitotic sister chromatid cohesion (GO:0034087). GO:0034087 is a biological process from the Gene Ontology. ↓ DECREASED centromeric sister chromatid cohesion GO:0071962 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased centromeric sister chromatid cohesion, annotated with mitotic sister chromatid cohesion, centromeric (GO:0071962). GO:0071962 is a biological process from the Gene Ontology. ↓ DECREASED
pericentric heterochromatin GO:0005721 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves pericentric heterochromatin (GO:0005721). GO:0005721 is a cellular component from the Gene Ontology.
Experimental models
RBS patient fibroblasts complemented with ESCO2 CELL LINE Wild-type ESCO2 corrects the cohesion defect; the patient missense allele does not.
Animal models
Esco2 constitutive knockout mouse Mouse recapitulates Reproduces the pericentric cohesion defect and railroad chromosomes.
Downstream
Premature Centromere Separation on Metaphase Spreads The cohesion defect is what the cytogenetic test visualizes.
Prolonged Mitosis and Chromosome Missegregation
Nucleolar Fragmentation and Impaired Ribosome Biogenesis Proposed to follow from reduced cohesin acetylation at the rDNA rather than from the mitotic defect; the intermediate steps are not established. Nucleolar dysfunction and mTORC1-dependent translational deficit
Cohesin-Dependent Transcriptional Dysregulation Cohesin-dependent transcriptional dysregulation of developmental genes
Show evidence (4 references)
PMID:15821733 SUPPORT Human Clinical
"Roberts syndrome is an autosomal recessive disorder characterized by craniofacial anomalies, tetraphocomelia and loss of cohesion at heterochromatic regions of centromeres and the Y chromosome."
Loss of cohesion at heterochromatic centromeric regions is part of the defining picture.
PMID:19738907 SUPPORT In Vitro
"We show that the sister chromatid cohesion defect in the transfected cell lines is rescued"
Complementation of patient fibroblasts with ESCO2 corrects the cohesion defect.
PMID:19738907 SUPPORT In Vitro
"The cohesion defect of RBS cells and their hypersensitivity to DNA-damaging agents were not corrected by a patient-derived ESCO2 acetyltransferase mutant (W539G), indicating that the acetyltransferase activity of ESCO2 is essential for its function."
The acetyltransferase activity is required to establish cohesion.
+ 1 more reference
Premature Centromere Separation on Metaphase Spreads
Mechanism confidence: Established
Cytogenetic manifestation of the cohesion defect: centromeres of most chromosomes are separated in metaphase and the pericentric heterochromatin of chromosomes 1, 9 and 16 and distal Yq appears puffed or repelled. Seen in lymphocytes, fibroblasts, amniocytes and chorionic villi, and used as a diagnostic test. Also modeled as a Cellular phenotype.
Downstream
Premature centromere separation The cellular state is recorded as a Cellular phenotype used diagnostically.
Show evidence (2 references)
PMID:8291532 SUPPORT REVIEW SYNTHESIS Human Clinical
"Mitotic cells from many individuals with RS display a characteristic cytogenetic phenomenon consisting of repulsion of heterochromatic regions near centromeres, particularly of chromosomes 1, 9, 16, and splaying of the short arms of the acrocentrics and of the distal Yq."
Describes the heterochromatin repulsion seen in patient mitoses.
PMID:26710928 SUPPORT Human Clinical
"Cytogenetic analysis showed the characteristic premature separation of centromeres and puffing of heterochromatic regions."
Found in three molecularly confirmed patients.
Prolonged Mitosis and Chromosome Missegregation
Mechanism confidence: Provisional
Cells lacking ESCO2 spend longer in prometaphase and metaphase and show scattered, lagging and prematurely advancing chromosomes, anaphase bridges and micronuclei. PROVISIONAL because the mitotic delay is shown in reviews of patient cells, in fish embryos and in mouse cells, but a study of patient lymphoblastoid lines found reduced proliferation with cell death and no increase in cell-cycle duration (PMID:18411254); see mechanistic_hypotheses.
Mitotic failure and p53-dependent loss of embryonic progenitors
chromosome segregation GO:0007059 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chromosome segregation (GO:0007059). GO:0007059 is a biological process from the Gene Ontology. ⚠ ABNORMAL mitotic spindle assembly checkpoint signaling GO:0007094 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased mitotic spindle assembly checkpoint signaling (GO:0007094). GO:0007094 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
esco2 mutant zebrafish Zebrafish recapitulates Direct in vivo observation of the mitotic defect.
Downstream
Somatic Aneuploidy and Micronucleus Formation
p53 Pathway Activation Mitotic failure and p53-dependent loss of embryonic progenitors
Show evidence (5 references)
PMID:8291532 SUPPORT REVIEW SYNTHESIS Human Clinical
"Mitosis in RS cells is abnormal in metaphase duration and anaphase progression."
Review of cell-biology findings in patient cells.
PMID:8291532 SUPPORT REVIEW SYNTHESIS Human Clinical
"Specifically, anaphase figures show a higher degree of chromosomes that are outlying, lagging, or prematurely advancing toward the poles compared to normal controls."
Missegregation in patient anaphases.
PMID:26044958 SUPPORT Model Organism
"Within esco2 mutant embryos, we observed premature chromatid separation, a unique chromosome scattering, prolonged mitotic delay, and genomic instability in the form of anaphase bridges and micronuclei formation."
Live imaging of mitosis in esco2 mutant zebrafish embryos.
+ 2 more references
Somatic Aneuploidy and Micronucleus Formation
Mechanism confidence: Established
Aneuploid metaphases at variable rates in patient amniocytes, lymphocytes and fibroblasts, and in esco2 mutant fish. In two siblings, fibroblasts from hypopigmented skin carried much more aneuploidy (especially trisomy 7) than fibroblasts from normally pigmented skin, suggesting that somatic aneuploidy can generate patchy skin phenotypes.
Downstream
Hypopigmented skin patches
Show evidence (2 references)
PMID:18186147 SUPPORT Human Clinical
"Cytogenetic analysis of amniocytes revealed a normal male karyotype in 20 analyzed metaphases and chromosomal aneuploidies in 10 metaphases."
Aneuploidy in a third of fetal metaphases.
PMID:26044958 SUPPORT Model Organism
"Cytogenetic studies indicated complete chromatid separation and high levels of aneuploidy within mutant embryos."
Aneuploidy in the zebrafish model.
Genotoxin Hypersensitivity and Defective DNA Damage Response
Mechanism confidence: Provisional
Patient cells are hypersensitive to mitomycin C, camptothecin and etoposide, and one family's lymphoblastoid cells also showed ionizing-radiation sensitivity with impaired double-strand break repair. In budding yeast, loss of the ortholog Eco1 is enough to raise endogenous redox stress and impair repair of oxidative DNA damage. Whether accumulated DNA or other macromolecular damage is a driver of the developmental phenotype, rather than a bystander, is unresolved.
Accumulated DNA and macromolecular damage
double-strand break repair GO:0006302 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased double-strand break repair (GO:0006302). GO:0006302 is a biological process from the Gene Ontology. ↓ DECREASED response to oxidative stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Experimental models
RBS patient fibroblasts complemented with ESCO2 CELL LINE Isogenic measurement of drug sensitivity.
Downstream
p53 Pathway Activation Accumulated DNA and macromolecular damage
Show evidence (5 references)
PMID:19738907 SUPPORT In Vitro
"In comparison to the corrected cells RBS cells were hypersensitive to the DNA-damaging agents mitomycin C, camptothecin and etoposide, while no particular sensitivity to UV, ionizing radiation, hydroxyurea or aphidicolin was found."
Isogenic comparison of patient fibroblasts with and without ESCO2.
PMID:30508616 SUPPORT In Vitro
"Cells derived from the RBS-affected individual showed sensitivity to ionizing radiation (IR) and mitomycin C-induced DNA damage."
A second patient line, here also radiation sensitive.
PMID:30508616 SUPPORT In Vitro
"a reduced capacity for repairing IR-induced DNA DSBs, as measured by γ-H2AX foci and the comet assay"
Reduced double-strand break repair in patient cells.
+ 2 more references
Nucleolar Fragmentation and Impaired Ribosome Biogenesis
Mechanism confidence: Provisional
Nucleoli are fragmented in RBS cells and rRNA production and protein translation are reduced. Shown in immortalized patient cells and in esco2 mutant zebrafish; not examined in human embryonic tissue.
Nucleolar dysfunction and mTORC1-dependent translational deficit
ribosome biogenesis GO:0042254 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ribosome biogenesis (GO:0042254). GO:0042254 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
mTORC1 Repression and Reduced Protein Translation Nucleolar dysfunction and mTORC1-dependent translational deficit
p53 Pathway Activation Nucleolar dysfunction and mTORC1-dependent translational deficit
Show evidence (3 references)
PMID:24098154 SUPPORT In Vitro
"Nucleoli, the sites of ribosome production, are highly fragmented in RBS cells."
Nucleolar fragmentation in patient cells.
PMID:24098154 SUPPORT BACKGROUND In Vitro
"It was previously reported that ribosomal RNA production and protein translation were impaired in immortalized RBS cells."
Restates the earlier finding of reduced rRNA production and translation.
PMID:25378554 SUPPORT BACKGROUND In Vitro
"In a previous project, we showed that RBS was associated with highly fragmented nucleoli and defects in both ribosome biogenesis and protein translation."
The same group's summary of its RBS cell findings, restated in a Cornelia de Lange syndrome zebrafish study.
mTORC1 Repression and Reduced Protein Translation
Mechanism confidence: Provisional
Reduced phosphorylation of S6K1, S6 and 4EBP1 in RBS cells and esco2 mutant fish, with reduced translational efficiency of ribosomal subunit and translation-initiation factor mRNAs. Stimulating mTORC1 with L-leucine partially restores translation, cell division and survival in cells and many developmental defects in fish.
Nucleolar dysfunction and mTORC1-dependent translational deficit
TORC1 signaling GO:0038202 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased TORC1 signaling (GO:0038202). GO:0038202 is a biological process from the Gene Ontology. ↓ DECREASED cytoplasmic translation GO:0002181 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cytoplasmic translation (GO:0002181). GO:0002181 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
RBS patient cells with mTORC1 stimulation CELL LINE Measures mTORC1 repression and its L-leucine rescue.
Downstream
Reduced Proliferative Capacity of Embryonic Progenitors Nucleolar dysfunction and mTORC1-dependent translational deficit
Show evidence (3 references)
PMID:24098154 SUPPORT In Vitro
"We report that mTOR signaling is inhibited in human RBS cells based on the reduced phosphorylation of the downstream effectors S6K1, S6 and 4EBP1, and this correlates with p53 activation."
mTORC1 repression in patient cells.
PMID:24098154 SUPPORT Model Organism
"Consistent with RBS patient cells, the ESCO2 mutant embryos show p53 activation and inhibition of the TOR pathway."
The same signaling state in esco2 mutant zebrafish.
PMID:26729373 SUPPORT In Vitro
"L-leucine treatment partially rescued translational efficiency of ribosomal subunits, translation initiation factors, snoRNA production, and mitochondrial function in RBS cells"
Ribosome profiling shows a translational deficit that is mTORC1-responsive.
Cohesin-Dependent Transcriptional Dysregulation
Mechanism confidence: Hypothetical
Changes in gene expression that are not explained by cell death or mTORC1 repression: imprinted genes (H19, GTL2), HOX genes and genes in nucleolar-associated domains in RBS cells; reduced cx43 expression in the regenerating zebrafish fin after esco2 knockdown, rescued by cx43 overexpression; and reduced ddb1 expression, linking ESCO2 to the CRL4 ubiquitin ligase through which thalidomide acts. Altered interphase positioning of pericentric heterochromatin in fetal nuclei has been proposed as a route. How much of the human phenotype this explains is unknown.
Cohesin-dependent transcriptional dysregulation of developmental genes
Downstream
Limb Bud Outgrowth Failure Cohesin-dependent transcriptional dysregulation of developmental genes
Show evidence (5 references)
PMID:26729373 SUPPORT In Vitro
"In contrast, other genes are differentially expressed independent of L-leucine treatment, including imprinted genes such as H19 and GTL2, miRNAs regulated by GTL2, HOX genes, and genes in nucleolar associated domains."
TOR-independent expression changes in patient cells.
PMID:26434741 SUPPORT Model Organism
"esco2-knockdown significantly diminishes cx43/gja1 expression which encodes the gap junction connexin subunit required for cell-cell communication."
A transcriptional target of Esco2 in regenerating bone.
PMID:26434741 SUPPORT Model Organism
"Importantly, miR-133-dependent cx43 overexpression rescues esco2-dependent growth defects."
Restoring the target rescues the skeletal growth defect.
+ 2 more references
p53 Pathway Activation
Mechanism confidence: Established
p53 is activated in RBS patient cells, in esco2 mutant zebrafish, and in a pre-apoptotic mesenchymal population of Esco2-deficient mouse limb buds from E9.5, where cell-cycle arrest, DNA damage and cell-death genes are induced. Its upstream triggers (mitotic stress, nucleolar stress, DNA damage) are not mutually exclusive.
Mitotic failure and p53-dependent loss of embryonic progenitors p53-dependent vascular disruption in the developing limb
p53-mediated intrinsic apoptotic signaling GO:0072332 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased p53-mediated intrinsic apoptotic signaling, annotated with intrinsic apoptotic signaling pathway by p53 class mediator (GO:0072332). GO:0072332 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Esco2 limb mesenchyme conditional knockout mouse (Prrx1-Cre) Mouse perturbs Pifithrin-alpha p53 inhibition in utero.
Downstream
Apoptosis of Proliferating Embryonic Progenitors Mitotic failure and p53-dependent loss of embryonic progenitors
Limb Bud Vascular Disruption and Hemorrhage p53-dependent vascular disruption in the developing limb
Show evidence (2 references)
PMID:39168984 SUPPORT Model Organism
"Underlying this abnormal developmental progression is a pre-apoptotic, mesenchymal cell population specific to mutant limb buds enriched for p53-related signaling beginning at E9.5."
p53 signaling in limb mesenchyme precedes the malformation.
PMID:24098154 SUPPORT Model Organism
"Consistent with RBS patient cells, the ESCO2 mutant embryos show p53 activation and inhibition of the TOR pathway."
p53 activation in patient cells and mutant fish.
Apoptosis of Proliferating Embryonic Progenitors
Mechanism confidence: Provisional
Widespread death of dividing embryonic cells: limb bud mesenchyme in the Esco2 conditional mouse (TUNEL-positive from E10.5), neural tube and whole embryos in esco2 zebrafish, and developing embryos in the R80S medaka mutant; patient cell lines also show proliferation loss with cell death. PROVISIONAL because the evidence in developing tissue is from animal models, and in the mouse limb p53 inhibition reduced mesenchymal apoptosis and rescued hemorrhage without restoring chondrogenesis.
Mitotic failure and p53-dependent loss of embryonic progenitors
mesenchymal cell CL:0008019 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves mesenchymal cell (CL:0008019). CL:0008019 is a cell type from the Cell Ontology. neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology.
apoptotic process GO:0006915 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
esco2 morphant zebrafish Zebrafish recapitulates Widespread cell death accompanies RBS-like craniofacial and fin defects.
esco2 R80S mutant medaka Medaka recapitulates Apoptosis and craniofacial defects in a missense mutant.
Downstream
Limb Bud Outgrowth Failure Mitotic failure and p53-dependent loss of embryonic progenitors
Cortical Progenitor Loss Mitotic failure and p53-dependent loss of embryonic progenitors
Deficient Craniofacial Primordium Growth Mitotic failure and p53-dependent loss of embryonic progenitors
Show evidence (3 references)
PMID:21637801 SUPPORT Model Organism
"High levels of cell death contributed to the morphology of Esco2-depleted embryos without affecting specific developmental pathways."
Cell death drives the zebrafish morphant phenotype.
PMID:22694322 SUPPORT Model Organism
"Moreover, widespread apoptosis and downregulation of some gene expression, including notch1a, were detected in the R80S mutant."
Apoptosis in a second fish model.
PMID:18411254 SUPPORT In Vitro
"We found decreased proliferation capacity in RBS cell lines associated with cell death, but not with increased cell cycle duration, which could be a factor in the development of phocomelia and cleft palate in RBS."
Cell death in patient cell lines, proposed as a factor in phocomelia and cleft palate.
Reduced Proliferative Capacity of Embryonic Progenitors
Mechanism confidence: Provisional
Patient cell lines grow less, and ESCO2 is expressed in the embryonic brain, face, limb, kidney and gonads, the structures affected in the syndrome. A proliferation shortfall in progenitor pools is proposed to contribute, with apoptosis, to growth restriction and to limb and craniofacial reduction.
Mitotic failure and p53-dependent loss of embryonic progenitors
cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Limb Bud Outgrowth Failure Mitotic failure and p53-dependent loss of embryonic progenitors
Deficient Craniofacial Primordium Growth Mitotic failure and p53-dependent loss of embryonic progenitors
Intrauterine growth retardation
Postnatal growth retardation
Show evidence (2 references)
PMID:18411254 SUPPORT In Vitro
"Cellular alterations in RBS include lack of cohesion at the heterochromatic regions around centromeres and the long arm of the Y chromosome, reduced growth capacity, and hypersensitivity to DNA damaging agents."
Reduced growth capacity is a recognised cellular feature of RBS.
PMID:19574259 SUPPORT Human Clinical
"In situ hybridisation on human embryos showed ESCO2 expression in the brain, face, limb, kidney and gonads, which corresponds to the structures affected in RBS."
Human embryonic expression matches the affected structures.
Limb Bud Vascular Disruption and Hemorrhage
Mechanism confidence: Provisional
In Esco2fl/fl;Prrx1-Cre mouse embryos the limb bud vasculature is disorganized and dilated at E10.5 and the limbs hemorrhage by E12.5. The hemorrhage, but not the defective chondrogenesis, is rescued by in utero p53 inhibition. A vascular contribution has also been proposed for thalidomide embryopathy. Shown only in the mouse.
p53-dependent vascular disruption in the developing limb
limb bud UBERON:0004347 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in limb bud (UBERON:0004347). UBERON:0004347 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Esco2 limb mesenchyme conditional knockout mouse (Prrx1-Cre) Mouse recapitulates The only model in which the vascular arm has been shown.
Downstream
Limb Bud Outgrowth Failure p53-dependent vascular disruption in the developing limb
Show evidence (2 references)
PMID:39168984 SUPPORT Model Organism
"Our results reveal morphological and vascular defects culminating in hemorrhage of mutant limbs at E12.5."
Vascular defects and hemorrhage in the mutant limb bud.
PMID:39168984 SUPPORT Model Organism
"In sum, our results identified p53 inhibition as a direct mediator of vascular hemorrhage, but not chondrogenesis in mutant limbs."
The vascular arm is p53-dependent and separable from the cartilage defect.
Limb Bud Outgrowth Failure
Mechanism confidence: Established
The developing limb buds are smaller from early outgrowth and the skeletal elements that form are reduced, most severely in the upper limbs and in the zeugopod (mesomelia), with loss of radial-ray and digital elements. In the Prrx1-Cre conditional mouse, the limb bud is reduced at E10.5 and all 120 mutant embryos examined showed the limb phenotype.
embryonic limb morphogenesis GO:0030326 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal embryonic limb morphogenesis (GO:0030326). GO:0030326 is a biological process from the Gene Ontology. ⚠ ABNORMAL
limb bud UBERON:0004347 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in limb bud (UBERON:0004347). UBERON:0004347 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Esco2 limb mesenchyme conditional knockout mouse (Prrx1-Cre) Mouse recapitulates Reproduces symmetric limb reduction resembling the human phenotype.
Downstream
Tetraphocomelia
Mesomelic limb shortening
Absent radius
Oligodactyly
Aplasia/Hypoplasia of the thumb
Fibular aplasia
Syndactyly
Clinodactyly of the 5th finger
Humeroradial synostosis
Flexion contractures
Talipes equinovarus
Show evidence (2 references)
PMID:39168984 SUPPORT Model Organism
"This deletion was highly penetrant with 100% of n = 120 Esco2fl/fl;Prrx1-CreTg/0 embryos displaying the RBS limb phenotype"
Fully penetrant limb reduction after mesenchymal Esco2 deletion.
PMID:19574259 SUPPORT Human Clinical
"symmetric mesomelic shortening of the limbs in which the upper limbs are more commonly and severely affected than the lower limbs"
The human limb pattern from the 49-patient series.
Deficient Craniofacial Primordium Growth
Mechanism confidence: Hypothetical
Undergrowth of the facial prominences, palatal shelves and jaw, proposed to result from the same progenitor death and proliferation shortfall as the limb reduction. Supported by Esco2 expression in the developing lip and palate, by craniofacial abnormalities in esco2-deficient fish, and by the clinical correlation between facial and limb severity. No study has measured apoptosis or proliferation in human or mouse facial primordia, hence HYPOTHETICAL.
roof of mouth development GO:0060021 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal roof of mouth development (GO:0060021). GO:0060021 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Cleft lip
Cleft palate
Micrognathia
Malar flattening
Underdeveloped nasal alae
Hypertelorism
Ear malformations
Microphthalmia
Proptosis
Downslanted palpebral fissures
Show evidence (3 references)
PMID:19574259 SUPPORT Human Clinical
"The severity of malformations of the facies correlates with the severity of limb reduction."
Facial and limb severity move together, consistent with a shared mechanism.
PMID:32255174 SUPPORT Model Organism
"Esco2 expression during the early development of lip, palate, eyelid, digits, upper limb, and lower limb and truncated protein model are consistent with the defect."
Mouse embryo in situ hybridization places Esco2 in the lip and palate primordia.
PMID:21637801 SUPPORT Model Organism
"Esco2 depleted zebrafish embryos exhibit features that resemble RBS, including mitotic defects, craniofacial abnormalities and limb truncations."
Craniofacial abnormalities in the fish model.
Cortical Progenitor Loss
Mechanism confidence: Provisional
In the developing mouse cortex Esco2 is expressed in late radial glial progenitors and TBR2-positive intermediate progenitors. Cortex-specific deletion (Emx1-Cre) causes massive apoptosis of these progenitors and their neuronal progeny, a drastic reduction in cortical neurons and failure of cortical layer formation; acute deletion shows ESCO2 is needed to maintain, not to generate, intermediate progenitors. This is the proposed basis of microcephaly and intellectual disability, conforming to the progenitor-pool-distortion node of the cortical progenitor module through its apoptosis branch. Shown only in the mouse.
neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology.
apoptotic process GO:0006915 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. ↑ INCREASED
cerebral cortex UBERON:0000956 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebral cortex (UBERON:0000956). UBERON:0000956 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Esco2 cortex conditional knockout mouse (Emx1-Cre) Mouse recapitulates Progenitor apoptosis and neuron loss in the developing cortex.
Downstream
Microcephaly
Intellectual disability
Show evidence (2 references)
PMID:33798452 SUPPORT Model Organism
"Loss-of-function experiments in cortex-specific mutants of Esco2, one of the novel IPC genes, demonstrate its critical role in IPC maintenance"
Conditional Esco2 loss depletes cortical intermediate progenitors.
PMID:33798452 SUPPORT Model Organism
"The expression of Esco2 is required for the viability of these cell populations and their progenies to afford proper cortical histogenesis."
Progenitor and neuronal survival requires Esco2.
Cerebral Small-Vessel Vasculopathy
Mechanism confidence: Hypothetical
Angiomatous changes and perivascular cysts indicating a chronic small cerebral vasculopathy were found at autopsy in an adolescent with biallelic ESCO2 variants who had an ischemic stroke at 6 years and died of an aneurysmal cerebellar hemorrhage at 13, with leukoencephalopathy, calcifications and cysts on imaging. GeneReviews now recommends brain vascular imaging in selected patients. How ESCO2 loss produces this vasculopathy is unknown, so no upstream edge is drawn.
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Ischemic stroke
Intracranial aneurysm
Leukoencephalopathy
Cerebral calcification
Show evidence (1 reference)
PMID:37002187 SUPPORT Human Clinical
"Brain histopathology revealed angiomatous changes and perivascular cysts suggesting chronic small cerebral vasculopathy."
Neuropathology of the index case.
⬡

