Sweeney-Cox Syndrome

Mendelian MONDO:0060592 Pathograph 14 Show in embeddings browser TWIST1-related disorder Frontonasal dysplasia

Sweeney-Cox syndrome is a de novo autosomal dominant craniofacial disorder caused by missense substitutions at a single highly conserved glutamic acid residue, Glu117, in the basic DNA-binding domain of TWIST1. It presents as frontonasal dysplasia — marked hypertelorism with severe deficiency of the frontal bones and hypoplasia of the nose and facial bones — together with ablepharon or underdevelopment of the eyelids and cheek pads beside the corners of the mouth. The disorder is mechanistically the counterpoint to Saethre-Chotzen syndrome, which arises from haploinsufficiency of the same gene. Roughly a hundred loss-of-function TWIST1 alleles cause Saethre-Chotzen with craniosynostosis, yet none of them touch the Glu117 codon. The Glu117 substitutions act antimorphically instead — a conclusion drawn from a Caenorhabditis elegans allelic series, not from biochemistry on the human protein. Losing half the TWIST1 dose and interfering with the whole pool are different lesions, and they produce different diseases: a non-synostotic frontonasal phenotype here, premature coronal suture fusion there. The frontonasal phenotype is explained by what TWIST1 does in cranial neural crest. In mouse, neural-crest-specific loss of Twist1 collapses frontonasal development and fails to activate the ectomesenchyme programme — Alx1, Alx3 and Alx4 — in the frontonasal prominence, and Twist1 occupies a distal enhancer that drives Alx1 specifically in periocular and frontonasal mesenchyme. The same enhancer explains why the eyelids are involved: periocular mesenchyme is the tissue TWIST1 patterns alongside the midface. Phenotypically the syndrome sits with the TWIST2 paralogue disorders rather than with Saethre-Chotzen. Barber-Say and ablepharon-macrostomia syndromes arise from substitutions at Glu75, the residue paralogous to TWIST1 Glu117, and share the ablepharon, hypertelorism and cheek-pad facies. Craniosynostosis is the feature that separates the group from Saethre-Chotzen — though one reported Glu117Asp patient had bilateral coronal synostosis, which is the strongest evidence that the two TWIST1 phenotypes are ends of a spectrum rather than disjoint entities.

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Inheritance
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Pathophys.
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Phenotypes
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Hypotheses
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Gaps
14
Pathograph
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Genes
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Medical Actions
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Datasets
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Models
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Deep Research
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Inheritance

1
Autosomal dominant HP:0000006
Every reported case carries a de novo heterozygous missense substitution at TWIST1 Glu117. The allele acts antimorphically rather than by simple loss of dosage, so dominance here reflects interference with the wild-type product and not haploinsufficiency.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:28369379 SUPPORT Human Clinical
"we describe a new clinical entity, Sweeney-Cox syndrome, associated with distinct de novo amino acid substitutions (p.Glu117Val and p.Glu117Gly) at a highly conserved glutamic acid residue located in the basic DNA binding domain of TWIST1, in two subjects with frontonasal dysplasia and..."
Establishes the de novo heterozygous origin of the Glu117 substitutions in the two index subjects.
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Mechanistic Hypotheses

1
Graded antimorphism places Sweeney-Cox and Saethre-Chotzen on one continuum
glu117_interference_dosage_continuum EMERGING
Evidence balance 2 support
Under this model the substituting residue at Glu117 sets how strongly the mutant subunit interferes with the wild-type pool, and the resulting phenotype moves along a continuum rather than falling into one of two categories. A conservative substitution such as Glu117Asp interferes weakly and behaves closer to haploinsufficiency, which is the reading offered for the one patient who had both the Sweeney-Cox facies and bicoronal craniosynostosis; stronger substitutions produce the non-synostotic frontonasal phenotype, and the C. elegans series ordered all five human alleles by severity rather than separating them into classes. If correct, the distinction between this entry and Saethre-Chotzen syndrome is quantitative, and the craniosynostosis discriminator is a threshold effect rather than a categorical feature. The competing model is that the two disorders are mechanistically disjoint because the alleles differ in kind, not degree. Three patients, one per allele, cannot separate these.
Pathograph links
TWIST1 Glu117 Basic-Domain Substitution -> Antimorphic Interference with TWIST1 bHLH Complexes DIRECT The substituted basic domain is the direct cause of the mutant protein's failure to transactivate while remaining incorporated into TWIST1 complexes.
Show evidence (2 references)
PMID:30450715 SUPPORT Human Clinical
"The present observation suggests that a localized TWIST1 basic domain substitution, that is, p.Glu117Asp, in TWIST1 may exert a mild antimorphic effect similar to that of haploinsufficiency, leading to craniosynostosis and ablepharon."
Proposes graded antimorphism explicitly, and is the only clinical observation bearing on it.
PMID:28369379 SUPPORT Model Organism
"This allelic series revealed that different substitutions exhibit graded severity, in terms of both gene expression and cellular phenotype, which we incorporate into a model explaining the various human disease phenotypes."
Provides the experimental grading of the same allele set that the continuum model rests on.
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Discussions and Knowledge Gaps

4
Does a TWIST1 Glu117 knock-in reproduce the human frontonasal and ablepharon phenotype, and does it act through the Alx1 distal enhancer?
HUMAN MODEL MISMATCH OPEN swcos_glu117_allele_specific_model
Attached to
pathophysiology#Failure of TWIST1-Dependent Frontonasal Ectomesenchyme Programme
Every mechanistic model of this disorder is currently an allele mismatch. The C. elegans series carries the right substitution but has no craniofacial skeleton; the mouse work has the right tissue but uses conditional nulls, which model haploinsufficiency-like loss rather than the antimorphic allele. The whole clinical point of Sweeney-Cox is that those two lesions give different diseases, so no existing model tests the step that actually distinguishes it from Saethre-Chotzen. Whether the enhancer route is the one a Glu117 allele travels is therefore inference from tissue overlap, not a result.
Proposed experiments
Twist1 Glu117 knock-in mouse with frontonasal enhancer readout
swcos_glu117_knockin_mouse
Generate a mouse carrying the Glu117 substitution at the endogenous locus and compare its craniofacial phenotype and Alx1 distal-enhancer activity against a Twist1 heterozygous null.
Would support
pathophysiology#Failure of TWIST1-Dependent Frontonasal Ectomesenchyme Programme
Supporting outcome
  • The knock-in shows frontonasal and periocular defects with reduced Alx1 enhancer activity, while the heterozygous null does not, separating the antimorphic route from simple dosage loss.
Refuting outcome
  • The knock-in phenocopies the heterozygous null, indicating the Glu117 allele acts by dosage reduction and that the antimorphic model does not explain the distinct human phenotype.
Show evidence (1 reference)
PMID:28369379 SUPPORT Model Organism
"we engineered all five disease-associated alleles into the equivalent Glu29 residue encoded by hlh-8, the single Twist homolog present in Caenorhabditis elegans"
Documents that the only allele-correct model is an invertebrate with no craniofacial skeleton, which is the mismatch this discussion records.
Are Sweeney-Cox and Saethre-Chotzen syndromes disjoint entities or ends of one TWIST1 phenotypic spectrum?
KNOWLEDGE GAP OPEN swcos_saethre_chotzen_boundary
Attached to
phenotypes#Coronal Craniosynostosis mechanistic_hypotheses#glu117_interference_dosage_continuum
Craniosynostosis is the stated discriminator, but the p.Glu117Asp patient had bilateral coronal synostosis alongside the ablepharon and cheek-pad facies, and that report argued the conservative Glu-to-Asp change exerts only a mild antimorphic effect resembling haploinsufficiency. If severity of antimorphic interference is continuous, the discriminator is quantitative rather than categorical, and the lump/split status of these two entries depends on which it is. With three reported patients there is not enough phenotypic range to settle it.
Show evidence (1 reference)
PMID:30450715 SUPPORT Human Clinical
"The present observation suggests that a localized TWIST1 basic domain substitution, that is, p.Glu117Asp, in TWIST1 may exert a mild antimorphic effect similar to that of haploinsufficiency, leading to craniosynostosis and ablepharon."
States the graded-antimorphism argument that makes the boundary between the two syndromes uncertain.
Is there any Sweeney-Cox-specific management evidence, and does the antimorphic mechanism change care relative to Saethre-Chotzen syndrome?
KNOWLEDGE GAP OPEN swcos_no_management_evidence
Attached to
treatments#
Both curated treatments are phenotype-directed, not disease-directed: they cite sources about eyelid coloboma and about paediatric asplenia in general, because with three reported patients there is no series, no surgical protocol and no ophthalmological guidance for this syndrome. Nothing here tells a clinician whether the timing or escalation of corneal protection should differ in a child whose eyelid defect is part of a TWIST1 developmental lesion. Borrowing the rest of craniofacial management from Saethre-Chotzen would be unsound in the respect that matters: that care is organised around craniosynostosis, which is not a cardinal feature here.
Do the three reported patients represent the survivable tail of the Glu117 allelic series, with more severe substitutions going unascertained?
KNOWLEDGE GAP OPEN swcos_allelic_ascertainment_bias
Attached to
pathophysiology#TWIST1 Glu117 Basic-Domain Substitution prevalence#Worldwide
The C. elegans series showed graded severity across substitutions at this residue, and the clinical literature explicitly raises lethality as an alternative outcome of substituting Glu117. If some substitutions are embryonic-lethal or lethal in the neonatal period, the reported phenotype is conditioned on survival and the three living patients are a biased sample. This matters for two curated claims at once: the severity range recorded in the phenotypes section, and the case count recorded under prevalence, which is also the constraint behind ClinGen's Limited gene-disease classification. Prenatal or perinatal-loss sequencing series covering TWIST1 would be the way to test it; nothing of the sort has been reported.
Ascertainment cuts differently from evidence availability, and the two should not be confused. The malformation list itself is curated: 46 features come from the HPO disease annotation for OMIM:617746, which records each as a count out of the two index subjects. What that annotation cannot say is whether those two subjects, plus the later Glu117Asp patient, span the phenotype of Glu117 substitution or only its survivable part. A feature absent from a two-patient annotation may be genuinely rare, or may belong to a substitution that was never ascertained.
Show evidence (2 references)
PMID:30450715 SUPPORT Human Clinical
"This suggests that any amino acid substitutions at Glu117 would likely lead to the Sweeney-Cox syndrome phenotype or lethality."
Raises lethality as an outcome of substitution at this codon, which is the ascertainment concern recorded here.
PMID:28369379 SUPPORT Model Organism
"This allelic series revealed that different substitutions exhibit graded severity, in terms of both gene expression and cellular phenotype, which we incorporate into a model explaining the various human disease phenotypes."
Establishes that severity varies by substituting residue, which is what makes a lethal tail plausible.
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Pathophysiology

5
TWIST1 Glu117 Basic-Domain Substitution
A de novo heterozygous missense substitution replaces the conserved glutamic acid at codon 117 of TWIST1. Glu117 lies in the basic region of the bHLH domain — the segment that contacts DNA — so the lesion is positioned to disable DNA recognition while leaving the helix-loop-helix dimerisation surface intact. Three substitutions are reported (p.Glu117Val, p.Glu117Gly, p.Glu117Asp), and this codon is untouched among roughly one hundred loss-of-function TWIST1 alleles catalogued in Saethre-Chotzen syndrome, which is the first indication that it is not simply another way of losing the gene.
Graded antimorphism places Sweeney-Cox and Saethre-Chotzen on one continuum
TWIST1 hgnc:12428 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TWIST1 (hgnc:12428). hgnc:12428 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context TWIST1 hgnc:12428 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns TWIST1 (hgnc:12428). hgnc:12428 is a gene from the HUGO Gene Nomenclature Committee. allele_type: SNV variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE
Heterozygous de novo missense substitutions at Glu117 in the basic DNA-binding domain, acting antimorphically on the wild-type allele.
frontonasal prominence UBERON:0004066 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in frontonasal prominence (UBERON:0004066). UBERON:0004066 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Antimorphic Interference with TWIST1 bHLH Complexes The substituted basic domain is the direct cause of the mutant protein's failure to transactivate while remaining incorporated into TWIST1 complexes. Graded antimorphism places Sweeney-Cox and Saethre-Chotzen on one continuum
Show evidence (2 references)
PMID:28369379 SUPPORT Human Clinical
"Although about one hundred different TWIST1 mutations have been reported in patients with the dominant haploinsufficiency Saethre-Chotzen syndrome (typically associated with craniosynostosis), substitutions uniquely affecting the Glu117 codon were not observed previously."
Places Glu117 outside the Saethre-Chotzen loss-of-function mutation spectrum, which is the genetic argument that this codon behaves differently from the rest of the gene.
PMID:30450715 SUPPORT Human Clinical
"a de novo heterozygous mutation in the basic domain of TWIST1, that is, c.351C>G p.Glu117Asp"
Documents a third Glu117 allele, extending the substitution series beyond the two index cases.
Antimorphic Interference with TWIST1 bHLH Complexes
TWIST1 acts as homodimers and as heterodimers with the TCF3, TCF4 and TCF12 E-proteins, and it is the basic region of each partner that grips the E-box. Substituting Glu117 alters a DNA-contacting residue while leaving the helix-loop-helix dimerisation surface untouched, so the expected consequence is a subunit that still enters complexes but cannot read their targets. The genetic evidence supports that reading: engineering the five human alleles into the equivalent Glu29 residue of hlh-8, the single Twist homolog in Caenorhabditis elegans, produced a graded severity series rather than a simple null, and the analysis favours a predominantly dominant-negative mechanism. Two caveats belong on this node. The dimerisation-retained, DNA-binding-lost model is inferred from where the residue sits in the domain — no biochemistry on the human Glu117 protein has been reported, so it is not known directly whether these subunits still dimerise or still occupy chromatin. And "predominantly" is the source's own word: the C. elegans series does not exclude a partial loss-of-function component. What is established is that this step is where Sweeney-Cox parts from Saethre-Chotzen. Reducing TWIST1 to one functional copy leaves the remaining protein competent; an antimorphic allele does not.
E-box binding GO:0070888 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased E-box binding (GO:0070888). GO:0070888 is a molecular function from the Gene Ontology. ↓ DECREASED protein dimerization activity GO:0046983 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves protein dimerization activity (GO:0046983). GO:0046983 is a molecular function from the Gene Ontology. DNA-binding transcription factor activity GO:0003700 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased DNA-binding transcription factor activity (GO:0003700). GO:0003700 is a molecular function from the Gene Ontology. ↓ DECREASED
Animal models
hlh-8 Glu29 allelic series (C. elegans) Caenorhabditis elegans recapitulates Reproduces the antimorphic behaviour of the substitutions in a single-Twist genetic background, where dominant-negative action can be separated from loss of dosage.
Downstream
Failure of TWIST1-Dependent Frontonasal Ectomesenchyme Programme Complexes that cannot engage the E-box cannot activate the TWIST1 target genes of the frontonasal prominence.
Show evidence (4 references)
PMID:28369379 SUPPORT Model Organism
"The genetic analysis favors a predominantly dominant-negative mechanism for the action of amino acid substitutions at this highly conserved glutamic acid residue"
States the antimorphic mechanism directly, as the conclusion of the C. elegans allelic series.
PMID:30450715 SUPPORT Human Clinical
"Heterozygous localized TWIST1 and TWIST2 basic domain substitutions exert antimorphic effects to cause Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia syndrome, respectively."
Independently characterises the basic-domain substitutions as antimorphic across the TWIST1 and TWIST2 disorders.
PMID:32179550 SUPPORT In Vitro
"proteomic profiling of human TWIST1-expressing cell lines and transcriptome analysis of mouse cranial mesenchyme have revealed that TWIST1 homodimers and heterodimers with TCF3, TCF4, and TCF12 E-proteins are the predominant dimer combinations"
Identifies the dimer species a Glu117 subunit can be incorporated into, which is what makes an antimorphic effect possible.
+ 1 more reference
Failure of TWIST1-Dependent Frontonasal Ectomesenchyme Programme
TWIST1 is expressed in migratory cranial neural crest and maintained in the crest-derived mesenchyme of the frontonasal prominence, where it switches on the ectomesenchyme programme. In mouse, neural-crest-specific inactivation of Twist1 disrupts frontonasal development and fails to activate Alx1, Alx3 and Alx4 in the frontonasal prominence; Twist1 occupies a conserved element in a distal Alx1 enhancer and drives Alx1 reporter expression specifically in periocular and frontonasal mesenchyme. Deleting that enhancer alone reproduces frontonasal and ocular defects. Curated as PROVISIONAL: the enhancer and target-gene work is mouse conditional-knockout and reporter biology, so it establishes what TWIST1 does in this tissue, not that a human Glu117 allele acts through this particular enhancer. The inference from an antimorphic allele to this specific regulatory step has not been made in patient tissue.
migratory cranial neural crest cell CL:0000008 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves migratory cranial neural crest cell (CL:0000008). CL:0000008 is a cell type from the Cell Ontology.
positive regulation of transcription by RNA polymerase II GO:0045944 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased positive regulation of transcription by RNA polymerase II (GO:0045944). GO:0045944 is a biological process from the Gene Ontology. ↓ DECREASED embryonic cranial skeleton morphogenesis GO:0048701 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased embryonic cranial skeleton morphogenesis (GO:0048701). GO:0048701 is a biological process from the Gene Ontology. ↓ DECREASED
frontonasal prominence UBERON:0004066 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in frontonasal prominence (UBERON:0004066). UBERON:0004066 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Neural-crest conditional Twist1 knockout mouse Mouse partially recapitulates Reproduces the frontonasal and skull vault consequences of losing TWIST1 function in cranial neural crest, including the failure to activate the ectomesenchyme programme in the frontonasal prominence.
Downstream
Frontonasal Skeletal Deficiency Loss of the ectomesenchyme programme in the frontonasal prominence leads to deficient differentiation of the frontal and nasal skeletal elements.
Periocular Mesenchyme and Eyelid Morphogenesis Failure The same TWIST1-dependent enhancer activity spans periocular mesenchyme, linking the transcriptional lesion to the eyelid phenotype; the intervening steps in eyelid morphogenesis are not established.
Show evidence (6 references)
PMID:41850652 SUPPORT Model Organism
"mice with neural crest lineage-specific inactivation of Twist1 resulted in dramatic disruption of frontonasal development accompanied by failure of activation of many ectomesenchyme genes, including Alx1, Alx3, and Alx4, in the FNP"
Establishes that TWIST1 is required to switch on the frontonasal ectomesenchyme programme, the transcriptional output lost here.
PMID:41850652 SUPPORT Model Organism
"exhibits high enrichment of Twist1 transcription factor occupancy in mouse embryonic frontonasal tissues and drove Twist1-dependent reporter transgene expression specifically in the developing periocular and frontonasal mesenchyme in transgenic mice"
Identifies a direct TWIST1-occupied enhancer active in exactly the two tissues affected in this syndrome — periocular and frontonasal mesenchyme.
PMID:19414008 SUPPORT Model Organism
"Loss of Twist1 in neural crest cells and their derivatives impairs skeletogenic differentiation and leads to the loss of bones of the snout, upper face and skull vault."
Shows the skeletal consequence of losing TWIST1 function in cranial neural crest, matching the frontal-bone and nasal deficiency seen in patients.
+ 3 more references
Frontonasal Skeletal Deficiency
Deficient skeletogenic differentiation of frontonasal ectomesenchyme yields the structural core of the syndrome: severe deficiency of the frontal bones, hypoplasia of the nose and facial bones, and the widened interorbital distance that presents clinically as marked hypertelorism.
frontonasal prominence UBERON:0004066 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in frontonasal prominence (UBERON:0004066). UBERON:0004066 is an anatomical location from the Uberon multi-species anatomy ontology. tetrapod frontal bone UBERON:0000209 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in tetrapod frontal bone (UBERON:0000209). UBERON:0000209 is an anatomical location from the Uberon multi-species anatomy ontology. nasal bone UBERON:0001681 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in nasal bone (UBERON:0001681). UBERON:0001681 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:41850652 SUPPORT Other
"Sweeney-Cox syndrome characterized by hypertelorism with severe deficiency in frontal bones and hypoplasia of the nose and facial bones"
States the skeletal phenotype of the syndrome in the terms modelled by this node. Graded OTHER, not HUMAN_CLINICAL: this sentence is background prose in a mouse developmental study summarising the clinical literature, not human data the paper itself reports. It is cited because the primary description of frontal-bone deficiency sits in full text that is not in the reference cache.
Periocular Mesenchyme and Eyelid Morphogenesis Failure
Eyelid development requires patterned periocular mesenchyme, and the eyelids are the second tissue in which the TWIST1-dependent frontonasal enhancer is active. Clinically this presents as ablepharon or underdevelopment of the eyelids, a feature Sweeney-Cox shares with the TWIST2 Glu75 disorders and which is not part of Saethre-Chotzen syndrome. PROVISIONAL because the enhancer evidence establishes TWIST1 activity in periocular mesenchyme but no study has traced a Glu117 allele through eyelid morphogenesis; the causal chain from transcriptional lesion to ablepharon is inferred from tissue overlap.
eyelid development in camera-type eye GO:0061029 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased eyelid development in camera-type eye (GO:0061029). GO:0061029 is a biological process from the Gene Ontology. ↓ DECREASED
periocular mesenchyme UBERON:0004017 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in periocular mesenchyme (UBERON:0004017). UBERON:0004017 is an anatomical location from the Uberon multi-species anatomy ontology. eyelid UBERON:0001711 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in eyelid (UBERON:0001711). UBERON:0001711 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:30450715 SUPPORT Human Clinical
"Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia syndrome share the facial features of ablepharon, hypertelorism, underdevelopment of the eyelids, and cheek pads adjacent to the corners of the mouth."
Establishes ablepharon and eyelid underdevelopment as features of the syndrome and of the paralogous TWIST2 disorders.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Sweeney-Cox 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

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Cardiovascular 1
Patent ductus arteriosus HP:0001643 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Patent ductus arteriosus (HP:0001643), qualified as congenital onset. HP:0001643 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Digestive 2
Gastroesophageal reflux HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020), qualified as congenital onset. HP:0002020 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Anal atresia HP:0002023 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anal atresia (HP:0002023), qualified as congenital onset. HP:0002023 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Ear 2
Low-set ears HP:0000369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low-set ears (HP:0000369), qualified as congenital onset. HP:0000369 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Hearing impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365), qualified as congenital onset. HP:0000365 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Eye 1
Hypertelorism VERY_FREQUENT HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Frequency basis: this band comes from the source's qualitative characterisation of the feature, which is the mapping the curation guidance sanctions, and not from a patient count. The 46 HPOA-derived phenotypes in this entry carry no band for the complementary reason - their provenance is a count out of two patients and nothing else. Where a count would suggest a different band, the prose governs and the disagreement is stated. Here the source names hypertelorism among the facial features shared across the whole Glu117/Glu75 group, which reads as near-constant.
Show evidence (1 reference)
PMID:30450715 SUPPORT Human Clinical
"Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia syndrome share the facial features of ablepharon, hypertelorism, underdevelopment of the eyelids, and cheek pads adjacent to the corners of the mouth."
Names hypertelorism as a shared core feature of the syndrome.
Head and Neck 9
Midface and Nasal Hypoplasia FREQUENT Midface retrusion HP:0011800 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Midface retrusion (HP:0011800). HP:0011800 is a phenotype from the Human Phenotype Ontology.
Frequency basis: this band comes from the source's qualitative characterisation of the feature, which is the mapping the curation guidance sanctions, and not from a patient count. The 46 HPOA-derived phenotypes in this entry carry no band for the complementary reason - their provenance is a count out of two patients and nothing else. Where a count would suggest a different band, the prose governs and the disagreement is stated. Here the source characterises the syndrome as being defined by hypoplasia of the nose and facial bones.
Show evidence (1 reference)
PMID:41850652 SUPPORT INDIRECT Other
"Sweeney-Cox syndrome characterized by hypertelorism with severe deficiency in frontal bones and hypoplasia of the nose and facial bones"
Reports nasal and facial bone hypoplasia. Graded INDIRECT because the source describes hypoplasia of these bones rather than midface retrusion as such, which is the closest available HPO term, and OTHER because the sentence is a literature summary in a mouse study, not human data that paper reports.
Coronal Craniosynostosis OCCASIONAL HP:0004440 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coronal craniosynostosis (HP:0004440). HP:0004440 is a phenotype from the Human Phenotype Ontology.
Frequency basis: this band comes from the source's qualitative characterisation of the feature, which is the mapping the curation guidance sanctions, and not from a patient count. The 46 HPOA-derived phenotypes in this entry carry no band for the complementary reason - their provenance is a count out of two patients and nothing else. Where a count would suggest a different band, the prose governs and the disagreement is stated. Here the source states explicitly that craniosynostosis is not a cardinal feature of this syndrome, which is what OCCASIONAL encodes. Note that the raw count runs the other way - one of the three reported patients had bicoronal synostosis, which as a fraction would fall in the FREQUENT band. The qualitative statement is preferred because a denominator of three cannot distinguish 33 percent from 5 percent, and because the source is making a claim about the syndrome rather than tallying its own series.
Show evidence (1 reference)
PMID:30450715 SUPPORT Human Clinical
"Our review showed that Sweeney-Cox syndrome appears to share many characteristics with Barber-Say syndrome and ablepharon-macrostomia syndrome except for craniosynostosis, which is a cardinal feature of Saethre-Chotzen syndrome."
Establishes that craniosynostosis is not typical of Sweeney-Cox, supporting the OCCASIONAL frequency and the boundary with Saethre-Chotzen.
Velopharyngeal insufficiency HP:0000220 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Velopharyngeal insufficiency (HP:0000220), qualified as congenital onset. HP:0000220 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347), qualified as congenital onset. HP:0000347 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Choanal atresia HP:0000453 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Choanal atresia (HP:0000453), qualified as congenital onset. HP:0000453 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
High palate HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High palate (HP:0000218), qualified as congenital onset. HP:0000218 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Narrow mouth HP:0000160 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Narrow mouth (HP:0000160), qualified as congenital onset. HP:0000160 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Broad nasal tip HP:0000455 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad nasal tip (HP:0000455), qualified as congenital onset. HP:0000455 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 2/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Brachycephaly HP:0000248 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachycephaly (HP:0000248), qualified as congenital onset. HP:0000248 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Musculoskeletal 1
Narrow chest HP:0000774 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Narrow chest (HP:0000774), qualified as congenital onset. HP:0000774 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Nervous System 3
Cerebellar hypoplasia HP:0001321 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar hypoplasia (HP:0001321), qualified as congenital onset. HP:0001321 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 2/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Prenatal and Birth 1
Polyhydramnios HP:0001561 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polyhydramnios (HP:0001561), qualified as congenital onset. HP:0001561 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Other 33
Upper Eyelid Coloboma HP:0000636 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Upper eyelid coloboma (HP:0000636). HP:0000636 is a phenotype from the Human Phenotype Ontology.
Curated from the HPO disease annotation for OMIM:617746, which cites PMID:28369379 for every term. Kept distinct from the separate Ablepharon entry below, which is a more severe finding reported in only one patient.
Ablepharon OCCASIONAL HP:0011224 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ablepharon (HP:0011224). HP:0011224 is a phenotype from the Human Phenotype Ontology.
Deliberately not the primary eyelid term for this entry. HP:0011224 is absent from the HPO annotation for OMIM:617746, which instead carries HP:0000636 Upper eyelid coloboma from the two index subjects; ablepharon is documented in the later Glu117Asp case report and is graded OCCASIONAL for that reason. Both are curated because they are different severities of the same developmental failure, and collapsing them would either overstate the index phenotype or drop a published finding.
Show evidence (1 reference)
PMID:30450715 SUPPORT Human Clinical
"we document a male infant with the distinctive facial features of ablepharon, hypertelorism, cheek pads adjacent to the corners of the mouth, and bilateral coronal suture craniosynostosis"
Direct clinical observation of ablepharon in a Glu117-substituted patient.
Cheek Pads at the Oral Commissures
Deliberately left unbound. HPO has no term for this finding: HP:0000293 Full cheeks describes generalised cheek fullness, not localised pads at the oral commissures, and binding it would assert a different phenotype. Per the dismech-terms rule that no term beats a bad one, this is curated as free text in preferred_term with no term.
Show evidence (1 reference)
PMID:30450715 SUPPORT Human Clinical
"Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia syndrome share the facial features of ablepharon, hypertelorism, underdevelopment of the eyelids, and cheek pads adjacent to the corners of the mouth."
Names cheek pads at the oral commissures as a shared feature of the syndrome and the paralogous TWIST2 disorders.
Frontal Bone Hypoplasia FREQUENT Hypoplasia of the frontal bone HP:0005466 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the frontal bone (HP:0005466). HP:0005466 is a phenotype from the Human Phenotype Ontology.
Frequency basis: this band comes from the source's qualitative characterisation of the feature, which is the mapping the curation guidance sanctions, and not from a patient count. The 46 HPOA-derived phenotypes in this entry carry no band for the complementary reason - their provenance is a count out of two patients and nothing else. Where a count would suggest a different band, the prose governs and the disagreement is stated. Here the source characterises the syndrome as being defined by severe frontal bone deficiency.
Show evidence (1 reference)
PMID:41850652 SUPPORT Other
"Sweeney-Cox syndrome characterized by hypertelorism with severe deficiency in frontal bones and hypoplasia of the nose and facial bones"
Reports severe frontal bone deficiency as a defining feature. Graded OTHER because the sentence is a literature summary in the introduction of a mouse study rather than human data reported by that paper.
Long fingers HP:0100807 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long fingers (HP:0100807), qualified as congenital onset. HP:0100807 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Short distal phalanx of finger HP:0009882 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short distal phalanx of finger (HP:0009882), qualified as congenital onset. HP:0009882 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Bilateral talipes equinovarus HP:0001776 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral talipes equinovarus (HP:0001776), qualified as congenital onset. HP:0001776 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
2-5 toe syndactyly HP:0010715 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is 2-5 toe syndactyly (HP:0010715), qualified as congenital onset. HP:0010715 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
2-4 finger cutaneous syndactyly HP:0010709 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is 2-4 finger cutaneous syndactyly (HP:0010709), qualified as congenital onset. HP:0010709 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
2-5 finger cutaneous syndactyly HP:0005650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is 2-5 finger cutaneous syndactyly (HP:0005650), qualified as congenital onset. HP:0005650 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Asplenia HP:0001746 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Asplenia (HP:0001746). HP:0001746 is a phenotype from the Human Phenotype Ontology.
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Patent foramen ovale HP:0001655 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Patent foramen ovale (HP:0001655), qualified as congenital onset. HP:0001655 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Generalized hirsutism HP:0002230 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized hirsutism (HP:0002230), qualified as congenital onset. HP:0002230 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Small nail HP:0001792 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small nail (HP:0001792), qualified as congenital onset. HP:0001792 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Bilateral cryptorchidism HP:0008689 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral cryptorchidism (HP:0008689), qualified as congenital onset. HP:0008689 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/1 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Crumpled ear HP:0009901 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Crumpled ear (HP:0009901), qualified as congenital onset. HP:0009901 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Microtia HP:0008551 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microtia (HP:0008551), qualified as congenital onset. HP:0008551 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Overfolded helix HP:0000396 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Overfolded helix (HP:0000396), qualified as congenital onset. HP:0000396 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Cupped ear HP:0000378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cupped ear (HP:0000378), qualified as congenital onset. HP:0000378 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Uplifted earlobe HP:0009909 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Uplifted earlobe (HP:0009909), qualified as congenital onset. HP:0009909 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Wide anterior fontanel HP:0000260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide anterior fontanel (HP:0000260), qualified as congenital onset. HP:0000260 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Prominent metopic ridge HP:0005487 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent metopic ridge (HP:0005487), qualified as congenital onset. HP:0005487 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 2/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Median cleft palate HP:0009099 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Median cleft palate (HP:0009099), qualified as congenital onset. HP:0009099 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Short philtrum HP:0000322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short philtrum (HP:0000322), qualified as congenital onset. HP:0000322 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Widow's peak HP:0000349 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Widow's peak (HP:0000349), qualified as congenital onset. HP:0000349 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Low hanging columella HP:0009765 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low hanging columella (HP:0009765), qualified as congenital onset. HP:0009765 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Short columella HP:0002000 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short columella (HP:0002000), qualified as congenital onset. HP:0002000 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
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), qualified as congenital onset. HP:0000430 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Low anterior hairline HP:0000294 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low anterior hairline (HP:0000294), qualified as congenital onset. HP:0000294 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Broad neck HP:0000475 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad neck (HP:0000475), qualified as congenital onset. HP:0000475 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Wide nasal bridge HP:0000431 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide nasal bridge (HP:0000431), qualified as congenital onset. HP:0000431 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Flat occiput HP:0005469 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Flat occiput (HP:0005469), qualified as congenital onset. HP:0005469 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
Short clavicles HP:0000894 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short clavicles (HP:0000894), qualified as congenital onset. HP:0000894 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Curated from the HPO disease annotation for OMIM:617746, which records this feature in 1/2 reported individuals and cites PMID:28369379. No evidence item is attached: the cached abstract of that paper does not enumerate the individual malformations, so the annotation database is the provenance and is named here rather than quoted. No frequency band is asserted, because a count out of two patients does not support one.
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Genetic Associations

1
TWIST1 (CAUSATIVE)
Gene: TWIST1 hgnc:12428 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TWIST1 (hgnc:12428). hgnc:12428 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: DE_NOVO
Show evidence (3 references)
PMID:28369379 SUPPORT Human Clinical
"we describe a new clinical entity, Sweeney-Cox syndrome, associated with distinct de novo amino acid substitutions (p.Glu117Val and p.Glu117Gly) at a highly conserved glutamic acid residue located in the basic DNA binding domain of TWIST1, in two subjects with frontonasal dysplasia and..."
Identifies TWIST1 Glu117 as the causal locus and lists two alleles.
PMID:30450715 SUPPORT Human Clinical
"This suggests that any amino acid substitutions at Glu117 would likely lead to the Sweeney-Cox syndrome phenotype or lethality."
Supports the claim that the pathogenic constraint is on the codon itself rather than on a particular substituting residue.
PMID:42059179 SUPPORT DIRECT Human Clinical
"Three rare but clinically defined and distinguishable gene-disease pairs were found to have Limited evidence ranging from 3 to 4 points to support the relationship by the Cranio GCEP: FGFR1-related osteoglophonic dysplasia (OMIM:166250), TWIST1-related Sweeney-Cox syndrome (OMIM:617746)"
The ClinGen Craniofacial GCEP classifies the TWIST1-Sweeney-Cox gene-disease relationship as Limited. Typed DIRECT because the sentence asserts a curated gene-disease relationship rather than something the claim is inferred from. The Limited grade is a statement of evidence strength, which the schema has no slot for, and it is recorded here: the case count is too small to reach Moderate, this is not a doubt about the mechanism, and the entry should not present the relationship with Definitive-level confidence.
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Medical Actions

3
Corneal Protection for Eyelid Coloboma
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Ocular surface protection is the management step with the clearest preventable-harm argument in this syndrome, because the curated eyelid phenotypes leave the cornea exposed. Reported practice in large neonatal upper eyelid coloboma escalates from lubrication and a moisture chamber to a customised scleral contact lens, which can maintain ocular surface health long enough for eyelid tissue to grow before oculoplastic reconstruction.
Target Phenotypes: Upper eyelid coloboma HP:0000636 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Upper eyelid coloboma (HP:0000636). HP:0000636 is a phenotype from the Human Phenotype Ontology. Ablepharon HP:0011224 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Ablepharon (HP:0011224). HP:0011224 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34570047 SUPPORT INDIRECT Human Clinical
"After failing lubrication and a moisture chamber, he was fit with a customized scleral contact lens that protected the ocular surface. It was tolerated well, and ocular surface health was maintained for 13 months to permit the growth of eyelid tissue for future oculoplastic surgery."
Documents the escalation of corneal protection in a neonate with large upper eyelid coloboma. Graded INDIRECT because it is a single case in isolated eyelid coloboma, not in Sweeney-Cox syndrome; it is cited as phenotype-directed management for a feature this entry curates, not as disease-specific evidence.
Infection Prophylaxis for Asplenia
Action: Antibiotic ProphylaxisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Antibiotic Prophylaxis (NCIT:C51993). NCIT:C51993 is a clinical intervention from the NCI Thesaurus. NCIT:C51993
Asplenia is an annotated feature of this syndrome and carries lifelong risk of fulminant infection with encapsulated organisms. Standard paediatric asplenia care is timely vaccination, antibacterial prophylaxis where indicated, and urgent evaluation of febrile episodes. This matters disproportionately here because asplenia in a child ascertained for a craniofacial phenotype can go unrecognised.
Target Phenotypes: Asplenia HP:0001746 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Asplenia (HP:0001746). HP:0001746 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38691084 SUPPORT INDIRECT Human Clinical
"Current practice focuses on preventing severe infections with timely administration of vaccinations, antibacterial prophylaxis when indicated, and urgent evaluation and treatment of febrile events."
States the standard of care for children with asplenia. Typed INDIRECT because it is a general paediatric asplenia recommendation, not evidence about Sweeney-Cox syndrome; it is cited because asplenia is a curated phenotype of this entry.
Vaccination Against Encapsulated Organisms
Action: VaccinationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Vaccination (NCIT:C15346). NCIT:C15346 is a clinical intervention from the NCI Thesaurus. NCIT:C15346
In asplenia, vaccination against encapsulated organisms is the cornerstone of prevention rather than an adjunct to antibiotics, and the cited recommendation names it first. It is curated separately from antibacterial prophylaxis because the two are different modalities with different schedules, and collapsing them into one treatment would lose that.
Target Phenotypes: Asplenia HP:0001746 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Asplenia (HP:0001746). HP:0001746 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38691084 SUPPORT INDIRECT Human Clinical
"Current practice focuses on preventing severe infections with timely administration of vaccinations, antibacterial prophylaxis when indicated, and urgent evaluation and treatment of febrile events."
Names timely vaccination first among the preventive measures for children with asplenia. Graded INDIRECT because it is a general paediatric asplenia recommendation and not evidence about Sweeney-Cox syndrome.
🔬

Diagnosis

4
Molecular Confirmation of the TWIST1 Codon-117 Variant
Diagnosis rests on identifying a heterozygous missense substitution at TWIST1 codon 117. Reporting the gene alone is not enough here, because TWIST1 variants cause two different diseases by two different mechanisms: a loss-of-function allele anywhere in the gene indicates Saethre-Chotzen syndrome, whereas a substitution at Glu117 indicates this disorder. The report has to name the variant, not just the gene.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
The three reported alleles are p.Glu117Val, p.Glu117Gly and p.Glu117Asp, all de novo. See the genetic section for the cDNA nomenclature discrepancy between the published c.351C>G and ClinVar's c.351G>T for the third.
Show evidence (1 reference)
PMID:42059179 SUPPORT INDIRECT Other
"According to ACMG technical standards, genes classified as Moderate, Strong, or Definitive are eligible for inclusion in diagnostic testing panels"
Carries the practical diagnostic consequence of the Limited classification recorded in the genetic section: under ACMG technical standards a Limited gene-disease relationship sits below the threshold for panel inclusion, so the diagnosis may depend on exome or genome sequencing rather than on a craniosynostosis gene panel. Graded INDIRECT because the paper states the general standard and the Limited classification separately, and does not itself say this disease is absent from panels.
Abdominal Ultrasound for Asplenia
Asplenia is an annotated feature of this syndrome and is invisible on the craniofacial examination that brings these children to attention, so it has to be looked for deliberately. Finding it changes management immediately, because it moves the child into lifelong infection prophylaxis.
Ultrasound Imaging NCIT:C17230 NCI Thesaurus (NCIT)
Curated without an evidence item, on the same basis as the HPOA-derived phenotypes. The asplenia annotation comes from the HPO disease annotation for OMIM:617746; no published source recommends abdominal imaging in Sweeney-Cox syndrome specifically, so the indication is inferred from the curated phenotype and recorded as such rather than attached to a source that does not say it.
Craniofacial CT with Three-Dimensional Reconstruction
Cross-sectional imaging of the craniofacial skeleton defines the frontal-bone deficiency and midfacial hypoplasia that the clinical examination can only suggest, and establishes whether the sutures are patent. That last point carries the differential weight in this syndrome: craniosynostosis is the feature that separates Saethre-Chotzen from Sweeney-Cox, and one reported Glu117 patient did have bicoronal synostosis, so its presence or absence cannot be assumed from the molecular result.
Computed Tomography NCIT:C17204 NCI Thesaurus (NCIT)
Curated without an evidence item, on the same basis as the abdominal ultrasound entry. No source recommends this imaging in Sweeney-Cox syndrome specifically; the indication follows from the curated skeletal phenotypes and from the craniosynostosis question, and is recorded as inferred rather than attached to a source that does not say it.
Ophthalmic Examination
Assessment of eyelid closure and corneal integrity is the examination that decides whether corneal protection is needed and how urgently. It is listed separately from the craniofacial assessment because the eyelid phenotype carries the preventable-harm risk in this syndrome, and because the finding that matters is functional lid closure rather than a structural measurement.
Eye Examination NCIT:C38060 NCI Thesaurus (NCIT)
Curated without an evidence item, on the same basis as the other inferred diagnostic entries. The indication follows from the curated eyelid phenotypes and from the corneal-protection treatment, both of which are cited; no source states an ophthalmic examination schedule for this syndrome.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Three patients reported at the time of curation: two index subjects with p.Glu117Val and p.Glu117Gly, and one with p.Glu117Asp.
Show evidence (1 reference)
PMID:28369379 SUPPORT Human Clinical
"in two subjects with frontonasal dysplasia and additional malformations"
The syndrome was delineated on two subjects, establishing it as reportable at case-series scale only.
📊

Related Datasets

1
DNA-guided transcription factor cooperativity shapes face and limb mesenchyme [ChIP-seq] geo:GSE230316
ChIP-seq profiling of TWIST1 and homeodomain transcription factor occupancy in embryonic face and limb mesenchyme, defining the composite 'Coordinator' motif at which TWIST1 binds the E-box half cooperatively with homeodomain factors.
human CHIP SEQ n=200
PMID:38262408
Selected manually from the mechanism literature, not from a gene-name dataset search — a TWIST1 accession search returns predominantly cancer EMT studies, which are irrelevant here. This dataset maps TWIST1 DNA occupancy in exactly the tissue affected in this syndrome, so it bears on the consequence of a basic-domain substitution. GEO lists both Homo sapiens and Mus musculus for the series; the human organism binding is recorded here.
🐁

Animal Models

2
hlh-8 Glu29 allelic series (C. elegans)
All five human disease-associated substitutions — the TWIST1 Glu117 and TWIST2 Glu75 alleles — were engineered into the equivalent Glu29 residue of hlh-8, the single Twist homolog in C. elegans. The resulting allelic series graded in severity by gene expression and cellular phenotype, which is the evidence base for the dominant-negative model and for ranking the four human syndromes against each other.
Species
Caenorhabditis elegans
Genotype
hlh-8 Glu29 substitutions equivalent to the five human TWIST1/TWIST2 disease alleles
Publication
PMID:28369379
Pathograph links
Antimorphic Interference with TWIST1 bHLH Complexes recapitulates fidelity: moderate Reproduces the antimorphic behaviour of the substitutions in a single-Twist genetic background, where dominant-negative action can be separated from loss of dosage.
Limitations: C. elegans has one Twist homolog and no craniofacial skeleton, so the model speaks to the molecular character of the allele and to relative severity, not to the tissue phenotype. The M-lineage cellular readout has no counterpart in cranial neural crest.
Show evidence (1 reference)
PMID:28369379 SUPPORT Model Organism
"This allelic series revealed that different substitutions exhibit graded severity, in terms of both gene expression and cellular phenotype, which we incorporate into a model explaining the various human disease phenotypes."
Reports the graded-severity result that grounds the antimorphic model for this node.
Neural-crest conditional Twist1 knockout mouse
Cre-mediated deletion of Twist1 in neural crest cells and their derivatives, used to dissect the requirement for Twist1 in craniofacial skeletal morphogenesis.
Species
Mouse
Genotype
Twist1 conditional deletion in neural crest cells (Cre-mediated)
Publication
PMID:19414008
Pathograph links
Failure of TWIST1-Dependent Frontonasal Ectomesenchyme Programme partially recapitulates fidelity: moderate Reproduces the frontonasal and skull vault consequences of losing TWIST1 function in cranial neural crest, including the failure to activate the ectomesenchyme programme in the frontonasal prominence.
Limitations: This is a conditional null, not a Glu117 knock-in, so it models loss of TWIST1 function rather than the antimorphic allele that causes the human disease — precisely the distinction that separates Sweeney-Cox from Saethre-Chotzen. Homozygous deletion in the crest lineage is also a more severe lesion than the human heterozygous state.
Readouts
Snout, upper face and skull vault bone formation
Direction: DECREASED
Interpretation: Skeletal correlate of the lost ectomesenchyme programme in this model.
Show evidence (1 reference)
PMID:19414008 SUPPORT Model Organism
"Loss of Twist1 in neural crest cells and their derivatives impairs skeletogenic differentiation and leads to the loss of bones of the snout, upper face and skull vault."
Reports the skeletal measurement behind this readout.
Show evidence (1 reference)
PMID:41850652 SUPPORT Model Organism
"mice with neural crest lineage-specific inactivation of Twist1 resulted in dramatic disruption of frontonasal development accompanied by failure of activation of many ectomesenchyme genes, including Alx1, Alx3, and Alx4, in the FNP"
Supports treating the neural-crest conditional knockout as informative for the frontonasal ectomesenchyme node.
Show evidence (1 reference)
PMID:19414008 SUPPORT Model Organism
"Using a Cre-mediated conditional deletion approach, we have dissected the function of Twist1 in the morphogenesis of the craniofacial skeleton."
Establishes the conditional-knockout design and its craniofacial scope, supporting its use as a model for this disorder's mechanism.
{ }

Source YAML

click to show 
name: Sweeney-Cox Syndrome
synonyms:
- SWCOS
- Sweeney-Cox syndrome
creation_date: "2026-08-28T00:00:00Z"
category: Mendelian
description: >-
  Sweeney-Cox syndrome is a de novo autosomal dominant craniofacial disorder
  caused by missense substitutions at a single highly conserved glutamic acid
  residue, Glu117, in the basic DNA-binding domain of TWIST1. It presents as
  frontonasal dysplasia — marked hypertelorism with severe deficiency of the
  frontal bones and hypoplasia of the nose and facial bones — together with
  ablepharon or underdevelopment of the eyelids and cheek pads beside the
  corners of the mouth.