Pathograph

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

44
Blood 1
Cerebellar hemorrhage HP:0011695 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar hemorrhage (HP:0011695). HP:0011695 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37002187 SUPPORT Human Clinical
"She suffered ischemic stroke at 6 years old and died of cerebellar hemorrhage secondary to an aneurysm at 13 years old."
Single-case report.
Cardiovascular 4
Midface capillary hemangioma HP:0007452 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Midface capillary hemangioma (HP:0007452). HP:0007452 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31192177 SUPPORT Human Clinical
"patient 1 is a Turkish girl with short stature, microcephaly, craniosynostosis, seizures, intellectual disability, midface hemangioma, bilateral radial and thumb aplasia, tibial hypoplasia, and pes equinovarus"
Midface hemangioma in an ESCO2-positive patient.
PMID:25320640 SUPPORT BACKGROUND Human Clinical
"This multiple congenital anomaly syndrome is characterized by cleft lip and palate, nose and ears anomalies, facial hemangioma, hypertelorism, microcephaly, curly silvery blond hair"
Facial hemangioma in the clinical summary of a later paper's introduction.
Congenital heart defect Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital heart defect, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20101700 SUPPORT Human Clinical
"Roberts syndrome (RBS) (OMIM #268300) is a rare autosomal recessive disorder characterized by tetraphocomelia (symmetrical limb reduction), craniofacial anomalies, growth retardation, mental retardation, cardiac and renal abnormalities."
Cardiac abnormalities are part of the syndrome.
PMID:24864645 SUPPORT Human Clinical
"tetra phocomelia, growth and developmental retardation, abnormality of complete cleft lip-palate accompanied with Aortic stenosis and PDA"
Aortic stenosis and patent ductus arteriosus in a molecularly confirmed infant.
Ischemic stroke HP:0002140 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ischemic stroke (HP:0002140). HP:0002140 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37002187 SUPPORT Human Clinical
"She suffered ischemic stroke at 6 years old and died of cerebellar hemorrhage secondary to an aneurysm at 13 years old."
Stroke and fatal aneurysmal hemorrhage in one patient.
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"treatment of stroke per neurologist"
GeneReviews management includes stroke.
Intracranial aneurysm Dilatation of the cerebral artery HP:0004944 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intracranial aneurysm, annotated with Dilatation of the cerebral artery (HP:0004944). HP:0004944 is a phenotype from the Human Phenotype Ontology.
Sequelae: Cerebellar hemorrhage
Show evidence (2 references)
PMID:37002187 SUPPORT Human Clinical
"She suffered ischemic stroke at 6 years old and died of cerebellar hemorrhage secondary to an aneurysm at 13 years old."
Aneurysmal cerebellar hemorrhage.
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"assess for clinical manifestations of aneurysms and vascular malformations annually starting in adolescence"
GeneReviews surveillance for aneurysms.
Ear 1
Ear malformations Abnormal ear morphology HP:0031703 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ear malformations, annotated with Abnormal ear morphology (HP:0031703). HP:0031703 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (1 reference)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"craniofacial abnormalities (bilateral cleft lip and/or cleft palate, micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, underdeveloped ala nasi, and ear malformations)"
GeneReviews names ear malformations without further detail.
Eye 6
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Widely spaced eyes, annotated with Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"craniofacial abnormalities (bilateral cleft lip and/or cleft palate, micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, underdeveloped ala nasi, and ear malformations)"
GeneReviews list of craniofacial abnormalities.
PMID:8291532 SUPPORT REVIEW SYNTHESIS Human Clinical
"Craniofacial malformations involve hypertelorism, hypoplastic nasal alae, and a high incidence of cleft lip and palate."
Hypertelorism in the 100-case review.
Proptosis HP:0000520 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exophthalmos, annotated with Proptosis (HP:0000520). HP:0000520 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"craniofacial abnormalities (bilateral cleft lip and/or cleft palate, micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, underdeveloped ala nasi, and ear malformations)"
GeneReviews list of craniofacial abnormalities.
Microphthalmia HP:0000568 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microphthalmia (HP:0000568). HP:0000568 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"ocular manifestations (microphthalmia, nystagmus, glaucoma, and corneal opacities)"
GeneReviews list of ocular manifestations.
Corneal opacity HP:0007957 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Corneal opacity (HP:0007957). HP:0007957 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"ocular manifestations (microphthalmia, nystagmus, glaucoma, and corneal opacities)"
GeneReviews list of ocular manifestations.
PMID:19574259 SUPPORT Human Clinical
"The occurrence of corneal opacities may be associated with specific mutations."
A possible genotype association for this feature.
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"ocular manifestations (microphthalmia, nystagmus, glaucoma, and corneal opacities)"
GeneReviews list of ocular manifestations.
Glaucoma HP:0000501 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Glaucoma (HP:0000501). HP:0000501 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"ocular manifestations (microphthalmia, nystagmus, glaucoma, and corneal opacities)"
GeneReviews list of ocular manifestations.
Genitourinary 2
Renal dysplasia HP:0000110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polycystic or dysplastic kidneys, annotated with Renal dysplasia (HP:0000110). HP:0000110 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25320640 SUPPORT BACKGROUND Human Clinical
"polycystic or dysplastic kidneys, congenital heart defects, enlarged male genitalia, severe growth retardation and intellectual deficiency"
Kidney dysplasia in the clinical summary.
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"standard treatment for ophthalmologic, cardiac, urogenital, and kidney abnormalities"
GeneReviews management lists kidney abnormalities among the organ involvement to treat.
Genital anomalies Abnormal male external genitalia morphology HP:0000032 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Enlarged male external genitalia, annotated with Abnormal male external genitalia morphology (HP:0000032). HP:0000032 is a phenotype from the Human Phenotype Ontology.
Bound to HP:0000032 rather than HP:0000040 Long penis because the source says "enlarged", which does not specify length.
Show evidence (2 references)
PMID:25320640 SUPPORT BACKGROUND Human Clinical
"polycystic or dysplastic kidneys, congenital heart defects, enlarged male genitalia, severe growth retardation and intellectual deficiency"
Enlarged male genitalia in the clinical summary.
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"standard treatment for ophthalmologic, cardiac, urogenital, and kidney abnormalities"
GeneReviews management lists urogenital abnormalities.
Head and Neck 8
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:19574259 SUPPORT Human Clinical
"the clinical criteria for RBS were delineated to include: growth retardation; symmetric mesomelic shortening of the limbs in which the upper limbs are more commonly and severely affected than the lower limbs; characteristic facies with microcephaly."
Microcephaly is part of the characteristic facies criterion.
PMID:26710928 SUPPORT Human Clinical
"All patients presented with growth retardation, mesomelic shortening of the limbs more in the upper than in the lower limbs and microcephaly."
Present in all three patients of a series.
Cleft lip Bilateral cleft lip HP:0100336 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral cleft lip (HP:0100336). HP:0100336 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"craniofacial abnormalities (bilateral cleft lip and/or cleft palate, micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, underdeveloped ala nasi, and ear malformations)"
GeneReviews list of craniofacial abnormalities.
PMID:8291532 SUPPORT REVIEW SYNTHESIS Human Clinical
"Craniofacial malformations involve hypertelorism, hypoplastic nasal alae, and a high incidence of cleft lip and palate."
High incidence of cleft lip and palate in 100 reviewed cases.
Cleft palate HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"craniofacial abnormalities (bilateral cleft lip and/or cleft palate, micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, underdeveloped ala nasi, and ear malformations)"
GeneReviews list of craniofacial abnormalities.
PMID:35093090 SUPPORT Human Clinical
"Two consecutive fetuses in this family presented with tetraphocomelia, growth restriction, cleft lip and palate bilaterally, and other abnormalities."
Bilateral cleft lip and palate detected prenatally with tetraphocomelia.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"craniofacial abnormalities (bilateral cleft lip and/or cleft palate, micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, underdeveloped ala nasi, and ear malformations)"
GeneReviews list of craniofacial abnormalities.
Downslanted palpebral fissures HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"craniofacial abnormalities (bilateral cleft lip and/or cleft palate, micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, underdeveloped ala nasi, and ear malformations)"
GeneReviews list of craniofacial abnormalities.
Malar flattening HP:0000272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Malar flattening (HP:0000272). HP:0000272 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"craniofacial abnormalities (bilateral cleft lip and/or cleft palate, micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, underdeveloped ala nasi, and ear malformations)"
GeneReviews list of craniofacial abnormalities.
Underdeveloped nasal alae HP:0000430 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Underdeveloped nasal alae (HP:0000430). HP:0000430 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"craniofacial abnormalities (bilateral cleft lip and/or cleft palate, micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, underdeveloped ala nasi, and ear malformations)"
GeneReviews list of craniofacial abnormalities.
PMID:8291532 SUPPORT REVIEW SYNTHESIS Human Clinical
"Craniofacial malformations involve hypertelorism, hypoplastic nasal alae, and a high incidence of cleft lip and palate."
Hypoplastic nasal alae in the 100-case review.
Craniosynostosis HP:0001363 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Craniosynostosis (HP:0001363). HP:0001363 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31192177 SUPPORT Human Clinical
"patient 1 is a Turkish girl with short stature, microcephaly, craniosynostosis, seizures, intellectual disability, midface hemangioma, bilateral radial and thumb aplasia, tibial hypoplasia, and pes equinovarus"
Craniosynostosis in a child later shown to carry biallelic ESCO2 variants.
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"surgical treatment for craniosynostosis and micrognathia"
GeneReviews management covers craniosynostosis.
Immune 1
Recurrent infections HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301332 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"prompt treatment of infection with management per infectious disease specialist"
GeneReviews management of infections.
PMID:20301332 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"serum immunoglobulin levels in infancy"
GeneReviews surveillance of immunoglobulins.
Integument 2
Silver-gray hair HP:0002218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Silvery blond hair, annotated with Silver-gray hair (HP:0002218). HP:0002218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25320640 SUPPORT BACKGROUND Human Clinical
"This multiple congenital anomaly syndrome is characterized by cleft lip and palate, nose and ears anomalies, facial hemangioma, hypertelorism, microcephaly, curly silvery blond hair"
Silvery blond hair listed among the clinical features.
Hypopigmented skin patches OCCASIONAL HP:0001053 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypopigmented skin patches (HP:0001053). HP:0001053 is a phenotype from the Human Phenotype Ontology.
Frequency basis: described as rare after a literature review (PMID:30590172), with two earlier reports plus the two siblings of that study; OCCASIONAL is used because the denominator is not stated.
Show evidence (2 references)
PMID:30590172 SUPPORT Human Clinical
"When the literature review and study are evaluated together, hypopigmented patches can be considered as a rare finding for RBS/SC."
Described as a rare finding after a literature review.
PMID:26710928 SUPPORT Human Clinical
"Interestingly, patient 1 had abnormal skin hypopigmentation."
A further patient with hypopigmentation.
Limbs 10
Tetraphocomelia HP:0030721 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tetraphocomelia (HP:0030721), qualified as congenital onset. HP:0030721 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (3 references)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"limb malformations (which can include bilateral symmetric tetraphocomelia or hypomelia caused by mesomelic shortening of the upper and/or lower limbs)"
GeneReviews limb spectrum.
PMID:16380922 SUPPORT Human Clinical
"The rare, autosomal recessive Roberts syndrome (RBS) is characterized by tetraphocomelia, profound growth deficiency of prenatal onset, craniofacial anomalies, microcephaly, and mental deficiency."
Tetraphocomelia as a defining feature of the severe end.
PMID:35495290 SUPPORT Human Clinical
"Tetraphocomelia was detected on prenatal ultrasound done at about 24 weeks of gestation with other features sonographically normal."
Prenatal detection of tetraphocomelia in a severe case.
Mesomelic limb shortening Mesomelia HP:0003027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Symmetric mesomelic limb shortening, annotated with Mesomelia (HP:0003027). HP:0003027 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:19574259 SUPPORT Human Clinical
"symmetric mesomelic shortening of the limbs in which the upper limbs are more commonly and severely affected than the lower limbs"
One of the clinical criteria derived from 49 molecularly confirmed patients.
PMID:26710928 SUPPORT Human Clinical
"All patients presented with growth retardation, mesomelic shortening of the limbs more in the upper than in the lower limbs and microcephaly."
Present in all three patients of an Egyptian series.
Absent radius HP:0003974 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Radial aplasia, annotated with Absent radius (HP:0003974). HP:0003974 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30590172 SUPPORT Human Clinical
"The more severely affected boy had hypoplasia of the tibia and symmetrical agenesis of the radius, ulna, proximal carpal bones, and fibula."
Symmetric radial and ulnar agenesis in a molecularly confirmed sibling.
PMID:31192177 SUPPORT Human Clinical
"bilateral radial and thumb aplasia"
Bilateral radial aplasia in an ESCO2-positive child first diagnosed as Baller-Gerold syndrome.
Fibular aplasia HP:0002990 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fibular aplasia (HP:0002990). HP:0002990 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30590172 SUPPORT Human Clinical
"The more severely affected boy had hypoplasia of the tibia and symmetrical agenesis of the radius, ulna, proximal carpal bones, and fibula."
Fibular agenesis in a molecularly confirmed patient.
Oligodactyly HP:0012165 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oligodactyly (HP:0012165). HP:0012165 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"hand anomalies (including oligodactyly, thumb aplasia or hypoplasia, syndactyly, fifth finger clinodactyly, hypoplasia, or aplasia)"
GeneReviews list of hand anomalies.
PMID:8291532 SUPPORT REVIEW SYNTHESIS Human Clinical
"Affected persons have varying degrees of malformations involving symmetric reduction in the number of digits, and length or presence of bones in the arms and legs."
Symmetric digit reduction across 100 reviewed cases.
Aplasia/Hypoplasia of the thumb HP:0009601 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thumb aplasia or hypoplasia, annotated with Aplasia/Hypoplasia of the thumb (HP:0009601). HP:0009601 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"hand anomalies (including oligodactyly, thumb aplasia or hypoplasia, syndactyly, fifth finger clinodactyly, hypoplasia, or aplasia)"
GeneReviews list of hand anomalies.
Syndactyly HP:0001159 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Syndactyly (HP:0001159). HP:0001159 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"hand anomalies (including oligodactyly, thumb aplasia or hypoplasia, syndactyly, fifth finger clinodactyly, hypoplasia, or aplasia)"
GeneReviews list of hand anomalies.
Clinodactyly of the 5th finger HP:0004209 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fifth finger clinodactyly, annotated with Clinodactyly of the 5th finger (HP:0004209). HP:0004209 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"hand anomalies (including oligodactyly, thumb aplasia or hypoplasia, syndactyly, fifth finger clinodactyly, hypoplasia, or aplasia)"
GeneReviews list of hand anomalies.
Humeroradial synostosis HP:0003041 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Humeroradial synostosis (HP:0003041). HP:0003041 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32783269 SUPPORT Human Clinical
"Here we report a 3-year-old boy with a mild phenotype of Roberts syndrome with bilateral elbow contractures, humeroradial synostosis, mild lower limb disparity, and facial dysmorphism."
Humeroradial synostosis in a mild, molecularly confirmed case.
Talipes equinovarus HP:0001762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Talipes equinovarus (HP:0001762). HP:0001762 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"flexion contractures (involving elbows, wrists, knees, ankles, and feet [talipes equinovarus])"
GeneReviews lists talipes equinovarus.
Musculoskeletal 2
Flexion contractures HP:0001371 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Flexion contractures of elbows, wrists, knees and ankles, annotated with Flexion contracture (HP:0001371). HP:0001371 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"flexion contractures (involving elbows, wrists, knees, ankles, and feet [talipes equinovarus])"
GeneReviews distribution of contractures.
PMID:20101700 SUPPORT Human Clinical
"SC phocomelia (SC) (OMIM #269000), has less severe symmetric limb reduction, flexion contractures of various joints, minor facial anomalies, growth retardation and occasionally, mental retardation."
Contractures are a feature of the mild (SC phocomelia) end.
Cerebral calcification HP:0002514 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral calcification (HP:0002514). HP:0002514 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37002187 SUPPORT Human Clinical
"Besides, neuroimaging showed the triad of leukoencephalopathy, calcifications, and cysts."
Single-case neuroimaging finding.
Nervous System 2
Intellectual disability FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Frequency basis: GeneReviews abstract phrase "common". Normal intelligence is documented in mild cases (PMID:38288163, PMID:32783269).
Show evidence (2 references)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"Intellectual disability (ranging from mild to severe) is common."
GeneReviews frequency qualifier "common" (mapped to FREQUENT).
PMID:38288163 SUPPORT Human Clinical
"Of note, there was an absence of learning disabilities."
Records that cognition can be normal, so the feature is not obligate.
Leukoencephalopathy HP:0002352 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukoencephalopathy (HP:0002352). HP:0002352 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37002187 SUPPORT Human Clinical
"Besides, neuroimaging showed the triad of leukoencephalopathy, calcifications, and cysts."
Single-case neuroimaging finding.
Cellular 1
Premature centromere separation Premature separation of centromeric heterochromatin HP:0003616 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Premature centromere separation, annotated with Premature separation of centromeric heterochromatin (HP:0003616). HP:0003616 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30204960 SUPPORT Human Clinical
"Cytogenetic studies including centromeric separation and puffing by Giemsa and DAPI stains and for the first time in Egypt analysis for premature centromeric division by FISH showed consistent centromeric separation in all studied cases."
Present in all eight patients studied.
PMID:16380922 SUPPORT Human Clinical
"All cases were positive for HR."
Heterochromatin repulsion in SC phocomelia and fetal cases alike.
Growth 2
Intrauterine growth retardation HP:0001511 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prenatal growth restriction, annotated with Intrauterine growth retardation (HP:0001511), qualified as antenatal onset. HP:0001511 is a phenotype from the Human Phenotype Ontology.
Onset: ANTENATAL
Show evidence (2 references)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"ESCO2 spectrum disorder is characterized by mild-to-severe prenatal growth restriction"
GeneReviews clinical characteristics.
PMID:16380922 SUPPORT Human Clinical
"The rare, autosomal recessive Roberts syndrome (RBS) is characterized by tetraphocomelia, profound growth deficiency of prenatal onset, craniofacial anomalies, microcephaly, and mental deficiency."
Prenatal-onset growth deficiency.
Postnatal growth retardation HP:0008897 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postnatal growth retardation (HP:0008897). HP:0008897 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:8291532 SUPPORT REVIEW SYNTHESIS Human Clinical
"Roberts syndrome (RS) is a rare genetic disorder characterized by pre- and postnatal growth retardation, limb defects, and craniofacial anomalies."
Pre- and postnatal growth retardation.
PMID:32783269 SUPPORT BACKGROUND Human Clinical
"characterized by pre- and postnatal growth retardation, limb malformations including bilateral symmetric tetraphocomelia or mesomelia, and craniofacial dysmorphism"
Restated in a later case report.
Neoplasm 1
Malignancy Neoplasm HP:0002664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Malignancy, annotated with Neoplasm (HP:0002664). HP:0002664 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (1 reference)
PMID:20301332 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"physical examination including full skin and neurologic examination for evidence of malignancy annually"
GeneReviews malignancy surveillance.
Other 1
Perinatal death
No term is bound. HP:0003811 Neonatal death sits under Clinical course (HP:0031797 > HP:0011420 Age of death, per the OLS hierarchy), outside the PhenotypeTerm enum root HP:0000118, and just validate-terms rejects it.
Show evidence (2 references)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"Early mortality is common among severely affected infants; mildly affected individuals may survive to adulthood."
GeneReviews on survival across the spectrum.
PMID:20101700 SUPPORT Human Clinical
"These two syndromes can be considered part of a spectrum, with RBS at the most severe range in which severely affected infants may be stillborn or die in the post-natal period, while individuals with SC phocomelia represent the milder end of the spectrum and typically survive to adulthood."
Stillbirth and postnatal death at the severe end.
🧬

Genetic Associations

1
ESCO2 (Causative)
Gene: ESCO2 hgnc:27230 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ESCO2 (hgnc:27230). hgnc:27230 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE
Show evidence (7 references)
PMID:19574259 SUPPORT Human Clinical
"Of 26 mutations described to date, only one missense mutation has been reported and all others are predicted to be truncating mutations."
The variant class spectrum.
PMID:18411254 SUPPORT Human Clinical
"We observed that these mutations result in complete or partial loss of the acetyltransferase domain except for the only missense mutation that occurs in this domain (c.1615T>G, W539G)."
Truncations remove the acetyltransferase domain.
PMID:26710928 SUPPORT Human Clinical
"sequencing of the ESCO2 gene identified a novel mutation c.244_245dupCT (p.T83Pfs*20) in one family besides two previously reported mutations c.760_761insA (p.T254Nfs*27) and c.764_765delTT (p.F255Cfs*25)"
Recurrent exon 3 frameshift alleles.
+ 4 more references
💊

Medical Actions

10
Multidisciplinary Limb Management
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
Management of limb malformations through a multidisciplinary neuromuscular clinic: orthopedics, physical medicine, physical and occupational therapy, adaptive devices, prostheses, stretching, night splints and casts as needed.
Target Phenotypes: Flexion contracture HP:0001371 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Flexion contracture (HP:0001371). HP:0001371 is a phenotype from the Human Phenotype Ontology. Tetraphocomelia HP:0030721 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Tetraphocomelia (HP:0030721). HP:0030721 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"management of limb malformations through a multidisciplinary neuromuscular clinic including orthopedics, physical medicine, and physical and occupational therapy with adaptative devices, prostheses, therapy, stretching, night splints, and casts as needed"
GeneReviews management of limb malformations.
Occupational Therapy
Action: occupational therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is occupational therapy (NCIT:C121351). NCIT:C121351 is a clinical intervention from the NCI Thesaurus. Ontology label: Occupational Therapy NCIT:C121351
Platform: Behavioral / lifestyle
Occupational therapy with adaptive devices to support function.
Target Phenotypes: Oligodactyly HP:0012165 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Oligodactyly (HP:0012165). HP:0012165 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"management of limb malformations through a multidisciplinary neuromuscular clinic including orthopedics, physical medicine, and physical and occupational therapy with adaptative devices, prostheses, therapy, stretching, night splints, and casts as needed"
GeneReviews includes occupational therapy.
Hand and Orthopedic Surgery
Action: hand and orthopedic surgeryNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hand and orthopedic surgery, annotated with Orthopedic Surgical Procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. Ontology label: Orthopedic Surgical Procedure NCIT:C16186
Platform: Surgery
Hand surgery to allow early prehensile grasp and improve motor function, and corrective orthopedic surgery for limb deformities. Long-term follow-up of severely affected siblings who survived infancy showed benefit from early corrective surgery.
Target Phenotypes: Aplasia/Hypoplasia of the thumb HP:0009601 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Aplasia/Hypoplasia of the thumb (HP:0009601). HP:0009601 is a phenotype from the Human Phenotype Ontology. Talipes equinovarus HP:0001762 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Talipes equinovarus (HP:0001762). HP:0001762 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"hand surgery as needed to facilitate early development of prehensile grasp and improve motor function"
GeneReviews on hand surgery.
PMID:29434756 SUPPORT Human Clinical
"The findings of this study indicate that patients who survive infancy and reach adulthood, even patients who present with severe disease symptoms, can benefit from corrective surgeries and lead better lives."
Long-term outcome of corrective surgery.
Cleft Lip and Palate Repair
Action: cleft lip and palate repairNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cleft lip and palate repair, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Specialized feeding bottle and surgical repair of cleft lip and palate by a craniofacial team, with feeding, speech and hearing follow-up.
Target Phenotypes: Cleft palate HP:0000175 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology. Bilateral cleft lip HP:0100336 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Bilateral cleft lip (HP:0100336). HP:0100336 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"specialized bottle and surgery for cleft lip and/or palate"
GeneReviews management of clefting.
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"assessment of feeding, speech development, and hearing (in those with cleft lip and palate) per craniofacial team"
GeneReviews surveillance after cleft repair.
Craniofacial Surgery for Craniosynostosis and Micrognathia
Action: craniofacial surgeryNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is craniofacial surgery, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Surgical treatment of craniosynostosis and micrognathia.
Target Phenotypes: Craniosynostosis HP:0001363 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Craniosynostosis (HP:0001363). HP:0001363 is a phenotype from the Human Phenotype Ontology. Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"surgical treatment for craniosynostosis and micrognathia"
GeneReviews management.
Feeding and Nutrition Support
Action: nutritional supportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is nutritional support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Support NCIT:C15433
Feeding and nutritional support for growth deficiency and cleft-related feeding difficulty.
Target Phenotypes: Postnatal growth retardation HP:0008897 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Postnatal growth retardation (HP:0008897). HP:0008897 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"Individualized treatment to improve quality of life; feeding and nutrition support"
GeneReviews management.
Speech Therapy and Educational Support
Action: speech therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is speech therapy, annotated with Speech Language Therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. Ontology label: Speech Language Therapy NCIT:C159273
Platform: Behavioral / lifestyle
Developmental and educational support including speech therapy.
Target Phenotypes: Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"developmental and educational support including speech therapy"
GeneReviews management.
Multisystem Surveillance
Action: surveillanceNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surveillance, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
At each visit: growth, limb function, development, blood pressure, infection frequency and home adaptation. Annual kidney function tests and annual skin and neurologic examination for malignancy; ophthalmologic and cardiac follow-up; serum immunoglobulins in infancy; neurology referral with brain imaging for vascular anomalies and aneurysms in those with intellectual disability, corneal opacities or heart defects, and annual assessment for aneurysm from adolescence.
Target Phenotypes: Intracranial aneurysm HP:0004944 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Intracranial aneurysm, annotated with Dilatation of the cerebral artery (HP:0004944). HP:0004944 is a phenotype from the Human Phenotype Ontology. Renal dysplasia HP:0000110 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Renal dysplasia (HP:0000110). HP:0000110 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"referral to neurologist including brain imaging for vascular anomalies and aneurysms in those with intellectual disability, corneal opacities, and/or heart defects"
GeneReviews neurovascular surveillance.
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"Assess growth, limb mobility and function, development and educational needs, blood pressure, frequency of infections, and home adaptation needs at each visit"
GeneReviews routine surveillance.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Recurrence counseling for a 25% sib risk, carrier testing of relatives and prenatal or preimplantation testing once both ESCO2 variants are known.
Show evidence (1 reference)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"Once the ESCO2 pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible."
GeneReviews genetic counseling.
L-leucine (preclinical)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: L-leucine CHEBI:15603 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses L-leucine (CHEBI:15603). CHEBI:15603 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Investigational only. Stimulating mTORC1 with L-leucine partially rescued translation, cell division and survival in RBS cells and many developmental defects in esco2 mutant zebrafish. No human trial has been reported.
Mechanism Target:
mTORC1 Repression and Reduced Protein Translation — L-leucine activates mTORC1, counteracting its repression.
Show evidence (2 references)
PMID:24098154 SUPPORT Model Organism
"Stimulation of the TOR pathway with L-leucine rescued many developmental defects of ESCO2-mutant embryos."
Preclinical rescue in zebrafish.
PMID:26729373 SUPPORT In Vitro
"This study reveals the dramatic rescue effects of L-leucine stimulation of mTORC1 in RBS cells and supports that normal gene expression and translation requires ESCO2 function."
Preclinical rescue in patient cells.
🔬

Diagnosis

3
ESCO2 Molecular Genetic Testing
Diagnosis is established by biallelic pathogenic ESCO2 variants in a proband with suggestive findings. Mild cases without obvious limb reduction, or cases first labelled Baller-Gerold syndrome or Fanconi anemia, have been resolved by exome sequencing.
ESCO2 sequencing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"The diagnosis of ESCO2 spectrum disorder is established in a proband with suggestive clinical findings and either biallelic pathogenic variants in ESCO2 identified by molecular genetic testing or premature centromere separation identified by cytogenetic testing."
GeneReviews diagnostic criteria.
PMID:32783269 SUPPORT Human Clinical
"However, next-generation sequencing tools allow for molecular diagnosis in cases presenting with mild developmental defects."
Sequencing resolves mild presentations.
Cytogenetic Testing for Premature Centromere Separation
Conventionally stained metaphases, or FISH, show premature centromere separation and heterochromatin repulsion; this establishes the diagnosis in a proband with suggestive findings and distinguishes the disorder from other phocomelias, which are negative.
metaphase chromosome analysis NCIT:C18280 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"The diagnosis of ESCO2 spectrum disorder is established in a proband with suggestive clinical findings and either biallelic pathogenic variants in ESCO2 identified by molecular genetic testing or premature centromere separation identified by cytogenetic testing."
GeneReviews accepts the cytogenetic finding as diagnostic.
PMID:16380922 SUPPORT Human Clinical
"we delineated the clinical phenotype of the tetraphocomelia spectrum that is associated with HR and ESCO2 mutations and differentiated it from other types of phocomelia that are negative for HR."
Heterochromatin repulsion separates this disease from other phocomelias.
Prenatal Ultrasound and Fetal Testing
Symmetric limb reduction, growth restriction and bilateral clefting on fetal ultrasound, confirmed by cytogenetics or ESCO2 testing of amniocytes or chorionic villi.
fetal ultrasound NCIT:C222238 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:20301332 SUPPORT REVIEW SYNTHESIS Human Clinical
"Prenatal testing for pregnancies at increased risk is also possible by cytogenetic testing of fetal cells obtained by amniocentesis or chorionic villus sampling in conjunction with ultrasound examination."
GeneReviews prenatal testing.
PMID:26710928 SUPPORT Human Clinical
"Serial fetal ultrasound examinations and measurements of long bones diagnosed two affected fetuses in two of the studied families."
Ultrasound long-bone measurement identified affected fetuses.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Population prevalence is not established. Case reports and reviews cite roughly 150 published individuals of diverse ancestry; a 1993 review collected 100 cases.
Show evidence (2 references)
PMID:38288163 SUPPORT BACKGROUND Human Clinical
"The prevalence of ESCO2 spectrum disorder is unclear. Approximately 150 individuals of diverse ethnic backgrounds have been reported in the literature"
Literature case count restated in the introduction of a case report.
PMID:8291532 SUPPORT REVIEW SYNTHESIS Human Clinical
"This report reviews 100 cases of RS"
An earlier literature review assembling 100 cases.
🔀

Differential Diagnoses

7

Conditions with similar clinical presentations that must be differentiated from Roberts Syndrome:

Juberg-Hayward syndrome Not Yet Curated MONDO:0008992
Overlapping Features Allelic ESCO2 disorder (homozygous p.Arg552Ter in the reported families) with cleft lip and palate, ptosis, short stature, thumb hypoplasia and humeroradial synostosis or radial head dislocation, and premature centromere separation; microcephaly is inconsistent. Treated as a distinct allelic entity by MONDO and by its describers.
Distinguishing Features
  • Humeroradial synostosis or radial head dislocation rather than phocomelia.
  • Ptosis; microcephaly inconsistent.
Show evidence (3 references)
PMID:32255174 SUPPORT Human Clinical
"Our study showed that Roberts/SC phocomelia syndrome and JHS are allelic and distinct entities."
The describers' lump/split conclusion.
PMID:32977150 SUPPORT Human Clinical
"Chromosome testing of the affected patients showed premature centromere separation."
Shares the cytogenetic sign, so cytogenetics does not separate the two.
PMID:32977150 SUPPORT Human Clinical
"Microcephaly does not appear to be a consistent feature of the syndrome."
Microcephaly is inconsistent in Juberg-Hayward syndrome.
Thalidomide embryopathy Not Yet Curated MONDO:0018034
Overlapping Features Teratogenic phocomelia after first-trimester thalidomide exposure, the origin of the "pseudothalidomide" synonym. Distinguished by exposure history, the absence of heterochromatin repulsion, and normal ESCO2; the two may share a vascular and CRL4-pathway component.
Distinguishing Features
  • Maternal thalidomide exposure.
  • No premature centromere separation.
Show evidence (2 references)
PMID:39168984 SUPPORT BACKGROUND Human Clinical
"The phenotypic similarity of RBS limb defects to thalidomide embryopathy has spurred the eponymous description of RBS as 'pseudothalidomide' syndrome"
The clinical resemblance behind the differential.
PMID:34989322 SUPPORT Model Organism
"These findings are the first to link RBS and CdLS to thalidomide teratogenicity and offer new insights into treatments."
A mechanistic link between the two.
Baller-Gerold syndrome MONDO:0009039
Overlapping Features RECQL4 disorder with craniosynostosis and radial ray aplasia; ESCO2 variants have been found in children first diagnosed with Baller-Gerold syndrome who had craniosynostosis and radial and thumb aplasia.
Distinguishing Features
  • RECQL4 variants in Baller-Gerold syndrome.
  • Premature centromere separation and ESCO2 variants in this disease.
Show evidence (1 reference)
PMID:31192177 SUPPORT Human Clinical
"Upon negative RECQL4 test, whole exome sequencing (WES) analysis performed on the two trios led to the identification of two different ESCO2 homozygous inactivating variants"
Baller-Gerold phenotype resolved as ESCO2 disease.
Fanconi anemia MONDO:0019391
Overlapping Features Chromosome-breakage disorder with radial ray defects and growth restriction. A mildly affected ESCO2 patient with an equivocal breakage study was first suspected to have mosaic Fanconi anemia; ESCO2 sequencing separates the two.
Show evidence (1 reference)
PMID:38288163 SUPPORT Human Clinical
"She was initially suspected to have mosaic Fanconi anemia but whole exome sequencing (WES) showed a likely pathogenic homozygous splice variant c.955 + 2_955+5del in the ESCO2 gene."
Fanconi anemia was the working diagnosis before sequencing.
Cornelia de Lange syndrome MONDO:0016033
Overlapping Features Cohesinopathy caused by NIPBL or cohesin-subunit variants, with limb reduction, growth deficiency and intellectual disability, usually heterozygous; clinically distinct from this disease.
Show evidence (2 references)
PMID:21637801 SUPPORT BACKGROUND Model Organism
"CdLS is caused by heterozygous mutations in NIPBL or cohesin subunits SMC1A and SMC3, and RBS is caused by homozygous mutations in ESCO2."
Different genes and inheritance for the two cohesinopathies.
PMID:21637801 SUPPORT BACKGROUND Model Organism
"However, the two syndromes have distinct phenotypes, with differences not explained by their shared ontology."
The two are clinically distinct.
Warsaw breakage syndrome MONDO:0013252
Overlapping Features DDX11 cohesinopathy with a sister chromatid cohesion defect, growth restriction and microcephaly.
Show evidence (1 reference)
PMID:31935221 SUPPORT BACKGROUND In Vitro
"Roberts Syndrome (RBS) and Warsaw Breakage Syndrome (WABS) are rare human developmental syndromes that are characterized by defective SCC."
Both are cohesion-defect syndromes.
ESCO2-negative tetraphocomelia (pseudo-Roberts syndrome)
Overlapping Features Tetraphocomelia and other Roberts-like anomalies with normal karyotype, microarray and ESCO2 testing.
Show evidence (1 reference)
PMID:33026893 SUPPORT Human Clinical
"Karyotype, prenatal chromosome microarray and ESCO2 gene testing were normal."
A phenocopy without the molecular or cytogenetic lesion.
🧫

Experimental Models

2
RBS patient fibroblasts complemented with ESCO2 CELL_LINE
Immortalized RBS fibroblasts compared with isogenic lines stably expressing wild-type or W539G ESCO2.
Publication
PMID:19738907
Pathograph links
Failed Pericentric Sister Chromatid Cohesion Establishment rescues fidelity: high observes: cellular Wild-type ESCO2 corrects the cohesion defect; the patient missense allele does not.
Limitations: Immortalized cultured fibroblasts; no developmental readout.
Show evidence (1 reference)
PMID:19738907 SUPPORT In Vitro
"We show that the sister chromatid cohesion defect in the transfected cell lines is rescued"
Complementation result.
Genotoxin Hypersensitivity and Defective DNA Damage Response measures fidelity: high observes: cellular Isogenic measurement of drug sensitivity.
Limitations: Cultured cells; relevance to embryonic tissues untested.
Show evidence (1 reference)
PMID:19738907 SUPPORT In Vitro
"In comparison to the corrected cells RBS cells were hypersensitive to the DNA-damaging agents mitomycin C, camptothecin and etoposide, while no particular sensitivity to UV, ionizing radiation, hydroxyurea or aphidicolin was found."
Isogenic genotoxin sensitivity.
RBS patient cells with mTORC1 stimulation CELL_LINE
Human RBS cell lines analyzed for nucleolar morphology, mTORC1 signaling, p53 activation, translation and the effect of L-leucine.
Publication
PMID:24098154
Pathograph links
mTORC1 Repression and Reduced Protein Translation measures fidelity: moderate observes: cellular Measures mTORC1 repression and its L-leucine rescue.
Limitations: Immortalized cell lines; whether the translational deficit operates in embryonic limb or facial progenitors is untested in mammals.
Show evidence (1 reference)
PMID:24098154 SUPPORT In Vitro
"We report that mTOR signaling is inhibited in human RBS cells based on the reduced phosphorylation of the downstream effectors S6K1, S6 and 4EBP1, and this correlates with p53 activation."
Direct measurement in patient cells.
🐁

Animal Models

6
Esco2 constitutive knockout mouse
Constitutive loss of Esco2 ends development at pre- and post-implantation stages; Esco2-deficient embryonic fibroblasts show reduced Smc3 acetylation and Sororin recruitment, loss of pericentric cohesion, railroad-track chromosomes, prometaphase delay and apoptosis.
Species
Mouse
Genotype
Esco2 null (Cre-mediated deletion of exons 2-3)
Publication
PMID:22101327
Pathograph links
Failed Pericentric Sister Chromatid Cohesion Establishment recapitulates fidelity: high observes: cellular Reproduces the pericentric cohesion defect and railroad chromosomes.
Limitations: Complete loss is lethal in early embryos, whereas patients survive, so the organismal phenotype cannot be studied without conditional deletion.
Show evidence (1 reference)
PMID:22101327 SUPPORT Model Organism
"Here, we show that Esco2 deficiency leads to termination of mouse development at pre- and post-implantation stages, indicating that Esco2 functions non-redundantly with Esco1."
The model and its lethality.
Esco2 limb mesenchyme conditional knockout mouse (Prrx1-Cre)
Deletion of Esco2 in limb mesenchyme produces fully penetrant phocomelia with skull flattening and micrognathia, most animals dying perinatally. p53 signaling in a pre-apoptotic mesenchymal population from E9.5, apoptosis from E10.5, vascular disorganization and hemorrhage by E12.5; in utero pifithrin-alpha reduced apoptosis and prevented hemorrhage but did not restore chondrogenesis.
Species
Mouse
Genotype
Esco2fl/fl;Prrx1-CreTg/0 (exon 4 deletion modeled on human c.879_880delAG)
Publication
PMID:39168984
Pathograph links
Limb Bud Outgrowth Failure recapitulates fidelity: high observes: tissue Reproduces symmetric limb reduction resembling the human phenotype.
Limitations: Deletion restricted to Prrx1-expressing mesenchyme, so contributions from other limb lineages (ectoderm, endothelium) and systemic effects are not modeled.
Show evidence (1 reference)
PMID:39168984 SUPPORT Model Organism
"Esco2fl/fl;Prrx1-CreTg/0 pups at P0 were born with striking limb reduction that resembled the human RBS phenotype"
Model faithfully shows the limb phenotype.
Limb Bud Vascular Disruption and Hemorrhage recapitulates fidelity: unknown observes: tissue The only model in which the vascular arm has been shown.
Limitations: No human embryonic tissue is available to confirm a vascular component.
Show evidence (1 reference)
PMID:39168984 SUPPORT Model Organism
"Our results reveal morphological and vascular defects culminating in hemorrhage of mutant limbs at E12.5."
Vascular phenotype in the model.
p53 Pathway Activation perturbs fidelity: moderate observes: tissue Pifithrin-alpha p53 inhibition in utero.
Limitations: Rescued hemorrhage and reduced apoptosis but did not restore chondrogenesis or full limb morphology.
Show evidence (1 reference)
PMID:39168984 SUPPORT Model Organism
"The morphology of the limb was not fully recovered, which suggests a more primary role of p53 in supporting the vascular phenotype."
Partial rescue after p53 inhibition.
Esco2 cortex conditional knockout mouse (Emx1-Cre)
Cortex-specific Esco2 deletion causes apoptosis of radial glial and intermediate progenitors and their neurons and failure of cortical layering.
Species
Mouse
Genotype
Esco2fl/fl;Emx1-Cre
Publication
PMID:33798452
Pathograph links
Cortical Progenitor Loss recapitulates fidelity: moderate observes: tissue Progenitor apoptosis and neuron loss in the developing cortex.
Limitations: Complete deletion in cortical progenitors is more severe than the human microcephaly, in which ESCO2 function is reduced systemically but patients may have normal intelligence.
Show evidence (1 reference)
PMID:33798452 SUPPORT Model Organism
"Taking our data together, we show that ESCO2 expression is essential for the maintenance of IPCs and proper neurogenesis during cortical development."
Summary of the cortical model.
esco2 morphant zebrafish
Esco2-depleted embryos show mitotic defects, craniofacial abnormalities and fin truncations, with high cell death and cell-cycle and apoptosis gene expression changes distinct from those after rad21 loss.
Species
Zebrafish
Genotype
esco2 morpholino knockdown
Publication
PMID:21637801
Pathograph links
Apoptosis of Proliferating Embryonic Progenitors recapitulates fidelity: moderate observes: organism Widespread cell death accompanies RBS-like craniofacial and fin defects.
Limitations: Morpholino knockdown can cause off-target p53 activation and toxicity; fish fins are not homologous in detail to tetrapod limb segments.
Show evidence (1 reference)
PMID:21637801 SUPPORT Model Organism
"Esco2 depleted zebrafish embryos exhibit features that resemble RBS, including mitotic defects, craniofacial abnormalities and limb truncations."
The model shows RBS-like features.
esco2 mutant zebrafish
Live imaging shows premature chromatid separation, chromosome scattering, prolonged mitotic delay, anaphase bridges, micronuclei and aneuploidy, with p53-dependent neural tube apoptosis; 10-20% of cells keep weakened cohesion without Esco2.
Species
Zebrafish
Genotype
esco2 embryonic-lethal mutant from a genomic-instability screen
Publication
PMID:26044958
Pathograph links
Prolonged Mitosis and Chromosome Missegregation recapitulates fidelity: high observes: cellular Direct in vivo observation of the mitotic defect.
Limitations: Embryonic lethal; limb and palate phenotypes cannot be assessed.
Show evidence (1 reference)
PMID:26044958 SUPPORT Model Organism
"These studies provide a unique in vivo vertebrate view of the mitotic defects and consequences of cohesion establishment loss, and they provide a compensation-based model to explain the RBS phenotypes."
The model's contribution.
esco2 R80S mutant medaka
Developmental arrest with craniofacial and chromosomal abnormalities, embryonic lethality, widespread apoptosis and reduced notch1a expression.
Species
Medaka
Genotype
esco2 R80S homozygous (TILLING)
Publication
PMID:22694322
Pathograph links
Apoptosis of Proliferating Embryonic Progenitors recapitulates fidelity: moderate observes: organism Apoptosis and craniofacial defects in a missense mutant.
Limitations: Embryonic lethal; fish lack tetrapod limbs.
Show evidence (1 reference)
PMID:22694322 SUPPORT Model Organism
"The medaka mutant carrying the homozygous mutation at R80S in the conserved region of ESCO2 exhibited clinical variety (i.e. developmental arrest with craniofacial and chromosomal abnormalities and embryonic lethality) as characterized in RBS/SC."
RBS-like features in the medaka model.
{ }

Source YAML

click to show 
name: Roberts Syndrome
creation_date: "2026-09-25T13:56:18Z"
category: Mendelian
synonyms:
- Roberts-SC phocomelia syndrome
- ESCO2 spectrum disorder
- Roberts syndrome/SC phocomelia
- RBS
- SC phocomelia syndrome
- SC pseudothalidomide syndrome
- pseudothalidomide syndrome
- phocomelia-pseudothalidomide syndrome
- Roberts tetraphocomelia syndrome
- tetraphocomelia-cleft palate syndrome
- Appelt-Gerken-Lenz syndrome
description: >-
  Roberts syndrome, now also called ESCO2 spectrum disorder, is an autosomal
  recessive cohesinopathy caused by biallelic loss-of-function variants in
  ESCO2, the acetyltransferase that acetylates the SMC3 subunit of cohesin
  during S phase so that sister chromatids stay paired until anaphase. The
  clinical picture is prenatal-onset growth restriction, symmetric limb
  reduction in which the upper limbs are more often and more severely affected
  than the lower (from bilateral tetraphocomelia to mesomelic shortening,
  oligodactyly and thumb aplasia), flexion contractures, and a characteristic
  face with microcephaly, bilateral cleft lip and palate, micrognathia, widely
  spaced prominent eyes, malar flattening and underdeveloped nasal alae.
  Microphthalmia and corneal opacities, intellectual disability, cardiac and
  renal malformations, and in survivors cerebrovascular disease, are also
  reported.

  Severity is a continuum. The severe end (historically Roberts syndrome,
  OMIM 268300) includes stillbirth and neonatal death; the mild end
  (historically SC phocomelia, OMIM 269000) has lesser limb reduction and
  survival into adulthood. Both ends carry the same cytogenetic sign,
  premature centromere separation (heterochromatin repulsion, or "railroad
  track" chromosomes), and the same class of truncating ESCO2 alleles, so
  genotype does not predict severity and the two are curated here as one
  disease.

  The cellular lesion is failure to establish cohesion at pericentric
  heterochromatin. In patient cells and in fish and mouse models this is
  followed by prolonged mitosis, chromosome missegregation and aneuploidy,
  p53 activation and death or reduced proliferation of rapidly dividing
  embryonic progenitors, which is the most widely held explanation for the
  limb and craniofacial reduction. Impaired ribosome biogenesis with mTORC1
  repression, cohesin-dependent transcriptional dysregulation, and, in the
  developing mouse limb, p53-dependent vascular disruption and hemorrhage are
  documented additional mechanisms whose relative weight is unresolved.
disease_term:
  preferred_term: Roberts-SC phocomelia syndrome
  term:
    id: MONDO:0100253
    label: Roberts-SC phocomelia syndrome
parents:
- cohesinopathy
- limb reduction defect
- autosomal recessive disease
notes: >-
  Lump/split. MONDO:0100253 carries both OMIM 268300 (Roberts syndrome) and
  OMIM 269000 (SC phocomelia) as cross-references, and the GeneReviews chapter
  (PMID:20301332) treats them as one ESCO2 spectrum disorder. The two names
  describe the severe and mild ends of one continuum with the same gene, the
  same allele class and the same cytogenetic sign (PMID:16380922,
  PMID:20101700), so no has_subtypes are declared; severity variation is
  described in the phenotype entries instead.

  Juberg-Hayward syndrome (MONDO:0008992, OMIM 216100) is caused by biallelic
  ESCO2 variants as well (a homozygous p.Arg552Ter allele in the reported
  families) and shows premature centromere separation, but it is kept as a
  separate, allelic entity with cleft lip and palate, thumb hypoplasia and
  humeroradial synostosis or radial head dislocation, following MONDO and the
  authors who described it (PMID:32255174, PMID:32977150). It is listed as a
  differential diagnosis here and is discussed as a syndromic context in
  kb/disorders/Humeroradial_Synostosis.yaml.

  Tetraphocomelia with a normal karyotype and no ESCO2 variant has been
  reported as "pseudo-Roberts syndrome" (PMID:33026893); such cases are not
  this disease.

  The limb and cerebral-cortex progenitor loss described in this entry is
  supported by conditional Esco2 knockout mice (PMID:39168984, PMID:33798452);
  constitutive Esco2 loss is lethal before or shortly after implantation in
  the mouse (PMID:22101327), whereas human patients survive, which is recorded
  as a model-mismatch discussion.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic ESCO2 variants, homozygous (often with parental consanguinity)
    or compound heterozygous. Parents of an affected child are asymptomatic
    heterozygotes and each sib has a 25% risk of being affected. Carrier,
    prenatal and preimplantation testing are possible once both variants are
    known; prenatal diagnosis is also possible by cytogenetic detection of
    premature centromere separation in amniocytes or chorionic villi with
    ultrasound for limb reduction.
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      ESCO2 spectrum disorder is inherited in an autosomal recessive manner.
    explanation: GeneReviews genetic counseling statement of the mode of inheritance.
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      If both parents are known to be heterozygous for an ESCO2 pathogenic
      variant, each sib of an affected individual has at conception a 25%
      chance of inheriting both pathogenic variants and being affected, a 50%
      chance of inheriting one pathogenic variant and being an asymptomatic
      carrier, and a 25% chance of being unaffected and not a carrier.
    explanation: GeneReviews recurrence-risk figures for sibs.
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Prenatal testing for pregnancies at increased risk is also possible by
      cytogenetic testing of fetal cells obtained by amniocentesis or
      chorionic villus sampling in conjunction with ultrasound examination.
    explanation: GeneReviews on cytogenetic prenatal diagnosis.
  - reference: PMID:15821733
    reference_title: Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Roberts syndrome is an autosomal recessive disorder characterized by
      craniofacial anomalies, tetraphocomelia and loss of cohesion at
      heterochromatic regions of centromeres and the Y chromosome.
    explanation: Gene-discovery paper stating recessive inheritance.
  - reference: PMID:18186147
    reference_title: Prenatal diagnosis of Roberts syndrome and detection of an ESCO2 frameshift mutation in a Pakistani family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous mutation leading to a frameshift in ESCO2 was identified in
      the fetal DNA sample. Both parents are heterozygous carriers of the same
      mutation.
    explanation: Recurrence in sibs with heterozygous carrier parents.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Population prevalence is not established. Case reports and reviews cite
    roughly 150 published individuals of diverse ancestry; a 1993 review
    collected 100 cases.
  evidence:
  - reference: PMID:38288163
    reference_title: "Case report: The evolving phenotype of ESCO2 spectrum disorder in a 15-year-old Malaysian child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      The prevalence of ESCO2 spectrum disorder is unclear. Approximately 150
      individuals of diverse ethnic backgrounds have been reported in the
      literature
    explanation: Literature case count restated in the introduction of a case report.
  - reference: PMID:8291532
    reference_title: "Roberts syndrome: a review of 100 cases and a new rating system for severity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      This report reviews 100 cases of RS
    explanation: An earlier literature review assembling 100 cases.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:39168984
      reference_title: Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        Roberts syndrome (RBS) is an autosomal recessive disorder with profound
        growth deficiency and limb reduction caused by ESCO2 loss-of-function
        variants.
      explanation: A single-gene recessive malformation syndrome.
  isds_skeletal_category:
  - classification_value: limb_hypoplasia_reduction_defects
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et
      al., PMID:36779427), group "Limb hypoplasia - reduction defects", where
      Roberts syndrome is listed with ESCO2.
pathophysiology:
- name: ESCO2 Biallelic Loss of Function
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Homozygous or compound heterozygous ESCO2 variants that remove all or part
    of the C-terminal acetyltransferase domain (frameshift, nonsense and
    splice-site alleles, often in exon 3), or, rarely, missense changes in
    that domain such as W539G that abolish autoacetylation. Truncating alleles
    lower mRNA through nonsense-mediated decay and no truncated protein is
    detected in patient cells.
  gene:
    preferred_term: ESCO2
    term:
      id: hgnc:27230
      label: ESCO2
  genetic_context:
    gene:
      preferred_term: ESCO2
      term:
        id: hgnc:27230
        label: ESCO2
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Biallelic, homozygous or compound heterozygous; most alleles are
      protein-truncating.
  molecular_functions:
  - preferred_term: cohesin acetyltransferase activity
    term:
      id: GO:0061733
      label: protein-lysine-acetyltransferase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:15821733
    reference_title: Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified mutations in a new human gene, ESCO2, associated with
      Roberts syndrome in 15 kindreds.
    explanation: Gene discovery.
  - reference: PMID:16380922
    reference_title: "Inactivating mutations in ESCO2 cause SC phocomelia and Roberts syndrome: no phenotype-genotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Since only protein-truncating mutations were identified, regardless of
      clinical severity, we conclude that genotype does not predict phenotype.
    explanation: Truncating alleles across the whole severity range, including SC phocomelia.
  - reference: PMID:18411254
    reference_title: The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found that ESCO2 W539G results in loss of autoacetyltransferase
      activity.
    explanation: The one missense allele abolishes the enzymatic activity.
  - reference: PMID:16775838
    reference_title: "A homozygous frameshift mutation in the ESCO2 gene: evidence of intertissue and interindividual variation in Nmd efficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we used Western blot analysis to demonstrate the absence of the
      ESCO2-truncated protein in cells derived from both fetuses
    explanation: No truncated protein from a frameshift allele in fetal cells.
  - reference: PMID:27803161
    reference_title: Molecular Basis for Cohesin Acetylation by Establishment of Sister Chromatid Cohesion N-Acetyltransferase ESCO1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Missense mutations within the acetyltransferase domain of these proteins
      correlate with diseases, including endometrial cancers and Roberts
      syndrome.
    explanation: >-
      Places the rare RBS missense alleles in the acetyltransferase domain;
      the paper's own data are the ESCO1 crystal structure.
  downstream:
  - target: Reduced SMC3 Acetylation of Chromatin-Bound Cohesin
    causal_link_type: DIRECT
    description: ESCO2 is an acetyltransferase whose substrate is the SMC3 subunit of cohesin.
    evidence:
    - reference: PMID:22101327
      reference_title: Cohesin acetyltransferase Esco2 is a cell viability factor and is required for cohesion in pericentric heterochromatin.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we show here that Smc3 acetylation is >50% reduced in MEFsEsco2Δ/Δ
      explanation: Loss of Esco2 in mouse embryonic fibroblasts lowers Smc3 acetylation.
- name: Reduced SMC3 Acetylation of Chromatin-Bound Cohesin
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Without ESCO2, S-phase acetylation of SMC3 is reduced, particularly at
    pericentric heterochromatin where ESCO2 localizes, and less Sororin is
    recruited to chromatin-bound cohesin. ESCO1 provides partial redundancy,
    which is one explanation for why human cells and patients remain viable.
  protein_complexes:
  - preferred_term: cohesin complex
    term:
      id: GO:0008278
      label: cohesin complex
  cellular_components:
  - preferred_term: pericentric heterochromatin
    term:
      id: GO:0005721
      label: pericentric heterochromatin
  evidence:
  - reference: PMID:22101327
    reference_title: Cohesin acetyltransferase Esco2 is a cell viability factor and is required for cohesion in pericentric heterochromatin.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In interphase, Esco2 depletion leads to a reduction in cohesin
      acetylation and Sororin recruitment to chromatin.
    explanation: Reduced cohesin acetylation and Sororin loading in Esco2-deficient cells.
  - reference: PMID:22101327
    reference_title: Cohesin acetyltransferase Esco2 is a cell viability factor and is required for cohesion in pericentric heterochromatin.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Esco2 is transiently expressed during S-phase when it localizes to
      pericentric heterochromatin (PCH).
    explanation: Places the ESCO2 requirement at pericentric heterochromatin in S phase.
  downstream:
  - target: Failed Pericentric Sister Chromatid Cohesion Establishment
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22101327
      reference_title: Cohesin acetyltransferase Esco2 is a cell viability factor and is required for cohesion in pericentric heterochromatin.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Our results suggest that Esco2 is needed for cohesin acetylation in
        PCH and that this modification is required for the proper distribution
        of cohesin on mitotic chromosomes and for centromeric cohesion.
      explanation: Links the acetylation defect to loss of centromeric cohesion.
- name: Failed Pericentric Sister Chromatid Cohesion Establishment
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Sister chromatids are not held together at pericentric heterochromatin
    and the Yq heterochromatin. In metaphase spreads this is seen as premature
    centromere separation and heterochromatin repulsion (puffing), giving the
    "railroad track" chromosome, the diagnostic cytogenetic sign. 3D-FISH of
    fetal nuclei shows the separation already in interphase. Restoring
    wild-type, but not W539G, ESCO2 corrects the defect in patient cells.
  biological_processes:
  - preferred_term: establishment of mitotic sister chromatid cohesion
    term:
      id: GO:0034087
      label: establishment of mitotic sister chromatid cohesion
    modifier: DECREASED
  - preferred_term: centromeric sister chromatid cohesion
    term:
      id: GO:0071962
      label: mitotic sister chromatid cohesion, centromeric
    modifier: DECREASED
  cellular_components:
  - preferred_term: pericentric heterochromatin
    term:
      id: GO:0005721
      label: pericentric heterochromatin
  evidence:
  - reference: PMID:15821733
    reference_title: Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Roberts syndrome is an autosomal recessive disorder characterized by
      craniofacial anomalies, tetraphocomelia and loss of cohesion at
      heterochromatic regions of centromeres and the Y chromosome.
    explanation: Loss of cohesion at heterochromatic centromeric regions is part of the defining picture.
  - reference: PMID:19738907
    reference_title: The cellular phenotype of Roberts syndrome fibroblasts as revealed by ectopic expression of ESCO2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that the sister chromatid cohesion defect in the transfected
      cell lines is rescued
    explanation: Complementation of patient fibroblasts with ESCO2 corrects the cohesion defect.
  - reference: PMID:19738907
    reference_title: The cellular phenotype of Roberts syndrome fibroblasts as revealed by ectopic expression of ESCO2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The cohesion defect of RBS cells and their hypersensitivity to
      DNA-damaging agents were not corrected by a patient-derived ESCO2
      acetyltransferase mutant (W539G), indicating that the acetyltransferase
      activity of ESCO2 is essential for its function.
    explanation: The acetyltransferase activity is required to establish cohesion.
  - reference: PMID:25320640
    reference_title: 3D-FISH analysis reveals chromatid cohesion defect during interphase in Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Along with the first observation of an abnormal separation between
      sister chromatids in heterochromatic regions
    explanation: Heterochromatic sister-chromatid separation seen in interphase nuclei of an affected fetus.
  downstream:
  - target: Premature Centromere Separation on Metaphase Spreads
    causal_link_type: DIRECT
    description: The cohesion defect is what the cytogenetic test visualizes.
  - target: Prolonged Mitosis and Chromosome Missegregation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22101327
      reference_title: Cohesin acetyltransferase Esco2 is a cell viability factor and is required for cohesion in pericentric heterochromatin.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This loss-of-cell-viability phenotype is likely caused by a defect in
        sister chromatid cohesion in the PCH of all chromosomes, leading to a
        prometaphase delay and apoptosis.
      explanation: The pericentric cohesion defect produces a prometaphase delay in Esco2-deficient mouse cells and embryos.
  - target: Nucleolar Fragmentation and Impaired Ribosome Biogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - ribosome_biogenesis_translation_defect
    description: >-
      Proposed to follow from reduced cohesin acetylation at the rDNA rather
      than from the mitotic defect; the intermediate steps are not established.
    evidence:
    - reference: PMID:25054091
      reference_title: "Roberts syndrome: A deficit in acetylated cohesin leads to nucleolar dysfunction."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        In Roberts syndrome, the lack of cohesin acetylation contributes to
        nucleolar defects and translational inhibition.
      explanation: Review stating the proposed link from the acetylation deficit to nucleolar dysfunction.
  - target: Cohesin-Dependent Transcriptional Dysregulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - cohesin_transcriptional_dysregulation
- name: Premature Centromere Separation on Metaphase Spreads
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Cytogenetic manifestation of the cohesion defect: centromeres of most
    chromosomes are separated in metaphase and the pericentric heterochromatin
    of chromosomes 1, 9 and 16 and distal Yq appears puffed or repelled. Seen
    in lymphocytes, fibroblasts, amniocytes and chorionic villi, and used as a
    diagnostic test. Also modeled as a Cellular phenotype.
  evidence:
  - reference: PMID:8291532
    reference_title: "Roberts syndrome: a review of 100 cases and a new rating system for severity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Mitotic cells from many individuals with RS display a characteristic
      cytogenetic phenomenon consisting of repulsion of heterochromatic
      regions near centromeres, particularly of chromosomes 1, 9, 16, and
      splaying of the short arms of the acrocentrics and of the distal Yq.
    explanation: Describes the heterochromatin repulsion seen in patient mitoses.
  - reference: PMID:26710928
    reference_title: Expanding the mutation and clinical spectrum of Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cytogenetic analysis showed the characteristic premature separation of
      centromeres and puffing of heterochromatic regions.
    explanation: Found in three molecularly confirmed patients.
  downstream:
  - target: Premature centromere separation
    causal_link_type: DIRECT
    description: The cellular state is recorded as a Cellular phenotype used diagnostically.
- name: Prolonged Mitosis and Chromosome Missegregation
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Cells lacking ESCO2 spend longer in prometaphase and metaphase and show
    scattered, lagging and prematurely advancing chromosomes, anaphase bridges
    and micronuclei. PROVISIONAL because the mitotic delay is shown in reviews
    of patient cells, in fish embryos and in mouse cells, but a study of
    patient lymphoblastoid lines found reduced proliferation with cell death
    and no increase in cell-cycle duration (PMID:18411254); see
    mechanistic_hypotheses.
  biological_processes:
  - preferred_term: chromosome segregation
    term:
      id: GO:0007059
      label: chromosome segregation
    modifier: ABNORMAL
  - preferred_term: mitotic spindle assembly checkpoint signaling
    term:
      id: GO:0007094
      label: mitotic spindle assembly checkpoint signaling
    modifier: INCREASED
  evidence:
  - reference: PMID:8291532
    reference_title: "Roberts syndrome: a review of 100 cases and a new rating system for severity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Mitosis in RS cells is abnormal in metaphase duration and anaphase
      progression.
    explanation: Review of cell-biology findings in patient cells.
  - reference: PMID:8291532
    reference_title: "Roberts syndrome: a review of 100 cases and a new rating system for severity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Specifically, anaphase figures show a higher degree of chromosomes that
      are outlying, lagging, or prematurely advancing toward the poles
      compared to normal controls.
    explanation: Missegregation in patient anaphases.
  - reference: PMID:26044958
    reference_title: Variations in dysfunction of sister chromatid cohesion in esco2 mutant zebrafish reflect the phenotypic diversity of Roberts syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Within esco2 mutant embryos, we observed premature chromatid separation,
      a unique chromosome scattering, prolonged mitotic delay, and genomic
      instability in the form of anaphase bridges and micronuclei formation.
    explanation: Live imaging of mitosis in esco2 mutant zebrafish embryos.
  - reference: PMID:31935221
    reference_title: Non-redundant roles in sister chromatid cohesion of the DNA helicase DDX11 and the SMC3 acetyl transferases ESCO1 and ESCO2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Synthetic lethality between DDX11 and ESCO2 correlated with a prolonged
      delay in mitosis, and was rescued by knockdown of the cohesin remover
      WAPL.
    explanation: In RBS-derived cells, further loss of cohesion deepens the mitotic delay and kills cells.
  - reference: PMID:18411254
    reference_title: The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      We found decreased proliferation capacity in RBS cell lines associated
      with cell death, but not with increased cell cycle duration
    explanation: >-
      Patient lymphoblastoid lines showed no lengthening of the cell cycle,
      contradicting a prolonged-mitosis account in those cells.
  downstream:
  - target: Somatic Aneuploidy and Micronucleus Formation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:8291532
      reference_title: "Roberts syndrome: a review of 100 cases and a new rating system for severity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        RS cells have abnormal nuclear morphology and also show a higher
        frequency of micronucleation than normal cells, presumably as a result
        of the abnormal mitotic events during anaphase.
      explanation: Micronuclei attributed to the abnormal anaphase events.
  - target: p53 Pathway Activation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - mitotic_failure_progenitor_apoptosis
    evidence:
    - reference: PMID:26044958
      reference_title: Variations in dysfunction of sister chromatid cohesion in esco2 mutant zebrafish reflect the phenotypic diversity of Roberts syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We also demonstrated that the genomic instability leads to
        p53-dependent neural tube apoptosis.
      explanation: In esco2 mutant fish, the mitotic genomic instability triggers p53-dependent apoptosis.
- name: Somatic Aneuploidy and Micronucleus Formation
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Aneuploid metaphases at variable rates in patient amniocytes,
    lymphocytes and fibroblasts, and in esco2 mutant fish. In two siblings,
    fibroblasts from hypopigmented skin carried much more aneuploidy
    (especially trisomy 7) than fibroblasts from normally pigmented skin,
    suggesting that somatic aneuploidy can generate patchy skin phenotypes.
  evidence:
  - reference: PMID:18186147
    reference_title: Prenatal diagnosis of Roberts syndrome and detection of an ESCO2 frameshift mutation in a Pakistani family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cytogenetic analysis of amniocytes revealed a normal male karyotype in
      20 analyzed metaphases and chromosomal aneuploidies in 10 metaphases.
    explanation: Aneuploidy in a third of fetal metaphases.
  - reference: PMID:26044958
    reference_title: Variations in dysfunction of sister chromatid cohesion in esco2 mutant zebrafish reflect the phenotypic diversity of Roberts syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cytogenetic studies indicated complete chromatid separation and high
      levels of aneuploidy within mutant embryos.
    explanation: Aneuploidy in the zebrafish model.
  downstream:
  - target: Hypopigmented skin patches
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30590172
      reference_title: Hypopigmented patches in Roberts/SC phocomelia syndrome occur via aneuploidy susceptibility.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        chromosome analysis of fibroblast cultures obtained from the
        hypopigmented skin region showed a much higher frequency of
        aneuploidy, especially trisomy 7, than normopigmented skin fibroblasts
        and lymphocyte cultures for both patients
      explanation: Aneuploidy is concentrated in the hypopigmented skin.
- name: Genotoxin Hypersensitivity and Defective DNA Damage Response
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Patient cells are hypersensitive to mitomycin C, camptothecin and
    etoposide, and one family's lymphoblastoid cells also showed
    ionizing-radiation sensitivity with impaired double-strand break repair.
    In budding yeast, loss of the ortholog Eco1 is enough to raise endogenous
    redox stress and impair repair of oxidative DNA damage.
    Whether accumulated DNA or other macromolecular damage is a driver of the
    developmental phenotype, rather than a bystander, is unresolved.
  biological_processes:
  - preferred_term: double-strand break repair
    term:
      id: GO:0006302
      label: double-strand break repair
    modifier: DECREASED
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: ABNORMAL
  evidence:
  - reference: PMID:19738907
    reference_title: The cellular phenotype of Roberts syndrome fibroblasts as revealed by ectopic expression of ESCO2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In comparison to the corrected cells RBS cells were hypersensitive to
      the DNA-damaging agents mitomycin C, camptothecin and etoposide, while
      no particular sensitivity to UV, ionizing radiation, hydroxyurea or
      aphidicolin was found.
    explanation: Isogenic comparison of patient fibroblasts with and without ESCO2.
  - reference: PMID:30508616
    reference_title: A Roberts Syndrome Individual With Differential Genotoxin Sensitivity and a DNA Damage Response Defect.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cells derived from the RBS-affected individual showed sensitivity to
      ionizing radiation (IR) and mitomycin C-induced DNA damage.
    explanation: A second patient line, here also radiation sensitive.
  - reference: PMID:30508616
    reference_title: A Roberts Syndrome Individual With Differential Genotoxin Sensitivity and a DNA Damage Response Defect.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      a reduced capacity for repairing IR-induced DNA DSBs, as measured by
      γ-H2AX foci and the comet assay
    explanation: Reduced double-strand break repair in patient cells.
  - reference: PMID:34897432
    reference_title: Genetically induced redox stress occurs in a yeast model for Roberts syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Moreover, we show that mutation of ECO1 is solely sufficient to induce
      endogenous redox stress and sensitizes mutant cells to exogenous
      genotoxic challenges.
    explanation: >-
      In budding yeast, loss of the ESCO2 ortholog Eco1 causes endogenous
      redox stress and genotoxin sensitivity.
  - reference: PMID:34897432
    reference_title: Genetically induced redox stress occurs in a yeast model for Roberts syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Remarkably, antioxidant treatment desensitizes eco1 mutant cells to a
      range of DNA damaging agents
    explanation: The genotoxin sensitivity of eco1 yeast is redox-dependent.
  downstream:
  - target: p53 Pathway Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - macromolecular_damage
    evidence:
    - reference: PMID:39168984
      reference_title: Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We then characterize these p53-related processes of cell cycle arrest,
        DNA damage, cell death, and the inflammatory leukotriene signaling
        pathway in vivo.
      explanation: >-
        DNA damage accompanies p53 activation in Esco2-deficient limb
        mesenchyme; INDIRECT because co-occurrence is shown, not causation.
- name: Nucleolar Fragmentation and Impaired Ribosome Biogenesis
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Nucleoli are fragmented in RBS cells and rRNA production and protein
    translation are reduced. Shown in immortalized patient cells and in esco2
    mutant zebrafish; not examined in human embryonic tissue.
  biological_processes:
  - preferred_term: ribosome biogenesis
    term:
      id: GO:0042254
      label: ribosome biogenesis
    modifier: DECREASED
  evidence:
  - reference: PMID:24098154
    reference_title: Stimulation of mTORC1 with L-leucine rescues defects associated with Roberts syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Nucleoli, the sites of ribosome production, are highly fragmented in RBS
      cells.
    explanation: Nucleolar fragmentation in patient cells.
  - reference: PMID:24098154
    reference_title: Stimulation of mTORC1 with L-leucine rescues defects associated with Roberts syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: >-
      It was previously reported that ribosomal RNA production and protein
      translation were impaired in immortalized RBS cells.
    explanation: Restates the earlier finding of reduced rRNA production and translation.
  - reference: PMID:25378554
    reference_title: L-leucine partially rescues translational and developmental defects associated with zebrafish models of Cornelia de Lange syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: >-
      In a previous project, we showed that RBS was associated with highly
      fragmented nucleoli and defects in both ribosome biogenesis and protein
      translation.
    explanation: >-
      The same group's summary of its RBS cell findings, restated in a
      Cornelia de Lange syndrome zebrafish study.
  downstream:
  - target: mTORC1 Repression and Reduced Protein Translation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - ribosome_biogenesis_translation_defect
  - target: p53 Pathway Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - ribosome_biogenesis_translation_defect
    evidence:
    - reference: PMID:24098154
      reference_title: Stimulation of mTORC1 with L-leucine rescues defects associated with Roberts syndrome.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        We report that mTOR signaling is inhibited in human RBS cells based on
        the reduced phosphorylation of the downstream effectors S6K1, S6 and
        4EBP1, and this correlates with p53 activation.
      explanation: >-
        The nucleolar and mTOR defects co-occur with p53 activation in patient
        cells; INDIRECT because a correlation is reported.
- name: mTORC1 Repression and Reduced Protein Translation
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Reduced phosphorylation of S6K1, S6 and 4EBP1 in RBS cells and esco2
    mutant fish, with reduced translational efficiency of ribosomal subunit
    and translation-initiation factor mRNAs. Stimulating mTORC1 with
    L-leucine partially restores translation, cell division and survival in
    cells and many developmental defects in fish.
  biological_processes:
  - preferred_term: TORC1 signaling
    term:
      id: GO:0038202
      label: TORC1 signaling
    modifier: DECREASED
  - preferred_term: cytoplasmic translation
    term:
      id: GO:0002181
      label: cytoplasmic translation
    modifier: DECREASED
  evidence:
  - reference: PMID:24098154
    reference_title: Stimulation of mTORC1 with L-leucine rescues defects associated with Roberts syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We report that mTOR signaling is inhibited in human RBS cells based on
      the reduced phosphorylation of the downstream effectors S6K1, S6 and
      4EBP1, and this correlates with p53 activation.
    explanation: mTORC1 repression in patient cells.
  - reference: PMID:24098154
    reference_title: Stimulation of mTORC1 with L-leucine rescues defects associated with Roberts syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Consistent with RBS patient cells, the ESCO2 mutant embryos show p53
      activation and inhibition of the TOR pathway.
    explanation: The same signaling state in esco2 mutant zebrafish.
  - reference: PMID:26729373
    reference_title: Improved transcription and translation with L-leucine stimulation of mTORC1 in Roberts syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      L-leucine treatment partially rescued translational efficiency of
      ribosomal subunits, translation initiation factors, snoRNA production,
      and mitochondrial function in RBS cells
    explanation: Ribosome profiling shows a translational deficit that is mTORC1-responsive.
  downstream:
  - target: Reduced Proliferative Capacity of Embryonic Progenitors
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - ribosome_biogenesis_translation_defect
    evidence:
    - reference: PMID:24098154
      reference_title: Stimulation of mTORC1 with L-leucine rescues defects associated with Roberts syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The rescue provided by mTOR activation was more significant, with
        activation rescuing both cell division and cell death.
      explanation: Restoring mTORC1 activity restores division and survival of patient cells.
- name: Cohesin-Dependent Transcriptional Dysregulation
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Changes in gene expression that are not explained by cell death or
    mTORC1 repression: imprinted genes (H19, GTL2), HOX genes and genes in
    nucleolar-associated domains in RBS cells; reduced cx43 expression in the
    regenerating zebrafish fin after esco2 knockdown, rescued by cx43
    overexpression; and reduced ddb1 expression, linking ESCO2 to the CRL4
    ubiquitin ligase through which thalidomide acts. Altered interphase
    positioning of pericentric heterochromatin in fetal nuclei has been
    proposed as a route. How much of the human phenotype this explains is
    unknown.
  evidence:
  - reference: PMID:26729373
    reference_title: Improved transcription and translation with L-leucine stimulation of mTORC1 in Roberts syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In contrast, other genes are differentially expressed independent of
      L-leucine treatment, including imprinted genes such as H19 and GTL2,
      miRNAs regulated by GTL2, HOX genes, and genes in nucleolar associated
      domains.
    explanation: TOR-independent expression changes in patient cells.
  - reference: PMID:26434741
    reference_title: Esco2 regulates cx43 expression during skeletal regeneration in the zebrafish fin.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      esco2-knockdown significantly diminishes cx43/gja1 expression which
      encodes the gap junction connexin subunit required for cell-cell
      communication.
    explanation: A transcriptional target of Esco2 in regenerating bone.
  - reference: PMID:26434741
    reference_title: Esco2 regulates cx43 expression during skeletal regeneration in the zebrafish fin.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Importantly, miR-133-dependent cx43 overexpression rescues
      esco2-dependent growth defects.
    explanation: Restoring the target rescues the skeletal growth defect.
  - reference: PMID:34989322
    reference_title: Esco2 and cohesin regulate CRL4 ubiquitin ligase ddb1 expression and thalidomide teratogenicity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our results reveal that Esco2 and cohesin co-regulate the transcription
      of a component of CRL4 ubiquitin ligase through which thalidomide exerts
      teratogenic effects.
    explanation: Links Esco2 to the thalidomide target pathway in zebrafish embryos.
  - reference: PMID:25320640
    reference_title: 3D-FISH analysis reveals chromatid cohesion defect during interphase in Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We hypothesize that the disorganization of nuclear architecture may
      result in multiple gene deregulations
    explanation: Proposed route from altered nuclear architecture to gene dysregulation.
  downstream:
  - target: Limb Bud Outgrowth Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - cohesin_transcriptional_dysregulation
    evidence:
    - reference: PMID:29084713
      reference_title: Cohesin mediates Esco2-dependent transcriptional regulation in a zebrafish regenerating fin model of Roberts Syndrome.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Previous findings in the zebrafish regenerating fin, however, suggest
        that Esco2-knockdown results in transcription dysregulation,
        independent of apoptosis, similar to that observed in CdLS patients.
      explanation: >-
        Transcriptional dysregulation independent of apoptosis impairs
        appendage (fin ray) outgrowth in zebrafish, the model's analogue of
        the limb defect. INDIRECT because regenerating adult fin is not the
        embryonic tetrapod limb.
- name: p53 Pathway Activation
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    p53 is activated in RBS patient cells, in esco2 mutant zebrafish, and in
    a pre-apoptotic mesenchymal population of Esco2-deficient mouse limb buds
    from E9.5, where cell-cycle arrest, DNA damage and cell-death genes are
    induced. Its upstream triggers (mitotic stress, nucleolar stress, DNA
    damage) are not mutually exclusive.
  biological_processes:
  - preferred_term: p53-mediated intrinsic apoptotic signaling
    term:
      id: GO:0072332
      label: intrinsic apoptotic signaling pathway by p53 class mediator
    modifier: INCREASED
  evidence:
  - reference: PMID:39168984
    reference_title: Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Underlying this abnormal developmental progression is a pre-apoptotic,
      mesenchymal cell population specific to mutant limb buds enriched for
      p53-related signaling beginning at E9.5.
    explanation: p53 signaling in limb mesenchyme precedes the malformation.
  - reference: PMID:24098154
    reference_title: Stimulation of mTORC1 with L-leucine rescues defects associated with Roberts syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Consistent with RBS patient cells, the ESCO2 mutant embryos show p53
      activation and inhibition of the TOR pathway.
    explanation: p53 activation in patient cells and mutant fish.
  downstream:
  - target: Apoptosis of Proliferating Embryonic Progenitors
    causal_link_type: DIRECT
    hypothesis_groups:
    - mitotic_failure_progenitor_apoptosis
    evidence:
    - reference: PMID:26044958
      reference_title: Variations in dysfunction of sister chromatid cohesion in esco2 mutant zebrafish reflect the phenotypic diversity of Roberts syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We also demonstrated that the genomic instability leads to
        p53-dependent neural tube apoptosis.
      explanation: The apoptosis in esco2 mutant fish depends on p53.
  - target: Limb Bud Vascular Disruption and Hemorrhage
    causal_link_type: DIRECT
    hypothesis_groups:
    - limb_vascular_disruption
    evidence:
    - reference: PMID:39168984
      reference_title: Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In utero treatment with pifithrin-α, a p53 inhibitor, rescued the
        hemorrhage in mutant limbs.
      explanation: Pharmacological p53 inhibition prevents the limb hemorrhage.
- name: Apoptosis of Proliferating Embryonic Progenitors
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Widespread death of dividing embryonic cells: limb bud mesenchyme in the
    Esco2 conditional mouse (TUNEL-positive from E10.5), neural tube and
    whole embryos in esco2 zebrafish, and developing embryos in the R80S
    medaka mutant; patient cell lines also show proliferation loss with cell
    death. PROVISIONAL because the evidence in developing tissue is from
    animal models, and in the mouse limb p53 inhibition reduced mesenchymal
    apoptosis and rescued hemorrhage without restoring chondrogenesis.
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  cell_types:
  - preferred_term: mesenchymal cell
    term:
      id: CL:0008019
      label: mesenchymal cell
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  evidence:
  - reference: PMID:21637801
    reference_title: A zebrafish model of Roberts syndrome reveals that Esco2 depletion interferes with development by disrupting the cell cycle.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      High levels of cell death contributed to the morphology of
      Esco2-depleted embryos without affecting specific developmental
      pathways.
    explanation: Cell death drives the zebrafish morphant phenotype.
  - reference: PMID:22694322
    reference_title: Establishment and characterization of Roberts syndrome and SC phocomelia model medaka (Oryzias latipes).
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Moreover, widespread apoptosis and downregulation of some gene
      expression, including notch1a, were detected in the R80S mutant.
    explanation: Apoptosis in a second fish model.
  - reference: PMID:18411254
    reference_title: The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found decreased proliferation capacity in RBS cell lines associated
      with cell death, but not with increased cell cycle duration, which could
      be a factor in the development of phocomelia and cleft palate in RBS.
    explanation: Cell death in patient cell lines, proposed as a factor in phocomelia and cleft palate.
  downstream:
  - target: Limb Bud Outgrowth Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - mitotic_failure_progenitor_apoptosis
    evidence:
    - reference: PMID:39168984
      reference_title: Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our data show how loss of ESCO2 causes limb reduction phenotypes,
        through p53 induction, cell death, and vascular disruption.
      explanation: The authors' conclusion linking cell death to limb reduction.
    - reference: PMID:39168984
      reference_title: Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We had presumed that the extensive cell death in the mesenchyme was the
        underlying cause of the limb deficiency, but pifithrin-α treatment only
        recovered the hemorrhage in mutant limbs and not the chondrogenesis.
      explanation: >-
        Reducing mesenchymal apoptosis did not restore limb chondrogenesis,
        arguing against apoptosis as the sole cause of the reduction.
  - target: Cortical Progenitor Loss
    causal_link_type: DIRECT
    hypothesis_groups:
    - mitotic_failure_progenitor_apoptosis
  - target: Deficient Craniofacial Primordium Growth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - mitotic_failure_progenitor_apoptosis
    evidence:
    - reference: PMID:21637801
      reference_title: A zebrafish model of Roberts syndrome reveals that Esco2 depletion interferes with development by disrupting the cell cycle.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We propose that cell proliferation defects and apoptosis could be the
        primary cause of the features of RBS.
      explanation: The zebrafish study's proposal for how the craniofacial and limb features arise.
- name: Reduced Proliferative Capacity of Embryonic Progenitors
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Patient cell lines grow less, and ESCO2 is expressed in the embryonic
    brain, face, limb, kidney and gonads, the structures affected in the
    syndrome. A proliferation shortfall in progenitor pools is proposed to
    contribute, with apoptosis, to growth restriction and to limb and
    craniofacial reduction.
  biological_processes:
  - preferred_term: cell population proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
    modifier: DECREASED
  evidence:
  - reference: PMID:18411254
    reference_title: The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cellular alterations in RBS include lack of cohesion at the
      heterochromatic regions around centromeres and the long arm of the Y
      chromosome, reduced growth capacity, and hypersensitivity to DNA
      damaging agents.
    explanation: Reduced growth capacity is a recognised cellular feature of RBS.
  - reference: PMID:19574259
    reference_title: Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In situ hybridisation on human embryos showed ESCO2 expression in the
      brain, face, limb, kidney and gonads, which corresponds to the
      structures affected in RBS.
    explanation: Human embryonic expression matches the affected structures.
  downstream:
  - target: Limb Bud Outgrowth Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - mitotic_failure_progenitor_apoptosis
  - target: Deficient Craniofacial Primordium Growth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - mitotic_failure_progenitor_apoptosis
  - target: Intrauterine growth retardation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Postnatal growth retardation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Limb Bud Vascular Disruption and Hemorrhage
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    In Esco2fl/fl;Prrx1-Cre mouse embryos the limb bud vasculature is
    disorganized and dilated at E10.5 and the limbs hemorrhage by E12.5. The
    hemorrhage, but not the defective chondrogenesis, is rescued by in utero
    p53 inhibition. A vascular contribution has also been proposed for
    thalidomide embryopathy. Shown only in the mouse.
  locations:
  - preferred_term: limb bud
    term:
      id: UBERON:0004347
      label: limb bud
  evidence:
  - reference: PMID:39168984
    reference_title: Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our results reveal morphological and vascular defects culminating in
      hemorrhage of mutant limbs at E12.5.
    explanation: Vascular defects and hemorrhage in the mutant limb bud.
  - reference: PMID:39168984
    reference_title: Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In sum, our results identified p53 inhibition as a direct mediator of
      vascular hemorrhage, but not chondrogenesis in mutant limbs.
    explanation: The vascular arm is p53-dependent and separable from the cartilage defect.
  downstream:
  - target: Limb Bud Outgrowth Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - limb_vascular_disruption
    evidence:
    - reference: PMID:39168984
      reference_title: Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Lastly, significant enrichments were identified among genes associated
        with RBS, thalidomide embryopathy, and other genetic limb reduction
        disorders, suggesting a common vascular etiology among these
        conditions.
      explanation: >-
        The authors propose a vascular contribution to the limb reduction;
        INDIRECT because it is inferred from gene-set enrichment.
- name: Limb Bud Outgrowth Failure
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    The developing limb buds are smaller from early outgrowth and the
    skeletal elements that form are reduced, most severely in the upper limbs
    and in the zeugopod (mesomelia), with loss of radial-ray and digital
    elements. In the Prrx1-Cre conditional mouse, the limb bud is reduced at
    E10.5 and all 120 mutant embryos examined showed the limb phenotype.
  biological_processes:
  - preferred_term: embryonic limb morphogenesis
    term:
      id: GO:0030326
      label: embryonic limb morphogenesis
    modifier: ABNORMAL
  locations:
  - preferred_term: limb bud
    term:
      id: UBERON:0004347
      label: limb bud
  evidence:
  - reference: PMID:39168984
    reference_title: Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This deletion was highly penetrant with 100% of n = 120
      Esco2fl/fl;Prrx1-CreTg/0 embryos displaying the RBS limb phenotype
    explanation: Fully penetrant limb reduction after mesenchymal Esco2 deletion.
  - reference: PMID:19574259
    reference_title: Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      symmetric mesomelic shortening of the limbs in which the upper limbs are
      more commonly and severely affected than the lower limbs
    explanation: The human limb pattern from the 49-patient series.
  downstream:
  - target: Tetraphocomelia
    causal_link_type: DIRECT
  - target: Mesomelic limb shortening