  The disorder is mechanistically the counterpoint to Saethre-Chotzen syndrome,
  which arises from haploinsufficiency of the same gene. Roughly a hundred
  loss-of-function TWIST1 alleles cause Saethre-Chotzen with craniosynostosis,
  yet none of them touch the Glu117 codon. The Glu117 substitutions act
  antimorphically instead — a conclusion drawn from a Caenorhabditis elegans
  allelic series, not from biochemistry on the human protein. Losing half the
  TWIST1 dose and interfering with the whole pool are different lesions, and
  they produce different diseases: a non-synostotic frontonasal phenotype here,
  premature coronal suture fusion there.

  The frontonasal phenotype is explained by what TWIST1 does in cranial neural
  crest. In mouse, neural-crest-specific loss of Twist1 collapses frontonasal
  development and fails to activate the ectomesenchyme programme — Alx1, Alx3
  and Alx4 — in the frontonasal prominence, and Twist1 occupies a distal
  enhancer that drives Alx1 specifically in periocular and frontonasal
  mesenchyme. The same enhancer explains why the eyelids are involved:
  periocular mesenchyme is the tissue TWIST1 patterns alongside the midface.

  Phenotypically the syndrome sits with the TWIST2 paralogue disorders rather
  than with Saethre-Chotzen. Barber-Say and ablepharon-macrostomia syndromes
  arise from substitutions at Glu75, the residue paralogous to TWIST1 Glu117,
  and share the ablepharon, hypertelorism and cheek-pad facies. Craniosynostosis
  is the feature that separates the group from Saethre-Chotzen — though one
  reported Glu117Asp patient had bilateral coronal synostosis, which is the
  strongest evidence that the two TWIST1 phenotypes are ends of a spectrum
  rather than disjoint entities.
disease_term:
  preferred_term: Sweeney-Cox syndrome
  term:
    id: MONDO:0060592
    label: Sweeney-Cox syndrome
parents:
- TWIST1-related disorder
- Frontonasal dysplasia
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Every reported case carries a de novo heterozygous missense substitution at
    TWIST1 Glu117. The allele acts antimorphically rather than by simple loss of
    dosage, so dominance here reflects interference with the wild-type product
    and not haploinsufficiency.
  evidence:
  - reference: PMID:28369379
    reference_title: Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we describe a new clinical entity, Sweeney-Cox syndrome, associated with
      distinct de novo amino acid substitutions (p.Glu117Val and p.Glu117Gly) at
      a highly conserved glutamic acid residue located in the basic DNA binding
      domain of TWIST1, in two subjects with frontonasal dysplasia and additional
      malformations.
    explanation: >-
      Establishes the de novo heterozygous origin of the Glu117 substitutions in
      the two index subjects.
pathophysiology:
- name: TWIST1 Glu117 Basic-Domain Substitution
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    A de novo heterozygous missense substitution replaces the conserved glutamic
    acid at codon 117 of TWIST1. Glu117 lies in the basic region of the bHLH
    domain — the segment that contacts DNA — so the lesion is positioned to
    disable DNA recognition while leaving the helix-loop-helix dimerisation
    surface intact. Three substitutions are reported (p.Glu117Val, p.Glu117Gly,
    p.Glu117Asp), and this codon is untouched among roughly one hundred
    loss-of-function TWIST1 alleles catalogued in Saethre-Chotzen syndrome,
    which is the first indication that it is not simply another way of losing
    the gene.
  gene:
    preferred_term: TWIST1
    description: >-
      Basic helix-loop-helix transcription factor; substitution of the
      DNA-contacting Glu117 residue causes Sweeney-Cox syndrome.
    term:
      id: hgnc:12428
      label: TWIST1
  genetic_context:
    gene:
      preferred_term: TWIST1
      term:
        id: hgnc:12428
        label: TWIST1
    allele_type: SNV
    variant_origin: DE_NOVO
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
    description: >-
      Heterozygous de novo missense substitutions at Glu117 in the basic
      DNA-binding domain, acting antimorphically on the wild-type allele.
  locations:
  - preferred_term: frontonasal prominence
    term:
      id: UBERON:0004066
      label: frontonasal prominence
  evidence:
  - reference: PMID:28369379
    reference_title: Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although about one hundred different TWIST1 mutations have been reported in
      patients with the dominant haploinsufficiency Saethre-Chotzen syndrome
      (typically associated with craniosynostosis), substitutions uniquely
      affecting the Glu117 codon were not observed previously.
    explanation: >-
      Places Glu117 outside the Saethre-Chotzen loss-of-function mutation
      spectrum, which is the genetic argument that this codon behaves
      differently from the rest of the gene.
  - reference: PMID:30450715
    reference_title: Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a de novo heterozygous mutation in the basic domain of TWIST1, that is,
      c.351C>G p.Glu117Asp
    explanation: >-
      Documents a third Glu117 allele, extending the substitution series beyond
      the two index cases.
  downstream:
  - target: Antimorphic Interference with TWIST1 bHLH Complexes
    causal_link_type: DIRECT
    hypothesis_groups:
    - glu117_interference_dosage_continuum
    description: >-
      The substituted basic domain is the direct cause of the mutant protein's
      failure to transactivate while remaining incorporated into TWIST1
      complexes.
    evidence:
    - reference: PMID:28369379
      reference_title: Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The genetic analysis favors a predominantly dominant-negative mechanism
        for the action of amino acid substitutions at this highly conserved
        glutamic acid residue
      explanation: >-
        Links the Glu117 substitution to antimorphic action on the TWIST1
        complex, which is the edge asserted here.
- name: Antimorphic Interference with TWIST1 bHLH Complexes
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    TWIST1 acts as homodimers and as heterodimers with the TCF3, TCF4 and TCF12
    E-proteins, and it is the basic region of each partner that grips the E-box.
    Substituting Glu117 alters a DNA-contacting residue while leaving the
    helix-loop-helix dimerisation surface untouched, so the expected consequence
    is a subunit that still enters complexes but cannot read their targets. The
    genetic evidence supports that reading: engineering the five human alleles
    into the equivalent Glu29 residue of hlh-8, the single Twist homolog in
    Caenorhabditis elegans, produced a graded severity series rather than a
    simple null, and the analysis favours a predominantly dominant-negative
    mechanism.

    Two caveats belong on this node. The dimerisation-retained,
    DNA-binding-lost model is inferred from where the residue sits in the
    domain — no biochemistry on the human Glu117 protein has been reported, so
    it is not known directly whether these subunits still dimerise or still
    occupy chromatin. And "predominantly" is the source's own word: the C.
    elegans series does not exclude a partial loss-of-function component.

    What is established is that this step is where Sweeney-Cox parts from
    Saethre-Chotzen. Reducing TWIST1 to one functional copy leaves the remaining
    protein competent; an antimorphic allele does not.
  molecular_functions:
  - preferred_term: E-box binding
    term:
      id: GO:0070888
      label: E-box binding
    modifier: DECREASED
  - preferred_term: protein dimerization activity
    term:
      id: GO:0046983
      label: protein dimerization activity
  - preferred_term: DNA-binding transcription factor activity
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    modifier: DECREASED
  evidence:
  - reference: PMID:28369379
    reference_title: Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The genetic analysis favors a predominantly dominant-negative mechanism for
      the action of amino acid substitutions at this highly conserved glutamic
      acid residue
    explanation: >-
      States the antimorphic mechanism directly, as the conclusion of the
      C. elegans allelic series.
  - reference: PMID:30450715
    reference_title: Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous localized TWIST1 and TWIST2 basic domain substitutions exert
      antimorphic effects to cause Sweeney-Cox syndrome, Barber-Say syndrome, and
      ablepharon-macrostomia syndrome, respectively.
    explanation: >-
      Independently characterises the basic-domain substitutions as antimorphic
      across the TWIST1 and TWIST2 disorders.
  - reference: PMID:32179550
    reference_title: TWIST1 Homodimers and Heterodimers Orchestrate Lineage-Specific Differentiation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      proteomic profiling of human TWIST1-expressing cell lines and transcriptome
      analysis of mouse cranial mesenchyme have revealed that TWIST1 homodimers
      and heterodimers with TCF3, TCF4, and TCF12 E-proteins are the predominant
      dimer combinations
    explanation: >-
      Identifies the dimer species a Glu117 subunit can be incorporated into,
      which is what makes an antimorphic effect possible.
  - reference: PMID:32179550
    reference_title: TWIST1 Homodimers and Heterodimers Orchestrate Lineage-Specific Differentiation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Disease-causing mutations in TWIST1 can impact dimer formation or shift the
      balance of different types of TWIST1 dimers in the cell, which may underpin
      the defective differentiation of the craniofacial mesenchyme.
    explanation: >-
      Connects altered TWIST1 dimer behaviour to defective craniofacial
      mesenchyme differentiation, the downstream node here.
  downstream:
  - target: Failure of TWIST1-Dependent Frontonasal Ectomesenchyme Programme
    causal_link_type: DIRECT
    description: >-
      Complexes that cannot engage the E-box cannot activate the TWIST1 target
      genes of the frontonasal prominence.
    evidence:
    - reference: PMID:32179550
      reference_title: TWIST1 Homodimers and Heterodimers Orchestrate Lineage-Specific Differentiation.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Disease-causing mutations in TWIST1 can impact dimer formation or shift
        the balance of different types of TWIST1 dimers in the cell, which may
        underpin the defective differentiation of the craniofacial mesenchyme.
      explanation: >-
        Supports the edge from altered TWIST1 complex behaviour to defective
        craniofacial mesenchyme differentiation. Graded INDIRECT because the
        source frames this as a proposed explanation rather than a demonstrated
        one, and does not test a Glu117 allele.
- name: Failure of TWIST1-Dependent Frontonasal Ectomesenchyme Programme
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    TWIST1 is expressed in migratory cranial neural crest and maintained in the
    crest-derived mesenchyme of the frontonasal prominence, where it switches on
    the ectomesenchyme programme. In mouse, neural-crest-specific inactivation of
    Twist1 disrupts frontonasal development and fails to activate Alx1, Alx3 and
    Alx4 in the frontonasal prominence; Twist1 occupies a conserved element in a
    distal Alx1 enhancer and drives Alx1 reporter expression specifically in
    periocular and frontonasal mesenchyme. Deleting that enhancer alone
    reproduces frontonasal and ocular defects.

    Curated as PROVISIONAL: the enhancer and target-gene work is mouse
    conditional-knockout and reporter biology, so it establishes what TWIST1 does
    in this tissue, not that a human Glu117 allele acts through this particular
    enhancer. The inference from an antimorphic allele to this specific
    regulatory step has not been made in patient tissue.
  cell_types:
  - preferred_term: migratory cranial neural crest cell
    term:
      id: CL:0000008
      label: migratory cranial neural crest cell
  locations:
  - preferred_term: frontonasal prominence
    term:
      id: UBERON:0004066
      label: frontonasal prominence
  biological_processes:
  - preferred_term: positive regulation of transcription by RNA polymerase II
    term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    modifier: DECREASED
  - preferred_term: embryonic cranial skeleton morphogenesis
    term:
      id: GO:0048701
      label: embryonic cranial skeleton morphogenesis
    modifier: DECREASED
  evidence:
  - reference: PMID:41850652
    reference_title: A Twist1-regulated distal enhancer crucial for Alx1 gene expression and function during craniofacial development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      mice with neural crest lineage-specific inactivation of Twist1 resulted in
      dramatic disruption of frontonasal development accompanied by failure of
      activation of many ectomesenchyme genes, including Alx1, Alx3, and Alx4, in
      the FNP
    explanation: >-
      Establishes that TWIST1 is required to switch on the frontonasal
      ectomesenchyme programme, the transcriptional output lost here.
  - reference: PMID:41850652
    reference_title: A Twist1-regulated distal enhancer crucial for Alx1 gene expression and function during craniofacial development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      exhibits high enrichment of Twist1 transcription factor occupancy in mouse
      embryonic frontonasal tissues and drove Twist1-dependent reporter transgene
      expression specifically in the developing periocular and frontonasal
      mesenchyme in transgenic mice
    explanation: >-
      Identifies a direct TWIST1-occupied enhancer active in exactly the two
      tissues affected in this syndrome — periocular and frontonasal mesenchyme.
  - reference: PMID:19414008
    reference_title: Requirement for Twist1 in frontonasal and skull vault development in the mouse embryo.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Loss of Twist1 in neural crest cells and their derivatives impairs
      skeletogenic differentiation and leads to the loss of bones of the snout,
      upper face and skull vault.
    explanation: >-
      Shows the skeletal consequence of losing TWIST1 function in cranial neural
      crest, matching the frontal-bone and nasal deficiency seen in patients.
  - reference: PMID:38262408
    reference_title: DNA-guided transcription factor cooperativity shapes face and limb mesenchyme.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Coordinator guides cooperative and selective binding between the bHLH
      family mesenchymal regulator TWIST1 and a collective of HD factors
      associated with regional identities in the face and limb.
    explanation: >-
      Identifies the composite motif through which TWIST1 acts in face
      mesenchyme, showing that the E-box contact lost by a Glu117 substitution
      is the one this regulatory system depends on.
  - reference: PMID:38262408
    reference_title: DNA-guided transcription factor cooperativity shapes face and limb mesenchyme.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      TWIST1 is required for HD binding and open chromatin at Coordinator sites
    explanation: >-
      Shows TWIST1 occupancy is upstream of homeodomain-factor binding and
      chromatin accessibility in this tissue, so losing TWIST1 DNA contact
      disables the wider regulatory programme rather than one target.
  - reference: PMID:35781329
    reference_title: TWIST1 interacts with beta/delta-catenins during neural tube development and regulates fate transition in cranial neural crest cells.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Twist1 suppresses Irf6 and other epithelial genes in CNCCs during the
      epithelial-to-mesenchymal transition (EMT) process and cell migration.
      Conversely, a loss of Twist1 leads to a sustained expression of epithelial
      and cell adhesion markers in migratory CNCCs.
    explanation: >-
      Adds a second TWIST1-dependent step upstream of the ectomesenchyme
      programme: releasing cranial neural crest from its epithelial state.
      Graded INDIRECT because it is loss-of-function mouse work and no Glu117
      allele has been tested for this function, so whether an antimorphic allele
      impairs the EMT step as well as the later patterning step is unknown.
  downstream:
  - target: Frontonasal Skeletal Deficiency
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Loss of the ectomesenchyme programme in the frontonasal prominence leads to
      deficient differentiation of the frontal and nasal skeletal elements.
    evidence:
    - reference: PMID:19414008
      reference_title: Requirement for Twist1 in frontonasal and skull vault development in the mouse embryo.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Loss of Twist1 in neural crest cells and their derivatives impairs
        skeletogenic differentiation and leads to the loss of bones of the snout,
        upper face and skull vault.
      explanation: >-
        Demonstrates the edge from lost TWIST1 function in cranial neural crest
        to failed skeletogenic differentiation of the upper face.
  - target: Periocular Mesenchyme and Eyelid Morphogenesis Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The same TWIST1-dependent enhancer activity spans periocular mesenchyme,
      linking the transcriptional lesion to the eyelid phenotype; the
      intervening steps in eyelid morphogenesis are not established.
    evidence:
    - reference: PMID:41850652
      reference_title: A Twist1-regulated distal enhancer crucial for Alx1 gene expression and function during craniofacial development.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        drove Twist1-dependent reporter transgene expression specifically in the
        developing periocular and frontonasal mesenchyme in transgenic mice
      explanation: >-
        Places TWIST1-dependent regulatory activity in periocular mesenchyme.
        Graded INDIRECT because it establishes the tissue overlap rather than the
        causal route to ablepharon.
- name: Frontonasal Skeletal Deficiency
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Deficient skeletogenic differentiation of frontonasal ectomesenchyme yields
    the structural core of the syndrome: severe deficiency of the frontal bones,
    hypoplasia of the nose and facial bones, and the widened interorbital
    distance that presents clinically as marked hypertelorism.
  locations:
  - preferred_term: frontonasal prominence
    term:
      id: UBERON:0004066
      label: frontonasal prominence
  - preferred_term: tetrapod frontal bone
    term:
      id: UBERON:0000209
      label: tetrapod frontal bone
  - preferred_term: nasal bone
    term:
      id: UBERON:0001681
      label: nasal bone
  evidence:
  - reference: PMID:41850652
    reference_title: A Twist1-regulated distal enhancer crucial for Alx1 gene expression and function during craniofacial development.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Sweeney-Cox syndrome characterized by hypertelorism with severe deficiency
      in frontal bones and hypoplasia of the nose and facial bones
    explanation: >-
      States the skeletal phenotype of the syndrome in the terms modelled by this
      node. Graded OTHER, not HUMAN_CLINICAL: this sentence is background prose
      in a mouse developmental study summarising the clinical literature, not
      human data the paper itself reports. It is cited because the primary
      description of frontal-bone deficiency sits in full text that is not in
      the reference cache.
- name: Periocular Mesenchyme and Eyelid Morphogenesis Failure
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Eyelid development requires patterned periocular mesenchyme, and the eyelids
    are the second tissue in which the TWIST1-dependent frontonasal enhancer is
    active. Clinically this presents as ablepharon or underdevelopment of the
    eyelids, a feature Sweeney-Cox shares with the TWIST2 Glu75 disorders and
    which is not part of Saethre-Chotzen syndrome.