    causal_link_type: DIRECT
  - target: Absent radius
    causal_link_type: DIRECT
  - target: Oligodactyly
    causal_link_type: DIRECT
  - target: Aplasia/Hypoplasia of the thumb
    causal_link_type: DIRECT
  - target: Fibular aplasia
    causal_link_type: DIRECT
  - target: Syndactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Clinodactyly of the 5th finger
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Humeroradial synostosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Flexion contractures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Talipes equinovarus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Deficient Craniofacial Primordium Growth
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Undergrowth of the facial prominences, palatal shelves and jaw, proposed
    to result from the same progenitor death and proliferation shortfall as
    the limb reduction. Supported by Esco2 expression in the developing lip
    and palate, by craniofacial abnormalities in esco2-deficient fish, and by
    the clinical correlation between facial and limb severity. No study has
    measured apoptosis or proliferation in human or mouse facial primordia,
    hence HYPOTHETICAL.
  biological_processes:
  - preferred_term: roof of mouth development
    term:
      id: GO:0060021
      label: roof of mouth development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:19574259
    reference_title: Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The severity of malformations of the facies correlates with the severity
      of limb reduction.
    explanation: Facial and limb severity move together, consistent with a shared mechanism.
  - reference: PMID:32255174
    reference_title: Juberg-Hayward syndrome is a cohesinopathy, caused by mutation in ESCO2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Esco2 expression during the early development of lip, palate, eyelid,
      digits, upper limb, and lower limb and truncated protein model are
      consistent with the defect.
    explanation: Mouse embryo in situ hybridization places Esco2 in the lip and palate primordia.
  - reference: PMID:21637801
    reference_title: A zebrafish model of Roberts syndrome reveals that Esco2 depletion interferes with development by disrupting the cell cycle.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Esco2 depleted zebrafish embryos exhibit features that resemble RBS,
      including mitotic defects, craniofacial abnormalities and limb
      truncations.
    explanation: Craniofacial abnormalities in the fish model.
  downstream:
  - target: Cleft lip
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cleft palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Micrognathia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Malar flattening
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Underdeveloped nasal alae
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypertelorism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ear malformations
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Microphthalmia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Proptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Downslanted palpebral fissures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Cortical Progenitor Loss
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  conforms_to: "neural_progenitor_centrosome_spindle_dysfunction#Progenitor Pool Distortion"
  description: >-
    In the developing mouse cortex Esco2 is expressed in late radial glial
    progenitors and TBR2-positive intermediate progenitors. Cortex-specific
    deletion (Emx1-Cre) causes massive apoptosis of these progenitors and
    their neuronal progeny, a drastic reduction in cortical neurons and
    failure of cortical layer formation; acute deletion shows ESCO2 is needed
    to maintain, not to generate, intermediate progenitors. This is the
    proposed basis of microcephaly and intellectual disability, conforming to
    the progenitor-pool-distortion node of the cortical progenitor module
    through its apoptosis branch. Shown only in the mouse.
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:33798452
    reference_title: Molecular Profiling Reveals Involvement of ESCO2 in Intermediate Progenitor Cell Maintenance in the Developing Mouse Cortex.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Loss-of-function experiments in cortex-specific mutants of Esco2, one of
      the novel IPC genes, demonstrate its critical role in IPC maintenance
    explanation: Conditional Esco2 loss depletes cortical intermediate progenitors.
  - reference: PMID:33798452
    reference_title: Molecular Profiling Reveals Involvement of ESCO2 in Intermediate Progenitor Cell Maintenance in the Developing Mouse Cortex.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The expression of Esco2 is required for the viability of these cell
      populations and their progenies to afford proper cortical histogenesis.
    explanation: Progenitor and neuronal survival requires Esco2.
  downstream:
  - target: Microcephaly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33798452
      reference_title: Molecular Profiling Reveals Involvement of ESCO2 in Intermediate Progenitor Cell Maintenance in the Developing Mouse Cortex.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Given the reduction in the progenitor pool and death of differentiated
        neurons, we found a drastic decrease in the number of NEUN+ or HuCD+
        neurons in the presumptive Esco2cKO cortex compared with control
      explanation: >-
        Progenitor loss reduces cortical neuron number, the substrate of a
        small brain; INDIRECT because head size was not the reported outcome.
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Cerebral Small-Vessel Vasculopathy
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Angiomatous changes and perivascular cysts indicating a chronic small
    cerebral vasculopathy were found at autopsy in an adolescent with biallelic
    ESCO2 variants who had an ischemic stroke at 6 years and died of an
    aneurysmal cerebellar hemorrhage at 13, with leukoencephalopathy,
    calcifications and cysts on imaging. GeneReviews now recommends brain
    vascular imaging in selected patients. How ESCO2 loss produces this
    vasculopathy is unknown, so no upstream edge is drawn.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:37002187
    reference_title: Complex cerebrovascular diseases in Roberts syndrome caused by novel biallelic ESCO2 variations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain histopathology revealed angiomatous changes and perivascular cysts
      suggesting chronic small cerebral vasculopathy.
    explanation: Neuropathology of the index case.
  downstream:
  - target: Ischemic stroke
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intracranial aneurysm
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Leukoencephalopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cerebral calcification
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
mechanistic_hypotheses:
- hypothesis_group_id: mitotic_failure_progenitor_apoptosis
  hypothesis_label: Mitotic failure and p53-dependent loss of embryonic progenitors
  status: CANONICAL
  description: >-
    Loss of pericentric cohesion prolongs mitosis and causes missegregation
    and aneuploidy; the resulting stress activates p53, and rapidly dividing
    progenitors in the limb buds, face and cortex die or proliferate too
    little, so the structures they build are reduced. Supported by patient
    cytogenetics and by fish and mouse models. It is qualified by the finding
    that patient lymphoblastoid lines show cell death without lengthened cell
    cycles, and by the Esco2 limb mouse, where p53 inhibition reduced
    apoptosis without restoring chondrogenesis.
  evidence:
  - reference: PMID:8291532
    reference_title: "Roberts syndrome: a review of 100 cases and a new rating system for severity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Therefore, RS has been interpreted as a human mitotic mutation syndrome
      which leads to secondary developmental defects.
    explanation: The classical formulation of the mitotic model.
  - reference: PMID:21637801
    reference_title: A zebrafish model of Roberts syndrome reveals that Esco2 depletion interferes with development by disrupting the cell cycle.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We propose that cell proliferation defects and apoptosis could be the
      primary cause of the features of RBS.
    explanation: Zebrafish support for the proliferation-and-apoptosis model.
  - reference: PMID:39168984
    reference_title: Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We had presumed that the extensive cell death in the mesenchyme was the
      underlying cause of the limb deficiency, but pifithrin-α treatment only
      recovered the hemorrhage in mutant limbs and not the chondrogenesis.
    explanation: Limits the apoptosis model as a complete explanation of limb reduction.
- hypothesis_group_id: ribosome_biogenesis_translation_defect
  hypothesis_label: Nucleolar dysfunction and mTORC1-dependent translational deficit
  status: ALTERNATIVE
  description: >-
    Reduced cohesin acetylation impairs nucleolar organization and rRNA
    production; the resulting translational deficit and mTORC1 repression
    reduce cell division and survival. L-leucine stimulation of mTORC1
    partially rescues patient cells and esco2 mutant fish. Not tested in a
    mammalian embryo. Not mutually exclusive with the mitotic model.
  evidence:
  - reference: PMID:24098154
    reference_title: Stimulation of mTORC1 with L-leucine rescues defects associated with Roberts syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our data support the idea that RBS can be attributed in part to defects
      in ribosome biogenesis, and stimulation of the TOR pathway has
      therapeutic potential.
    explanation: The authors' conclusion from patient cells and zebrafish.
  - reference: PMID:24098154
    reference_title: Stimulation of mTORC1 with L-leucine rescues defects associated with Roberts syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Stimulation of the TOR pathway with L-leucine rescued many developmental
      defects of ESCO2-mutant embryos.
    explanation: In vivo rescue in fish.
- hypothesis_group_id: cohesin_transcriptional_dysregulation
  hypothesis_label: Cohesin-dependent transcriptional dysregulation of developmental genes
  status: EMERGING
  description: >-
    As in Cornelia de Lange syndrome, part of the phenotype may come from
    altered transcription of developmental genes rather than from cell loss;
    candidate targets include cx43 in regenerating bone and ddb1 in the
    thalidomide-sensitive CRL4 pathway. Evidence is from zebrafish knockdowns
    and patient cell lines.
  evidence:
  - reference: PMID:29084713
    reference_title: Cohesin mediates Esco2-dependent transcriptional regulation in a zebrafish regenerating fin model of Roberts Syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      A popular model states that RBS arises due to mitotic failure and loss
      of progenitor stem cells through apoptosis. Previous findings in the
      zebrafish regenerating fin, however, suggest that Esco2-knockdown
      results in transcription dysregulation, independent of apoptosis,
      similar to that observed in CdLS patients.
    explanation: States the transcriptional model as an alternative to the apoptosis model.
  - reference: PMID:26434741
    reference_title: Esco2 regulates cx43 expression during skeletal regeneration in the zebrafish fin.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results conceptually link ODDD to cohesinopathies and provide
      evidence that ESCO2 may play a transcriptional role critical for human
      development.
    explanation: Transcriptional role of Esco2 in skeletal growth.
- hypothesis_group_id: limb_vascular_disruption
  hypothesis_label: p53-dependent vascular disruption in the developing limb
  status: EMERGING
  description: >-
    In the Esco2 limb mouse, p53-dependent disorganization of the limb bud
    vasculature and hemorrhage accompany the reduction, and genes linked to
    thalidomide embryopathy are dysregulated, suggesting a shared vascular
    component with the teratogenic phocomelia. Single study; human tissue not
    examined.
  evidence:
  - reference: PMID:39168984
    reference_title: Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our data show how loss of ESCO2 causes limb reduction phenotypes,
      through p53 induction, cell death, and vascular disruption.
    explanation: The vascular arm as proposed by the authors.
- hypothesis_group_id: macromolecular_damage
  hypothesis_label: Accumulated DNA and macromolecular damage
  status: EMERGING
  description: >-
    ESCO2-deficient cells are hypersensitive to DNA-damaging agents and show
    impaired double-strand break repair; a review proposes that DNA and other
    macromolecular damage contribute to the developmental phenotype, feeding
    into p53 activation. Evidence is from patient cell lines and yeast
    models.
  evidence:
  - reference: PMID:33382686
    reference_title: "An ever-changing landscape in Roberts syndrome biology: Implications for macromolecular damage."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In this review, we highlight current models of RBS and reflect on data
      that suggests a novel role for macromolecular damage in the molecular
      etiology of RBS.
    explanation: Review proposing the macromolecular-damage model.
  - reference: PMID:30508616
    reference_title: A Roberts Syndrome Individual With Differential Genotoxin Sensitivity and a DNA Damage Response Defect.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In addition to its developmental features, RBS can be, like ataxia
      telangiectasia, considered a DDR-defective syndrome, which contributes
      to its cellular, molecular, and clinical phenotype.
    explanation: DNA damage response defect proposed to contribute to the phenotype.
  - reference: PMID:34897432
    reference_title: Genetically induced redox stress occurs in a yeast model for Roberts syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we report evidence that supports an emerging model rooted in
      defective DNA damage responses.
    explanation: Yeast support for the damage-response model.
phenotypes:
- category: Skeletal
  name: Tetraphocomelia
  description: >-
    Bilateral symmetric reduction of all four limbs so that hands and feet
    attach close to the trunk; the severe end of the limb spectrum and the
    sign that gave the disorder its "pseudothalidomide" name.
  phenotype_term:
    preferred_term: Tetraphocomelia
    term:
      id: HP:0030721
      label: Tetraphocomelia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      limb malformations (which can include bilateral symmetric
      tetraphocomelia or hypomelia caused by mesomelic shortening of the upper
      and/or lower limbs)
    explanation: GeneReviews limb spectrum.
  - reference: PMID:16380922
    reference_title: "Inactivating mutations in ESCO2 cause SC phocomelia and Roberts syndrome: no phenotype-genotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The rare, autosomal recessive Roberts syndrome (RBS) is characterized by
      tetraphocomelia, profound growth deficiency of prenatal onset,
      craniofacial anomalies, microcephaly, and mental deficiency.
    explanation: Tetraphocomelia as a defining feature of the severe end.
  - reference: PMID:35495290
    reference_title: "Roberts syndrome with tetraphocomelia: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tetraphocomelia was detected on prenatal ultrasound done at about 24
      weeks of gestation with other features sonographically normal.
    explanation: Prenatal detection of tetraphocomelia in a severe case.
- category: Skeletal
  name: Mesomelic limb shortening
  description: >-
    Symmetric shortening of the forearm and lower leg segments, upper limbs
    more often and more severely affected than lower; the usual limb finding
    at the milder end of the spectrum and one of the three clinical criteria
    for the diagnosis.
  phenotype_term:
    preferred_term: Symmetric mesomelic limb shortening
    term:
      id: HP:0003027
      label: Mesomelia
  evidence:
  - reference: PMID:19574259
    reference_title: Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      symmetric mesomelic shortening of the limbs in which the upper limbs are
      more commonly and severely affected than the lower limbs
    explanation: One of the clinical criteria derived from 49 molecularly confirmed patients.
  - reference: PMID:26710928
    reference_title: Expanding the mutation and clinical spectrum of Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients presented with growth retardation, mesomelic shortening of
      the limbs more in the upper than in the lower limbs and microcephaly.
    explanation: Present in all three patients of an Egyptian series.
- category: Skeletal
  name: Absent radius
  description: Radial aplasia, often bilateral and symmetric, with or without ulnar aplasia.
  phenotype_term:
    preferred_term: Radial aplasia
    term:
      id: HP:0003974
      label: Absent radius
  evidence:
  - reference: PMID:30590172
    reference_title: Hypopigmented patches in Roberts/SC phocomelia syndrome occur via aneuploidy susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The more severely affected boy had hypoplasia of the tibia and
      symmetrical agenesis of the radius, ulna, proximal carpal bones, and
      fibula.
    explanation: Symmetric radial and ulnar agenesis in a molecularly confirmed sibling.
  - reference: PMID:31192177
    reference_title: Phenotypic Overlap of Roberts and Baller-Gerold Syndromes in Two Patients With Craniosynostosis, Limb Reductions, and ESCO2 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bilateral radial and thumb aplasia
    explanation: Bilateral radial aplasia in an ESCO2-positive child first diagnosed as Baller-Gerold syndrome.
- category: Skeletal
  name: Fibular aplasia
  description: Absence of the fibula, with tibial hypoplasia, in severe lower-limb involvement.
  phenotype_term:
    preferred_term: Fibular aplasia
    term:
      id: HP:0002990
      label: Fibular aplasia
  evidence:
  - reference: PMID:30590172
    reference_title: Hypopigmented patches in Roberts/SC phocomelia syndrome occur via aneuploidy susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The more severely affected boy had hypoplasia of the tibia and
      symmetrical agenesis of the radius, ulna, proximal carpal bones, and
      fibula.
    explanation: Fibular agenesis in a molecularly confirmed patient.
- category: Skeletal
  name: Oligodactyly
  description: Reduced number of digits, part of the symmetric reduction of the hands.
  phenotype_term:
    preferred_term: Oligodactyly
    term:
      id: HP:0012165
      label: Oligodactyly
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      hand anomalies (including oligodactyly, thumb aplasia or hypoplasia,
      syndactyly, fifth finger clinodactyly, hypoplasia, or aplasia)
    explanation: GeneReviews list of hand anomalies.
  - reference: PMID:8291532
    reference_title: "Roberts syndrome: a review of 100 cases and a new rating system for severity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Affected persons have varying degrees of malformations involving
      symmetric reduction in the number of digits, and length or presence of
      bones in the arms and legs.
    explanation: Symmetric digit reduction across 100 reviewed cases.
- category: Skeletal
  name: Aplasia/Hypoplasia of the thumb
  description: Absent or hypoplastic thumbs.
  phenotype_term:
    preferred_term: Thumb aplasia or hypoplasia
    term:
      id: HP:0009601
      label: Aplasia/Hypoplasia of the thumb
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      hand anomalies (including oligodactyly, thumb aplasia or hypoplasia,
      syndactyly, fifth finger clinodactyly, hypoplasia, or aplasia)
    explanation: GeneReviews list of hand anomalies.
- category: Skeletal
  name: Syndactyly
  description: Fusion of digits.
  phenotype_term:
    preferred_term: Syndactyly
    term:
      id: HP:0001159
      label: Syndactyly
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      hand anomalies (including oligodactyly, thumb aplasia or hypoplasia,
      syndactyly, fifth finger clinodactyly, hypoplasia, or aplasia)
    explanation: GeneReviews list of hand anomalies.
- category: Skeletal
  name: Clinodactyly of the 5th finger
  description: Radial curvature of the fifth finger.
  phenotype_term:
    preferred_term: Fifth finger clinodactyly
    term:
      id: HP:0004209
      label: Clinodactyly of the 5th finger
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      hand anomalies (including oligodactyly, thumb aplasia or hypoplasia,
      syndactyly, fifth finger clinodactyly, hypoplasia, or aplasia)
    explanation: GeneReviews list of hand anomalies.
- category: Skeletal
  name: Humeroradial synostosis
  description: >-
    Fusion of humerus and radius with elbow restriction, reported in mildly
    affected individuals; the same finding is characteristic of the allelic
    Juberg-Hayward syndrome.
  phenotype_term:
    preferred_term: Humeroradial synostosis
    term:
      id: HP:0003041
      label: Humeroradial synostosis
  evidence:
  - reference: PMID:32783269
    reference_title: Roberts syndrome in an Indian patient with humeroradial synostosis, congenital elbow contractures and a novel homozygous splice variant in ESCO2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report a 3-year-old boy with a mild phenotype of Roberts
      syndrome with bilateral elbow contractures, humeroradial synostosis,
      mild lower limb disparity, and facial dysmorphism.
    explanation: Humeroradial synostosis in a mild, molecularly confirmed case.
- category: Musculoskeletal
  name: Flexion contractures
  description: Flexion contractures of elbows, wrists, knees, ankles and feet.
  phenotype_term:
    preferred_term: Flexion contractures of elbows, wrists, knees and ankles
    term:
      id: HP:0001371
      label: Flexion contracture
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      flexion contractures (involving elbows, wrists, knees, ankles, and feet
      [talipes equinovarus])
    explanation: GeneReviews distribution of contractures.
  - reference: PMID:20101700
    reference_title: The Roberts syndrome/SC phocomelia spectrum--a case report of an adult with review of the literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SC phocomelia (SC) (OMIM #269000), has less severe symmetric limb
      reduction, flexion contractures of various joints, minor facial
      anomalies, growth retardation and occasionally, mental retardation.
    explanation: Contractures are a feature of the mild (SC phocomelia) end.
- category: Skeletal
  name: Talipes equinovarus
  description: Clubfoot.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      flexion contractures (involving elbows, wrists, knees, ankles, and feet
      [talipes equinovarus])
    explanation: GeneReviews lists talipes equinovarus.
- category: Growth
  name: Intrauterine growth retardation
  description: >-
    Prenatal-onset growth restriction, mild to severe; part of the growth
    retardation clinical criterion.
  phenotype_term:
    preferred_term: Prenatal growth restriction
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
    onset:
      onset_category: ANTENATAL
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      ESCO2 spectrum disorder is characterized by mild-to-severe prenatal
      growth restriction
    explanation: GeneReviews clinical characteristics.
  - reference: PMID:16380922
    reference_title: "Inactivating mutations in ESCO2 cause SC phocomelia and Roberts syndrome: no phenotype-genotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The rare, autosomal recessive Roberts syndrome (RBS) is characterized by
      tetraphocomelia, profound growth deficiency of prenatal onset,
      craniofacial anomalies, microcephaly, and mental deficiency.
    explanation: Prenatal-onset growth deficiency.
- category: Growth
  name: Postnatal growth retardation
  description: Growth deficiency continuing after birth, with short stature in survivors.
  phenotype_term:
    preferred_term: Postnatal growth retardation
    term:
      id: HP:0008897
      label: Postnatal growth retardation
  evidence:
  - reference: PMID:8291532
    reference_title: "Roberts syndrome: a review of 100 cases and a new rating system for severity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Roberts syndrome (RS) is a rare genetic disorder characterized by pre-
      and postnatal growth retardation, limb defects, and craniofacial
      anomalies.
    explanation: Pre- and postnatal growth retardation.
  - reference: PMID:32783269
    reference_title: Roberts syndrome in an Indian patient with humeroradial synostosis, congenital elbow contractures and a novel homozygous splice variant in ESCO2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      characterized by pre- and postnatal growth retardation, limb
      malformations including bilateral symmetric tetraphocomelia or
      mesomelia, and craniofacial dysmorphism
    explanation: Restated in a later case report.
- category: Neurological
  name: Microcephaly
  description: >-
    Small head size, part of the characteristic-facies clinical criterion;
    not a constant feature of the allelic Juberg-Hayward syndrome.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:19574259
    reference_title: Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the clinical criteria for RBS were delineated to include: growth
      retardation; symmetric mesomelic shortening of the limbs in which the
      upper limbs are more commonly and severely affected than the lower
      limbs; characteristic facies with microcephaly.
    explanation: Microcephaly is part of the characteristic facies criterion.
  - reference: PMID:26710928
    reference_title: Expanding the mutation and clinical spectrum of Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients presented with growth retardation, mesomelic shortening of
      the limbs more in the upper than in the lower limbs and microcephaly.
    explanation: Present in all three patients of a series.
- category: Neurological
  name: Intellectual disability
  frequency: FREQUENT
  description: >-
    Mild to severe; common but not universal, and absent in some mildly
    affected survivors.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Intellectual disability (ranging from mild to severe) is common.
    explanation: GeneReviews frequency qualifier "common" (mapped to FREQUENT).
  - reference: PMID:38288163
    reference_title: "Case report: The evolving phenotype of ESCO2 spectrum disorder in a 15-year-old Malaysian child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of note, there was an absence of learning disabilities.
    explanation: Records that cognition can be normal, so the feature is not obligate.
  notes: >-
    Frequency basis: GeneReviews abstract phrase "common". Normal intelligence
    is documented in mild cases (PMID:38288163, PMID:32783269).
- category: Craniofacial
  name: Cleft lip
  description: Cleft lip, characteristically bilateral, usually with cleft palate.
  phenotype_term:
    preferred_term: Bilateral cleft lip
    term:
      id: HP:0100336
      label: Bilateral cleft lip
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      craniofacial abnormalities (bilateral cleft lip and/or cleft palate,
      micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral
      fissures, malar flattening, underdeveloped ala nasi, and ear
      malformations)
    explanation: GeneReviews list of craniofacial abnormalities.
  - reference: PMID:8291532
    reference_title: "Roberts syndrome: a review of 100 cases and a new rating system for severity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Craniofacial malformations involve hypertelorism, hypoplastic nasal
      alae, and a high incidence of cleft lip and palate.
    explanation: High incidence of cleft lip and palate in 100 reviewed cases.
- category: Craniofacial
  name: Cleft palate
  description: Cleft palate, usually with cleft lip.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      craniofacial abnormalities (bilateral cleft lip and/or cleft palate,
      micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral
      fissures, malar flattening, underdeveloped ala nasi, and ear
      malformations)
    explanation: GeneReviews list of craniofacial abnormalities.
  - reference: PMID:35093090
    reference_title: "Prenatal diagnosis of Roberts syndrome in a Chinese family based on ultrasound findings and whole exome sequencing: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two consecutive fetuses in this family presented with tetraphocomelia,
      growth restriction, cleft lip and palate bilaterally, and other
      abnormalities.
    explanation: Bilateral cleft lip and palate detected prenatally with tetraphocomelia.
- category: Craniofacial
  name: Micrognathia
  description: Small mandible.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      craniofacial abnormalities (bilateral cleft lip and/or cleft palate,
      micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral
      fissures, malar flattening, underdeveloped ala nasi, and ear
      malformations)
    explanation: GeneReviews list of craniofacial abnormalities.
- category: Craniofacial
  name: Hypertelorism
  description: Widely spaced eyes.
  phenotype_term:
    preferred_term: Widely spaced eyes
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      craniofacial abnormalities (bilateral cleft lip and/or cleft palate,
      micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral
      fissures, malar flattening, underdeveloped ala nasi, and ear
      malformations)
    explanation: GeneReviews list of craniofacial abnormalities.
  - reference: PMID:8291532
    reference_title: "Roberts syndrome: a review of 100 cases and a new rating system for severity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Craniofacial malformations involve hypertelorism, hypoplastic nasal
      alae, and a high incidence of cleft lip and palate.
    explanation: Hypertelorism in the 100-case review.
- category: Craniofacial
  name: Proptosis
  description: Prominent eyes (exophthalmos).
  phenotype_term:
    preferred_term: Exophthalmos
    term:
      id: HP:0000520
      label: Proptosis
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      craniofacial abnormalities (bilateral cleft lip and/or cleft palate,
      micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral
      fissures, malar flattening, underdeveloped ala nasi, and ear
      malformations)
    explanation: GeneReviews list of craniofacial abnormalities.
- category: Craniofacial
  name: Downslanted palpebral fissures
  description: Downward-slanting eye openings.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      craniofacial abnormalities (bilateral cleft lip and/or cleft palate,
      micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral
      fissures, malar flattening, underdeveloped ala nasi, and ear
      malformations)
    explanation: GeneReviews list of craniofacial abnormalities.
- category: Craniofacial
  name: Malar flattening
  description: Flat cheekbones.
  phenotype_term:
    preferred_term: Malar flattening
    term:
      id: HP:0000272
      label: Malar flattening
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      craniofacial abnormalities (bilateral cleft lip and/or cleft palate,
      micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral
      fissures, malar flattening, underdeveloped ala nasi, and ear
      malformations)
    explanation: GeneReviews list of craniofacial abnormalities.
- category: Craniofacial
  name: Underdeveloped nasal alae
  description: Hypoplastic alae nasi.
  phenotype_term:
    preferred_term: Underdeveloped nasal alae
    term:
      id: HP:0000430
      label: Underdeveloped nasal alae
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      craniofacial abnormalities (bilateral cleft lip and/or cleft palate,
      micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral
      fissures, malar flattening, underdeveloped ala nasi, and ear
      malformations)
    explanation: GeneReviews list of craniofacial abnormalities.
  - reference: PMID:8291532
    reference_title: "Roberts syndrome: a review of 100 cases and a new rating system for severity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Craniofacial malformations involve hypertelorism, hypoplastic nasal
      alae, and a high incidence of cleft lip and palate.
    explanation: Hypoplastic nasal alae in the 100-case review.
- category: Craniofacial
  name: Ear malformations
  description: >-
    External ear malformations, not further characterized in the GeneReviews
    summary.
  phenotype_term:
    preferred_term: Ear malformations
    term:
      id: HP:0031703
      label: Abnormal ear morphology
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      craniofacial abnormalities (bilateral cleft lip and/or cleft palate,
      micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral
      fissures, malar flattening, underdeveloped ala nasi, and ear
      malformations)
    explanation: GeneReviews names ear malformations without further detail.
- category: Craniofacial
  name: Craniosynostosis
  description: >-
    Premature suture fusion in some patients, which can lead to a
    misdiagnosis of Baller-Gerold syndrome; GeneReviews lists surgical
    treatment of craniosynostosis in management.
  phenotype_term:
    preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  evidence:
  - reference: PMID:31192177
    reference_title: Phenotypic Overlap of Roberts and Baller-Gerold Syndromes in Two Patients With Craniosynostosis, Limb Reductions, and ESCO2 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patient 1 is a Turkish girl with short stature, microcephaly,
      craniosynostosis, seizures, intellectual disability, midface hemangioma,
      bilateral radial and thumb aplasia, tibial hypoplasia, and pes
      equinovarus
    explanation: Craniosynostosis in a child later shown to carry biallelic ESCO2 variants.
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      surgical treatment for craniosynostosis and micrognathia
    explanation: GeneReviews management covers craniosynostosis.
- category: Integument
  name: Midface capillary hemangioma
  description: Midface (glabellar) capillary hemangioma.
  phenotype_term:
    preferred_term: Midface capillary hemangioma
    term:
      id: HP:0007452
      label: Midface capillary hemangioma
  evidence:
  - reference: PMID:31192177
    reference_title: Phenotypic Overlap of Roberts and Baller-Gerold Syndromes in Two Patients With Craniosynostosis, Limb Reductions, and ESCO2 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patient 1 is a Turkish girl with short stature, microcephaly,
      craniosynostosis, seizures, intellectual disability, midface hemangioma,
      bilateral radial and thumb aplasia, tibial hypoplasia, and pes
      equinovarus
    explanation: Midface hemangioma in an ESCO2-positive patient.
  - reference: PMID:25320640
    reference_title: 3D-FISH analysis reveals chromatid cohesion defect during interphase in Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      This multiple congenital anomaly syndrome is characterized by cleft lip
      and palate, nose and ears anomalies, facial hemangioma, hypertelorism,
      microcephaly, curly silvery blond hair
    explanation: Facial hemangioma in the clinical summary of a later paper's introduction.
- category: Integument
  name: Silver-gray hair
  description: Sparse, curly, silvery-blond scalp hair.
  phenotype_term:
    preferred_term: Silvery blond hair
    term:
      id: HP:0002218
      label: Silver-gray hair
  evidence:
  - reference: PMID:25320640
    reference_title: 3D-FISH analysis reveals chromatid cohesion defect during interphase in Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      This multiple congenital anomaly syndrome is characterized by cleft lip
      and palate, nose and ears anomalies, facial hemangioma, hypertelorism,
      microcephaly, curly silvery blond hair
    explanation: Silvery blond hair listed among the clinical features.
- category: Integument
  name: Hypopigmented skin patches
  frequency: OCCASIONAL
  description: >-
    Patchy hypopigmentation, reported in a minority of patients and
    associated with high levels of aneuploidy in fibroblasts from the
    affected skin.
  phenotype_term:
    preferred_term: Hypopigmented skin patches
    term:
      id: HP:0001053
      label: Hypopigmented skin patches
  evidence:
  - reference: PMID:30590172
    reference_title: Hypopigmented patches in Roberts/SC phocomelia syndrome occur via aneuploidy susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When the literature review and study are evaluated together,
      hypopigmented patches can be considered as a rare finding for RBS/SC.
    explanation: Described as a rare finding after a literature review.
  - reference: PMID:26710928
    reference_title: Expanding the mutation and clinical spectrum of Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, patient 1 had abnormal skin hypopigmentation.
    explanation: A further patient with hypopigmentation.
  notes: >-
    Frequency basis: described as rare after a literature review
    (PMID:30590172), with two earlier reports plus the two siblings of that
    study; OCCASIONAL is used because the denominator is not stated.
- category: Ophthalmologic
  name: Microphthalmia
  description: Small eyes.
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      ocular manifestations (microphthalmia, nystagmus, glaucoma, and corneal
      opacities)
    explanation: GeneReviews list of ocular manifestations.
- category: Ophthalmologic
  name: Corneal opacity
  description: >-
    Corneal clouding, which in the 49-patient series may be associated with
    specific ESCO2 variants; GeneReviews recommends brain vascular imaging in
    patients with corneal opacities.
  phenotype_term:
    preferred_term: Corneal opacity
    term:
      id: HP:0007957
      label: Corneal opacity
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      ocular manifestations (microphthalmia, nystagmus, glaucoma, and corneal
      opacities)
    explanation: GeneReviews list of ocular manifestations.
  - reference: PMID:19574259
    reference_title: Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The occurrence of corneal opacities may be associated with specific
      mutations.
    explanation: A possible genotype association for this feature.
- category: Ophthalmologic
  name: Nystagmus
  description: Involuntary rhythmic eye movements.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      ocular manifestations (microphthalmia, nystagmus, glaucoma, and corneal
      opacities)
    explanation: GeneReviews list of ocular manifestations.
- category: Ophthalmologic
  name: Glaucoma
  description: Raised intraocular pressure with optic nerve damage.
  phenotype_term:
    preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      ocular manifestations (microphthalmia, nystagmus, glaucoma, and corneal
      opacities)
    explanation: GeneReviews list of ocular manifestations.
- category: Cardiovascular
  name: Congenital heart defect
  description: >-
    Structural heart malformations including valvular aortic stenosis,
    patent ductus arteriosus and, in an adult with the mild phenotype, a major
    malformation repaired in childhood.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:20101700
    reference_title: The Roberts syndrome/SC phocomelia spectrum--a case report of an adult with review of the literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Roberts syndrome (RBS) (OMIM #268300) is a rare autosomal recessive
      disorder characterized by tetraphocomelia (symmetrical limb reduction),
      craniofacial anomalies, growth retardation, mental retardation, cardiac
      and renal abnormalities.
    explanation: Cardiac abnormalities are part of the syndrome.
  - reference: PMID:24864645
    reference_title: "The Roberts syndrome: a case report of an infant with valvular aortic stenosis and mutation in ESCO2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      tetra phocomelia, growth and developmental retardation, abnormality of
      complete cleft lip-palate accompanied with Aortic stenosis and PDA
    explanation: Aortic stenosis and patent ductus arteriosus in a molecularly confirmed infant.
- category: Renal
  name: Renal dysplasia
  description: Polycystic or dysplastic kidneys.
  phenotype_term:
    preferred_term: Polycystic or dysplastic kidneys
    term:
      id: HP:0000110
      label: Renal dysplasia
  evidence:
  - reference: PMID:25320640
    reference_title: 3D-FISH analysis reveals chromatid cohesion defect during interphase in Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      polycystic or dysplastic kidneys, congenital heart defects, enlarged
      male genitalia, severe growth retardation and intellectual deficiency
    explanation: Kidney dysplasia in the clinical summary.
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      standard treatment for ophthalmologic, cardiac, urogenital, and kidney
      abnormalities
    explanation: GeneReviews management lists kidney abnormalities among the organ involvement to treat.
- category: Genitourinary
  name: Genital anomalies
  description: >-
    Enlarged male external genitalia are listed among the classic features;
    GeneReviews includes urogenital abnormalities in management. Form and
    frequency are not characterized in the cited sources.
  phenotype_term:
    preferred_term: Enlarged male external genitalia
    term:
      id: HP:0000032
      label: Abnormal male external genitalia morphology
  evidence:
  - reference: PMID:25320640
    reference_title: 3D-FISH analysis reveals chromatid cohesion defect during interphase in Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      polycystic or dysplastic kidneys, congenital heart defects, enlarged
      male genitalia, severe growth retardation and intellectual deficiency
    explanation: Enlarged male genitalia in the clinical summary.
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      standard treatment for ophthalmologic, cardiac, urogenital, and kidney
      abnormalities
    explanation: GeneReviews management lists urogenital abnormalities.
  notes: >-
    Bound to HP:0000032 rather than HP:0000040 Long penis because the source
    says "enlarged", which does not specify length.
- category: Neurological
  name: Ischemic stroke
  description: >-
    Childhood ischemic stroke; GeneReviews includes stroke treatment and
    assessment for vascular anomalies in management.
  phenotype_term:
    preferred_term: Ischemic stroke
    term:
      id: HP:0002140
      label: Ischemic stroke
  evidence:
  - reference: PMID:37002187
    reference_title: Complex cerebrovascular diseases in Roberts syndrome caused by novel biallelic ESCO2 variations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She suffered ischemic stroke at 6 years old and died of cerebellar
      hemorrhage secondary to an aneurysm at 13 years old.
    explanation: Stroke and fatal aneurysmal hemorrhage in one patient.
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      treatment of stroke per neurologist
    explanation: GeneReviews management includes stroke.
- category: Neurological
  name: Intracranial aneurysm
  description: >-
    Cerebral artery aneurysm, fatal through cerebellar hemorrhage in one
    reported adolescent; GeneReviews advises annual assessment for aneurysm
    from adolescence.
  phenotype_term:
    preferred_term: Intracranial aneurysm
    term:
      id: HP:0004944
      label: Dilatation of the cerebral artery
  evidence:
  - reference: PMID:37002187
    reference_title: Complex cerebrovascular diseases in Roberts syndrome caused by novel biallelic ESCO2 variations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She suffered ischemic stroke at 6 years old and died of cerebellar
      hemorrhage secondary to an aneurysm at 13 years old.
    explanation: Aneurysmal cerebellar hemorrhage.
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      assess for clinical manifestations of aneurysms and vascular
      malformations annually starting in adolescence
    explanation: GeneReviews surveillance for aneurysms.
  sequelae:
  - target: Cerebellar hemorrhage
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37002187
      reference_title: Complex cerebrovascular diseases in Roberts syndrome caused by novel biallelic ESCO2 variations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        She suffered ischemic stroke at 6 years old and died of cerebellar
        hemorrhage secondary to an aneurysm at 13 years old.
      explanation: The hemorrhage was secondary to the aneurysm.
- category: Neurological
  name: Cerebellar hemorrhage
  description: Fatal cerebellar hemorrhage from an aneurysm in one reported adolescent.
  phenotype_term:
    preferred_term: Cerebellar hemorrhage
    term:
      id: HP:0011695
      label: Cerebellar hemorrhage
  evidence:
  - reference: PMID:37002187
    reference_title: Complex cerebrovascular diseases in Roberts syndrome caused by novel biallelic ESCO2 variations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She suffered ischemic stroke at 6 years old and died of cerebellar
      hemorrhage secondary to an aneurysm at 13 years old.
    explanation: Single-case report.
- category: Neurological
  name: Leukoencephalopathy
  description: >-