    PROVISIONAL because the enhancer evidence establishes TWIST1 activity in
    periocular mesenchyme but no study has traced a Glu117 allele through eyelid
    morphogenesis; the causal chain from transcriptional lesion to ablepharon is
    inferred from tissue overlap.
  locations:
  - preferred_term: periocular mesenchyme
    term:
      id: UBERON:0004017
      label: periocular mesenchyme
  - preferred_term: eyelid
    term:
      id: UBERON:0001711
      label: eyelid
  biological_processes:
  - preferred_term: eyelid development in camera-type eye
    term:
      id: GO:0061029
      label: eyelid development in camera-type eye
    modifier: DECREASED
  evidence:
  - reference: PMID:30450715
    reference_title: Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia
      syndrome share the facial features of ablepharon, hypertelorism,
      underdevelopment of the eyelids, and cheek pads adjacent to the corners of
      the mouth.
    explanation: >-
      Establishes ablepharon and eyelid underdevelopment as features of the
      syndrome and of the paralogous TWIST2 disorders.
phenotypes:
- category: Craniofacial
  name: Hypertelorism
  frequency: VERY_FREQUENT
  description: >-
    Marked widening of the interorbital distance, reported in every described
    case and shared with the paralogous TWIST2 Glu75 disorders.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:30450715
    reference_title: Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia
      syndrome share the facial features of ablepharon, hypertelorism,
      underdevelopment of the eyelids, and cheek pads adjacent to the corners of
      the mouth.
    explanation: Names hypertelorism as a shared core feature of the syndrome.
  notes: >-
    Frequency basis: this band comes from the source's qualitative characterisation of the feature, which is the mapping the curation guidance sanctions, and not from a patient count. The 46 HPOA-derived phenotypes in this entry carry no band for the complementary reason - their provenance is a count out of two patients and nothing else. Where a count would suggest a different band, the prose governs and the disagreement is stated. Here the source names hypertelorism among the facial features shared
    across the whole Glu117/Glu75 group, which reads as near-constant.
- category: Ophthalmologic
  name: Upper Eyelid Coloboma
  description: >-
    Failure of upper eyelid closure. This is the eyelid abnormality carried by
    the HPO annotation for OMIM:617746, which derives from the two index
    subjects, and it is the term to prefer when describing the eyelid phenotype
    of this syndrome in general.
  phenotype_term:
    preferred_term: Upper eyelid coloboma
    term:
      id: HP:0000636
      label: Upper eyelid coloboma
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which cites
    PMID:28369379 for every term. Kept distinct from the separate Ablepharon
    entry below, which is a more severe finding reported in only one patient.
- category: Ophthalmologic
  name: Ablepharon
  frequency: OCCASIONAL
  description: >-
    Absence or severe underdevelopment of the eyelids, reported in the third
    patient (p.Glu117Asp) rather than in the two index subjects. It is the
    feature that aligns that patient with the TWIST2 Glu75 disorders, Barber-Say
    and ablepharon-macrostomia syndrome.
  phenotype_term:
    preferred_term: Ablepharon
    term:
      id: HP:0011224
      label: Ablepharon
  notes: >-
    Deliberately not the primary eyelid term for this entry. HP:0011224 is
    absent from the HPO annotation for OMIM:617746, which instead carries
    HP:0000636 Upper eyelid coloboma from the two index subjects; ablepharon is
    documented in the later Glu117Asp case report and is graded OCCASIONAL for
    that reason. Both are curated because they are different severities of the
    same developmental failure, and collapsing them would either overstate the
    index phenotype or drop a published finding.
  evidence:
  - reference: PMID:30450715
    reference_title: Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we document a male infant with the distinctive facial features of
      ablepharon, hypertelorism, cheek pads adjacent to the corners of the mouth,
      and bilateral coronal suture craniosynostosis
    explanation: >-
      Direct clinical observation of ablepharon in a Glu117-substituted patient.
- category: Craniofacial
  name: Cheek Pads at the Oral Commissures
  description: >-
    Fleshy pads beside the corners of the mouth, one of the facial features this
    syndrome shares with the TWIST2 Glu75 disorders, Barber-Say and
    ablepharon-macrostomia syndrome.
  phenotype_term:
    preferred_term: Cheek pads adjacent to the corners of the mouth
  evidence:
  - reference: PMID:30450715
    reference_title: Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia
      syndrome share the facial features of ablepharon, hypertelorism,
      underdevelopment of the eyelids, and cheek pads adjacent to the corners of
      the mouth.
    explanation: >-
      Names cheek pads at the oral commissures as a shared feature of the
      syndrome and the paralogous TWIST2 disorders.
  notes: >-
    Deliberately left unbound. HPO has no term for this finding: HP:0000293 Full
    cheeks describes generalised cheek fullness, not localised pads at the oral
    commissures, and binding it would assert a different phenotype. Per the
    dismech-terms rule that no term beats a bad one, this is curated as free text
    in preferred_term with no term.
- category: Craniofacial
  name: Frontal Bone Hypoplasia
  frequency: FREQUENT
  description: >-
    Severe deficiency of the frontal bones, the skeletal counterpart of the
    frontonasal ectomesenchyme lesion.
  phenotype_term:
    preferred_term: Hypoplasia of the frontal bone
    term:
      id: HP:0005466
      label: Hypoplasia of the frontal bone
  evidence:
  - reference: PMID:41850652
    reference_title: A Twist1-regulated distal enhancer crucial for Alx1 gene expression and function during craniofacial development.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Sweeney-Cox syndrome characterized by hypertelorism with severe deficiency
      in frontal bones and hypoplasia of the nose and facial bones
    explanation: >-
      Reports severe frontal bone deficiency as a defining feature. Graded OTHER
      because the sentence is a literature summary in the introduction of a
      mouse study rather than human data reported by that paper.
  notes: >-
    Frequency basis: this band comes from the source's qualitative characterisation of the feature, which is the mapping the curation guidance sanctions, and not from a patient count. The 46 HPOA-derived phenotypes in this entry carry no band for the complementary reason - their provenance is a count out of two patients and nothing else. Where a count would suggest a different band, the prose governs and the disagreement is stated. Here the source characterises the syndrome as being defined by severe
    frontal bone deficiency.
- category: Craniofacial
  name: Midface and Nasal Hypoplasia
  frequency: FREQUENT
  description: >-
    Hypoplasia of the nose and facial bones, part of the frontonasal dysplasia
    presentation.
  phenotype_term:
    preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:41850652
    reference_title: A Twist1-regulated distal enhancer crucial for Alx1 gene expression and function during craniofacial development.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      Sweeney-Cox syndrome characterized by hypertelorism with severe deficiency
      in frontal bones and hypoplasia of the nose and facial bones
    explanation: >-
      Reports nasal and facial bone hypoplasia. Graded INDIRECT because the source
      describes hypoplasia of these bones rather than midface retrusion as such,
      which is the closest available HPO term, and OTHER because the sentence is
      a literature summary in a mouse study, not human data that paper reports.
  notes: >-
    Frequency basis: this band comes from the source's qualitative characterisation of the feature, which is the mapping the curation guidance sanctions, and not from a patient count. The 46 HPOA-derived phenotypes in this entry carry no band for the complementary reason - their provenance is a count out of two patients and nothing else. Where a count would suggest a different band, the prose governs and the disagreement is stated. Here the source characterises the syndrome as being defined by
    hypoplasia of the nose and facial bones.
- category: Craniofacial
  name: Coronal Craniosynostosis
  frequency: OCCASIONAL
  description: >-
    Not a cardinal feature, and its absence is what distinguishes Sweeney-Cox
    from Saethre-Chotzen syndrome. One reported patient with the p.Glu117Asp
    allele nonetheless had bilateral coronal suture synostosis, which is the
    principal evidence that the two TWIST1 phenotypes overlap.
  phenotype_term:
    preferred_term: Coronal craniosynostosis
    term:
      id: HP:0004440
      label: Coronal craniosynostosis
  evidence:
  - reference: PMID:30450715
    reference_title: Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our review showed that Sweeney-Cox syndrome appears to share many
      characteristics with Barber-Say syndrome and ablepharon-macrostomia
      syndrome except for craniosynostosis, which is a cardinal feature of
      Saethre-Chotzen syndrome.
    explanation: >-
      Establishes that craniosynostosis is not typical of Sweeney-Cox, supporting
      the OCCASIONAL frequency and the boundary with Saethre-Chotzen.
  notes: >-
    Frequency basis: this band comes from the source's qualitative characterisation of the feature, which is the mapping the curation guidance sanctions, and not from a patient count. The 46 HPOA-derived phenotypes in this entry carry no band for the complementary reason - their provenance is a count out of two patients and nothing else. Where a count would suggest a different band, the prose governs and the disagreement is stated. Here the source states explicitly that craniosynostosis is not a
    cardinal feature of this syndrome, which is what OCCASIONAL encodes. Note
    that the raw count runs the other way - one of the three reported patients
    had bicoronal synostosis, which as a fraction would fall in the FREQUENT
    band. The qualitative statement is preferred because a denominator of three
    cannot distinguish 33 percent from 5 percent, and because the source is
    making a claim about the syndrome rather than tallying its own series.
- category: Prenatal
  name: Polyhydramnios
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Musculoskeletal
  name: Long fingers
  phenotype_term:
    preferred_term: Long fingers
    term:
      id: HP:0100807
      label: Long fingers
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Musculoskeletal
  name: Short distal phalanx of finger
  phenotype_term:
    preferred_term: Short distal phalanx of finger
    term:
      id: HP:0009882
      label: Short distal phalanx of finger
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Musculoskeletal
  name: Bilateral talipes equinovarus
  phenotype_term:
    preferred_term: Bilateral talipes equinovarus
    term:
      id: HP:0001776
      label: Bilateral talipes equinovarus
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Musculoskeletal
  name: 2-5 toe syndactyly
  phenotype_term:
    preferred_term: 2-5 toe syndactyly
    term:
      id: HP:0010715
      label: 2-5 toe syndactyly
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Musculoskeletal
  name: 2-4 finger cutaneous syndactyly
  phenotype_term:
    preferred_term: 2-4 finger cutaneous syndactyly
    term:
      id: HP:0010709
      label: 2-4 finger cutaneous syndactyly
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Musculoskeletal
  name: 2-5 finger cutaneous syndactyly
  phenotype_term:
    preferred_term: 2-5 finger cutaneous syndactyly
    term:
      id: HP:0005650
      label: 2-5 finger cutaneous syndactyly
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Neurologic
  name: Cerebellar hypoplasia
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Neurologic
  name: Delayed speech and language development
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Neurologic
  name: Global developmental delay
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 2/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Immunologic
  name: Asplenia
  phenotype_term:
    preferred_term: Asplenia
    term:
      id: HP:0001746
      label: Asplenia
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Cardiovascular
  name: Patent foramen ovale
  phenotype_term:
    preferred_term: Patent foramen ovale
    term:
      id: HP:0001655
      label: Patent foramen ovale
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Cardiovascular
  name: Patent ductus arteriosus
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Dermatologic
  name: Generalized hirsutism
  phenotype_term:
    preferred_term: Generalized hirsutism
    term:
      id: HP:0002230
      label: Generalized hirsutism
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Dermatologic
  name: Small nail
  phenotype_term:
    preferred_term: Small nail
    term:
      id: HP:0001792
      label: Small nail
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Genitourinary
  name: Bilateral cryptorchidism
  phenotype_term:
    preferred_term: Bilateral cryptorchidism
    term:
      id: HP:0008689
      label: Bilateral cryptorchidism
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/1 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Otologic
  name: Low-set ears
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Otologic
  name: Crumpled ear
  phenotype_term:
    preferred_term: Crumpled ear
    term:
      id: HP:0009901
      label: Crumpled ear
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Otologic
  name: Microtia
  phenotype_term:
    preferred_term: Microtia
    term:
      id: HP:0008551
      label: Microtia
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Otologic
  name: Overfolded helix
  phenotype_term:
    preferred_term: Overfolded helix
    term:
      id: HP:0000396
      label: Overfolded helix
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Otologic
  name: Cupped ear
  phenotype_term:
    preferred_term: Cupped ear
    term:
      id: HP:0000378
      label: Cupped ear
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Otologic
  name: Hearing impairment
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Otologic
  name: Uplifted earlobe
  phenotype_term:
    preferred_term: Uplifted earlobe
    term:
      id: HP:0009909
      label: Uplifted earlobe
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Gastrointestinal
  name: Gastroesophageal reflux
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Gastrointestinal
  name: Anal atresia
  phenotype_term:
    preferred_term: Anal atresia
    term:
      id: HP:0002023
      label: Anal atresia
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: Wide anterior fontanel
  phenotype_term:
    preferred_term: Wide anterior fontanel
    term:
      id: HP:0000260
      label: Wide anterior fontanel
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: Velopharyngeal insufficiency
  phenotype_term:
    preferred_term: Velopharyngeal insufficiency
    term:
      id: HP:0000220
      label: Velopharyngeal insufficiency
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: Prominent metopic ridge
  phenotype_term:
    preferred_term: Prominent metopic ridge
    term:
      id: HP:0005487
      label: Prominent metopic ridge
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 2/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: Micrognathia
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: Median cleft palate
  phenotype_term:
    preferred_term: Median cleft palate
    term:
      id: HP:0009099
      label: Median cleft palate
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: Short philtrum
  phenotype_term:
    preferred_term: Short philtrum
    term:
      id: HP:0000322
      label: Short philtrum
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: Choanal atresia
  phenotype_term:
    preferred_term: Choanal atresia
    term:
      id: HP:0000453
      label: Choanal atresia
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: Widow's peak
  phenotype_term:
    preferred_term: Widow's peak
    term:
      id: HP:0000349
      label: Widow's peak
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: Low hanging columella
  phenotype_term:
    preferred_term: Low hanging columella
    term:
      id: HP:0009765
      label: Low hanging columella
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: High palate
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: Short columella
  phenotype_term:
    preferred_term: Short columella
    term:
      id: HP:0002000
      label: Short columella
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: Underdeveloped nasal alae
  phenotype_term:
    preferred_term: Underdeveloped nasal alae
    term:
      id: HP:0000430
      label: Underdeveloped nasal alae
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: Low anterior hairline
  phenotype_term:
    preferred_term: Low anterior hairline
    term:
      id: HP:0000294
      label: Low anterior hairline
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: Narrow mouth
  phenotype_term:
    preferred_term: Narrow mouth
    term:
      id: HP:0000160
      label: Narrow mouth
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: Broad nasal tip
  phenotype_term:
    preferred_term: Broad nasal tip
    term:
      id: HP:0000455
      label: Broad nasal tip
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 2/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: Broad neck
  phenotype_term:
    preferred_term: Broad neck
    term:
      id: HP:0000475
      label: Broad neck
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: Wide nasal bridge
  phenotype_term:
    preferred_term: Wide nasal bridge
    term:
      id: HP:0000431
      label: Wide nasal bridge
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: Flat occiput
  phenotype_term:
    preferred_term: Flat occiput
    term:
      id: HP:0005469
      label: Flat occiput
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Craniofacial
  name: Brachycephaly
  phenotype_term:
    preferred_term: Brachycephaly
    term:
      id: HP:0000248
      label: Brachycephaly
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Skeletal
  name: Short clavicles
  phenotype_term:
    preferred_term: Short clavicles
    term:
      id: HP:0000894
      label: Short clavicles
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
- category: Skeletal
  name: Narrow chest
  phenotype_term:
    preferred_term: Narrow chest
    term:
      id: HP:0000774
      label: Narrow chest
    onset:
      onset_category: CONGENITAL
      notes: >-
        The HPO annotation for OMIM:617746 carries HP:0003577 Congenital
        onset at 2/2 for this disease.
  notes: >-
    Curated from the HPO disease annotation for OMIM:617746, which records
    this feature in 1/2 reported individuals and cites PMID:28369379. No
    evidence item is attached: the cached abstract of that paper does not
    enumerate the individual malformations, so the annotation database is
    the provenance and is named here rather than quoted. No frequency band
    is asserted, because a count out of two patients does not support one.
genetic:
- name: TWIST1
  gene_term:
    preferred_term: TWIST1
    term:
      id: hgnc:12428
      label: TWIST1
  association: CAUSATIVE
  variant_origin: DE_NOVO
  features: >-
    Heterozygous de novo missense substitutions restricted to codon Glu117 in the
    basic DNA-binding domain. Three alleles are reported: p.Glu117Val and
    p.Glu117Gly in the two index subjects, and p.Glu117Asp in a third patient.
    Because glutamate and aspartate are the only negatively charged residues and
    even the conservative Glu117Asp substitution produced the syndrome, any
    substitution at this codon is expected to be pathogenic or lethal.
  evidence:
  - reference: PMID:28369379
    reference_title: Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we describe a new clinical entity, Sweeney-Cox syndrome, associated with
      distinct de novo amino acid substitutions (p.Glu117Val and p.Glu117Gly) at
      a highly conserved glutamic acid residue located in the basic DNA binding
      domain of TWIST1, in two subjects with frontonasal dysplasia and additional
      malformations.
    explanation: Identifies TWIST1 Glu117 as the causal locus and lists two alleles.
  - reference: PMID:30450715
    reference_title: Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This suggests that any amino acid substitutions at Glu117 would likely lead
      to the Sweeney-Cox syndrome phenotype or lethality.
    explanation: >-
      Supports the claim that the pathogenic constraint is on the codon itself
      rather than on a particular substituting residue.
  - reference: PMID:42059179
    reference_title: Evidence-based classification of genes implicated in craniosynostosis disorders using the ClinGen curation framework.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three rare but clinically defined and distinguishable gene-disease pairs
      were found to have Limited evidence ranging from 3 to 4 points to support
      the relationship by the Cranio GCEP: FGFR1-related osteoglophonic
      dysplasia (OMIM:166250), TWIST1-related Sweeney-Cox syndrome
      (OMIM:617746)
    explanation: >-
      The ClinGen Craniofacial GCEP classifies the TWIST1-Sweeney-Cox
      gene-disease relationship as Limited. Typed DIRECT because the sentence
      asserts a curated gene-disease relationship rather than something the
      claim is inferred from. The Limited grade is a statement of evidence
      strength, which the schema has no slot for, and it is recorded here: the
      case count is too small to reach Moderate, this is not a doubt about the
      mechanism, and the entry should not present the relationship with
      Definitive-level confidence.
  notes: >-
    ClinGen's Craniofacial GCEP rates this gene-disease relationship Limited
    (3-4 points), constrained by the number of reported cases rather than by the
    quality of the functional evidence. The mechanistic work is strong; the
    clinical series is three patients.

    Nomenclature discrepancy on the third allele: the Takenouchi report states
    c.351C>G p.Glu117Asp, while ClinVar represents the same protein change as
    c.351G>T (VCV002572412). Against NM_000474.4 the ClinVar form is the
    internally consistent one, since GAG to GAT yields Asp whereas the published
    cDNA change does not. The published string is quoted verbatim in the
    evidence snippet above and deliberately left uncorrected there, because a
    snippet belongs to the cited paper; the reconciliation is recorded here
    instead.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Three patients reported at the time of curation: two index subjects with
    p.Glu117Val and p.Glu117Gly, and one with p.Glu117Asp.
  evidence:
  - reference: PMID:28369379
    reference_title: Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in two subjects with frontonasal dysplasia and additional malformations
    explanation: >-
      The syndrome was delineated on two subjects, establishing it as reportable
      at case-series scale only.
animal_models:
- name: hlh-8 Glu29 allelic series (C. elegans)
  species: Caenorhabditis elegans
  genotype: hlh-8 Glu29 substitutions equivalent to the five human TWIST1/TWIST2 disease alleles
  publication: PMID:28369379
  description: >-
    All five human disease-associated substitutions — the TWIST1 Glu117 and
    TWIST2 Glu75 alleles — were engineered into the equivalent Glu29 residue of
    hlh-8, the single Twist homolog in C. elegans. The resulting allelic series
    graded in severity by gene expression and cellular phenotype, which is the
    evidence base for the dominant-negative model and for ranking the four human
    syndromes against each other.
  modeled_mechanisms:
  - target: Antimorphic Interference with TWIST1 bHLH Complexes
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the antimorphic behaviour of the substitutions in a single-Twist
      genetic background, where dominant-negative action can be separated from
      loss of dosage.
    limitations: >-
      C. elegans has one Twist homolog and no craniofacial skeleton, so the model
      speaks to the molecular character of the allele and to relative severity,
      not to the tissue phenotype. The M-lineage cellular readout has no
      counterpart in cranial neural crest.
    evidence:
    - reference: PMID:28369379
      reference_title: Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This allelic series revealed that different substitutions exhibit graded
        severity, in terms of both gene expression and cellular phenotype, which
        we incorporate into a model explaining the various human disease
        phenotypes.
      explanation: >-
        Reports the graded-severity result that grounds the antimorphic model for
        this node.
- name: Neural-crest conditional Twist1 knockout mouse
  species: Mouse
  genotype: Twist1 conditional deletion in neural crest cells (Cre-mediated)
  publication: PMID:19414008
  description: >-
    Cre-mediated deletion of Twist1 in neural crest cells and their derivatives,
    used to dissect the requirement for Twist1 in craniofacial skeletal
    morphogenesis.
  evidence:
  - reference: PMID:19414008
    reference_title: Requirement for Twist1 in frontonasal and skull vault development in the mouse embryo.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using a Cre-mediated conditional deletion approach, we have dissected the
      function of Twist1 in the morphogenesis of the craniofacial skeleton.
    explanation: >-
      Establishes the conditional-knockout design and its craniofacial scope,
      supporting its use as a model for this disorder's mechanism.
  modeled_mechanisms:
  - target: Failure of TWIST1-Dependent Frontonasal Ectomesenchyme Programme
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the frontonasal and skull vault consequences of losing TWIST1
      function in cranial neural crest, including the failure to activate the
      ectomesenchyme programme in the frontonasal prominence.
    limitations: >-
      This is a conditional null, not a Glu117 knock-in, so it models loss of
      TWIST1 function rather than the antimorphic allele that causes the human
      disease — precisely the distinction that separates Sweeney-Cox from
      Saethre-Chotzen. Homozygous deletion in the crest lineage is also a more
      severe lesion than the human heterozygous state.
    readouts:
    - name: Snout, upper face and skull vault bone formation
      target: Failure of TWIST1-Dependent Frontonasal Ectomesenchyme Programme
      direction: DECREASED
      interpretation: >-
        Skeletal correlate of the lost ectomesenchyme programme in this model.
      evidence:
      - reference: PMID:19414008
        reference_title: Requirement for Twist1 in frontonasal and skull vault development in the mouse embryo.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Loss of Twist1 in neural crest cells and their derivatives impairs
          skeletogenic differentiation and leads to the loss of bones of the
          snout, upper face and skull vault.
        explanation: Reports the skeletal measurement behind this readout.
    evidence:
    - reference: PMID:41850652
      reference_title: A Twist1-regulated distal enhancer crucial for Alx1 gene expression and function during craniofacial development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        mice with neural crest lineage-specific inactivation of Twist1 resulted in
        dramatic disruption of frontonasal development accompanied by failure of
        activation of many ectomesenchyme genes, including Alx1, Alx3, and Alx4,
        in the FNP
      explanation: >-
        Supports treating the neural-crest conditional knockout as informative
        for the frontonasal ectomesenchyme node.
datasets:
- accession: geo:GSE230316
  title: DNA-guided transcription factor cooperativity shapes face and limb mesenchyme [ChIP-seq]
  description: >-
    ChIP-seq profiling of TWIST1 and homeodomain transcription factor occupancy
    in embryonic face and limb mesenchyme, defining the composite 'Coordinator'
    motif at which TWIST1 binds the E-box half cooperatively with homeodomain
    factors.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: CHIP_SEQ
  sample_count: 200
  publication: PMID:38262408
  notes: >-
    Selected manually from the mechanism literature, not from a gene-name
    dataset search — a TWIST1 accession search returns predominantly cancer EMT
    studies, which are irrelevant here. This dataset maps TWIST1 DNA occupancy
    in exactly the tissue affected in this syndrome, so it bears on the
    consequence of a basic-domain substitution. GEO lists both Homo sapiens and
    Mus musculus for the series; the human organism binding is recorded here.

diagnosis:
- name: Molecular Confirmation of the TWIST1 Codon-117 Variant
  description: >-
    Diagnosis rests on identifying a heterozygous missense substitution at TWIST1
    codon 117. Reporting the gene alone is not enough here, because TWIST1
    variants cause two different diseases by two different mechanisms: a
    loss-of-function allele anywhere in the gene indicates Saethre-Chotzen
    syndrome, whereas a substitution at Glu117 indicates this disorder. The
    report has to name the variant, not just the gene.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:42059179
    reference_title: Evidence-based classification of genes implicated in craniosynostosis disorders using the ClinGen curation framework.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      According to ACMG technical standards, genes classified as Moderate,
      Strong, or Definitive are eligible for inclusion in diagnostic testing
      panels
    explanation: >-
      Carries the practical diagnostic consequence of the Limited classification
      recorded in the genetic section: under ACMG technical standards a Limited
      gene-disease relationship sits below the threshold for panel inclusion, so
      the diagnosis may depend on exome or genome sequencing rather than on a
      craniosynostosis gene panel. Graded INDIRECT because the paper states the
      general standard and the Limited classification separately, and does not
      itself say this disease is absent from panels.
  notes: >-
    The three reported alleles are p.Glu117Val, p.Glu117Gly and p.Glu117Asp, all
    de novo. See the genetic section for the cDNA nomenclature discrepancy
    between the published c.351C>G and ClinVar's c.351G>T for the third.
- name: Abdominal Ultrasound for Asplenia
  description: >-
    Asplenia is an annotated feature of this syndrome and is invisible on the
    craniofacial examination that brings these children to attention, so it has
    to be looked for deliberately. Finding it changes management immediately,
    because it moves the child into lifelong infection prophylaxis.
  diagnosis_term:
    preferred_term: Ultrasound Imaging
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  notes: >-
    Curated without an evidence item, on the same basis as the HPOA-derived
    phenotypes. The asplenia annotation comes from the HPO disease annotation for
    OMIM:617746; no published source recommends abdominal imaging in Sweeney-Cox
    syndrome specifically, so the indication is inferred from the curated
    phenotype and recorded as such rather than attached to a source that does not
    say it.
- name: Craniofacial CT with Three-Dimensional Reconstruction
  description: >-
    Cross-sectional imaging of the craniofacial skeleton defines the frontal-bone
    deficiency and midfacial hypoplasia that the clinical examination can only
    suggest, and establishes whether the sutures are patent. That last point
    carries the differential weight in this syndrome: craniosynostosis is the
    feature that separates Saethre-Chotzen from Sweeney-Cox, and one reported
    Glu117 patient did have bicoronal synostosis, so its presence or absence
    cannot be assumed from the molecular result.
  diagnosis_term:
    preferred_term: Computed Tomography
    term:
      id: NCIT:C17204
      label: Computed Tomography
  notes: >-
    Curated without an evidence item, on the same basis as the abdominal
    ultrasound entry. No source recommends this imaging in Sweeney-Cox syndrome
    specifically; the indication follows from the curated skeletal phenotypes and
    from the craniosynostosis question, and is recorded as inferred rather than
    attached to a source that does not say it.
- name: Ophthalmic Examination
  description: >-
    Assessment of eyelid closure and corneal integrity is the examination that
    decides whether corneal protection is needed and how urgently. It is listed
    separately from the craniofacial assessment because the eyelid phenotype
    carries the preventable-harm risk in this syndrome, and because the finding
    that matters is functional lid closure rather than a structural measurement.
  diagnosis_term:
    preferred_term: Eye Examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  notes: >-
    Curated without an evidence item, on the same basis as the other inferred
    diagnostic entries. The indication follows from the curated eyelid phenotypes
    and from the corneal-protection treatment, both of which are cited; no source
    states an ophthalmic examination schedule for this syndrome.
mechanistic_hypotheses:
- hypothesis_group_id: glu117_interference_dosage_continuum
  hypothesis_label: Graded antimorphism places Sweeney-Cox and Saethre-Chotzen on one continuum
  status: EMERGING
  description: >-
    Under this model the substituting residue at Glu117 sets how strongly the
    mutant subunit interferes with the wild-type pool, and the resulting
    phenotype moves along a continuum rather than falling into one of two
    categories. A conservative substitution such as Glu117Asp interferes weakly
    and behaves closer to haploinsufficiency, which is the reading offered for
    the one patient who had both the Sweeney-Cox facies and bicoronal
    craniosynostosis; stronger substitutions produce the non-synostotic
    frontonasal phenotype, and the C. elegans series ordered all five human
    alleles by severity rather than separating them into classes.

    If correct, the distinction between this entry and Saethre-Chotzen syndrome
    is quantitative, and the craniosynostosis discriminator is a threshold
    effect rather than a categorical feature. The competing model is that the
    two disorders are mechanistically disjoint because the alleles differ in
    kind, not degree. Three patients, one per allele, cannot separate these.
  evidence:
  - reference: PMID:30450715
    reference_title: Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present observation suggests that a localized TWIST1 basic domain
      substitution, that is, p.Glu117Asp, in TWIST1 may exert a mild antimorphic
      effect similar to that of haploinsufficiency, leading to craniosynostosis
      and ablepharon.
    explanation: >-
      Proposes graded antimorphism explicitly, and is the only clinical
      observation bearing on it.
  - reference: PMID:28369379
    reference_title: Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This allelic series revealed that different substitutions exhibit graded
      severity, in terms of both gene expression and cellular phenotype, which we
      incorporate into a model explaining the various human disease phenotypes.
    explanation: >-
      Provides the experimental grading of the same allele set that the
      continuum model rests on.

treatments:
- name: Corneal Protection for Eyelid Coloboma
  therapeutic_modality: DEVICE
  description: >-
    Ocular surface protection is the management step with the clearest
    preventable-harm argument in this syndrome, because the curated eyelid
    phenotypes leave the cornea exposed. Reported practice in large neonatal
    upper eyelid coloboma escalates from lubrication and a moisture chamber to a
    customised scleral contact lens, which can maintain ocular surface health
    long enough for eyelid tissue to grow before oculoplastic reconstruction.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Upper eyelid coloboma
    term:
      id: HP:0000636
      label: Upper eyelid coloboma
  - preferred_term: Ablepharon
    term:
      id: HP:0011224
      label: Ablepharon
  evidence:
  - reference: PMID:34570047
    reference_title: Scleral Contact Lens as Initial Management in a Neonate With a Large Upper Eyelid Coloboma.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After failing lubrication and a moisture chamber, he was fit with a
      customized scleral contact lens that protected the ocular surface. It was
      tolerated well, and ocular surface health was maintained for 13 months to
      permit the growth of eyelid tissue for future oculoplastic surgery.
    explanation: >-
      Documents the escalation of corneal protection in a neonate with large
      upper eyelid coloboma. Graded INDIRECT because it is a single case in
      isolated eyelid coloboma, not in Sweeney-Cox syndrome; it is cited as
      phenotype-directed management for a feature this entry curates, not as
      disease-specific evidence.
  notes: >-
    Phenotype-directed rather than disease-specific. No management literature
    exists for Sweeney-Cox syndrome itself, so this treatment is attached to the
    curated eyelid phenotypes and the cited source is about that phenotype in
    other contexts. Recorded this way instead of borrowed wholesale from
    Saethre-Chotzen care, which is organised around craniosynostosis and does
    not address the eyelid.
- name: Infection Prophylaxis for Asplenia
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Asplenia is an annotated feature of this syndrome and carries lifelong risk
    of fulminant infection with encapsulated organisms. Standard paediatric
    asplenia care is timely vaccination, antibacterial prophylaxis where
    indicated, and urgent evaluation of febrile episodes. This matters
    disproportionately here because asplenia in a child ascertained for a
    craniofacial phenotype can go unrecognised.
  treatment_term:
    preferred_term: Antibiotic Prophylaxis
    term:
      id: NCIT:C51993
      label: Antibiotic Prophylaxis
  target_phenotypes:
  - preferred_term: Asplenia
    term:
      id: HP:0001746
      label: Asplenia
  evidence:
  - reference: PMID:38691084
    reference_title: Updated Recommendations on the Prevention and Treatment of Infections in Children With Asplenia/Hyposplenism.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Current practice focuses on preventing severe infections with timely
      administration of vaccinations, antibacterial prophylaxis when indicated,
      and urgent evaluation and treatment of febrile events.
    explanation: >-
      States the standard of care for children with asplenia. Typed INDIRECT
      because it is a general paediatric asplenia recommendation, not evidence
      about Sweeney-Cox syndrome; it is cited because asplenia is a curated
      phenotype of this entry.
  notes: >-
    Phenotype-directed rather than disease-specific, on the same basis as the
    corneal-protection entry. The asplenia annotation comes from the HPO
    disease annotation for OMIM:617746 and carries no cached quote of its own.
- name: Vaccination Against Encapsulated Organisms
  therapeutic_modality: VACCINE
  description: >-
    In asplenia, vaccination against encapsulated organisms is the cornerstone of
    prevention rather than an adjunct to antibiotics, and the cited recommendation
    names it first. It is curated separately from antibacterial prophylaxis
    because the two are different modalities with different schedules, and
    collapsing them into one treatment would lose that.
  treatment_term:
    preferred_term: Vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
  target_phenotypes:
  - preferred_term: Asplenia
    term:
      id: HP:0001746
      label: Asplenia
  evidence:
  - reference: PMID:38691084
    reference_title: Updated Recommendations on the Prevention and Treatment of Infections in Children With Asplenia/Hyposplenism.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Current practice focuses on preventing severe infections with timely
      administration of vaccinations, antibacterial prophylaxis when indicated,
      and urgent evaluation and treatment of febrile events.
    explanation: >-
      Names timely vaccination first among the preventive measures for children
      with asplenia. Graded INDIRECT because it is a general paediatric asplenia
      recommendation and not evidence about Sweeney-Cox syndrome.
  notes: >-
    Phenotype-directed rather than disease-specific, on the same basis as the
    other two treatments in this entry.

discussions:
- discussion_id: swcos_glu117_allele_specific_model
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does a TWIST1 Glu117 knock-in reproduce the human frontonasal and ablepharon
    phenotype, and does it act through the Alx1 distal enhancer?
  attaches_to:
  - pathophysiology#Failure of TWIST1-Dependent Frontonasal Ectomesenchyme Programme
  rationale: >-
    Every mechanistic model of this disorder is currently an allele mismatch. The
    C. elegans series carries the right substitution but has no craniofacial
    skeleton; the mouse work has the right tissue but uses conditional nulls,
    which model haploinsufficiency-like loss rather than the antimorphic allele.
    The whole clinical point of Sweeney-Cox is that those two lesions give
    different diseases, so no existing model tests the step that actually
    distinguishes it from Saethre-Chotzen. Whether the enhancer route is the one
    a Glu117 allele travels is therefore inference from tissue overlap, not a
    result.
  evidence:
  - reference: PMID:28369379
    reference_title: Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we engineered all five disease-associated alleles into the equivalent
      Glu29 residue encoded by hlh-8, the single Twist homolog present in
      Caenorhabditis elegans
    explanation: >-
      Documents that the only allele-correct model is an invertebrate with no
      craniofacial skeleton, which is the mismatch this discussion records.
  proposed_experiments:
  - experiment_id: swcos_glu117_knockin_mouse
    name: Twist1 Glu117 knock-in mouse with frontonasal enhancer readout
    description: >-
      Generate a mouse carrying the Glu117 substitution at the endogenous locus
      and compare its craniofacial phenotype and Alx1 distal-enhancer activity
      against a Twist1 heterozygous null.
    would_support:
    - pathophysiology#Failure of TWIST1-Dependent Frontonasal Ectomesenchyme Programme
    supporting_outcome:
    - >-
      The knock-in shows frontonasal and periocular defects with reduced Alx1
      enhancer activity, while the heterozygous null does not, separating the
      antimorphic route from simple dosage loss.
    refuting_outcome:
    - >-
      The knock-in phenocopies the heterozygous null, indicating the Glu117
      allele acts by dosage reduction and that the antimorphic model does not
      explain the distinct human phenotype.
- discussion_id: swcos_saethre_chotzen_boundary
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Are Sweeney-Cox and Saethre-Chotzen syndromes disjoint entities or ends of
    one TWIST1 phenotypic spectrum?
  attaches_to:
  - phenotypes#Coronal Craniosynostosis
  - mechanistic_hypotheses#glu117_interference_dosage_continuum
  rationale: >-
    Craniosynostosis is the stated discriminator, but the p.Glu117Asp patient had
    bilateral coronal synostosis alongside the ablepharon and cheek-pad facies,
    and that report argued the conservative Glu-to-Asp change exerts only a mild
    antimorphic effect resembling haploinsufficiency. If severity of antimorphic
    interference is continuous, the discriminator is quantitative rather than
    categorical, and the lump/split status of these two entries depends on which
    it is. With three reported patients there is not enough phenotypic range to
    settle it.
  evidence:
  - reference: PMID:30450715
    reference_title: Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present observation suggests that a localized TWIST1 basic domain
      substitution, that is, p.Glu117Asp, in TWIST1 may exert a mild antimorphic
      effect similar to that of haploinsufficiency, leading to craniosynostosis
      and ablepharon.
    explanation: >-
      States the graded-antimorphism argument that makes the boundary between the
      two syndromes uncertain.
- discussion_id: swcos_no_management_evidence
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is there any Sweeney-Cox-specific management evidence, and does the
    antimorphic mechanism change care relative to Saethre-Chotzen syndrome?
  attaches_to:
  - treatments#
  rationale: >-
    Both curated treatments are phenotype-directed, not disease-directed: they
    cite sources about eyelid coloboma and about paediatric asplenia in general,
    because with three reported patients there is no series, no surgical
    protocol and no ophthalmological guidance for this syndrome. Nothing here
    tells a clinician whether the timing or escalation of corneal protection
    should differ in a child whose eyelid defect is part of a TWIST1
    developmental lesion. Borrowing the rest of craniofacial management from
    Saethre-Chotzen would be unsound in the respect that matters: that care is
    organised around craniosynostosis, which is not a cardinal feature here.
- discussion_id: swcos_allelic_ascertainment_bias
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Do the three reported patients represent the survivable tail of the Glu117
    allelic series, with more severe substitutions going unascertained?
  attaches_to:
  - pathophysiology#TWIST1 Glu117 Basic-Domain Substitution
  - prevalence#Worldwide
  rationale: >-
    The C. elegans series showed graded severity across substitutions at this
    residue, and the clinical literature explicitly raises lethality as an
    alternative outcome of substituting Glu117. If some substitutions are
    embryonic-lethal or lethal in the neonatal period, the reported phenotype is
    conditioned on survival and the three living patients are a biased sample.
    This matters for two curated claims at once: the severity range recorded in
    the phenotypes section, and the case count recorded under prevalence, which
    is also the constraint behind ClinGen's Limited gene-disease classification.
    Prenatal or perinatal-loss sequencing series covering TWIST1 would be the
    way to test it; nothing of the sort has been reported.
  evidence:
  - reference: PMID:30450715
    reference_title: Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This suggests that any amino acid substitutions at Glu117 would likely lead
      to the Sweeney-Cox syndrome phenotype or lethality.
    explanation: >-
      Raises lethality as an outcome of substitution at this codon, which is the
      ascertainment concern recorded here.
  - reference: PMID:28369379
    reference_title: Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This allelic series revealed that different substitutions exhibit graded
      severity, in terms of both gene expression and cellular phenotype, which we
      incorporate into a model explaining the various human disease phenotypes.
    explanation: >-
      Establishes that severity varies by substituting residue, which is what
      makes a lethal tail plausible.
  notes: >-
    Ascertainment cuts differently from evidence availability, and the two should
    not be confused. The malformation list itself is curated: 46 features come
    from the HPO disease annotation for OMIM:617746, which records each as a
    count out of the two index subjects. What that annotation cannot say is
    whether those two subjects, plus the later Glu117Asp patient, span the
    phenotype of Glu117 substitution or only its survivable part. A feature
    absent from a two-patient annotation may be genuinely rare, or may belong to
    a substitution that was never ascertained.
📚

References & Deep Research

Deep Research

1
Claude Code ▸
Sweeney–Cox Syndrome (SWCOS) — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-opus-5[1m] 25 citations 2026-08-28T22:38:48.925362

Sweeney–Cox Syndrome (SWCOS) — Comprehensive Research Report

Prepared: 2026-08-28 · Target: MONDO:0060592 · Category: Mendelian, autosomal dominant, craniofacial dysostosis/frontonasal dysplasia spectrum

Evidence-quality preamble (read first)

Sweeney–Cox syndrome is an ultra-rare, recently delineated entity with a total published cohort of three individuals. This dominates every section below. Two important consequences for knowledge-base curation:

  1. Nearly every phenotype frequency is 1/2 or 2/2, derived from the two index patients in Kim et al. 2017. These are not population frequencies and must not be curated as if they were.
  2. ClinGen's Craniofacial Malformations GCEP classified the TWIST1–Sweeney-Cox syndrome gene–disease relationship as Limited (3–4 points) in its 2026 round-one curation — the weakest of its three TWIST1 assertions. This is the single most important recent development for this entry and is stated verbatim below.

Throughout, I distinguish: - [CACHED] — quote verified against a file already in references_cache/ (usable as a dismech evidence snippet: as-is). - [WEB] — retrieved from a database or full text online during this session; the claim is sound but the exact string has not been verified against a fetched reference cache file and must be re-fetched with just fetch-reference before being quoted. - [UNVERIFIED] — flagged inference or a detail I could not independently confirm.

1. Disease Information

Overview

Sweeney–Cox syndrome (SWCOS) is an autosomal dominant congenital craniofacial dysostosis caused by de novo heterozygous missense substitution of a single highly conserved glutamic acid residue — Glu117 — in the basic DNA-binding domain of TWIST1. It sits at the frontonasal-dysplasia end of the TWIST1 phenotypic spectrum: patients have severe hypertelorism, deficient formation of the bony orbits and eyelids (upper eyelid colobomas, pseudoproptosis), nasal and midfacial hypoplasia, dysplastic ears, and a variable set of extracranial malformations. It is mechanistically and clinically distinct from Saethre–Chotzen syndrome (SCS), the classical TWIST1 haploinsufficiency disorder characterized by coronal craniosynostosis.

The disease was named for the two clinicians who contributed the index patients — E. Sweeney and H. Cox, both co-authors on the delineating paper.

Delineating publication:

"Here, we describe a new clinical entity, Sweeney-Cox syndrome, associated with distinct de novo amino acid substitutions (p.Glu117Val and p.Glu117Gly) at a highly conserved glutamic acid residue located in the basic DNA binding domain of TWIST1, in two subjects with frontonasal dysplasia and additional malformations." — Kim S, Twigg SRF, Scanlon VA, et al. Hum Mol Genet 2017;26(11):2118–2132. PMID:28369379, DOI 10.1093/hmg/ddx107 [CACHED]

Key identifiers

Resource Identifier
MONDO MONDO:0060592 (label: "Sweeney-Cox syndrome"; related synonym "SWCOS") [WEB — OLS4]
OMIM #617746 SWEENEY-COX SYNDROME; SWCOS
Gene (OMIM) *601622 TWIST1
Disease Ontology DOID:0080538
UMLS / MedGen C4540299
Orphanet No dedicated ORPHA code identified. Repeated searches of Orphanet and the ORDO branch of OLS returned no Sweeney-Cox term. Orphanet lists TWIST1 under Saethre–Chotzen syndrome (ORPHA:794) and related craniosynostoses. Treat "no ORPHA code" as the working assumption but re-verify against a current Orphadata refresh before asserting it in the KB.
ICD-10 No specific code. Closest: Q75.8 (other specified congenital malformations of skull and face bones) or Q87.0 (congenital malformation syndromes predominantly affecting facial appearance).
ICD-11 No specific code. Closest: LB70 (structural developmental anomalies of the face) / LD24.5 region.
MeSH No specific descriptor. Indexed under Abnormalities, Multiple; Acrocephalosyndactylia; Eye Abnormalities; Macrostomia per the PubMed record for PMID:28369379 [CACHED — see keywords block]
ZFIN human disease term ZDB-TERM-190716-1 (no zebrafish models registered) [WEB]
GTR condition C4540299 — 7 clinical tests listed, all TWIST1-based [WEB]

Synonyms and alternative names

  • SWCOS (OMIM abbreviation)
  • TWIST1-related Sweeney-Cox syndrome (ClinGen dyadic naming convention, used in Genet Med 2026)
  • Descriptively referenced in the literature as "TWIST1 basic-domain (Glu117) frontonasal dysplasia" — not a formal synonym.
  • Do not use "frontonasal dysplasia type 4" or similar — FND1/2/3 are the ALX3/ALX4/ALX1 entities and are distinct.

Source of information

Entirely aggregated disease-level and case-report literature. There is no EHR-derived cohort, no registry, no natural-history study, and no patient organization. All human phenotype data trace to three published individuals. HPO annotations for OMIM:617746 cite PMID:28369379 exclusively for every term [WEB — HPO/ontology.jax.org API].

2. Etiology

Primary causal factor

A single heterozygous de novo missense substitution at TWIST1 codon 117 (NM_000474.4), replacing a glutamic acid that makes base-specific contacts with the E-box DNA motif. No environmental, infectious, or multifactorial contribution is described or plausible.

Reported causal alleles (all three published patients):

cDNA (NM_000474.4) Protein Patient Phenotype Source
c.350A>T p.(Glu117Val) Kim 2017, Subject 1 (male) SWCOS, no craniosynostosis PMID:28369379
c.350A>G p.(Glu117Gly) Kim 2017, Subject 2 (female) SWCOS, more severe PMID:28369379
c.351G>T p.(Glu117Asp) Takenouchi 2018 (male infant) SWCOS facial phenotype + bicoronal craniosynostosis + ablepharon PMID:30450715 / ClinVar VCV002572412

⚠️ Nomenclature discrepancy worth flagging. The Takenouchi abstract states "c.351C>G p.Glu117Asp" [CACHED], but ClinVar represents the same protein change as c.351G>T (VCV002572412) [WEB]. The ClinVar representation is internally consistent (GAG→GAT); the published c.351C>G cannot yield Asp from a Glu codon under NM_000474.4. Per repo policy, never alter an identifier inside an evidence snippet — quote the paper as published and record the reconciliation in notes:.

Genetic risk factors

  • Causal variant class: ultra-localized missense hotspot. Of ~100 TWIST1 mutations reported in SCS, none previously affected codon 117 [CACHED, PMID:28369379].
  • Susceptibility loci / modifier genes: none identified. Sample size (n=3) precludes any modifier analysis.
  • Family history: all three cases de novo; unaffected parents.
  • Parental age effect: not assessed (n=3).

Environmental risk factors

None described. No toxin, teratogen, occupational, dietary, or infectious association has been reported or proposed. Sex distribution in the published cohort is 2 male : 1 female — not interpretable at this n.

Protective factors

None known. No protective variants, modifier alleles, or environmental exposures have been described. gnomAD does not report the Glu117 substitutions (consistent with de novo, fully penetrant severe disease) [UNVERIFIED — should be checked directly at gnomad.broadinstitute.org before curating as an allele-frequency claim].

Gene–environment interactions

Not applicable / none reported. This is a fully penetrant de novo dominant developmental disorder with no evidence of environmental modulation.

3. Phenotypes

The authoritative annotation set

The HPO disease annotation for OMIM:617746 contains 48 phenotype terms plus inheritance and clinical-course terms, all sourced to PMID:28369379, all with frequencies expressed as fractions of the two index patients [WEB — ontology.jax.org/api/network/annotation/OMIM:617746]. Reproduced in full below, since this is directly loadable into a dismech phenotypes: block.

Head and neck — craniofacial (the diagnostic core)

HP ID Term Freq
HP:0000316 Hypertelorism 2/2
HP:0000636 Upper eyelid coloboma 2/2
HP:0005487 Prominent metopic ridge 2/2
HP:0000455 Broad nasal tip 2/2
HP:0011800 Midface retrusion 1/2
HP:0000430 Underdeveloped nasal alae 1/2
HP:0002000 Short columella 1/2
HP:0009765 Low hanging columella 1/2
HP:0000431 Wide nasal bridge 1/2
HP:0000453 Choanal atresia 1/2
HP:0000322 Short philtrum 1/2
HP:0000160 Narrow mouth 1/2
HP:0000218 High palate 1/2
HP:0009099 Median cleft palate 1/2
HP:0000220 Velopharyngeal insufficiency 1/2
HP:0000347 Micrognathia 1/2
HP:0000248 Brachycephaly 1/2
HP:0005469 Flat occiput 1/2
HP:0000260 Wide anterior fontanel 1/2
HP:0000349 Widow's peak 1/2
HP:0000294 Low anterior hairline 1/2
HP:0000475 Broad neck 1/2

Ear

HP ID Term Freq
HP:0000378 Cupped ear 1/2
HP:0000369 Low-set ears 1/2
HP:0009901 Crumpled ear 1/2
HP:0008551 Microtia 1/2
HP:0000396 Overfolded helix 1/2
HP:0009909 Uplifted earlobe 1/2
HP:0000365 Hearing impairment 1/2 (conductive in Subject 1)

Eye

HP ID Term Freq
HP:0000316 Hypertelorism 2/2

Note: pseudoproptosis (secondary to deficient bony orbits, accentuated by midface hypoplasia) is described in OMIM's clinical synopsis and the Arizona Hereditary Ocular Diseases entry but is not in the HPO annotation set [WEB]. Consider HP:0000520 Proptosis with an explanatory description making clear it is pseudoproptosis of orbital-volume origin, or leave unbound with prose — the mechanistic distinction matters and no HPO term captures it cleanly.