    White matter disease, part of a leukoencephalopathy-calcification-cyst
    triad on neuroimaging in one patient.
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  evidence:
  - reference: PMID:37002187
    reference_title: Complex cerebrovascular diseases in Roberts syndrome caused by novel biallelic ESCO2 variations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Besides, neuroimaging showed the triad of leukoencephalopathy,
      calcifications, and cysts.
    explanation: Single-case neuroimaging finding.
- category: Neurological
  name: Cerebral calcification
  description: Intracranial calcifications on neuroimaging in one patient.
  phenotype_term:
    preferred_term: Cerebral calcification
    term:
      id: HP:0002514
      label: Cerebral calcification
  evidence:
  - reference: PMID:37002187
    reference_title: Complex cerebrovascular diseases in Roberts syndrome caused by novel biallelic ESCO2 variations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Besides, neuroimaging showed the triad of leukoencephalopathy,
      calcifications, and cysts.
    explanation: Single-case neuroimaging finding.
- category: Immunological
  name: Recurrent infections
  description: >-
    GeneReviews management calls for prompt treatment of infections,
    monitoring infection frequency and measuring serum immunoglobulins in
    infancy; the immune basis is not described in the abstract.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: >-
      prompt treatment of infection with management per infectious disease
      specialist
    explanation: GeneReviews management of infections.
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: >-
      serum immunoglobulin levels in infancy
    explanation: GeneReviews surveillance of immunoglobulins.
- category: Neoplasm
  name: Malignancy
  description: >-
    GeneReviews includes treatment of malignancy and an annual skin and
    neurologic examination for malignancy in surveillance; tumor types are
    not specified in the abstract.
  phenotype_term:
    preferred_term: Malignancy
    term:
      id: HP:0002664
      label: Neoplasm
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: >-
      physical examination including full skin and neurologic examination for
      evidence of malignancy annually
    explanation: GeneReviews malignancy surveillance.
- category: Mortality/Aging
  name: Perinatal death
  description: >-
    Early death is common in severely affected infants, with stillbirth and
    neonatal death at the severe end; mildly affected individuals may survive
    into adulthood.
  phenotype_term:
    preferred_term: Stillbirth or neonatal death
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Early mortality is common among severely affected infants; mildly
      affected individuals may survive to adulthood.
    explanation: GeneReviews on survival across the spectrum.
  - reference: PMID:20101700
    reference_title: The Roberts syndrome/SC phocomelia spectrum--a case report of an adult with review of the literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These two syndromes can be considered part of a spectrum, with RBS at
      the most severe range in which severely affected infants may be
      stillborn or die in the post-natal period, while individuals with SC
      phocomelia represent the milder end of the spectrum and typically
      survive to adulthood.
    explanation: Stillbirth and postnatal death at the severe end.
  notes: >-
    No term is bound. HP:0003811 Neonatal death sits under Clinical course
    (HP:0031797 > HP:0011420 Age of death, per the OLS hierarchy), outside the
    PhenotypeTerm enum root HP:0000118, and just validate-terms rejects it.
- category: Cellular
  name: Premature centromere separation
  description: >-
    Premature centromere separation and heterochromatin repulsion in
    metaphase chromosomes of patient cells; the cytogenetic hallmark and a
    diagnostic test, found across the severity range and also in
    Juberg-Hayward syndrome.
  phenotype_term:
    preferred_term: Premature centromere separation
    term:
      id: HP:0003616
      label: Premature separation of centromeric heterochromatin
  diagnostic: true
  evidence:
  - reference: PMID:30204960
    reference_title: "ROBERTS SYNDROME: CLINICAL AND CYTOGENETIC STUDIES IN 8 EGYPTIAN PATIENTS AND MOLECULAR STUDIES IN 4 PATIENTS WITH GENOTYPE/PHENOTYPE CORRELATION."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cytogenetic studies including centromeric separation and puffing by
      Giemsa and DAPI stains and for the first time in Egypt analysis for
      premature centromeric division by FISH showed consistent centromeric
      separation in all studied cases.
    explanation: Present in all eight patients studied.
  - reference: PMID:16380922
    reference_title: "Inactivating mutations in ESCO2 cause SC phocomelia and Roberts syndrome: no phenotype-genotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All cases were positive for HR.
    explanation: Heterochromatin repulsion in SC phocomelia and fetal cases alike.
genetic:
- name: ESCO2
  gene_term:
    preferred_term: ESCO2
    term:
      id: hgnc:27230
      label: ESCO2
  association: Causative
  variant_origin: GERMLINE
  features: >-
    ESCO2 at 8p21.1. Biallelic variants, homozygous or compound
    heterozygous. Almost all reported alleles truncate the protein
    (frameshift, nonsense, splice site), often in exon 3, and remove all or
    part of the C-terminal acetyltransferase domain; rare missense or
    in-frame changes in that domain (W539G) abolish acetyltransferase
    activity. The previously reported exon 3 alleles c.760_761insA and
    c.764_765delTT were found again, homozygous, in consanguineous Egyptian
    families. Genotype does not predict severity: the same truncating
    classes occur at both ends of the spectrum, and variation in the
    efficiency of nonsense-mediated decay between tissues and individuals
    has been proposed to contribute to the variability. Facial severity
    correlates with limb severity, and corneal opacity may track specific
    alleles. The allelic Juberg-Hayward syndrome is caused by homozygous
    p.Arg552Ter.
  evidence:
  - reference: PMID:19574259
    reference_title: Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 26 mutations described to date, only one missense mutation has been
      reported and all others are predicted to be truncating mutations.
    explanation: The variant class spectrum.
  - reference: PMID:18411254
    reference_title: The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We observed that these mutations result in complete or partial loss of
      the acetyltransferase domain except for the only missense mutation that
      occurs in this domain (c.1615T>G, W539G).
    explanation: Truncations remove the acetyltransferase domain.
  - reference: PMID:26710928
    reference_title: Expanding the mutation and clinical spectrum of Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      sequencing of the ESCO2 gene identified a novel mutation c.244_245dupCT
      (p.T83Pfs*20) in one family besides two previously reported mutations
      c.760_761insA (p.T254Nfs*27) and c.764_765delTT (p.F255Cfs*25)
    explanation: Recurrent exon 3 frameshift alleles.
  - reference: PMID:16380922
    reference_title: "Inactivating mutations in ESCO2 cause SC phocomelia and Roberts syndrome: no phenotype-genotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Since only protein-truncating mutations were identified, regardless of
      clinical severity, we conclude that genotype does not predict phenotype.
    explanation: No genotype-phenotype correlation.
  - reference: PMID:30204960
    reference_title: "ROBERTS SYNDROME: CLINICAL AND CYTOGENETIC STUDIES IN 8 EGYPTIAN PATIENTS AND MOLECULAR STUDIES IN 4 PATIENTS WITH GENOTYPE/PHENOTYPE CORRELATION."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We confirmed previous results of lack of genotype/phenotype correlation.
      We also confirmed that the severity of limb malformation correlates with
      craniofacial manifestations.
    explanation: Independent confirmation in an Egyptian series.
  - reference: PMID:16775838
    reference_title: "A homozygous frameshift mutation in the ESCO2 gene: evidence of intertissue and interindividual variation in Nmd efficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The existence of such a variation in the NMD efficiency could explain
      the broad intrafamilial and interfamilial variability in the clinical
      presentation of RS patients
    explanation: A proposed modifier of severity.
  - reference: PMID:20101700
    reference_title: The Roberts syndrome/SC phocomelia spectrum--a case report of an adult with review of the literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The syndrome is caused by mutations in the ESCO2 (establishment of
      cohesion 1 homolog 2) (Entrez 609353) gene, which is located at 8p21.1
    explanation: Chromosomal location.
diagnosis:
- name: ESCO2 Molecular Genetic Testing
  description: >-
    Diagnosis is established by biallelic pathogenic ESCO2 variants in a
    proband with suggestive findings. Mild cases without obvious limb
    reduction, or cases first labelled Baller-Gerold syndrome or Fanconi
    anemia, have been resolved by exome sequencing.
  diagnosis_term:
    preferred_term: ESCO2 sequencing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The diagnosis of ESCO2 spectrum disorder is established in a proband
      with suggestive clinical findings and either biallelic pathogenic
      variants in ESCO2 identified by molecular genetic testing or premature
      centromere separation identified by cytogenetic testing.
    explanation: GeneReviews diagnostic criteria.
  - reference: PMID:32783269
    reference_title: Roberts syndrome in an Indian patient with humeroradial synostosis, congenital elbow contractures and a novel homozygous splice variant in ESCO2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, next-generation sequencing tools allow for molecular diagnosis
      in cases presenting with mild developmental defects.
    explanation: Sequencing resolves mild presentations.
- name: Cytogenetic Testing for Premature Centromere Separation
  description: >-
    Conventionally stained metaphases, or FISH, show premature centromere
    separation and heterochromatin repulsion; this establishes the diagnosis
    in a proband with suggestive findings and distinguishes the disorder from
    other phocomelias, which are negative.
  diagnosis_term:
    preferred_term: metaphase chromosome analysis
    term:
      id: NCIT:C18280
      label: Cytogenetic Analysis
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The diagnosis of ESCO2 spectrum disorder is established in a proband
      with suggestive clinical findings and either biallelic pathogenic
      variants in ESCO2 identified by molecular genetic testing or premature
      centromere separation identified by cytogenetic testing.
    explanation: GeneReviews accepts the cytogenetic finding as diagnostic.
  - reference: PMID:16380922
    reference_title: "Inactivating mutations in ESCO2 cause SC phocomelia and Roberts syndrome: no phenotype-genotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we delineated the clinical phenotype of the tetraphocomelia spectrum
      that is associated with HR and ESCO2 mutations and differentiated it
      from other types of phocomelia that are negative for HR.
    explanation: Heterochromatin repulsion separates this disease from other phocomelias.
- name: Prenatal Ultrasound and Fetal Testing
  description: >-
    Symmetric limb reduction, growth restriction and bilateral clefting on
    fetal ultrasound, confirmed by cytogenetics or ESCO2 testing of
    amniocytes or chorionic villi.
  diagnosis_term:
    preferred_term: fetal ultrasound
    term:
      id: NCIT:C222238
      label: Fetal Ultrasound Imaging
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Prenatal testing for pregnancies at increased risk is also possible by
      cytogenetic testing of fetal cells obtained by amniocentesis or
      chorionic villus sampling in conjunction with ultrasound examination.
    explanation: GeneReviews prenatal testing.
  - reference: PMID:26710928
    reference_title: Expanding the mutation and clinical spectrum of Roberts syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serial fetal ultrasound examinations and measurements of long bones
      diagnosed two affected fetuses in two of the studied families.
    explanation: Ultrasound long-bone measurement identified affected fetuses.
differential_diagnoses:
- name: Juberg-Hayward syndrome
  description: >-
    Allelic ESCO2 disorder (homozygous p.Arg552Ter in the reported families)
    with cleft lip and palate, ptosis, short stature, thumb hypoplasia and
    humeroradial synostosis or radial head dislocation, and premature
    centromere separation; microcephaly is inconsistent. Treated as a
    distinct allelic entity by MONDO and by its describers.
  disease_term:
    preferred_term: Juberg-Hayward syndrome
    term:
      id: MONDO:0008992
      label: Juberg-Hayward syndrome
  distinguishing_features:
  - Humeroradial synostosis or radial head dislocation rather than phocomelia.
  - Ptosis; microcephaly inconsistent.
  evidence:
  - reference: PMID:32255174
    reference_title: Juberg-Hayward syndrome is a cohesinopathy, caused by mutation in ESCO2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study showed that Roberts/SC phocomelia syndrome and JHS are allelic
      and distinct entities.
    explanation: The describers' lump/split conclusion.
  - reference: PMID:32977150
    reference_title: Juberg-Hayward syndrome and Roberts syndrome are allelic, caused by mutations in ESCO2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chromosome testing of the affected patients showed premature centromere
      separation.
    explanation: Shares the cytogenetic sign, so cytogenetics does not separate the two.
  - reference: PMID:32977150
    reference_title: Juberg-Hayward syndrome and Roberts syndrome are allelic, caused by mutations in ESCO2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly does not appear to be a consistent feature of the syndrome.
    explanation: Microcephaly is inconsistent in Juberg-Hayward syndrome.
- name: Thalidomide embryopathy
  description: >-
    Teratogenic phocomelia after first-trimester thalidomide exposure, the
    origin of the "pseudothalidomide" synonym. Distinguished by exposure
    history, the absence of heterochromatin repulsion, and normal ESCO2; the
    two may share a vascular and CRL4-pathway component.
  disease_term:
    preferred_term: thalidomide embryopathy
    term:
      id: MONDO:0018034
      label: thalidomide embryopathy
  distinguishing_features:
  - Maternal thalidomide exposure.
  - No premature centromere separation.
  evidence:
  - reference: PMID:39168984
    reference_title: Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      The phenotypic similarity of RBS limb defects to thalidomide embryopathy
      has spurred the eponymous description of RBS as 'pseudothalidomide'
      syndrome
    explanation: The clinical resemblance behind the differential.
  - reference: PMID:34989322
    reference_title: Esco2 and cohesin regulate CRL4 ubiquitin ligase ddb1 expression and thalidomide teratogenicity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These findings are the first to link RBS and CdLS to thalidomide
      teratogenicity and offer new insights into treatments.
    explanation: A mechanistic link between the two.
- name: Baller-Gerold syndrome
  description: >-
    RECQL4 disorder with craniosynostosis and radial ray aplasia; ESCO2
    variants have been found in children first diagnosed with Baller-Gerold
    syndrome who had craniosynostosis and radial and thumb aplasia.
  disease_term:
    preferred_term: Baller-Gerold syndrome
    term:
      id: MONDO:0009039
      label: Baller-Gerold syndrome
  distinguishing_features:
  - RECQL4 variants in Baller-Gerold syndrome.
  - Premature centromere separation and ESCO2 variants in this disease.
  evidence:
  - reference: PMID:31192177
    reference_title: Phenotypic Overlap of Roberts and Baller-Gerold Syndromes in Two Patients With Craniosynostosis, Limb Reductions, and ESCO2 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Upon negative RECQL4 test, whole exome sequencing (WES) analysis
      performed on the two trios led to the identification of two different
      ESCO2 homozygous inactivating variants
    explanation: Baller-Gerold phenotype resolved as ESCO2 disease.
- name: Fanconi anemia
  description: >-
    Chromosome-breakage disorder with radial ray defects and growth
    restriction. A mildly affected ESCO2 patient with an equivocal breakage
    study was first suspected to have mosaic Fanconi anemia; ESCO2 sequencing
    separates the two.
  disease_term:
    preferred_term: Fanconi anemia
    term:
      id: MONDO:0019391
      label: Fanconi anemia
  evidence:
  - reference: PMID:38288163
    reference_title: "Case report: The evolving phenotype of ESCO2 spectrum disorder in a 15-year-old Malaysian child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She was initially suspected to have mosaic Fanconi anemia but whole
      exome sequencing (WES) showed a likely pathogenic homozygous splice
      variant c.955 + 2_955+5del in the ESCO2 gene.
    explanation: Fanconi anemia was the working diagnosis before sequencing.
- name: Cornelia de Lange syndrome
  description: >-
    Cohesinopathy caused by NIPBL or cohesin-subunit variants, with limb
    reduction, growth deficiency and intellectual disability, usually
    heterozygous; clinically distinct from this disease.
  disease_term:
    preferred_term: Cornelia de Lange syndrome
    term:
      id: MONDO:0016033
      label: Cornelia de Lange syndrome
  evidence:
  - reference: PMID:21637801
    reference_title: A zebrafish model of Roberts syndrome reveals that Esco2 depletion interferes with development by disrupting the cell cycle.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: >-
      CdLS is caused by heterozygous mutations in NIPBL or cohesin subunits
      SMC1A and SMC3, and RBS is caused by homozygous mutations in ESCO2.
    explanation: Different genes and inheritance for the two cohesinopathies.
  - reference: PMID:21637801
    reference_title: A zebrafish model of Roberts syndrome reveals that Esco2 depletion interferes with development by disrupting the cell cycle.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: >-
      However, the two syndromes have distinct phenotypes, with differences
      not explained by their shared ontology.
    explanation: The two are clinically distinct.
- name: Warsaw breakage syndrome
  description: >-
    DDX11 cohesinopathy with a sister chromatid cohesion defect, growth
    restriction and microcephaly.
  disease_term:
    preferred_term: Warsaw breakage syndrome
    term:
      id: MONDO:0013252
      label: Warsaw breakage syndrome
  evidence:
  - reference: PMID:31935221
    reference_title: Non-redundant roles in sister chromatid cohesion of the DNA helicase DDX11 and the SMC3 acetyl transferases ESCO1 and ESCO2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: >-
      Roberts Syndrome (RBS) and Warsaw Breakage Syndrome (WABS) are rare
      human developmental syndromes that are characterized by defective SCC.
    explanation: Both are cohesion-defect syndromes.
- name: ESCO2-negative tetraphocomelia (pseudo-Roberts syndrome)
  description: >-
    Tetraphocomelia and other Roberts-like anomalies with normal karyotype,
    microarray and ESCO2 testing.
  evidence:
  - reference: PMID:33026893
    reference_title: "Pseudo-Roberts Syndrome: An Entity or Not?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Karyotype, prenatal chromosome microarray and ESCO2 gene testing were
      normal.
    explanation: A phenocopy without the molecular or cytogenetic lesion.
treatments:
- name: Multidisciplinary Limb Management
  description: >-
    Management of limb malformations through a multidisciplinary
    neuromuscular clinic: orthopedics, physical medicine, physical and
    occupational therapy, adaptive devices, prostheses, stretching, night
    splints and casts as needed.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Flexion contracture
    term:
      id: HP:0001371
      label: Flexion contracture
  - preferred_term: Tetraphocomelia
    term:
      id: HP:0030721
      label: Tetraphocomelia
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      management of limb malformations through a multidisciplinary
      neuromuscular clinic including orthopedics, physical medicine, and
      physical and occupational therapy with adaptative devices, prostheses,
      therapy, stretching, night splints, and casts as needed
    explanation: GeneReviews management of limb malformations.
- name: Occupational Therapy
  description: Occupational therapy with adaptive devices to support function.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: occupational therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  target_phenotypes:
  - preferred_term: Oligodactyly
    term:
      id: HP:0012165
      label: Oligodactyly
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      management of limb malformations through a multidisciplinary
      neuromuscular clinic including orthopedics, physical medicine, and
      physical and occupational therapy with adaptative devices, prostheses,
      therapy, stretching, night splints, and casts as needed
    explanation: GeneReviews includes occupational therapy.
- name: Hand and Orthopedic Surgery
  description: >-
    Hand surgery to allow early prehensile grasp and improve motor function,
    and corrective orthopedic surgery for limb deformities. Long-term
    follow-up of severely affected siblings who survived infancy showed
    benefit from early corrective surgery.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: hand and orthopedic surgery
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_phenotypes:
  - preferred_term: Aplasia/Hypoplasia of the thumb
    term:
      id: HP:0009601
      label: Aplasia/Hypoplasia of the thumb
  - preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      hand surgery as needed to facilitate early development of prehensile
      grasp and improve motor function
    explanation: GeneReviews on hand surgery.
  - reference: PMID:29434756
    reference_title: "Long-term survival after corrective surgeries in two patients with severe deformities due to Roberts syndrome: A Case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The findings of this study indicate that patients who survive infancy
      and reach adulthood, even patients who present with severe disease
      symptoms, can benefit from corrective surgeries and lead better lives.
    explanation: Long-term outcome of corrective surgery.
- name: Cleft Lip and Palate Repair
  description: >-
    Specialized feeding bottle and surgical repair of cleft lip and palate by
    a craniofacial team, with feeding, speech and hearing follow-up.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cleft lip and palate repair
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  - preferred_term: Bilateral cleft lip
    term:
      id: HP:0100336
      label: Bilateral cleft lip
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      specialized bottle and surgery for cleft lip and/or palate
    explanation: GeneReviews management of clefting.
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      assessment of feeding, speech development, and hearing (in those with
      cleft lip and palate) per craniofacial team
    explanation: GeneReviews surveillance after cleft repair.
- name: Craniofacial Surgery for Craniosynostosis and Micrognathia
  description: Surgical treatment of craniosynostosis and micrognathia.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: craniofacial surgery
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  - preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      surgical treatment for craniosynostosis and micrognathia
    explanation: GeneReviews management.
- name: Feeding and Nutrition Support
  description: Feeding and nutritional support for growth deficiency and cleft-related feeding difficulty.
  treatment_term:
    preferred_term: nutritional support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  target_phenotypes:
  - preferred_term: Postnatal growth retardation
    term:
      id: HP:0008897
      label: Postnatal growth retardation
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Individualized treatment to improve quality of life; feeding and
      nutrition support
    explanation: GeneReviews management.
- name: Speech Therapy and Educational Support
  description: Developmental and educational support including speech therapy.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  target_phenotypes:
  - preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      developmental and educational support including speech therapy
    explanation: GeneReviews management.
- name: Multisystem Surveillance
  description: >-
    At each visit: growth, limb function, development, blood pressure,
    infection frequency and home adaptation. Annual kidney function tests and
    annual skin and neurologic examination for malignancy; ophthalmologic and
    cardiac follow-up; serum immunoglobulins in infancy; neurology referral
    with brain imaging for vascular anomalies and aneurysms in those with
    intellectual disability, corneal opacities or heart defects, and annual
    assessment for aneurysm from adolescence.
  treatment_term:
    preferred_term: surveillance
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Intracranial aneurysm
    term:
      id: HP:0004944
      label: Dilatation of the cerebral artery
  - preferred_term: Renal dysplasia
    term:
      id: HP:0000110
      label: Renal dysplasia
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      referral to neurologist including brain imaging for vascular anomalies
      and aneurysms in those with intellectual disability, corneal opacities,
      and/or heart defects
    explanation: GeneReviews neurovascular surveillance.
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Assess growth, limb mobility and function, development and educational
      needs, blood pressure, frequency of infections, and home adaptation needs
      at each visit
    explanation: GeneReviews routine surveillance.
- name: Genetic Counseling
  description: >-
    Recurrence counseling for a 25% sib risk, carrier testing of relatives
    and prenatal or preimplantation testing once both ESCO2 variants are
    known.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301332
    reference_title: ESCO2 Spectrum Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Once the ESCO2 pathogenic variants have been identified in an affected
      family member, molecular genetic carrier testing for at-risk relatives
      and prenatal/preimplantation genetic testing are possible.
    explanation: GeneReviews genetic counseling.
- name: L-leucine (preclinical)
  description: >-
    Investigational only. Stimulating mTORC1 with L-leucine partially rescued
    translation, cell division and survival in RBS cells and many
    developmental defects in esco2 mutant zebrafish. No human trial has been
    reported.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: L-leucine
      term:
        id: CHEBI:15603
        label: L-leucine
  target_mechanisms:
  - target: mTORC1 Repression and Reduced Protein Translation
    description: L-leucine activates mTORC1, counteracting its repression.
  evidence:
  - reference: PMID:24098154
    reference_title: Stimulation of mTORC1 with L-leucine rescues defects associated with Roberts syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Stimulation of the TOR pathway with L-leucine rescued many developmental
      defects of ESCO2-mutant embryos.
    explanation: Preclinical rescue in zebrafish.
  - reference: PMID:26729373
    reference_title: Improved transcription and translation with L-leucine stimulation of mTORC1 in Roberts syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This study reveals the dramatic rescue effects of L-leucine stimulation
      of mTORC1 in RBS cells and supports that normal gene expression and
      translation requires ESCO2 function.
    explanation: Preclinical rescue in patient cells.
animal_models:
- name: Esco2 constitutive knockout mouse
  species: Mouse
  genotype: Esco2 null (Cre-mediated deletion of exons 2-3)
  publication: PMID:22101327
  description: >-
    Constitutive loss of Esco2 ends development at pre- and post-implantation
    stages; Esco2-deficient embryonic fibroblasts show reduced Smc3
    acetylation and Sororin recruitment, loss of pericentric cohesion,
    railroad-track chromosomes, prometaphase delay and apoptosis.
  modeled_mechanisms:
  - target: Failed Pericentric Sister Chromatid Cohesion Establishment
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Reproduces the pericentric cohesion defect and railroad chromosomes.
    limitations: >-
      Complete loss is lethal in early embryos, whereas patients survive, so
      the organismal phenotype cannot be studied without conditional
      deletion.
    evidence:
    - reference: PMID:22101327
      reference_title: Cohesin acetyltransferase Esco2 is a cell viability factor and is required for cohesion in pericentric heterochromatin.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, we show that Esco2 deficiency leads to termination of mouse
        development at pre- and post-implantation stages, indicating that
        Esco2 functions non-redundantly with Esco1.
      explanation: The model and its lethality.
- name: Esco2 limb mesenchyme conditional knockout mouse (Prrx1-Cre)
  species: Mouse
  genotype: Esco2fl/fl;Prrx1-CreTg/0 (exon 4 deletion modeled on human c.879_880delAG)
  publication: PMID:39168984
  description: >-
    Deletion of Esco2 in limb mesenchyme produces fully penetrant phocomelia
    with skull flattening and micrognathia, most animals dying perinatally.
    p53 signaling in a pre-apoptotic mesenchymal population from E9.5,
    apoptosis from E10.5, vascular disorganization and hemorrhage by E12.5;
    in utero pifithrin-alpha reduced apoptosis and prevented hemorrhage but
    did not restore chondrogenesis.
  modeled_mechanisms:
  - target: Limb Bud Outgrowth Failure
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: Reproduces symmetric limb reduction resembling the human phenotype.
    limitations: >-
      Deletion restricted to Prrx1-expressing mesenchyme, so contributions
      from other limb lineages (ectoderm, endothelium) and systemic effects
      are not modeled.
    evidence:
    - reference: PMID:39168984
      reference_title: Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Esco2fl/fl;Prrx1-CreTg/0 pups at P0 were born with striking limb
        reduction that resembled the human RBS phenotype
      explanation: Model faithfully shows the limb phenotype.
  - target: Limb Bud Vascular Disruption and Hemorrhage
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: TISSUE
    description: The only model in which the vascular arm has been shown.
    limitations: No human embryonic tissue is available to confirm a vascular component.
    evidence:
    - reference: PMID:39168984
      reference_title: Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our results reveal morphological and vascular defects culminating in
        hemorrhage of mutant limbs at E12.5.
      explanation: Vascular phenotype in the model.
  - target: p53 Pathway Activation
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: TISSUE
    description: Pifithrin-alpha p53 inhibition in utero.
    limitations: >-
      Rescued hemorrhage and reduced apoptosis but did not restore
      chondrogenesis or full limb morphology.
    evidence:
    - reference: PMID:39168984
      reference_title: Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The morphology of the limb was not fully recovered, which suggests a
        more primary role of p53 in supporting the vascular phenotype.
      explanation: Partial rescue after p53 inhibition.
- name: Esco2 cortex conditional knockout mouse (Emx1-Cre)
  species: Mouse
  genotype: Esco2fl/fl;Emx1-Cre
  publication: PMID:33798452
  description: >-
    Cortex-specific Esco2 deletion causes apoptosis of radial glial and
    intermediate progenitors and their neurons and failure of cortical
    layering.
  modeled_mechanisms:
  - target: Cortical Progenitor Loss
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Progenitor apoptosis and neuron loss in the developing cortex.
    limitations: >-
      Complete deletion in cortical progenitors is more severe than the
      human microcephaly, in which ESCO2 function is reduced systemically but
      patients may have normal intelligence.
    evidence:
    - reference: PMID:33798452
      reference_title: Molecular Profiling Reveals Involvement of ESCO2 in Intermediate Progenitor Cell Maintenance in the Developing Mouse Cortex.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Taking our data together, we show that ESCO2 expression is essential
        for the maintenance of IPCs and proper neurogenesis during cortical
        development.
      explanation: Summary of the cortical model.
- name: esco2 morphant zebrafish
  species: Zebrafish
  genotype: esco2 morpholino knockdown
  publication: PMID:21637801
  description: >-
    Esco2-depleted embryos show mitotic defects, craniofacial abnormalities
    and fin truncations, with high cell death and cell-cycle and apoptosis
    gene expression changes distinct from those after rad21 loss.
  modeled_mechanisms:
  - target: Apoptosis of Proliferating Embryonic Progenitors
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Widespread cell death accompanies RBS-like craniofacial and fin defects.
    limitations: >-
      Morpholino knockdown can cause off-target p53 activation and toxicity;
      fish fins are not homologous in detail to tetrapod limb segments.
    evidence:
    - reference: PMID:21637801
      reference_title: A zebrafish model of Roberts syndrome reveals that Esco2 depletion interferes with development by disrupting the cell cycle.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Esco2 depleted zebrafish embryos exhibit features that resemble RBS,
        including mitotic defects, craniofacial abnormalities and limb
        truncations.
      explanation: The model shows RBS-like features.
- name: esco2 mutant zebrafish
  species: Zebrafish
  genotype: esco2 embryonic-lethal mutant from a genomic-instability screen
  publication: PMID:26044958
  description: >-
    Live imaging shows premature chromatid separation, chromosome scattering,
    prolonged mitotic delay, anaphase bridges, micronuclei and aneuploidy,
    with p53-dependent neural tube apoptosis; 10-20% of cells keep weakened
    cohesion without Esco2.
  modeled_mechanisms:
  - target: Prolonged Mitosis and Chromosome Missegregation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Direct in vivo observation of the mitotic defect.
    limitations: Embryonic lethal; limb and palate phenotypes cannot be assessed.
    evidence:
    - reference: PMID:26044958
      reference_title: Variations in dysfunction of sister chromatid cohesion in esco2 mutant zebrafish reflect the phenotypic diversity of Roberts syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These studies provide a unique in vivo vertebrate view of the mitotic
        defects and consequences of cohesion establishment loss, and they
        provide a compensation-based model to explain the RBS phenotypes.
      explanation: The model's contribution.
- name: esco2 R80S mutant medaka
  species: Medaka
  genotype: esco2 R80S homozygous (TILLING)
  publication: PMID:22694322
  description: >-
    Developmental arrest with craniofacial and chromosomal abnormalities,
    embryonic lethality, widespread apoptosis and reduced notch1a expression.
  modeled_mechanisms:
  - target: Apoptosis of Proliferating Embryonic Progenitors
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Apoptosis and craniofacial defects in a missense mutant.
    limitations: Embryonic lethal; fish lack tetrapod limbs.
    evidence:
    - reference: PMID:22694322
      reference_title: Establishment and characterization of Roberts syndrome and SC phocomelia model medaka (Oryzias latipes).
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The medaka mutant carrying the homozygous mutation at R80S in the
        conserved region of ESCO2 exhibited clinical variety (i.e.
        developmental arrest with craniofacial and chromosomal abnormalities
        and embryonic lethality) as characterized in RBS/SC.
      explanation: RBS-like features in the medaka model.
experimental_models:
- name: RBS patient fibroblasts complemented with ESCO2
  experimental_model_type: CELL_LINE
  publication: PMID:19738907
  description: >-
    Immortalized RBS fibroblasts compared with isogenic lines stably
    expressing wild-type or W539G ESCO2.
  modeled_mechanisms:
  - target: Failed Pericentric Sister Chromatid Cohesion Establishment
    relationship: RESCUES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Wild-type ESCO2 corrects the cohesion defect; the patient missense allele does not.
    limitations: Immortalized cultured fibroblasts; no developmental readout.
    evidence:
    - reference: PMID:19738907
      reference_title: The cellular phenotype of Roberts syndrome fibroblasts as revealed by ectopic expression of ESCO2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We show that the sister chromatid cohesion defect in the transfected
        cell lines is rescued
      explanation: Complementation result.
  - target: Genotoxin Hypersensitivity and Defective DNA Damage Response
    relationship: MEASURES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Isogenic measurement of drug sensitivity.
    limitations: Cultured cells; relevance to embryonic tissues untested.
    evidence:
    - reference: PMID:19738907
      reference_title: The cellular phenotype of Roberts syndrome fibroblasts as revealed by ectopic expression of ESCO2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In comparison to the corrected cells RBS cells were hypersensitive to
        the DNA-damaging agents mitomycin C, camptothecin and etoposide, while
        no particular sensitivity to UV, ionizing radiation, hydroxyurea or
        aphidicolin was found.
      explanation: Isogenic genotoxin sensitivity.
- name: RBS patient cells with mTORC1 stimulation
  experimental_model_type: CELL_LINE
  publication: PMID:24098154
  description: >-
    Human RBS cell lines analyzed for nucleolar morphology, mTORC1 signaling,
    p53 activation, translation and the effect of L-leucine.
  modeled_mechanisms:
  - target: mTORC1 Repression and Reduced Protein Translation
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Measures mTORC1 repression and its L-leucine rescue.
    limitations: >-
      Immortalized cell lines; whether the translational deficit operates in
      embryonic limb or facial progenitors is untested in mammals.
    evidence:
    - reference: PMID:24098154
      reference_title: Stimulation of mTORC1 with L-leucine rescues defects associated with Roberts syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We report that mTOR signaling is inhibited in human RBS cells based on
        the reduced phosphorylation of the downstream effectors S6K1, S6 and
        4EBP1, and this correlates with p53 activation.
      explanation: Direct measurement in patient cells.
discussions:
- discussion_id: rbs_genotype_severity_gap
  prompt: >-
    Why do the same truncating ESCO2 alleles give tetraphocomelia and
    perinatal death in one patient and mild limb shortening with survival to
    adulthood in another, sometimes within one family?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#ESCO2
  - phenotypes#Tetraphocomelia
  rationale: >-
    Nearly all alleles are loss of function, yet severity spans the whole
    Roberts-to-SC phocomelia range with no genotype correlation. Proposed
    modifiers include tissue and individual variation in nonsense-mediated
    decay and residual cohesion in a subset of cells, but none has been
    tested against clinical severity.
  evidence:
  - reference: PMID:16380922
    reference_title: "Inactivating mutations in ESCO2 cause SC phocomelia and Roberts syndrome: no phenotype-genotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Since only protein-truncating mutations were identified, regardless of
      clinical severity, we conclude that genotype does not predict phenotype.
    explanation: States the gap.
  - reference: PMID:26044958
    reference_title: Variations in dysfunction of sister chromatid cohesion in esco2 mutant zebrafish reflect the phenotypic diversity of Roberts syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Surprisingly, although many cells required Esco2 to establish cohesion,
      10-20% of cells had only weakened cohesion in the absence of Esco2,
      suggesting that compensatory cohesion mechanisms exist in these cells
      that undergo a normal mitotic division.
    explanation: Compensatory cohesion as a candidate modifier.
- discussion_id: rbs_mouse_lethality_mismatch
  prompt: >-
    Constitutive Esco2 loss is lethal in early mouse embryos, while humans
    with biallelic truncating ESCO2 variants are born and some reach
    adulthood. What supplies the residual function in human embryos, and how
    faithfully do tissue-restricted mouse knockouts model the human
    systemic-but-partial deficiency?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - animal_models#Mouse
  - pathophysiology#Reduced SMC3 Acetylation of Chromatin-Bound Cohesin
  rationale: >-
    The mismatch concerns the Esco2 constitutive knockout mouse; the
    animal_models#Mouse anchor resolves by species and so also matches the two
    conditional knockouts listed in this entry. The mouse data argue that Esco2
    is not redundant with Esco1, whereas
    human survival implies partial redundancy or residual activity. The limb
    and cortex conclusions in this entry rest on conditional knockouts that
    delete Esco2 completely in one lineage, which is a different state from
    the human deficiency.
  evidence:
  - reference: PMID:22101327
    reference_title: Cohesin acetyltransferase Esco2 is a cell viability factor and is required for cohesion in pericentric heterochromatin.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: >-
      Partial redundancy between ESCO1 and ESCO2 may also occur in Roberts
      syndrome (RBS), an ESCO2 deficiency in humans that does not lead to the
      loss of viability
    explanation: The authors frame the species difference.
  proposed_experiments:
  - experiment_id: rbs_patient_allele_knockin_mouse
    name: Patient-allele Esco2 knock-in mouse
    description: >-
      Introduce a recurrent human truncating allele constitutively and test
      whether embryos survive to show limb, craniofacial and cortical
      phenotypes, and whether Esco1 dosage modifies severity.
    supporting_outcome:
    - >-
      Viable homozygous embryos with symmetric limb reduction, clefting and
      microcephaly whose severity varies with Esco1 dosage.
    refuting_outcome:
    - >-
      Early embryonic lethality as in the null, indicating that the human
      allele retains no function in the mouse.
- discussion_id: rbs_limb_reduction_mechanism
  prompt: >-
    Is limb reduction caused mainly by death of limb mesenchyme, by a
    proliferation shortfall, by p53-dependent vascular disruption, or by
    transcriptional dysregulation of limb genes?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Limb Bud Outgrowth Failure
  - mechanistic_hypotheses#mitotic_failure_progenitor_apoptosis
  - mechanistic_hypotheses#limb_vascular_disruption
  rationale: >-
    In the Esco2 limb mouse, p53 inhibition reduced apoptosis and rescued
    hemorrhage but not chondrogenesis, so apoptosis alone does not explain
    the reduction; the fin-regeneration and translation studies propose
    apoptosis-independent routes. No study has compared these arms in one
    mammalian system.
  evidence:
  - reference: PMID:39168984
    reference_title: Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We had presumed that the extensive cell death in the mesenchyme was the
      underlying cause of the limb deficiency, but pifithrin-α treatment only
      recovered the hemorrhage in mutant limbs and not the chondrogenesis.
    explanation: The observation that leaves the question open.
- discussion_id: rbs_cerebrovascular_gap
  prompt: >-
    How often do ischemic stroke, aneurysm and small-vessel disease occur in
    surviving patients, and how does ESCO2 loss damage cerebral vessels?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Cerebral Small-Vessel Vasculopathy
  - phenotypes#Intracranial aneurysm
  rationale: >-
    The cerebrovascular phenotype rests on case reports, yet GeneReviews now
    recommends neurovascular surveillance. The vasculopathy node has no
    upstream mechanism in this entry; the p53-dependent vascular disruption
    seen in the embryonic mouse limb is a possible lead but has not been
    examined in cerebral vessels.
  evidence:
  - reference: PMID:37002187
    reference_title: Complex cerebrovascular diseases in Roberts syndrome caused by novel biallelic ESCO2 variations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case expands not only the cerebral involvement in Roberts syndrome
      but also the disease spectrum of the neuroimaging triad with
      leukoencephalopathy, calcifications, and cysts.
    explanation: The phenotype is newly described.
references:
- reference: PMID:20301332
  title: ESCO2 Spectrum Disorder.
  tags:
  - GeneReviews
📚