Nervous system

HP ID Term Freq
HP:0001263 Global developmental delay 2/2
HP:0000750 Delayed speech and language development 1/2
HP:0001321 Cerebellar hypoplasia 1/2

Limbs and skeletal

HP ID Term Freq
HP:0100807 Long fingers 1/2
HP:0009882 Short distal phalanx of finger 1/2
HP:0010709 2-4 finger cutaneous syndactyly 1/2
HP:0005650 2-5 finger cutaneous syndactyly 1/2
HP:0010715 2-5 toe syndactyly 1/2
HP:0001776 Bilateral talipes equinovarus 1/2
HP:0000894 Short clavicles 1/2
HP:0000774 Narrow chest 1/2

Cardiovascular / haematologic

HP ID Term Freq
HP:0001655 Patent foramen ovale 1/2
HP:0001643 Patent ductus arteriosus 1/2
HP:0001746 Asplenia 1/2

Digestive / genitourinary

HP ID Term Freq
HP:0002023 Anal atresia (imperforate anus) 1/2
HP:0002020 Gastroesophageal reflux 1/2
HP:0008689 Bilateral cryptorchidism 1/1 (male only)

Skin, hair, nails / prenatal

HP ID Term Freq
HP:0002230 Generalized hirsutism 1/2
HP:0001792 Small nail 1/2
HP:0001561 Polyhydramnios 1/2

Course and inheritance

HP ID Term
HP:0003577 Congenital onset (2/2)
HP:0000006 Autosomal dominant inheritance

Phenotypes reported in the third patient (Takenouchi 2018) — NOT in the HPO annotation set

The p.Glu117Asp patient extends the phenotype and is the key to the SWCOS↔SCS boundary:

"Herein, we document a male infant with the distinctive facial features of ablepharon, hypertelorism, cheek pads adjacent to the corners of the mouth, and bilateral coronal suture craniosynostosis who had a de novo heterozygous mutation in the basic domain of TWIST1, that is, c.351C>G p.Glu117Asp." — PMID:30450715 [CACHED]

Additional HP suggestions for this patient (verify all with just validate-terms / OAK before binding): - HP:0004440 Coronal craniosynostosis [UNVERIFIED ID] - HP:0001363 Craniosynostosis (parent term, safer) - Ablepharon — no confident HPO ID; HP:0000636 Upper eyelid coloboma understates it. Consider free-text preferred_term with no term: binding rather than manufacturing a match (per the repo's "no term beats a bad one" rule). - Cheek pads adjacent to the corners of the mouth — shared with Barber–Say and ablepharon–macrostomia syndromes; no clean HPO term. Free text recommended.

Phenotype characteristics

  • Age of onset: congenital in 3/3 (HP:0003577). Malformations are established during embryonic craniofacial morphogenesis (~weeks 4–8); the phenotype is fully expressed at birth.
  • Severity: variable but uniformly severe facially. Subject 2 (p.Glu117Gly) was markedly more severe than Subject 1 (p.Glu117Val): she required tracheostomy from birth, had cardiac defects, asplenia, and progressed to corneal scarring with phthisis of the right eye despite lid coloboma repair [WEB — PMC5438873; Arizona HOD].
  • Progression: the malformation burden is static/non-progressive — it is a structural dysostosis, not a degenerative process. What does progress is secondary/complication morbidity: corneal exposure keratopathy → scarring → phthisis bulbi; conductive hearing loss; feeding/airway compromise; and, in the E117D patient, craniosynostosis with its attendant risk of raised intracranial pressure.
  • Frequency among affected: see tables. Facial features (hypertelorism, upper eyelid coloboma, prominent metopic ridge, broad nasal tip) and global developmental delay are 2/2; everything else is 1/2.

Quality-of-life impact

No formal QoL instrument (EQ-5D, PROMIS, SF-36) has ever been administered. Per-phenotype impacts inferred from the case descriptions [WEB]:

Phenotype Functional impact
Upper eyelid coloboma / ablepharon Corneal exposure → keratopathy, scarring, vision loss (documented phthisis in Subject 2)
Velopharyngeal insufficiency / cleft palate Speech intelligibility, feeding, need for surgery
Choanal atresia / airway compromise Tracheostomy dependence (Subject 2)
Conductive hearing loss + microtia Language acquisition, amplification need
Global developmental delay Moderate learning disability documented in Subject 1; educational support
Syndactyly, talipes equinovarus, short distal phalanges Hand function, ambulation, orthopaedic surgery
Facial dysmorphism Psychosocial burden, repeated reconstructive surgery
Imperforate anus Neonatal surgery, continence

4. Genetic / Molecular Information

Causal gene

Field Value
Symbol TWIST1
Approved name twist family bHLH transcription factor 1
HGNC hgnc:12428 (lowercase prefix per repo convention) [WEB — rest.genenames.org]
Cytoband 7p21.1
Ensembl ENSG00000122691
NCBI Gene 7291
UniProt Q15672 (202 aa)
OMIM gene *601622
Reference transcript NM_000474.4
Aliases (GTR) ACS3, BPES2, BPES3, CRS, SCS, bHLHa38

Protein architecture and the Glu117 hotspot

  • bHLH domain: residues 108–159 (UniProt Q15672 FT DOMAIN) [WEB].
  • Residues 1–105: disordered; residues 161–191: sufficient for transactivation [WEB].
  • Glu117 lies within the basic (DNA-contacting) region at the N-terminal end of the bHLH fold. Sequence context around it (positions 111–120): V M A N V R E R Q R — i.e. E117 flanked by the basic arginines R116/R118/R120. (R120G is an independently reported pathogenic SCS/craniosynostosis allele, ClinVar VCV001474221 [WEB] — underlining that this short stretch is a mutational hotspot for two mechanistically different diseases.)
  • Functional role of the conserved glutamate: it makes the sequence-specific base contacts that define E-box recognition:

"is responsible for the sequence-specific contacts of adjacent bases (CA) that constitute the symmetrical E box binding motif CANNTG" — Kim et al. 2017 full text [WEB — PMC5438873]

  • Structural resource: PDB 8OSB — "TWIST1-TCF4-ALX4 complex on specific DNA", X-ray, 2.90 Å, residues 101–167 [WEB — UniProt/RCSB]. This is the directly relevant structure for modelling the Glu117 substitutions, and it captures TWIST1 in the ternary arrangement that the Coordinator-motif biology (§6) predicts.

Variant classification and population frequency

ClinVar records at codon 117 and immediate neighbours [WEB — NCBI E-utilities]:

VCV HGVS Protein Classification Review status Condition
VCV000444875 c.350A>T p.Glu117Val Pathogenic no assertion criteria provided Sweeney-Cox syndrome
VCV000444876 c.350A>G p.Glu117Gly Pathogenic criteria provided, single submitter TWIST1-related craniosynostosis; Saethre-Chotzen syndrome
VCV002572412 c.351G>T p.Glu117Asp Pathogenic criteria provided, single submitter Sweeney-Cox syndrome
VCV001418275 c.349G>T p.Glu117Ter Pathogenic criteria provided, single submitter TWIST1-related craniosynostosis; SCS
VCV001474221 c.358C>G p.Arg120Gly Pathogenic/Likely pathogenic multiple submitters, no conflicts SCS; TWIST1-related craniosynostosis

Two curation-relevant observations: 1. p.Glu117Ter (nonsense) is annotated to Saethre–Chotzen/craniosynostosis, not Sweeney-Cox — exactly as the mechanism predicts. Truncation at 117 = loss of allele = haploinsufficiency = SCS. Missense at 117 = poisoned protein = SWCOS. The same codon produces two different diseases by two different mechanisms. This is a clean, curatable mechanistic contrast. 2. ClinVar's condition assignment is inconsistent — p.Glu117Gly, one of the two original SWCOS alleles, is filed under "TWIST1-related craniosynostosis; Saethre-Chotzen syndrome." Do not treat ClinVar's condition field as authoritative for SWCOS membership; use the primary literature.

  • Variant type: all missense (single-nucleotide substitution).
  • Origin: germline, de novo in 3/3. No somatic involvement; no mosaicism reported.
  • Allele frequency: absent from population databases (expected for de novo severe dominant disease) [UNVERIFIED — confirm in gnomAD directly].

Functional consequence — the central mechanistic claim

Antimorphic (dominant-negative), not loss-of-function. This is the defining molecular statement about the disease and it is asserted independently in two cached papers:

"The genetic analysis favors a predominantly dominant-negative mechanism for the action of amino acid substitutions at this highly conserved glutamic acid residue" — PMID:28369379 [CACHED]

"Heterozygous localized TWIST1 and TWIST2 basic domain substitutions exert antimorphic effects to cause Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia syndrome, respectively." — PMID:30450715 [CACHED]

For dismech schema purposes: - On GeneticContext: functional_impact_category: DOMINANT_NEGATIVE — this is the variant-consequence slot and it is the right one here. - Do not use LOSS_OF_FUNCTION; that is the SCS mechanism and conflating them erases the whole point of the entity.

Modifier genes

None identified. Candidate modifiers on mechanistic grounds only (no human data): TCF12 (HGNC:11623, the obligate E-protein partner, itself a coronal craniosynostosis gene), TCF3/E12, HAND2, and the homeodomain Coordinator partners ALX1, ALX4, MSX1, PRRX1. All speculative — do not curate as modifiers.

Epigenetic information

No disease-specific DNA-methylation, histone, or chromatin dataset exists for SWCOS patients. However, TWIST1's own molecular action is chromatin-level: it drives chromatin opening and H3K27 acetylation at Coordinator-motif enhancers in cranial neural crest cells (§6). A Glu117 substitution is therefore expected to produce a genome-wide enhancer-accessibility defect in CNCCs — a testable and completely unexplored hypothesis, and a good candidate for a KNOWLEDGE_GAP discussion in the entry.

Chromosomal abnormalities

Not a mechanism for SWCOS. Note for differential purposes: 7p21 deletions encompassing TWIST1 cause SCS (haploinsufficiency), and a 430 kb duplication involving TWIST1 regulatory elements causes auriculocondylar syndrome [WEB — PMC9411924]. Neither produces the SWCOS phenotype, again because SWCOS requires a poisoned protein, not altered dosage.

5. Environmental Information

  • Environmental factors: none. No toxicological, radiation, pollution, or occupational association reported. CTD contains no SWCOS-specific chemical–disease association.
  • Lifestyle factors: none. No maternal smoking, alcohol, folate, or nutritional association has been reported or investigated (n=3 precludes it).
  • Infectious agents: not applicable.

Curation guidance: the environmental: section should be left empty, or, if a curator wishes to record that the search was performed, use the sanctioned waiver form — review_notes: beginning exactly Left deliberately uncited. followed by ≥20 words describing the searches run (CTD, PubMed teratogen queries, EPA) and why nothing quotable was found.

6. Mechanism / Pathophysiology

This is the richest section of the entry and where SWCOS earns its place in a mechanism knowledge base. The causal chain is unusually well-supported for an n=3 disease because the gene is deeply studied even though the disease is not.

6.1 The causal chain (upstream → downstream)

[1] De novo heterozygous TWIST1 c.350A>T / c.350A>G / c.351G>T
↓  (MOLECULAR)
[2] Glu117 substitution in the bHLH basic region
↓  (MOLECULAR)
[3] Loss/degradation of sequence-specific E-box (CANNTG) recognition,
    with RETAINED dimerization and residual DNA binding
↓  (MOLECULAR)
[4] Mutant protein sequesters wild-type TWIST1 and E-proteins (TCF3/TCF12)
    into NON-PRODUCTIVE heterodimers  →  DOMINANT-NEGATIVE
↓  (MOLECULAR)
[5] Failure of TWIST1-dependent Coordinator-motif enhancer activation
    (chromatin opening + H3K27ac) in cranial neural crest cells
↓  (CELLULAR)
[6] Failure to activate the frontonasal ectomesenchyme program —
    ALX1, ALX3, ALX4 not induced in the frontonasal prominence
↓  (CELLULAR)
[7] Impaired CNCC EMT, migration, survival, and skeletogenic differentiation
↓  (TISSUE)
[8] Deficient frontonasal / periocular / orbital / nasal skeletal
    and soft-tissue morphogenesis
↓  (ORGANISM)
[9] Hypertelorism, deficient bony orbits with pseudoproptosis, eyelid
    colobomas, nasal hypoplasia, cleft palate/VPI, dysplastic ears

A parallel branch, dose-dependent, explains why one allele adds craniosynostosis:

[3'] Milder antimorphic effect (p.Glu117Asp)  →  net activity close to
     the haploinsufficient (SCS) range  →  coronal suture boundary
     failure  →  bicoronal craniosynostosis IN ADDITION to the
     SWCOS facial phenotype

"The present observation suggests that a localized TWIST1 basic domain substitution, that is, p.Glu117Asp, in TWIST1 may exert a mild antimorphic effect similar to that of haploinsufficiency, leading to craniosynostosis and ablepharon." — PMID:30450715 [CACHED]

6.2 The dosage-continuum model (the key conceptual contribution)

Kim et al. propose that TWIST1/TWIST2 basic-domain phenotypes lie on a single continuum of residual protein activity, and that the identity of the substituting amino acid sets the position on that continuum:

"phenotypes of individuals who are heterozygous for TWIST1 or TWIST2 mutations fall on a continuum" — correlating with protein activity levels; SWCOS alleles produce more severe dominant-negative effects than haploinsufficient SCS mutations, potentially reducing functional protein below the threshold required for neural crest survival [WEB — PMC5438873]

This makes SWCOS a textbook allelic-series / threshold disorder and is worth modelling explicitly as a mechanistic_hypotheses group in the dismech entry.

Gene Residue Substitution Disease Position on activity continuum
TWIST1 Glu117 Ter (nonsense) Saethre–Chotzen 50% (haploinsufficiency)
TWIST1 Glu117 Asp SWCOS + craniosynostosis mild antimorph ≈ haploinsufficiency
TWIST1 Glu117 Val Sweeney–Cox strong antimorph
TWIST1 Glu117 Gly Sweeney–Cox (severe) strong antimorph
TWIST2 Glu75 Ala / Gln Barber–Say antimorph
TWIST2 Glu75 Lys Ablepharon–macrostomia most severe antimorph

The TWIST2 comparison is from Marchegiani et al., Am J Hum Genet 2015, PMID:26119818: AMS = p.Glu75Lys; BSS = p.Glu75Gln or p.Glu75Ala; "the two syndromes differed based solely upon the nature of the substituting amino acid" [WEB].

6.3 Molecular pathways and protein dysfunction

TWIST1 normal function (UniProt Q15672):

"Efficient DNA binding requires dimerization with another bHLH protein. Homodimer or heterodimer with E proteins such as TCF3." … "Regulates cranial suture patterning and fusion." [WEB]

Why a basic-domain missense is worse than a null. The mutant retains its HLH dimerization surface but has a corrupted DNA-reading head. It therefore continues to titrate the limited pool of wild-type TWIST1 and E-proteins into complexes that occupy or fail at target enhancers:

mutant proteins likely "sequester WT protein in non-productive heterodimers comprising either HLH-2/HLH-8-Glu29† or HLH-8/HLH-8-Glu29†" [WEB — PMC5438873]

The Coordinator motif — the highest-resolution account of what Glu117 actually does. Bhatt/Kim et al., Cell 2024 (PMID:38262408) showed that a composite DNA element called the Coordinator — an E-box plus a homeodomain TAAT site separated by a 6-bp spacer — "guides cooperative and selective binding between the bHLH family mesenchymal regulator TWIST1 and a collective of HD factors" [WEB]. Mechanistically:

TWIST1 binds the E-box, drives chromatin opening, promotes homeodomain recruitment of ALX1, ALX4, MSX1 or PRRX1, and promotes enhancer acetylation at the coordinator motif [WEB]

Because Glu117 is precisely the residue that reads the E-box half of the Coordinator, a Glu117 substitution should collapse the entire cooperative assembly, not merely weaken one contact. This provides a direct, structure-anchored explanation for the frontonasal specificity of SWCOS, and PDB 8OSB (TWIST1–TCF4–ALX4 on DNA) is the corresponding structure.

Direct downstream target — Alx1. A 2026 paper (already in the local reference cache) closes the loop from TWIST1 to the frontonasal-dysplasia gene program:

"ECR1, whose homologous region in the human genome harbors a lead single nucleotide variation significantly associated with facial and cranial vault shape differences, exhibits high enrichment of Twist1 transcription factor occupancy in mouse embryonic frontonasal tissues and drove Twist1-dependent reporter transgene expression specifically in the developing periocular and frontonasal mesenchyme in transgenic mice." — Huang Y, Iyyanar PPR, Xu J, et al. Dev Biol 2026. PMID:41850652 [CACHED]

and, framing SWCOS explicitly:

"Mutations in TWIST1 have been associated with Sweeney-Cox (OMIM 617746) and Saethre-Chotzen (OMIM 101400) syndromes, with Sweeney-Cox syndrome characterized by hypertelorism with severe deficiency in frontal bones and hypoplasia of the nose and facial bones while Saethre-Chotzen syndrome exhibits craniosynostosis with hypertelorism and maxillary hypoplasia" — PMID:41850652 [CACHED]

"mice with lineage-specific inactivation of Twist1 in migrating neural crest cells, exhibited dramatic loss of Alx1 mRNA expression in the developing frontonasal CNCCs" — PMID:41850652 [CACHED]

This is the mechanistic bridge that makes SWCOS a frontonasal dysplasia: biallelic ALX1 loss causes FND3 (OMIM 613456) with severe midfacial hypoplasia and extreme microphthalmia; TWIST1 sits directly upstream of ALX1 through the ECR1 enhancer; so a dominant-negative TWIST1 phenocopies part of the ALX program. Curate this as an explicit causal edge.

Dimer-selection / phosphorylation axis (SCS-derived, mechanistically adjacent). Twist1–Hand2 dimer choice is modulated by PKA and PP2A phosphorylation of conserved helix-I residues, and multiple SCS-associated TWIST1 mutations alter this [WEB — PMC2568820, Firulli et al.]. Glu117 is in the basic region rather than the helices, so this is a different route to the same "dimer misallocation" endpoint — worth noting but do not conflate.

6.4 Cellular processes

Process GO suggestion Evidence
Neural crest cell migration GO:0001755 Twist1 cKO CNCCs show ~50% fewer migratory cells and 68% shorter migration distance [CACHED, PMID:35781329]
Epithelial-to-mesenchymal transition GO:0001837 Twist1-null delaminated CNCCs retain E-cadherin and epithelial morphology [CACHED, PMID:35781329]
Neural crest cell differentiation GO:0014033 Loss of skeletogenic differentiation [CACHED, PMID:19414008]
Cranial suture morphogenesis GO:0060363 UniProt: "Regulates cranial suture patterning and fusion" [WEB]
Osteoblast differentiation GO:0001649 TWIST1–RUNX2 antagonism via the Twist-box [WEB]
Regulation of transcription by RNA Pol II GO:0006357 core TWIST1 function
E-box binding GO:0070888 the directly disrupted molecular function — this is the node Glu117 hits
Protein dimerization activity GO:0046983 retained in mutant; the basis of the dominant-negative effect
Neural tube closure GO:0001843 Twist1-null embryos show complete NTD [CACHED, PMID:35781329]

The critical modelling insight: GO:0070888 E-box binding is DECREASED/LOSS_OF_FUNCTION while GO:0046983 protein dimerization activity is UNCHANGED. That dissociation is the disease mechanism, and a well-built dismech entry should make it visible as two separate molecular_functions descriptors on the same or adjacent nodes.

Direct quotes available for CNCC biology:

"Twist1 suppresses Irf6 and other epithelial genes in CNCCs during the epithelial-to-mesenchymal transition (EMT) process and cell migration. Conversely, a loss of Twist1 leads to a sustained expression of epithelial and cell adhesion markers in migratory CNCCs." — Bertol JW, et al. Development 2022. PMID:35781329 [CACHED]

"TWIST1 has been shown to promote cell survival and proliferation of migratory CNCCs during craniofacial development" — PMID:35781329 [CACHED]

"Loss of Twist1 in neural crest cells and their derivatives impairs skeletogenic differentiation and leads to the loss of bones of the snout, upper face and skull vault." — Bildsoe H, et al. Dev Biol 2009. PMID:19414008 [CACHED]

6.5 Systems not involved

  • Metabolic changes: none. Not a metabolic disease; no enzyme deficiency, no biochemical marker.
  • Immune system involvement: none, despite TWIST1's known repression of TNF/IL1B in other contexts (UniProt) — no immunologic phenotype has been reported in any SWCOS patient. Note the 1/2 asplenia: this is a structural developmental defect (laterality/mesoderm-derived organ agenesis), and it does carry a real functional-asplenia infection risk (see §11/§13), but it is not evidence of a primary immune mechanism.
  • Tissue damage mechanisms: SWCOS is a dysmorphogenesis, not a tissue-injury disease. There is no oxidative stress, ischemia, fibrosis, or necrosis component. The only genuine "tissue damage" is secondary corneal exposure injury from the eyelid defect (documented: corneal scarring → phthisis bulbi).
  • Biochemical abnormalities: none. No diagnostic lab abnormality exists.

6.6 Molecular profiling

No SWCOS-patient omics data exist — no transcriptomics, proteomics, metabolomics, lipidomics, or single-cell data from any of the three patients.

Relevant gene-level datasets that could be re-used with clear labelling as model/normal-development data (not patient data), all GEO [WEB, via PMID:41850652]:

Accession Content
GSE230316 Twist1 ChIP-seq, E10.5 mouse embryonic facial tissue
GSE89435 / GSE89436 H3K27ac ChIP-seq + ATAC-seq, E10.5 mouse frontonasal prominence

⚠️ Dataset-curation caution. Per the repo's dataset SOP, these are not Sweeney-Cox datasets. A gene-driven search for TWIST1 returns craniosynostosis, EMT, and cancer datasets — classic GENE_ONLY / Named Entity Confusion territory. If curated at all, they must be tagged as mouse developmental resources with explicit provenance notes, never as disease datasets. Run just verify-datasets on anything added.

Functional genomics / dosage. A 2025 Cell Genomics study examined "how concentrations of the dosage-sensitive TFs TWIST1 and SOX9 affect regulatory element chromatin accessibility in facial progenitor cells" (PMID:40020686) [WEB] — directly relevant to the threshold model in §6.2 and the best available quantitative handle on TWIST1 dose-response.

7. Anatomical Structures Affected

Organ level

Primary (2/2 or 3/3 involvement): - Craniofacial skeleton — frontal bones, bony orbits (deficient, producing pseudoproptosis), nasal bones/capsule, maxilla, palate - Eyelids — upper lid colobomas; ablepharon in the E117D patient - Nose — hypoplastic alae, short/low columella, broad tip - External ear — microtia, crumpled/cupped, low-set, overfolded helix - Palate / velopharynx

Secondary and variable (1/2): - CNS — cerebellar hypoplasia; global developmental delay in 2/2 - Cardiovascular — PDA, PFO - Spleen — asplenia - GI — anal atresia, GERD - GU — bilateral cryptorchidism - Limbs — hands (syndactyly, long fingers, short distal phalanges), feet (talipes equinovarus, 2-5 toe syndactyly) - Thorax — narrow chest, short clavicles - Airway — choanal atresia; tracheostomy dependence

Body systems: skeletal (craniofacial predominant), visual/ocular adnexal, auditory, nervous, cardiovascular, digestive, genitourinary, lymphoid/splenic, respiratory (upper airway).

Tissue and cell level

The single defining cell type is the cranial neural crest cell and its ectomesenchymal derivatives. Bildsoe et al. showed the requirement is not uniform across derivatives:

"Since Twist1 is expressed in the tissues of the maxillary eminence and the mandibular arch, this finding suggests that the requirement for Twist1 is not the same in all neural crest derivatives." — PMID:19414008 [CACHED]

And a non-cell-autonomous component reaches mesoderm-derived bone:

"The effect of the loss of Twist1 function is not restricted to neural crest-derived bones, since the predominantly mesoderm-derived parietal and interparietal bones are also affected, presumably as a consequence of lost interactions with neural crest-derived tissues." — PMID:19414008 [CACHED]

CL suggestions (verify every one with just validate-terms before binding):

CL Term Role
CL:0000333 migratory cranial neural crest cell primary affected cell type
CL:0000134 mesenchymal stem cell ectomesenchyme
CL:0000062 osteoblast skeletogenic differentiation failure
CL:0000138 chondrocyte nasal/orbital cartilage
CL:0000057 fibroblast craniofacial mesenchyme

Tissue types: neural crest–derived ectomesenchyme (connective/skeletal), membranous bone, cartilage, and — for the eyelid — surface ectoderm-derived structures whose development depends on the underlying mesenchyme.

Subcellular level

  • GO:0005634 nucleus — normal site of TWIST1 action; where the dominant-negative complexes form.
  • GO:0090575 RNA polymerase II transcription regulator complex.
  • Unexpected non-nuclear pool: TWIST1 is also found in apical endocytic vesicles in the neuroepithelium and physically interacts with β- and δ-catenin:

    "TWIST1 is expressed in endocytic vesicles at the apical surface and interacts with β/δ-catenins during neural tube closure" — PMID:35781329 [CACHED]

Relevant GO: GO:0030139 endocytic vesicle; GO:0016342/adherens-junction associations. Whether a Glu117 substitution affects this cytoplasmic pool is completely unknown — a good KNOWLEDGE_GAP.

Localization

UBERON suggestions — treat ALL as leads requiring OAK verification (uv run runoak -i sqlite:obo:uberon info "l^<label>"): - face, head, nose, orbit / orbital region, eyelid, external ear, palate, mandible, maxilla, frontal bone, skull vault, coronal suture, frontonasal prominence, neural crest, spleen, anus, testis, limb.

Lateralization: predominantly bilateral and symmetric — bilateral upper eyelid colobomas, bilateral talipes, bilateral cryptorchidism, bilateral coronal synostosis (E117D patient), bilateral syndactyly. Asymmetry is not a feature (contrast Saethre–Chotzen, where facial asymmetry is characteristic — a useful differential discriminator).

8. Temporal Development

Onset

  • Congenital — HP:0003577, 2/2. Malformations are complete at birth.
  • Embryologic critical window: cranial neural crest specification, delamination, migration, and frontonasal patterning — approximately weeks 3–8 of human gestation (mouse E8.5–E11.5, the window across which the Twist1 phenotypes are established).
  • Prenatal detectability: polyhydramnios in 1/2. Severe hypertelorism, orbital deficiency and nasal hypoplasia are in principle detectable on second-trimester ultrasound, but no prenatally diagnosed case has been published.
  • Onset pattern: not acute/subacute/chronic — it is a structural developmental anomaly, present ab initio.

Progression

  • Disease course: stable / non-progressive for the primary malformations. There is no degeneration, no relapsing-remitting pattern, no end-stage.
  • What does change over time is complication burden. Documented trajectory in Subject 2: eyelid coloboma → surgical repair → corneal scarring → phthisis of the right eye [WEB — PMC5438873, Arizona HOD]. This is treatment-modifiable secondary damage, not disease progression, and should be modelled as a downstream complication edge rather than a progression: phase.
  • In the E117D patient, craniosynostosis introduces the one genuinely time-critical element: untreated bicoronal synostosis risks raised intracranial pressure and requires surgical release in infancy.
  • Duration: lifelong.
  • Progression rate: not applicable.

Patterns

  • Remission: none — the concept does not apply.
  • Critical periods for intervention:
  • Neonatal (days): airway (tracheostomy for choanal atresia/airway compromise), imperforate anus (colostomy/anoplasty), corneal protection — arguably the most time-critical and most under-appreciated, since sight loss is preventable.
  • Infancy (0–12 mo): cranial vault surgery if synostosis present; hearing assessment and amplification (language window).
  • Early childhood: palate repair / VPI management for speech; syndactyly release; orchidopexy.
  • Childhood–adolescence: staged craniofacial and orbital reconstruction; ongoing developmental support.

9. Inheritance and Population

Epidemiology

  • Prevalence: not established. No Orphanet prevalence class; no registry; no population estimate anywhere in the literature.
  • Total published cases: 3 (2 in Kim 2017; 1 in Takenouchi 2018).
  • Incidence: unknown.

Recommended dismech Prevalence record (per the structured-prevalence policy in CLAUDE.md — do not use the deprecated free-text percentage):

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Three published individuals as of August 2026 (two in the delineating
    report, one subsequent case). No prevalence or incidence estimate has
    been published; no Orphanet epidemiology record exists.

Do not populate rate_per_100000 — there is no numeric estimate to normalize, and inventing one would be fabrication.

Genetic parameters

  • Inheritance: Autosomal dominant (HP:0000006), all cases de novo. Confirmed across sources including the Asian craniosynostosis series:

    "The pattern of inheritance is autosomal dominant in Saethre-Chotzen syndrome, Robinow-Sorauf syndrome, and Sweeney-Cox syndrome." — Dhiman S, et al. J Pediatr Genet 2024. PMID:39502847 [CACHED]

  • Penetrance: presumed complete — 3/3 carriers affected, all severely. No unaffected carrier has been reported. (With n=3 and no transmitting parents, this is an assumption, not a measurement.)
  • Expressivity: variable, and — importantly — the variability tracks the substituting amino acid rather than being stochastic. Val vs Gly vs Asp gives three distinguishable severity/feature profiles.
  • Recurrence risk: for parents of a de novo proband, low but not zero (gonadal mosaicism cannot be excluded); for an affected individual, 50%. No SWCOS patient has reproduced, so vertical transmission has never been observed.
  • Genetic anticipation: not applicable (not a repeat expansion).
  • Germline mosaicism: not reported; theoretically possible.
  • Founder effects: none — three unrelated individuals, three different substitutions.
  • Consanguinity: irrelevant (dominant, de novo).
  • Carrier frequency: not applicable.

Population demographics

  • Affected populations: no ethnic predilection. Reported patients came from UK-based clinical genetics services (Kim 2017, contributed by E. Sweeney and H. Cox) and Japan (Takenouchi 2018) — consistent with ascertainment through specialist craniofacial centres rather than any population enrichment.
  • Geographic distribution: no clustering; sporadic worldwide.
  • Variant geography: none — each allele reported once.
  • Sex ratio: 2 male : 1 female. Not interpretable; no sex bias is expected for an autosomal dominant de novo condition. Do not curate a sex ratio.
  • Age distribution: all identified in infancy/childhood. No adult SWCOS patient has been described in the literature, so nothing is known about the adult phenotype.

10. Diagnostics

The diagnostic pathway in one sentence

Recognition of the characteristic facial gestalt → molecular confirmation of a TWIST1 codon-117 missense variant. There is no biochemical or imaging test that makes the diagnosis.

Clinical tests

  • Laboratory tests: none diagnostic. No enzyme assay, metabolite, or blood/urine marker. No LOINC-codable disease-specific analyte exists.
  • Biomarkers: none. The only "biomarker" is the genotype.
  • Imaging:
  • Craniofacial CT with 3D reconstruction — the key structural study; defines orbital bone deficiency, suture status, and midface hypoplasia. Takenouchi et al. used spiral CT (MeSH keyword "Tomography, Spiral Computed" on the PubMed record, [CACHED]).
  • Brain MRI — for cerebellar hypoplasia (1/2) and developmental-delay workup.
  • Echocardiography — PDA/PFO.
  • Abdominal ultrasound — essential, to detect asplenia, which is otherwise silent and carries real infection risk.
  • Ophthalmic assessment including corneal examination — for exposure keratopathy.
  • Functional tests: audiologic assessment (conductive loss); speech/VPI evaluation (nasendoscopy, videofluoroscopy).
  • Electrophysiology: electrodiagnostic testing was normal in Subject 1 despite small eyes and no vision concerns [WEB — Arizona HOD]. ECG as part of cardiac workup.
  • Biopsy / histopathology: no role. No characteristic histopathology has been described. Do not curate a histopathology: block.

Genetic testing — the diagnostic modality

Approach Utility for SWCOS
Trio whole-exome sequencing (WES) First-line and highest-yield. The de novo status, the non-classical phenotype, and the broad frontonasal-dysplasia differential all favour unbiased exome. This is how the E117D case was identified.
Whole-genome sequencing (WGS) Reasonable alternative; adds regulatory/structural variant detection (relevant given TWIST1 regulatory-region duplications cause other phenotypes)
Craniosynostosis / craniofacial gene panels Will include TWIST1 (present on ≥85% of GTR craniosynostosis panels — the criterion by which ClinGen selected it for curation [CACHED, PMID:42059179]). Adequate if the clinician already suspects a TWIST1 disorder, but a panel chosen for craniosynostosis may not be reached for a frontonasal dysplasia presentation.
Single-gene TWIST1 sequencing Appropriate only when the gestalt is recognized. TWIST1's coding region is small (202 aa, principally one coding exon) so this is cheap and fast.
Chromosomal microarray (CMA) Will not detect SWCOS. Useful only to exclude 7p21 deletions (→ SCS) and other CNV syndromes in the differential. Used in the Dhiman 2024 series alongside WES and Sanger [CACHED, PMID:39502847].
Karyotype / FISH No role beyond excluding gross rearrangements.
mtDNA testing No role.
Repeat-expansion testing No role.

Critical interpretive point: because SWCOS and SCS are caused by variants in the same gene, at the same codon, the report must specify the variant, not just the gene. A laboratory report reading "pathogenic TWIST1 variant → Saethre-Chotzen syndrome" is a real misdiagnosis risk — and ClinVar's own condition assignment for p.Glu117Gly demonstrates it happening in practice (§4).

Omics-based diagnostics

None applicable. No RNA-seq, proteomic, metabolomic, epigenomic (methylation episignature), or liquid-biopsy test exists or is under development for SWCOS. A DNA-methylation episignature has not been sought — a plausible but purely speculative future avenue given n=3.

Clinical criteria

No formal diagnostic criteria, consensus statement, or society guideline exists. Diagnosis is: characteristic facial gestalt + confirmed TWIST1 codon-117 missense.

Proposed working gestalt (synthesized from the 3 published patients — explicitly not a validated criterion set): 1. Marked hypertelorism, and 2. Upper eyelid coloboma or ablepharon with deficient bony orbits/pseudoproptosis, and 3. Nasal hypoplasia (hypoplastic alae, short columella, broad tip), and 4. De novo heterozygous TWIST1 p.Glu117 missense substitution.

Differential diagnosis

Condition Gene How to distinguish
Saethre–Chotzen syndrome (OMIM 101400) TWIST1 (haploinsufficiency) Coronal synostosis dominant, facial asymmetry, ptosis, low frontal hairline, broad hallux; lacks eyelid coloboma and severe orbital bone deficiency. Same gene, different mechanism. Note the E117D patient blurs this boundary.
Barber–Say syndrome TWIST2 p.Glu75Gln/Ala Ablepharon, macrostomia, hypertelorism, hypertrichosis, redundant/atrophic skin; no craniosynostosis
Ablepharon–macrostomia syndrome TWIST2 p.Glu75Lys Most severe ablepharon + macrostomia; no craniosynostosis
Robinow–Sorauf syndrome TWIST1 Craniosynostosis + bifid hallux
Craniofrontonasal syndrome EFNB1 (X-linked) Hypertelorism, bifid nasal tip, coronal synostosis, longitudinally grooved nails, sternal anomalies; paradoxical female-severe X-linked inheritance
Frontonasal dysplasia 1/2/3 ALX3 / ALX4 / ALX1 Autosomal recessive; FND3 has extreme microphthalmia and bilateral facial clefting
Acromelic frontonasal dysostosis ZSWIM6 FND + distinctive limb (tibial/preaxial) anomalies
Teebi hypertelorism syndrome SPECC1L Hypertelorism, prominent forehead; milder
Treacher Collins / mandibulofacial dysostosis TCOF1, POLR1C/D Downslanting palpebral fissures, lower lid coloboma (vs upper in SWCOS), malar and mandibular hypoplasia
RNA Pol I–related craniofacial syndromes POLR1A/B/C/D A 2025 report describes a patient with "features overlapping with Sweeney-Cox, Saethre-Cox, Robinow-Sorauf, and Treacher-Collins" (PMID:41010008) [WEB] — direct evidence that SWCOS enters real-world differential lists

The framing from Takenouchi is the cleanest single statement of the differential:

"Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia syndrome share the facial features of ablepharon, hypertelorism, underdevelopment of the eyelids, and cheek pads adjacent to the corners of the mouth." — PMID:30450715 [CACHED]

"Our review showed that Sweeney-Cox syndrome appears to share many characteristics with Barber-Say syndrome and ablepharon-macrostomia syndrome except for craniosynostosis, which is a cardinal feature of Saethre-Chotzen syndrome." — PMID:30450715 [CACHED]

Screening

  • Newborn screening: not applicable and not appropriate (no treatable metabolic component).
  • Carrier screening: not applicable (de novo dominant).
  • Cascade screening: not applicable (no familial cases).
  • Prenatal testing: available on request for a couple with a previously affected child — targeted testing for the known familial variant by amniocentesis/CVS, or PGT-M. Recurrence risk is low (gonadal mosaicism only), so this is a counselling decision rather than a recommendation.

11. Outcome / Prognosis

All prognostic statements below are extrapolations from three patients. There is no survival data, no natural-history study, and no cohort. Curate accordingly.

Survival and mortality

  • Survival rate (5-/10-year/overall): unknown — no data. All three published patients were alive at report.
  • Life expectancy: not established. Not obviously reduced by the malformation complex itself in the absence of lethal cardiac or CNS anomalies, but the two known severe-end features that plausibly affect it are (a) airway compromise requiring tracheostomy and (b) asplenia, which confers lifelong overwhelming-post-splenectomy-infection–type risk if unrecognized.
  • Mortality rate / disease-specific mortality: no data.
  • Note on the allelic series: Takenouchi raises the possibility that some codon-117 substitutions may be lethal and therefore unascertained:

    "This suggests that any amino acid substitutions at Glu117 would likely lead to the Sweeney-Cox syndrome phenotype or lethality." — PMID:30450715 [CACHED]

This is a strong candidate for an ascertainment-bias discussions entry: the three living patients may represent the survivable tail of the allelic series.

Morbidity and function

  • Developmental outcome: global developmental delay in 2/2; moderate learning disability documented in Subject 1 [WEB — PMC5438873]. Whether delay is intrinsic (cerebellar hypoplasia, CNS involvement) or partly secondary (hearing loss, prolonged hospitalization, tracheostomy) is unresolved — a genuine knowledge gap.
  • Sensory outcome: conductive hearing loss (1/2); vision loss from corneal exposure is documented and is the most clearly preventable morbidity (phthisis of the right eye in Subject 2 despite lid repair).
  • Communication: delayed speech and language; velopharyngeal insufficiency and cleft palate compound this.
  • Disability outcomes: surgical burden across craniofacial, ophthalmic, ENT, orthopaedic, urologic and colorectal domains; long-term multidisciplinary dependence.
  • Quality-of-life measures: never assessed with any instrument.

Complications

Airway obstruction; exposure keratopathy → corneal scarring → phthisis bulbi; recurrent otitis media / conductive hearing loss; feeding difficulty and GERD; speech impairment from VPI; infection risk from asplenia; raised intracranial pressure if craniosynostosis is untreated; anaesthetic risk from difficult airway across repeated surgeries.

Recovery potential

The structural anomalies are not recoverable, only reconstructable. Functional outcomes for airway, feeding, hearing and speech are substantially improvable with timely intervention; vision is preservable only if corneal protection is instituted early.

Prognostic factors

Entirely inferential, but the strongest candidate is the identity of the substituting amino acid at codon 117 — the same variable that drives the phenotypic continuum. On current evidence: Asp → milder antimorph, adds synostosis; Val → intermediate; Gly → most severe (tracheostomy, cardiac defects, asplenia, eye loss). n=1 per allele. This is a hypothesis, not a genotype–phenotype rule, and should be curated with status: EMERGING if modelled as a mechanistic_hypotheses group.

Other plausible prognostic factors: presence of asplenia, presence of cardiac defect, degree of airway compromise, timeliness of corneal protection.

Prognostic biomarkers

None.

12. Treatment

The honest summary

There is no disease-modifying therapy, no drug, no clinical trial, and no published management guideline for Sweeney-Cox syndrome. Management is entirely symptomatic, surgical, and supportive, delivered by a multidisciplinary craniofacial team. The Arizona Hereditary Ocular Diseases entry states it plainly: no specific treatment exists for the underlying condition; individual malformations receive targeted care [WEB].

Pharmacotherapy

None. No drug targets the mechanism. No pharmacogenomic considerations. Leave therapeutic_agent absent throughout.

Surgical and interventional (the mainstay)

Intervention Indication NCIT suggestion (all require runoak verification)
Eyelid coloboma repair / oculoplastic reconstruction Corneal protection — highest priority NCIT:C15329 Surgical Procedure
Corneal protection (lubricants, tarsorrhaphy, moisture chambers) Exposure keratopathy NCIT:C15747 Supportive Care
Tracheostomy Airway obstruction (performed in Subject 2 from birth) NCIT:C15329 Surgical Procedure
Choanal atresia repair Nasal airway NCIT:C15329
Cranial vault remodelling / fronto-orbital advancement Craniosynostosis (E117D patient) NCIT:C15329
Orbital / midface reconstruction, hypertelorism correction (facial bipartition, box osteotomy) Orbital bone deficiency, hypertelorism NCIT:C15329
Palatoplasty; pharyngoplasty for VPI Cleft palate, velopharyngeal insufficiency NCIT:C15329
Anoplasty / colostomy Imperforate anus NCIT:C15329
Orchidopexy Bilateral cryptorchidism NCIT:C15329
Syndactyly release 2-4 / 2-5 cutaneous syndactyly NCIT:C16186 Orthopedic Surgical Procedure
Clubfoot management (Ponseti casting ± surgery) Bilateral talipes equinovarus NCIT:C16186
Auricular reconstruction Microtia NCIT:C15329
Gastrostomy Feeding failure NCIT:C15329

therapeutic_modality: SURGERY for all of the above (mechanically inferable from the NCIT surgical-action terms per the CLAUDE.md backfill table); DEVICE for hearing aids and tracheostomy hardware, which cannot be inferred mechanically and needs a per-entry decision.

Supportive and rehabilitative

Intervention NCIT suggestion Modality
Hearing amplification / audiologic management (no reliable NCIT action term for device usage) DEVICE
Speech and language therapy NCIT:C159273 Speech Therapy BEHAVIORAL
Occupational therapy NCIT:C121351 Occupational Therapy BEHAVIORAL
Physical therapy NCIT:C15302 Physical Therapy BEHAVIORAL
Nutritional support / feeding management NCIT:C15433 Nutritional Support ⚠️ do not auto-tag BEHAVIORAL — see the CLAUDE.md caution
Developmental / educational support NCIT:C15747 Supportive Care BEHAVIORAL
Genetic counselling NCIT:C15240 Genetic Counseling BEHAVIORAL
Antibiotic prophylaxis + immunization for functional asplenia NCIT:C15986 Pharmacotherapy SMALL_MOLECULE

The asplenia management item is worth curating explicitly: it is standard of care for asplenia generally (penicillin prophylaxis + pneumococcal/meningococcal/Hib vaccination), it is genuinely life-saving, and it is easy to miss in a patient whose clinical attention is dominated by the face.

Advanced therapeutics

  • Gene therapy / gene editing: none for SWCOS. Conceptually, a dominant-negative allele is an allele-specific silencing target (ASO or siRNA knockdown of the mutant transcript, or base editing of the c.350/c.351 substitution) — but the disease is established embryonically, so postnatal correction cannot reverse existing dysmorphogenesis. This is a fundamental, not merely practical, barrier and should be stated as such rather than presented as a pipeline.
  • A relevant adjacent result: RNA nanoparticle gene therapy has been used successfully in Twist1 mutant mice — PEGylated-peptide nanoparticles delivering plasmid DNA expressing miR-200a, injected subscalp at P7–P10, inhibited premature suture fusion, increased Gli1⁺/Six2⁺ suture stem cells, and sustained the effect to 56 days (Science Advances 2025) [WEB — PMC12372882].

    ⚠️ This targets craniosynostosis in a Twist1-haploinsufficient (SCS) model, not Sweeney-Cox. It is postnatal suture biology, not embryonic frontonasal patterning, and it would not address the SWCOS phenotype. Cite it only with that scope explicitly stated, and grade it evidence_source: MODEL_ORGANISM.

  • Cell therapy, RNA therapies, targeted therapy, immunotherapy: none applicable.

Experimental treatments / clinical trials

Zero. A search of ClinicalTrials.gov and ICTRP returns no interventional or observational study for Sweeney-Cox syndrome. The clinical_trials: block should be empty.

Treatment outcomes, algorithms, personalized medicine

  • Response rates: no data.
  • Adverse events: those of the individual procedures; the cumulative anaesthetic risk of a difficult airway across many operations is the notable syndrome-specific concern.
  • Treatment algorithms: none published. Care follows general craniofacial-team principles.
  • Combination therapy / genotype-guided treatment: not applicable — genotype currently informs prognosis and counselling only, not therapy choice.

13. Prevention

Primary prevention

Not possible. De novo dominant variants are not preventable by any known intervention. There is no modifiable risk factor, no periconceptional supplement, and no exposure to avoid.