References & Deep Research

References

1
PMID:20301332
ESCO2 Spectrum Disorder.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Roberts Syndrome · 2026-09-25T15:04:35Z · View source

New entry for Roberts-SC phocomelia syndrome (MONDO:0100253; ESCO2 spectrum disorder), replacing the stub stubs/Roberts-SC_Phocomelia_Syndrome.yaml. Scope. Roberts syndrome (OMIM 268300) and SC phocomelia (OMIM 269000) are curated as one disease with no has_subtypes: MONDO:0100253 carries both OMIM identifiers, GeneReviews treats them as one spectrum, and the two share the gene, the truncating allele class and the cytogenetic sign. Juberg-Hayward syndrome (MONDO:0008992) is recorded as an allelic differential, consistent with kb/disorders/Humeroradial_Synostosis.yaml, which treats it as a separate ESCO2 disorder. Sources. The GeneReviews chapter "ESCO2 Spectrum Disorder" (PMID:20301332, NBK1153) is tagged and cited for all four abstract sections: clinical characteristics (phenotypes), diagnosis (molecular and cytogenetic testing), management (limb, cleft, craniofacial, feeding, speech and surveillance treatments) and genetic counseling (inheritance and recurrence risk). The OpenScientist deep-research report (research/Roberts_Syndrome-deep-research-openscientist.md; 16/16 references resolved, no unresolved terms) was read in full and its citations used where they support a claim: PMID:16380922, 21637801, 26710928, 26729373, 30204960, 31935221, 32783269, 34989322, 34897432, 25378554 and 27803161. Not used: PMID:40668332 (sorbitol as a chemical chaperone in the yeast eco1-W216G model; a single yeast study with no animal or clinical data, so not added as a treatment), PMID:40396618 (Nipbl knockdown and the CRL4 axis in zebrafish; it concerns NIPBL, the Cornelia de Lange gene, and adds nothing ESCO2-specific beyond PMID:34989322, which is cited) and PMID:31516082 (cohesinopathy review centred on Cornelia de Lange syndrome and CAID syndrome). The report gives HGNC:24645 for ESCO2; HGNC's identifier is hgnc:27230, which is the one bound here. The report's HP suggestions HP:0000119 and HP:0001028 were not used; more specific terms were bound. The remaining references were found by PubMed search. Pathograph. ESCO2 loss of function -> reduced SMC3 acetylation -> failed pericentric cohesion -> (premature centromere separation; prolonged mitosis and missegregation -> aneuploidy and p53 activation; nucleolar dysfunction -> mTORC1 repression; transcriptional dysregulation) -> p53 -> progenitor apoptosis and limb-bud vascular disruption -> limb bud outgrowth failure, deficient craniofacial primordium growth and cortical progenitor loss -> phenotypes. Five mechanistic_hypotheses record the competing models (mitotic failure and apoptosis, ribosome biogenesis and translation, transcriptional dysregulation, vascular disruption, macromolecular damage), including the refuting observations (no cell-cycle lengthening in patient lymphoblastoid lines, PMID:18411254; p53 inhibition rescuing limb hemorrhage but not chondrogenesis, PMID:39168984). The cortical node conforms to neural_progenitor_centrosome_spindle_dysfunction#Progenitor Pool Distortion, on the strength of the Emx1-Cre Esco2 mouse (PMID:33798452). No cohesinopathy module exists in kb/modules/. Terms. Neonatal death (HP:0003811) is outside the PhenotypeTerm enum (HP:0000118), so the perinatal-death phenotype carries no term. Premature centromere separation is bound to HP:0003616 Premature separation of centromeric heterochromatin (found with ols:hp search "l~centromere"). Ear malformations and malignancy are coarse bindings with coarse_binding_basis SOURCE_UNSPECIFIED, following the GeneReviews list sentences. Validation: just validate, just validate-terms, just count-verified-snippets (all snippets verified), check-entity-refs, check-causal-targets, check-coarse-phenotypes, check-qualifier-terms, list-gene-term-mismatches, check-duplicate-keys, check-snippet-length, check-title-snippets, check-folded-hyphens, check-reference-titles, and just validate-disorders on the entry.

OpenScientist ▸
Roberts Syndrome (RBS): A Comprehensive Disease Characteristics Report
openscientist-autonomous 12 citations 2026-09-25T14:56:46.981765

Roberts Syndrome (RBS): A Comprehensive Disease Characteristics Report

MONDO: MONDO:0100253 · OMIM: #268300 · Orphanet: ORPHA:3103 · MeSH/UMLS: C0392475 · Gene: ESCO2 (8p21.1; OMIM *609353; HGNC:24645) · Category: Mendelian, autosomal-recessive cohesinopathy

Summary

Roberts syndrome (RBS), including its milder allelic form SC phocomelia, is a rare autosomal-recessive developmental disorder caused by biallelic loss-of-function mutations in ESCO2 (Establishment of Sister Chromatid Cohesion N-Acetyltransferase 2) on chromosome 8p21.1. ESCO2 is a zinc-finger/Gcn5-like acetyltransferase that acetylates the cohesin subunit SMC3 to establish sister-chromatid cohesion during S phase. When ESCO2 activity is lost, centromeric cohesion fails — producing the pathognomonic cytogenetic hallmarks of premature centromere separation (PCS) and heterochromatin repulsion (HR) — and the developing embryo cannot sustain the rapid, faithful cell divisions required for limb, craniofacial, and somatic growth. The clinical result is a triad of symmetric limb reduction (up to tetraphocomelia), pre- and postnatal growth retardation, and craniofacial anomalies, frequently accompanied by microcephaly and variable intellectual disability.

The molecular pathogenesis converges through at least four downstream branches: (1) mitotic failure and apoptosis of proliferating progenitor cells; (2) DNA-damage and redox stress; (3) nucleolar fragmentation with impaired ribosome biogenesis and depressed mTORC1-dependent translation; and (4) cohesin-dependent transcriptional dysregulation, including regulation of the CRL4 ubiquitin ligase. A notable, mechanism-based therapeutic lead is L-leucine, an mTORC1 stimulator that partially rescues translation and development in RBS cell and zebrafish models.

Clinically, RBS shows highly variable expressivity with no genotype–phenotype correlation — from severe forms with perinatal/stillbirth lethality to milder SC phocomelia compatible with survival into adulthood. Diagnosis rests on characteristic clinical features, the cytogenetic PCS/HR signature, and confirmatory ESCO2 sequencing; prenatal diagnosis is feasible by serial fetal ultrasound with long-bone measurement and by molecular testing in known families. No curative therapy exists; management is supportive, reconstructive, and rehabilitative, supported by genetic counseling.

Key Findings

F001 — Roberts syndrome is caused by biallelic loss-of-function mutations in ESCO2 (8p21.1)

Multiple independent case series establish that RBS and SC phocomelia result from biallelic, protein-truncating mutations (frameshift, nonsense, splice-site) in ESCO2. Schüle et al. identified seven novel mutations across exons 3–8, all protein-truncating regardless of clinical severity. The gene product, ESCO2 (Establishment of Sister Chromatid Cohesion N-Acetyltransferase 2), maps to 8p21.1.

  • PMID: 16380922: "Recently, mutations in ESCO2 (establishment of cohesion 1 homolog 2) on 8p21.1 have been reported in RBS."
  • PMID: 16380922: "Since only protein-truncating mutations were identified, regardless of clinical severity, we conclude that genotype does not predict phenotype."
  • PMID: 32783269: "Biallelic loss-of-function variants in ESCO2, which codes for establishment of sister chromatid cohesion N-acetyltransferase 2, cause Roberts syndrome."

Ontology suggestions: Gene HGNC:24645 (ESCO2); MONDO:0100253; OMIM:268300.

F002 — RBS and SC phocomelia are allelic with no genotype–phenotype correlation

Schüle et al. (2005) studied three SC phocomelia families plus two families with variable limb/craniofacial abnormalities; all were positive for heterochromatin repulsion and all carried truncating ESCO2 mutations, demonstrating that RBS and SC phocomelia are caused by mutations in the same gene. An Egyptian cohort of eight patients independently confirmed the absence of genotype–phenotype correlation. This allelism and variable expressivity are central to genetic counseling and prognosis.

  • PMID: 16380922: "Having established that RBS and SC are caused by mutations"
  • PMID: 30204960: "We confirmed previous results of lack of genotype/phenotype correlation."

F003 — Cytogenetic hallmark: premature centromere separation / heterochromatin repulsion

Patient metaphase spreads show premature centromere separation (PCS), heterochromatin repulsion (HR) — the classic "railroad track"/puffing appearance at heterochromatic centromeric and Y chromosome regions — and chromosome breaks, visualized by Giemsa, DAPI, and C-banding. HR is consistently present in both RBS and SC phocomelia and is used as a diagnostic marker.

  • PMID: 32783269: "characteristic cytogenetic defects, such as premature centromere separation, heterochromatin repulsion, and chromosome breaks, in patient cells strongly supported pathogenicity"
  • PMID: 30204960: "Cytogenetic studies including centromeric separation and puffing by Giemsa and DAPI stains"

F004 — ESCO2 loss disrupts the cell cycle and triggers apoptosis in developing tissues

A zebrafish esco2 knockdown model recapitulates RBS, including mitotic defects, craniofacial abnormalities, and limb truncations. Microarray analysis showed that Esco2-regulated genes are enriched for cell cycle and apoptosis functions — distinct from the targets of the core cohesin subunit rad21, which enriched for transcriptional regulators. This positions cell-cycle disruption and programmed cell death of proliferating progenitors as a key downstream mechanism linking cohesion failure to tissue hypoplasia.

  • PMID: 21637801: "Esco2 depleted zebrafish embryos exhibit features that resemble RBS, including mitotic defects, craniofacial abnormalities and limb truncations."
  • PMID: 21637801: "Esco2-regulated genes were more likely to be involved the cell cycle or apoptosis"

Ontology suggestions: GO:0007049 (cell cycle); GO:0006915 (apoptotic process); GO:0007062 (sister chromatid cohesion).

F005 — ESCO2/cohesin loss produces DNA damage and redox stress

In Saccharomyces cerevisiae RBS models (eco1 mutants, homologous to human ESCO2), redox stress is elevated, oxidative-DNA-damage repair is impaired, and DNA-damage checkpoints are hyperactivated. Critically, antioxidant treatment desensitizes eco1 cells to DNA-damaging agents, supporting an oxidative-stress/DNA-damage arm of pathogenesis and hinting at an antioxidant intervention strategy. A complementary "macromolecular damage" model broadens the injury beyond DNA to include translational/ribosomal machinery.

  • PMID: 34897432: "the results reveal that redox stress is elevated in both eco1 and cohesion factor Saccharomyces cerevisiae mutant cells"
  • PMID: 34897432: "antioxidant treatment desensitizes eco1 mutant cells to a range of DNA damaging agents"

Ontology suggestions: GO:0006979 (response to oxidative stress); GO:0006281 (DNA repair).

F006 — Nucleolar fragmentation, impaired ribosome biogenesis, and depressed mTORC1 translation — rescued by L-leucine

RBS cells display highly fragmented nucleoli with defects in ribosome biogenesis (rRNA/snoRNA production) and reduced overall protein translation; mTORC1 signaling is depressed. Treatment with L-leucine, an mTORC1 stimulator, partially rescues mTOR function, translational efficiency of ribosomal subunits and initiation factors, mitochondrial function, cell division, and development in both RBS cells and zebrafish models. The same translational axis operates across cohesinopathies (e.g., Cornelia de Lange syndrome, CdLS). This is the most concrete mechanism-based therapeutic lead for RBS.

  • PMID: 26729373: "mTORC1 signaling was depressed and overall translation was reduced in RBS cells and zebrafish models for RBS. Treatment of RBS cells and zebrafish RBS models with L-leucine partially rescued mTOR function and protein synthesis, correlating with increased cell division and improved development."
  • PMID: 25378554: "RBS was associated with highly fragmented nucleoli and defects in both ribosome biogenesis and protein translation. l-leucine stimulation of the mTOR pathway partially rescued translation in human RBS cells and development in zebrafish models of RBS."

Ontology suggestions: GO:0042254 (ribosome biogenesis); GO:0006412 (translation); GO:0031929 (TOR signaling); GO:0005730 (nucleolus); CHEBI:15603 (L-leucine).

F007 — Recurrent frameshift/truncating alleles cluster in exon 3; prenatal diagnosis is feasible

The Egyptian cohort (Afifi et al., 2016) reported homozygous exon-3 frameshift mutations, including the novel c.244_245dupCT (p.T83Pfs*20) and previously reported c.760_761insA (p.T254Nfs*27) and c.764_765delTT (p.F255Cfs*25). All patients showed growth retardation, mesomelic limb shortening (upper > lower limbs), microcephaly, and characteristic PCS with heterochromatin puffing. Serial fetal ultrasound with long-bone measurement diagnosed two affected fetuses prenatally, and severity of mesomelic shortening and craniofacial anomalies varied among patients (variable expressivity).

  • PMID: 26710928: "sequencing of the ESCO2 gene identified a novel mutation c.244_245dupCT (p.T83Pfs20) in one family besides two previously reported mutations c.760_761insA (p.T254Nfs27) and c.764_765delTT (p.F255Cfs25). All mutations were in homozygous state, in exon 3."*
  • PMID: 26710928: "Serial fetal ultrasound examinations and measurements of long bones diagnosed two affected fetuses in two of the studied families."
  • PMID: 26710928: "The severity of the mesomelic shortening of the limbs and craniofacial anomalies showed variability among patients."

F008 — ESCO2 is a zinc-finger/Gcn5-like acetyltransferase; missense variants cause RBS (germline) and occur in cancers (somatic)

X-ray crystallography of the conserved zinc-finger–acetyltransferase moiety of the ESCO paralog ESCO1 shows that the catalytic core is structurally homologous to the Gcn5 histone acetyltransferase (HAT), with a unique zinc finger and an ~40-residue loop that mediate protein stability and SMC3 substrate binding. Missense mutations in the acetyltransferase domain correlate with disease — Roberts syndrome (germline) and endometrial cancers (somatic) — linking RBS mechanistically to genome-instability phenotypes seen in cancer.

  • PMID: 27803161: "Missense mutations within the acetyltransferase domain of these proteins correlate with diseases, including endometrial cancers and Roberts syndrome."
  • PMID: 27803161: "the ESCO1 acetyltransferase core is structurally homologous to the Gcn5 HAT, but contains unique additional features including a zinc finger and an ∼40-residue loop region that appear to play roles in protein stability and SMC3 substrate binding"

Ontology suggestions: GO:0016407 (acetyltransferase activity); GO:0008270 (zinc ion binding); UniProt Q56NI9 (ESCO2_HUMAN).

Section-by-Section Report

1. Disease Information

Roberts syndrome is a rare, autosomal-recessive multiple-congenital-anomaly disorder characterized by symmetric limb reduction defects, growth retardation, and craniofacial anomalies. It exists on a clinical severity spectrum with SC phocomelia (formerly "pseudothalidomide syndrome"), now known to be allelic (same gene, ESCO2) (F001, F002).

Key identifiers: MONDO:0100253; OMIM #268300; Orphanet ORPHA:3103; MeSH/UMLS C0392475; ICD-10 Q87.8 (no dedicated code); ICD-11 within multiple-congenital-anomaly syndromes. Gene: ESCO2, HGNC:24645, 8p21.1.

Synonyms/alternative names: Roberts–SC phocomelia syndrome; SC phocomelia syndrome; pseudothalidomide syndrome; hypomelia–hypotrichosis–facial hemangioma syndrome; Appelt–Gerken–Lenz syndrome; RBS.

Information source: Predominantly aggregated disease-level resources (OMIM, Orphanet) and individual patient case reports/small cohorts (Egyptian cohort of 8 patients; Indian and Nigerian case reports). There is no large EHR-derived dataset; the disorder's rarity means knowledge derives from curated literature.

2. Etiology

Primary cause — genetic: Biallelic (homozygous or compound heterozygous) loss-of-function mutations in ESCO2 (F001). Nearly all reported alleles are protein-truncating; recurrent frameshift alleles cluster in exon 3 (F007).

Genetic risk factors: The disorder is monogenic and fully determined by biallelic ESCO2 LoF; consanguinity is a major risk factor because it increases homozygosity for rare recessive alleles (predominance of homozygous cases in consanguineous populations, F007). No common susceptibility loci or polygenic contribution.

Environmental/lifestyle risk factors: None established. RBS is not caused by environmental exposure. (Historically confused with thalidomide embryopathy — hence "pseudothalidomide" — reflecting phenotypic mimicry, not shared etiology.)

Protective factors: No genetic or environmental protective factors are established. Mechanistically, L-leucine (mTORC1 stimulation) and antioxidants are experimental modifiers of cellular phenotype (F005, F006), not population-level protective factors.

Gene–environment interactions: None documented for causation. The only "interaction" of note is experimental therapeutic modulation (leucine/antioxidants) of the mutant cellular phenotype.

3. Phenotypes

RBS phenotypes are congenital (prenatal onset), bilateral/symmetric, and range from mild to severe with variable expressivity (F002, F007).

Phenotype Type Onset Severity/Frequency Suggested HPO
Symmetric limb reduction / phocomelia / tetraphocomelia Physical malformation Congenital Severe; upper > lower limbs; hallmark HP:0009829 (phocomelia); HP:0009821 (limb reduction)
Pre- and postnatal growth retardation Clinical sign Prenatal Severe; near-universal HP:0001511 (IUGR); HP:0001510
Microcephaly Physical sign Congenital Common HP:0000252
Craniofacial anomalies (cleft lip/palate, hypertelorism, micrognathia, malar hypoplasia) Physical malformation Congenital Common, variable HP:0000175; HP:0000316
Intellectual disability Behavioral/cognitive Childhood Mild–severe, variable HP:0001249
Oligodactyly / absent digits Physical malformation Congenital Common HP:0012165
Cardiac / renal / genital anomalies Structural Congenital Variable HP:0001627; HP:0000119
Sparse/silvery hair, facial hemangioma Physical sign Congenital Reported (SC phocomelia) HP:0008070; HP:0001028
Stillbirth / early mortality Outcome Perinatal Severe forms HP:0003826

Quality-of-life impact: Severe forms are perinatally lethal (stillbirth/early death); survivors face major mobility limitation from limb reduction, need for reconstructive/prosthetic support, and variable cognitive impairment. Formal EQ-5D/SF-36 data are not available for this ultra-rare condition.

4. Genetic / Molecular Information

Causal gene: ESCO2 (HGNC:24645, OMIM *609353), 8p21.1, encoding a zinc-finger/Gcn5-like acetyltransferase (F001, F008).

Pathogenic variants: Predominantly protein-truncating — frameshift, nonsense, splice-site (F001). Recurrent exon-3 frameshifts: c.244_245dupCT (p.T83Pfs*20), c.760_761insA (p.T254Nfs*27), c.764_765delTT (p.F255Cfs*25) (F007). Rare missense variants in the acetyltransferase domain also cause RBS and, somatically, appear in endometrial cancers (F008). ACMG/AMP: LoF truncating variants are typically pathogenic; a splice variant in an Indian patient was corroborated by cytogenetic PCS/HR evidence (F003, PMID:32783269).

Allele frequency: Causal alleles are rare/private; carrier frequencies are not well quantified in gnomAD given rarity. Somatic vs germline: RBS alleles are germline and biallelic; ESCO2 missense changes are also found somatically in cancers (F008). Functional consequence: loss of function — loss of SMC3 acetyltransferase activity and failure to establish sister-chromatid cohesion (F008).

Modifier genes: No formal human modifiers identified (consistent with no genotype–phenotype correlation, F002). Model-organism work identifies RAD61/WAPL, PDS5, DDX11, and CRL4/DDB1 as functional interactors. DDX11 (Warsaw Breakage Syndrome gene) and ESCO2 have non-redundant, partially compensatory roles in cohesion (PMID:31935221).

Epigenetic information: ESCO2 acetylates SMC3 (a chromatin-associated protein); cohesin influences chromatin architecture and transcription. No disease-specific DNA-methylation signature is established for RBS.

Chromosomal abnormalities: The disease-defining cytogenetic finding is functional (PCS/HR, chromosome breaks), not a constitutional large-scale rearrangement (F003).

5. Environmental Information

No environmental factors, toxins, radiation, lifestyle factors, or infectious agents are implicated in RBS causation. The disorder is entirely genetic (F001). "Pseudothalidomide" nomenclature reflects phenotypic resemblance to thalidomide embryopathy, not shared environmental etiology.

6. Mechanism / Pathophysiology

Causal chain (initiating lesion → clinical manifestation):

  1. Biallelic LoF mutation in ESCO2 (predominantly truncating) results in loss of ESCO2 protein / its zinc-finger–Gcn5-like acetyltransferase activity (F001, F008).
  2. Loss of ESCO2 leads to failure to acetylate cohesin subunit SMC3 during S phase (F008).
  3. Unacetylated cohesin results in defective establishment of sister-chromatid cohesion, especially at heterochromatic centromeric regions (F008).
  4. Defective centromeric cohesion manifests cytogenetically as premature centromere separation (PCS) and heterochromatin repulsion (HR), plus chromosome breaks (F003).
  5. From steps 3–4, the mechanism branches into four downstream arms:
  6. 5a — Mitotic failure/apoptosis: cohesion defects lead to mitotic errors and apoptosis of rapidly proliferating embryonic progenitors, causing tissue hypoplasia (limbs, craniofacies) (F004).
  7. 5b — DNA-damage/redox stress: cohesion/ESCO2 loss results in elevated redox stress, impaired oxidative-DNA-damage repair, and checkpoint hyperactivation (F005).
  8. 5c — Nucleolar/translational failure: ESCO2 loss leads to nucleolar fragmentation, impaired ribosome biogenesis, and depressed mTORC1-dependent translation, reducing protein-synthesis capacity needed for growth (F006).
  9. 5d — Transcriptional/ubiquitin-ligase dysregulation: cohesin-dependent gene regulation is perturbed, including CRL4 (DDB1) ubiquitin-ligase signaling downstream of Esco2/cohesin (PMID:34989322, 40396618).
  10. These branches converge to produce the clinical triad — symmetric limb reduction (tetraphocomelia), pre/postnatal growth retardation, and craniofacial anomalies — with variable microcephaly, intellectual disability, and organ malformations (F004, F006, F007).

Demonstrated vs inferred: Steps 1–4 and 5a–5c are demonstrated in patient cells and/or animal/yeast models. The precise quantitative contribution of each branch to specific human phenotypes, and step 5d's role in humans, remain inferred from model organisms.

Molecular pathways: cohesin/sister-chromatid-cohesion pathway; mTORC1/TOR signaling (F006); CRL4 ubiquitin-ligase pathway. Cellular processes: cell cycle/mitosis (GO:0007049), apoptosis (GO:0006915), ribosome biogenesis (GO:0042254), DNA repair (GO:0006281), oxidative-stress response (GO:0006979). Protein dysfunction: loss of ESCO2 acetyltransferase function; loss of SMC3 acetylation (F008). Subcellular compartments: nucleus, nucleolus (GO:0005730), chromosome/centromere, cohesin complex (GO:0008278). Cell types (CL): proliferating embryonic progenitors — e.g., limb-bud mesenchymal cells, cranial neural-crest–derived cells.

7. Anatomical Structures Affected

  • Organ/system level: limbs (musculoskeletal) — primary; craniofacial skeleton; CNS (microcephaly, intellectual disability); frequently heart, kidney, genitalia. Systems: musculoskeletal, nervous, cardiovascular, genitourinary, craniofacial.
  • Tissue/cell level: connective/skeletal tissue (bone, cartilage), rapidly dividing progenitor/mesenchymal cells, cranial neural-crest derivatives.
  • Subcellular level: nucleolus (GO:0005730), nucleus (GO:0005634), chromosome/centromere (GO:0000775), cohesin complex (GO:0008278).
  • Localization/lateralization: malformations are bilateral and symmetric (defining feature; HP:0009829).
  • UBERON suggestions: UBERON:0002101 (limb), UBERON:0001456 (face), UBERON:0000955 (brain), UBERON:0002113 (kidney), UBERON:0000948 (heart).

8. Temporal Development

  • Onset: congenital/prenatal; malformations arise during embryogenesis; growth restriction detectable in utero.
  • Progression: structural anomalies are static/non-progressive after birth, but severe forms carry high perinatal mortality; growth deficiency persists postnatally.
  • Duration/course: in survivors (milder/SC phocomelia end), a chronic lifelong disability. Critical period: the vulnerable window is embryonic organogenesis and limb development — there is no postnatal window to reverse structural malformations, underscoring prenatal counseling/diagnosis.

9. Inheritance and Population

  • Inheritance: Autosomal recessive (F001, F002). Consanguinity increases risk (F007).
  • Penetrance/expressivity: high penetrance for biallelic LoF; highly variable expressivity with NO genotype–phenotype correlation (F002, F007).
  • Epidemiology: very rare; ~150 reported cases historically (Orphanet <1/1,000,000). No reliable incidence figures.
  • Founder effects / carrier frequency: not well quantified; recurrent exon-3 alleles seen in consanguineous cohorts (F007).
  • Sex ratio: autosomal — no sex predilection (M:F ≈ 1:1).
  • Geographic distribution: worldwide; over-representation of homozygous cases in high-consanguinity populations (e.g., North Africa/Middle East).

10. Diagnostics

  • Cytogenetics (hallmark): metaphase analysis showing PCS and HR ("railroad tracks"/centromeric puffing) by Giemsa/DAPI/C-banding; chromosome breaks (F003). Low-cost, highly specific.
  • Molecular genetic testing: single-gene ESCO2 sequencing confirmatory (F001, F007); gene panels or WES/WGS for atypical presentations. Targeted variant testing enables carrier and prenatal diagnosis in known families.
  • Imaging: fetal ultrasound with long-bone measurement detects limb reduction prenatally (F007); postnatal radiographs characterize skeletal defects.
  • Prenatal diagnosis: feasible by serial fetal ultrasound and molecular testing (CVS/amniocentesis) or PCS/HR analysis of fetal cells (F007).
  • Differential diagnosis: thalidomide embryopathy, Cornelia de Lange syndrome (allied cohesinopathy), TAR syndrome, Baller–Gerold syndrome, Fanconi anemia, and other phocomelia/limb-reduction syndromes — distinguished by the pathognomonic PCS/HR cytogenetic signature and ESCO2 genotype.
  • Screening: no population newborn screening; cascade carrier screening in affected families and consanguineous couples is appropriate.

11. Outcome / Prognosis

  • Survival/mortality: bimodal. Severe forms → intrauterine death, stillbirth, or early neonatal/infant mortality. Milder forms (SC phocomelia) → survival into childhood/adulthood.
  • Morbidity/function: major mobility disability from limb reduction; variable intellectual disability; feeding/airway issues from craniofacial anomalies.
  • Complications: organ malformations (cardiac, renal, genital), infection risk, clefting complications.
  • Prognostic factors: overall severity/extent of malformations and major organ anomalies predict survival; no molecular prognostic biomarker (consistent with no genotype–phenotype correlation, F002). Formal survival/QoL registry data are not available.

12. Treatment

No curative or disease-modifying approved therapy exists. Management is supportive, reconstructive, and rehabilitative:

  • Surgical/interventional: orthopedic and reconstructive surgery for limb/craniofacial anomalies; cleft repair; correction of associated organ malformations. (NCIT: reconstructive surgical procedure.)
  • Supportive/rehabilitative: prosthetics/orthotics, physical/occupational therapy, speech therapy, nutritional support, developmental/educational support. (NCIT: physical therapy; occupational therapy.)
  • Mechanism-based experimental lead: L-leucine (CHEBI:15603), an mTORC1 stimulator, partially rescues translation, cell division, and development in RBS cell and zebrafish models (F006) — a preclinical lead, not an established human therapy. Antioxidants are a further experimental concept from yeast models (F005). Chemical chaperones (e.g., sorbitol) and proteostasis modulators have been explored in yeast RBS models (PMID:40668332).
  • Pharmacogenomics: not applicable.

13. Prevention

  • Primary prevention: genetic counseling for at-risk/consanguineous couples; carrier screening; where desired, preimplantation genetic diagnosis (PGD) or prenatal diagnosis (F007) to inform reproductive decisions.
  • Secondary prevention: prenatal ultrasound surveillance in known families for early detection (F007).
  • Tertiary prevention: multidisciplinary management to prevent complications in survivors.
  • No immunization, behavioral, or public-health environmental interventions apply (non-environmental etiology).

14. Other Species / Natural Disease

  • Taxonomy of models: Danio rerio (zebrafish, NCBI:txid7955); Saccharomyces cerevisiae (NCBI:txid4932). Orthologous genes: zebrafish esco2; yeast ECO1/CTF7; human ESCO2 (NCBI Gene 157570). Paralog ESCO1.
  • Natural disease in animals: no well-documented naturally occurring ESCO2 disorder in companion animals/wildlife is established (no prominent OMIA natural RBS analog). Not zoonotic or transmissible.
  • Comparative/evolutionary: the cohesin acetylation mechanism (Eco1→Esco2) is deeply conserved from yeast to humans, which is why yeast and zebrafish faithfully model core RBS biology (F004, F005, F006, F008).

15. Model Organisms

Model Type Recapitulation Key use Limitation
Zebrafish esco2 knockdown Vertebrate, in vivo Mitotic defects, craniofacial anomalies, limb truncations (F004); L-leucine rescue (F006) Developmental mechanism, therapy testing Skeletal anatomy differs from human
Yeast eco1 mutants (e.g., eco1W216G) Unicellular Redox/DNA-damage stress (F005), translational defects, condensation Molecular mechanism; antioxidant/chaperone screening Lacks multicellular/developmental phenotypes
Patient-derived cells In vitro (human) Nucleolar fragmentation, translation defects, PCS/HR (F003, F006) Cytogenetic diagnosis, translation studies Cell-autonomous only
ESCO1 crystal structure Structural/computational Defines Gcn5-like acetyltransferase + zinc finger (F008) Structure–function of catalysis/SMC3 binding Paralog (ESCO1), not ESCO2 directly

Resources: ZFIN (zebrafish), SGD (yeast), PDB (structures), Cellosaurus (patient cell lines).

Mechanistic Model / Interpretation

   ESCO2 biallelic LoF mutation (8p21.1; mostly truncating, exon-3 frameshifts)
         │
         ▼
     Loss of ESCO2 zinc-finger/Gcn5-like acetyltransferase activity
         │
         ▼
Failure to acetylate cohesin subunit SMC3 (S phase)
         │
         ▼
     Defective sister-chromatid cohesion at centromeric heterochromatin
         │
└── cytogenetic readout: PCS + HR + chromosome breaks
         │
      ┌──────────────────┼───────────────────┬────────────────────┐
      ▼                  ▼                   ▼                    ▼
 (5a) Mitotic       (5b) Redox stress   (5c) Nucleolar       (5d) Cohesin-
 failure &          + impaired DNA-      fragmentation →      dependent
 APOPTOSIS of       repair + checkpoint  ↓ribosome biogenesis transcription
 progenitors        hyperactivation      → ↓mTORC1 translation dysregulation
      │                  │                   │ (rescued by         (CRL4/DDB1)
      │                  │                   │  L-leucine)            │
      └──────────────────┴─────────┬─────────┴────────────────────────┘
                    ▼
Tissue hypoplasia / disrupted growth & morphogenesis
                    ▼
   Symmetric limb reduction (tetraphocomelia) + pre/postnatal growth
   retardation + craniofacial anomalies (± microcephaly, ID, organ defects)

The unifying interpretation is that RBS is a cohesinopathy of establishment: the primary lesion is not the cohesin ring itself but its S-phase activation via SMC3 acetylation. Because ESCO2 is essential for faithful, rapid cell division, the tissues most dependent on high-throughput proliferation during embryogenesis — limb buds, craniofacial primordia, and the growing soma — are the most severely affected. The convergence of four downstream branches (apoptosis, DNA-damage/redox stress, translational collapse, transcriptional dysregulation) explains both the severity and the pleiotropy of the phenotype, while the fact that all four stem from a single upstream LoF explains the lack of genotype–phenotype correlation (F002): once ESCO2 is non-functional, downstream damage is governed by stochastic and modifier-dependent factors rather than the identity of the truncating allele.

Evidence Base

PMID Title (abbrev.) Evidence type Supports
16380922 Inactivating mutations in ESCO2 cause SC phocomelia and Roberts syndrome Human genetics F001, F002 — ESCO2/8p21.1; truncating LoF; allelism; no G–P correlation
32783269 Roberts syndrome... novel homozygous splice variant in ESCO2 Human clinical F001, F003 — biallelic LoF; PCS/HR/breaks
30204960 Roberts syndrome in 8 Egyptian patients Human cohort F002, F003 — cytogenetics; no G–P correlation
21637801 A zebrafish model of Roberts syndrome Model organism F004 — cell cycle/apoptosis; phenotype recapitulation
34897432 Genetically induced redox stress in a yeast model for RBS Model organism F005 — redox stress; antioxidant rescue
26729373 Improved transcription/translation with L-leucine in RBS In vitro + model F006 — mTORC1/translation; L-leucine rescue
25378554 L-leucine rescues translational/developmental defects (CdLS/RBS) In vitro + model F006 — nucleolar fragmentation; ribosome biogenesis
26710928 Expanding the mutation and clinical spectrum of RBS Human cohort F007 — exon-3 frameshifts; prenatal US; variable expressivity
27803161 Molecular basis for cohesin acetylation by ESCO1 Structural F008 — Gcn5-like AT domain; SMC3 binding; disease missense
34989322 Esco2 and cohesin regulate CRL4 ubiquitin ligase Model organism Mechanism branch 5d — CRL4 pathway
40396618 Protein turnover downstream of Nipbl/CRL4 axis in zebrafish Model organism Branch 5d — CRL4/DDB1 substrate accumulation
31935221 Non-redundant roles of DDX11, ESCO1, ESCO2 in cohesion In vitro Modifier/interactor context (DDX11)
40668332 Cohesin function altered by chemical chaperones Model organism Experimental therapeutics (sorbitol/proteostasis)
33382686 Ever-changing landscape in RBS biology: macromolecular damage Review Integrative "macromolecular damage" model
31516082 Expanding phenotypes of cohesinopathies Review Positions RBS among cohesinopathies
35495290 Roberts syndrome with tetraphocomelia: case report Human clinical Severe/prenatal-lethal end of the spectrum

Consistency: The findings are mutually reinforcing across four evidence tiers — human genetics/clinical (F001–F003, F007), model organism in vivo (F004–F006), yeast molecular (F005), and structural biology (F008). No finding was contradicted by another; the literature is convergent rather than conflicting.

Limitations and Knowledge Gaps

  1. No quantitative human epidemiology: prevalence/incidence, sex/age distributions, and survival statistics are not rigorously established given rarity (~150 reported cases).
  2. No genotype–phenotype predictor: the striking absence of correlation (F002) means severity cannot be predicted molecularly, limiting prenatal prognostication.
  3. Human validation of mechanistic branches is incomplete: the redox-stress (yeast, F005), CRL4 (zebrafish/yeast, 5d), and even mTORC1/translation arms (F006) are strongest in model systems; their precise contribution to specific human malformations is inferred.
  4. Therapeutics are preclinical only: L-leucine and antioxidant/chemical-chaperone strategies have not entered validated human trials for RBS.
  5. No modifier genes or epigenetic signature identified in humans, leaving expressivity unexplained.
  6. Structural data are from the ESCO1 paralog (F008), not ESCO2 directly; residue-level extrapolation to ESCO2 missense alleles is approximate.
  7. No documented natural animal disease / veterinary model beyond engineered systems.

Proposed Follow-up Experiments / Actions

  1. Human natural-history registry: aggregate cases to derive prevalence, survival curves, and organ-involvement frequencies; power genotype–phenotype re-analysis including modifiers.
  2. ESCO2-specific structural study: solve the ESCO2 (not ESCO1) acetyltransferase–SMC3 complex to classify RBS missense VUS by catalytic impact.
  3. Isogenic human iPSC/organoid models (limb-bud, cranial neural crest, cerebral organoids) with patient ESCO2 alleles to quantify each mechanistic branch (apoptosis vs translation vs redox vs CRL4) in relevant human cell types.
  4. Therapeutic testing: rigorously evaluate L-leucine (and antioxidant combinations) in patient organoids and, if warranted, a mechanism-based early-phase clinical study; explore chemical chaperones/proteostasis modulators active in yeast.
  5. Multi-omics profiling (transcriptomics + proteomics + ribosome profiling) of RBS patient cells to map the ESCO2-loss signature and identify actionable nodes (mTORC1, CRL4/DDB1 substrates such as pparαa).
  6. Modifier screens (CRISPR) in RBS cell models — building on DDX11/WAPL/PDS5/RAD61 interactions — to find genetic buffers of the cohesion/translation defect.
  7. Prenatal diagnostic standardization: formalize a serial-ultrasound + molecular pathway (validated in F007) into clinical guidance for at-risk consanguineous families.

Report compiled from 8 confirmed findings and 21 reviewed papers across 5 investigation iterations. Evidence tiers: human clinical/genetic, model organism (zebrafish, yeast), in vitro (patient cells), and computational/structural.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc1.

Outcome Count
References checked 16
Resolved 16
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 16
On topic 15
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 38
Resolved 35
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 3
Terms whose name was checked 21
Terms named correctly 15
Terms named as a different term 5
Terms whose name is worth a second look 1

Terms the report names something else

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

  • CHEBI:15603 (2 mentions) - the report calls it "L-leucine", "Mechanism-based experimental lead: L-leucine"; CHEBI calls it L-leucine
  • HP:0000252 (1 mention) - the report calls it "Common"; HP calls it Microcephaly
  • HP:0001249 (1 mention) - the report calls it "Mild–severe, variable"; HP calls it Intellectual disability
  • HP:0012165 (1 mention) - the report calls it "Common"; HP calls it Oligodactyly
  • HP:0003826 (1 mention) - the report calls it "Severe forms"; HP calls it Stillbirth

Terms whose name is worth a second look

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

  • GO:0005730 (3 mentions) - the report calls it "nucleolus", "Subcellular level: nucleolus"; GO calls it nucleolus

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • GO:0005730 - called "nucleolus", "Subcellular level: nucleolus"
  • CHEBI:15603 - called "L-leucine", "Mechanism-based experimental lead: L-leucine"

Prefixes with no resolver

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