Secondary prevention (early detection)

This is where prevention is actually meaningful in SWCOS — not preventing the disease, but preventing its avoidable sequelae:

  1. Corneal protection from day one. The documented loss of an eye to exposure keratopathy in Subject 2 is the strongest argument in the literature for aggressive, immediate ocular surface management in any infant with eyelid coloboma/ablepharon.
  2. Abdominal ultrasound to detect asplenia, followed by prophylaxis and immunization.
  3. Newborn hearing screening and ongoing audiologic surveillance.
  4. Cranial imaging for suture status — the E117D case establishes that craniosynostosis can accompany SWCOS, so it should be actively excluded rather than assumed absent, with ICP surveillance if present.
  5. Airway assessment for choanal atresia at birth.
  6. Developmental surveillance from infancy.

Tertiary prevention

Staged reconstructive surgery to prevent functional deterioration; ICP monitoring; speech therapy to prevent entrenched articulation patterns; antibiotic prophylaxis for asplenia; dental and orthodontic follow-up given midface hypoplasia.

Immunization

Routine childhood schedule, plus asplenia-indicated vaccines (pneumococcal, meningococcal, Hib) where asplenia is present. There is no SWCOS-specific vaccine.

Genetic screening and counselling

  • Population/carrier screening: not applicable.
  • Prenatal testing / PGT-M: available for the known familial variant after an affected child; recurrence risk low (gonadal mosaicism only).
  • Genetic counselling (NCIT:C15240): the essential preventive intervention. Must cover: de novo origin, ~50% transmission risk from an affected individual, low sibling recurrence risk, the SWCOS-vs-SCS distinction (so the family is not given SCS prognostic information), and the limits of what is known from three patients.

Behavioural, public-health, environmental interventions, prophylaxis

Not applicable, except the asplenia antibiotic prophylaxis noted above.

14. Other Species / Natural Disease

  • Species affected (natural disease): none known. No naturally occurring Sweeney-Cox syndrome has been reported in any non-human species. Nothing in OMIA corresponds to it.
  • Breed (VBO): not applicable.
  • Orthologous genes:
Species NCBI Taxon Gene Note
Human NCBITaxon:9606 TWIST1 (Gene 7291) Glu117
Mouse NCBITaxon:10090 Twist1 equivalent glutamate; extensively studied
Zebrafish NCBITaxon:7955 twist1a, twist1b ZFIN lists no models for this disease
C. elegans NCBITaxon:6239 hlh-8 — the single Twist homolog equivalent residue Glu29 — the basis of the disease model
Drosophila NCBITaxon:7227 twist founding member; mesoderm specification
  • Veterinary relevance: none. TWIST1-adjacent note of comparative interest: a severe craniofacial phenotype in Burmese cats is caused by homozygous disruption of Alx1 — the gene TWIST1 directly regulates through the ECR1 enhancer [CACHED, PMID:41850652, citing Lyons et al. 2016]. This is a natural animal model of the downstream node, not of SWCOS itself, and should not be curated as a SWCOS animal model.
  • Comparative pathology: the mouse Twist1 neural-crest conditional knockout reproduces the direction of the human defect — loss of snout, upper face and skull vault bones — but as a recessive tissue-specific null, not as a dominant-negative heterozygote.
  • Evolutionary conservation: exceptional. The glutamate is conserved from C. elegans HLH-8 (Glu29) through Drosophila Twist to human TWIST1 (Glu117) and TWIST2 (Glu75). This conservation is what licensed the worm allelic series and is itself the strongest a priori evidence for pathogenicity.
  • Zoonotic potential / cross-species transmission: not applicable.

15. Model Organisms

15.1 Caenorhabditis elegans — the definitive SWCOS model

This is the only model organism in which the actual SWCOS disease alleles have been engineered and studied, and it is the source of the dominant-negative conclusion.

  • Model type: invertebrate; CRISPR-engineered knock-in allelic series at the endogenous hlh-8 locus.
  • Rationale: C. elegans has a single Twist homolog (hlh-8), eliminating the paralogue redundancy that confounds vertebrate models, and permitting single-cell-resolution readouts in the developing mesoderm.
  • Alleles engineered: all five human disease substitutions at the equivalent Glu29 residue — Glu29Val and Glu29Gly (SWCOS), Glu29Ala and Glu29Gln (Barber–Say), Glu29Lys (AMS). A Glu29Asp allele corresponding to the Takenouchi patient is also described in this line of work [UNVERIFIED — confirm which paper generated the Asp allele before citing].
  • Readouts: target-gene expression in vulval and enteric muscle; constipation/defecation defect; egg-laying/embryo-retention phenotype.
  • Result — graded severity:

    "This allelic series revealed that different substitutions exhibit graded severity, in terms of both gene expression and cellular phenotype, which we incorporate into a model explaining the various human disease phenotypes." — PMID:28369379 [CACHED]

Reported ordering, most to least severe: Glu29Lys (AMS) > Glu29Val (and Glu29Asp) > Glu29Gly ≈ Glu29Ala ≈ Glu29Gln, with the weaker alleles retaining residual target-gene expression (74–100% in intestinal muscles) [WEB — PMC5438873]. - Dominant-negative evidence: hlh-8 null alleles behave recessively, whereas all Glu29 heterozygotes showed semi-dominant embryo retention and reduced target-gene expression in vulval muscle — i.e. the mutant proteins interfere with wild-type HLH-8 [WEB — PMC5438873]. This heterozygote-vs-null contrast is the crux of the argument and is exactly what a RECAPITULATES link with a mechanism-level target should point at. - Tissue-specific sensitivity: vulval muscles (heterodimer-dependent) were more sensitive than enteric muscles (where HLH-8 homodimers matter) [WEB] — an elegant internal control showing the defect is dimer-context-dependent. - Phenotype recapitulation: excellent for mechanism, nil for morphology. The worm reproduces the molecular logic (allele-specific graded antimorphism, heterozygous interference) but has no craniofacial structures, no neural crest, and no vertebrate skeleton. This is the textbook case for PARTIALLY_RECAPITULATES with an explicit limitations string. - Suggested dismech link: yaml animal_models: - name: C. elegans hlh-8 Glu29 disease-allele series species: Caenorhabditis elegans genotype: hlh-8(Glu29Val), hlh-8(Glu29Gly) knock-in heterozygotes and homozygotes publication: PMID:28369379 modeled_mechanisms: - target: <the dominant-negative dimer-sequestration node> relationship: PARTIALLY_RECAPITULATES fidelity: MODERATE limitations: >- C. elegans has no neural crest, no craniofacial skeleton, and no vertebrate suture biology; the model recapitulates the allele-specific antimorphic logic and heterozygous interference, not the human frontonasal phenotype. Readouts are mesodermal muscle lineages. - Database: WormBase.

15.2 Mouse — the gene model, not the disease model

No mouse carrying a Twist1 Glu117-equivalent knock-in has been reported. This is the single largest experimental gap for SWCOS.

Model Phenotype Relevance
Twist1−/− null Embryonic lethal at mid-gestation; complete neural tube closure defect at E11.5 [CACHED, PMID:35781329] Establishes requirement; not a disease model
Twist1+/− heterozygote 100% craniosynostosis (though not complete coronal fusion); acrocephalic, brachycephalic, wide skull; shortened cranial base [WEB] Established Saethre–Chotzen model — NOT a SWCOS model. Do not curate it as one.
Twist1fl/fl; Wnt1-Cre / Wnt1-Cre2 (NCC-conditional) Loss of snout, upper face and skull vault bones; no recognizable maxilla; malformed mandible; exencephaly; ~50% fewer migratory CNCCs, 68% shorter migration [CACHED, PMID:19414008 + PMID:35781329] Closest phenocopy of the SWCOS craniofacial defect — but as a tissue-specific null, not a dominant negative
Twist1fl/fl; Sox10-Cre Dramatic disruption of frontonasal development; failure to activate Alx1, Alx3, Alx4 in the FNP [CACHED, PMID:41850652] The mechanistic link to the frontonasal gene program
Alx1ΔDE1/ΔDE1 (Twist1-bound enhancer deletion) Hypoplastic/disrupted nasal cartilages, shortened premaxilla (10/10), malocclusion (7/10), disorganized extraocular muscles; >80% loss of Alx1 mRNA at E10.5 [CACHED, PMID:41850652] Models the downstream node; shows what losing the TWIST1→ALX1 edge does
Twist1 phospho-incompetent knock-in lines Epidermal blebbing, edema, neural tube defects, CNCC-derived structural abnormalities [CACHED, PMID:35781329] Dimer-regulation axis (SCS-adjacent)
Irf6+/−; Twist1+/− compound Mandibular agnathia, fused maxilla, cleft palate, holoprosencephaly [CACHED, PMID:35781329] Genetic-interaction model

Curation warning. The temptation to attach Twist1+/− mice to a Sweeney-Cox entry should be resisted — that genotype models haploinsufficiency, the mechanism SWCOS explicitly is not. If included at all, it belongs with relationship: FAILS_TO_RECAPITULATE against the dominant-negative node, with limitations and evidence supplied (both required for that relationship value by test_failure_to_recapitulate_links_are_substantiated).

15.3 Zebrafish

  • ZFIN carries the human disease term ZDB-TERM-190716-1 for Sweeney-Cox syndrome with no genes and no models registered [WEB].
  • A zebrafish twist model of Saethre-Chotzen craniosynostosis exists (altered bone growth dynamics prefiguring suture fusion) [WEB — PMC6207424] — again, SCS not SWCOS.
  • The paralogue duplication (twist1a/twist1b) makes zebrafish a poorer choice than C. elegans for a dominant-negative allelic series.

15.4 Cellular / in vitro systems

  • hPSC-derived cranial neural crest cells (hCNCCs) — the most promising unexploited system. The Coordinator-motif work (PMID:38262408) and the TF-dosage work (PMID:40020686) both use hCNCC differentiation and directly interrogate TWIST1 binding, chromatin opening, and dose-response. Knocking a p.Glu117Val allele into hPSCs and differentiating to CNCC would be the single highest-value experiment for this disease and is, as far as I can determine, not yet published.
  • Structural/biophysical: PDB 8OSB (TWIST1–TCF4–ALX4 on DNA) supports in silico modelling of E117V/G/D.
  • Patient-derived lines: none reported. No fibroblast or iPSC line from any of the three patients is described or deposited.

15.5 Applications and gaps

Answerable with existing models: the dominant-negative-vs-null distinction; graded allele severity; the TWIST1→ALX1 regulatory edge; CNCC EMT/migration/survival requirements; suture biology.

Not answerable with existing models — recommended discussions entries: - HUMAN_MODEL_MISMATCH — the antimorphic mechanism is demonstrated only in C. elegans mesodermal muscle; it has never been tested in a vertebrate craniofacial context, and no mammalian model of a Glu117-equivalent substitution exists. - KNOWLEDGE_GAP — why is the frontonasal/periocular region specifically vulnerable, when TWIST1 is expressed throughout CNCCs and pharyngeal arches? (The Coordinator/homeodomain-partner hypothesis is the leading answer but is untested for Glu117.) - KNOWLEDGE_GAP — is the developmental delay intrinsic (cerebellar hypoplasia, CNS TWIST1 function) or secondary (hearing loss, hospitalization, airway)? - KNOWLEDGE_GAP — does a Glu117 substitution affect the non-nuclear, β/δ-catenin-associated TWIST1 pool described in PMID:35781329? - KNOWLEDGE_GAP — Takenouchi's lethality conjecture: are the three known patients the survivable tail of the codon-117 allelic series?

Curation appendix — ready-to-use evidence items

These snippets are exact substrings of files already in references_cache/ and will pass just count-verified-snippets / just validate-references without further fetching. Everything else in this report must be fetched with just fetch-reference <ID> before it can be quoted.

# Disease definition / delineation
- reference: PMID:28369379
  supports: SUPPORT
  evidence_source: HUMAN_CLINICAL
  snippet: "Here, we describe a new clinical entity, Sweeney-Cox syndrome, associated with distinct de novo amino acid substitutions (p.Glu117Val and p.Glu117Gly) at a highly conserved glutamic acid residue located in the basic DNA binding domain of TWIST1, in two subjects with frontonasal dysplasia and additional malformations."
  explanation: Delineates the entity and its two founding de novo TWIST1 alleles.

# Codon-117 specificity vs the SCS mutation spectrum
- reference: PMID:28369379
  supports: SUPPORT
  evidence_source: HUMAN_CLINICAL
  snippet: "Although about one hundred different TWIST1 mutations have been reported in patients with the dominant haploinsufficiency Saethre-Chotzen syndrome (typically associated with craniosynostosis), substitutions uniquely affecting the Glu117 codon were not observed previously."
  explanation: Establishes codon 117 as a distinct hotspot separate from the SCS haploinsufficiency spectrum.

# Dominant-negative mechanism
- reference: PMID:28369379
  supports: SUPPORT
  evidence_source: MODEL_ORGANISM
  snippet: "The genetic analysis favors a predominantly dominant-negative mechanism for the action of amino acid substitutions at this highly conserved glutamic acid residue"
  explanation: C. elegans allelic series supports antimorphic rather than loss-of-function action.

# Graded severity across the allelic series
- reference: PMID:28369379
  supports: SUPPORT
  evidence_source: MODEL_ORGANISM
  snippet: "This allelic series revealed that different substitutions exhibit graded severity, in terms of both gene expression and cellular phenotype, which we incorporate into a model explaining the various human disease phenotypes."
  explanation: Basis for the activity-continuum model relating substituting residue to disease.

# Antimorphic effect shared with the TWIST2 disorders
- reference: PMID:30450715
  supports: SUPPORT
  evidence_source: HUMAN_CLINICAL
  snippet: "Heterozygous localized TWIST1 and TWIST2 basic domain substitutions exert antimorphic effects to cause Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia syndrome, respectively."
  explanation: Independent statement of the antimorphic mechanism across the paralogous hotspots.

# Third patient: craniosynostosis + ablepharon with p.Glu117Asp
- reference: PMID:30450715
  supports: SUPPORT
  evidence_source: HUMAN_CLINICAL
  snippet: "Herein, we document a male infant with the distinctive facial features of ablepharon, hypertelorism, cheek pads adjacent to the corners of the mouth, and bilateral coronal suture craniosynostosis who had a de novo heterozygous mutation in the basic domain of TWIST1, that is, c.351C>G p.Glu117Asp."
  explanation: Extends the phenotype to include craniosynostosis and adds the third causal allele.

# The SWCOS / SCS boundary
- reference: PMID:30450715
  supports: SUPPORT
  evidence_source: HUMAN_CLINICAL
  snippet: "Our review showed that Sweeney-Cox syndrome appears to share many characteristics with Barber-Say syndrome and ablepharon-macrostomia syndrome except for craniosynostosis, which is a cardinal feature of Saethre-Chotzen syndrome."
  explanation: Positions SWCOS in the differential against the TWIST2 disorders and SCS.

# Mild-antimorph model for the Asp allele
- reference: PMID:30450715
  supports: SUPPORT
  evidence_source: HUMAN_CLINICAL
  snippet: "The present observation suggests that a localized TWIST1 basic domain substitution, that is, p.Glu117Asp, in TWIST1 may exert a mild antimorphic effect similar to that of haploinsufficiency, leading to craniosynostosis and ablepharon."
  explanation: Supports the dose-continuum edge linking milder antimorphism to a synostosis phenotype.

# Inheritance
- reference: PMID:39502847
  supports: SUPPORT
  evidence_source: HUMAN_CLINICAL
  snippet: "The pattern of inheritance is autosomal dominant in Saethre-Chotzen syndrome, Robinow-Sorauf syndrome, and Sweeney-Cox syndrome."
  explanation: Confirms autosomal dominant inheritance for SWCOS.

# Twist1 requirement in frontonasal / skull vault development (mouse)
- reference: PMID:19414008
  supports: SUPPORT
  evidence_source: MODEL_ORGANISM
  snippet: "Loss of Twist1 in neural crest cells and their derivatives impairs skeletogenic differentiation and leads to the loss of bones of the snout, upper face and skull vault."
  explanation: Mouse NCC-conditional null supports the neural-crest skeletogenic node.

# Non-cell-autonomous extension to mesodermal bone
- reference: PMID:19414008
  supports: SUPPORT
  evidence_source: MODEL_ORGANISM
  snippet: "The effect of the loss of Twist1 function is not restricted to neural crest-derived bones, since the predominantly mesoderm-derived parietal and interparietal bones are also affected, presumably as a consequence of lost interactions with neural crest-derived tissues."
  explanation: Supports a non-cell-autonomous edge from NCC dysfunction to mesoderm-derived skull vault bone.

# TWIST1 in CNCC EMT
- reference: PMID:35781329
  supports: SUPPORT
  evidence_source: MODEL_ORGANISM
  snippet: "Twist1 suppresses Irf6 and other epithelial genes in CNCCs during the epithelial-to-mesenchymal transition (EMT) process and cell migration. Conversely, a loss of Twist1 leads to a sustained expression of epithelial and cell adhesion markers in migratory CNCCs."
  explanation: Supports the EMT/migration node downstream of TWIST1 dysfunction.

# TWIST1 as a CNCC survival/proliferation factor
- reference: PMID:35781329
  supports: SUPPORT
  evidence_source: MODEL_ORGANISM
  snippet: "TWIST1 has been shown to promote cell survival and proliferation of migratory CNCCs during craniofacial development"
  explanation: Supports the CNCC survival node in the causal chain.

# SWCOS vs SCS phenotype framing (2026)
- reference: PMID:41850652
  supports: SUPPORT
  evidence_source: OTHER
  snippet: "Mutations in TWIST1 have been associated with Sweeney-Cox (OMIM 617746) and Saethre-Chotzen (OMIM 101400) syndromes, with Sweeney-Cox syndrome characterized by hypertelorism with severe deficiency in frontal bones and hypoplasia of the nose and facial bones while Saethre-Chotzen syndrome exhibits craniosynostosis with hypertelorism and maxillary hypoplasia"
  explanation: Current framing of the SWCOS phenotype in contrast with SCS.

# TWIST1 -> ALX1 regulatory edge
- reference: PMID:41850652
  supports: SUPPORT
  evidence_source: MODEL_ORGANISM
  snippet: "mice with lineage-specific inactivation of Twist1 in migrating neural crest cells, exhibited dramatic loss of Alx1 mRNA expression in the developing frontonasal CNCCs"
  explanation: Supports the causal edge from TWIST1 dysfunction to failure of the frontonasal ALX gene program.

The finding that most changes how this entry should be written

ClinGen's Craniofacial Malformations GCEP evaluated TWIST1 against three separate disease assertions and reached three different verdicts — Definitive for Saethre-Chotzen, Moderate for TWIST1-related craniosynostosis, and Limited for Sweeney-Cox:

"Three rare but clinically defined and distinguishable gene-disease pairs were found to have Limited evidence ranging from 3 to 4 points to support the relationship by the Cranio GCEP: FGFR1-related osteoglophonic dysplasia (OMIM:166250), TWIST1-related Sweeney-Cox syndrome (OMIM:617746), and FGFR2 and lacrimo-auriculo-dento-digital (LADD) syndrome (OMIM:149730)" — Edoh EYA, et al. Genet Med 2026. PMID:42059179 [CACHED]

with the operational consequence spelled out in the same paper:

"According to ACMG technical standards, genes classified as Moderate, Strong, or Definitive are eligible for inclusion in diagnostic testing panels, whereas those below this threshold should not be considered." — PMID:42059179 [CACHED]

Two things follow. First, this is a clinically distinguishable entity with a well-supported mechanism whose gene–disease validity is nonetheless formally Limited — the constraint is case count (3), not evidence quality, and the paper is explicit that Moderate and Limited curations are revisited every three years. Second, a dismech entry that presents SWCOS with the same confidence as a Definitive relationship would be overstating the field's own position. State the Limited classification in the entry, cite it, and let the mechanism sections carry the weight they legitimately can.

Sources

Next step: if you want this turned into the KB entry, the highest-value first pass is the pathophysiology chain in §6.1 — nine nodes with biological_scale tags already assigned, the GO:0070888 E-box-binding-lost / GO:0046983 dimerization-retained contrast as the mechanistic core, and eleven cache-verified snippets ready to attach. Say the word and I'll draft it against the untracked kb/disorders/Sweeney-Cox_Syndrome.yaml on this branch.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 21
Resolved 21
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 2
Quoted claims found in source 1
Quoted claims not found in source 1
References weighed for topical relevance 21
On topic 12
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:40020686 (abstract only): "how concentrations of the dosage-sensitive TFs TWIST1 and SOX9 affect regulatory element chromatin accessibility in facial progenitor cells"
  • closest text in source: "We applied transfer learning to predict how concentrations of the dosage-sensitive TFs TWIST1 and SOX9 affect regulatory element (RE) chromatin accessibility in facial progenitor cells, achieving near-experimental accuracy"

Term Validation

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

Outcome Count
Terms checked 94
Resolved 88
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 6
Terms whose name was checked 73
Terms named correctly 64
Terms named as a different term 3
Terms whose name is worth a second look 6

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:

  • DOID:0080538 (4 mentions) - the report calls it "Disease Ontology"; DOID calls it Sweeney-Cox syndrome
  • NCIT:C15329 (10 mentions) - the report calls it "Nasal airway", "Craniosynostosis (E117D patient)", "Orbital bone deficiency, hypertelorism", "Cleft palate, velopharyngeal insufficiency", "Imperforate anus", "Bilateral cryptorchidism", "Microtia", "Feeding failure"; NCIT calls it Surgical Procedure
  • NCIT:C16186 (2 mentions) - the report calls it "Bilateral talipes equinovarus"; NCIT calls it Orthopedic Surgical Procedure

Terms whose name is worth a second look

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

  • HP:0002023 (1 mention) - the report calls it "Anal atresia (imperforate anus)"; HP calls it Anal atresia**, and lists "Imperforate anus" among its other names
  • HP:0003577 (3 mentions) - the report calls it "Congenital onset (2/2)"; HP calls it Congenital onset**
  • GO:0006357 (1 mention) - the report calls it "Regulation of transcription by RNA Pol II"; GO calls it regulation of transcription by RNA polymerase II
  • CL:0000333 (1 mention) - the report calls it "migratory cranial neural crest cell"; CL calls it migratory neural crest cell
  • NCBITaxon:6239 (1 mention) - the report calls it "C. elegans"; NCBITaxon calls it Caenorhabditis elegans, and lists "Rhabditis elegans" among its other names
  • NCBITaxon:7227 (1 mention) - the report calls it "Drosophila"; NCBITaxon calls it Drosophila melanogaster

Terms named inconsistently

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

  • NCIT:C15329 - called "Nasal airway", "Craniosynostosis (E117D patient)", "Orbital bone deficiency, hypertelorism", "Cleft palate, velopharyngeal insufficiency", "Imperforate anus", "Bilateral cryptorchidism", "Microtia", "Feeding failure"

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.