Skraban-Deardorff Syndrome

Mendelian MONDO:0054636 Pathograph 25 Show in embeddings browser Neurodevelopmental Disorder Syndromic Intellectual Disability

Skraban-Deardorff syndrome (SKDEAS; WDR26-related neurodevelopmental disorder; intellectual developmental disorder, autosomal dominant 47, OMIM 617616) is an ultra-rare autosomal dominant neurodevelopmental disorder caused by heterozygous, typically de novo, loss-of-function variants (and 1q42.12 microdeletions) in WDR26, producing WDR26 haploinsufficiency. WDR26 encodes a WD40-repeat scaffold/substrate-recognition subunit of the C-terminal to LisH (CTLH) E3 ubiquitin-ligase complex. Affected individuals show intellectual disability with delayed or absent speech, developmental delay, febrile and non-febrile seizures, a wide-based/spastic/stiff-legged gait, hypotonia, feeding difficulties, autistic-like behaviour, minor skeletal anomalies, and a recognisable facial gestalt (a prominent maxilla and upper lip revealing the upper gingiva, widely spaced teeth, and a broad nasal tip).

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1
Inheritance
6
Pathophys.
17
Phenotypes
25
Pathograph
1
Genes
4
Medical Actions
1
Models
👪

Inheritance

1
Autosomal dominant, typically de novo HP:0000006
Skraban-Deardorff syndrome is autosomal dominant and in nearly all reported individuals arises from a de novo heterozygous loss-of-function variant or a 1q42.12 microdeletion encompassing WDR26.
Autosomal dominant inheritance Expressivity: VARIABLE
Show evidence (1 reference)
PMID:33675273 SUPPORT Human Clinical
"This condition is an ultra-rare autosomal dominant neurodevelopmental disorder characterized by a broad range of clinical signs"
States the autosomal dominant inheritance of the disorder.
⚙

Pathophysiology

6
WDR26 Haploinsufficiency
Heterozygous nonsense, frameshift and splice-site variants, and 1q42.12 microdeletions, reduce the functional dosage of WDR26. Loss-of-function single-nucleotide variants trigger nonsense-mediated decay, reducing WDR26 RNA and protein levels; missense variants localise to highly conserved residues of the WD40-repeat protein. The single-gene dosage reduction is the core lesion.
WDR26 hgnc:21208 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves WDR26 (hgnc:21208). hgnc:21208 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired CTLH E3 Ubiquitin Ligase Complex Function Reduced WDR26 protein depletes the scaffold/substrate-recognition subunit of the CTLH E3 ubiquitin-ligase complex.
Abnormal Craniofacial and Skeletal Development In parallel with its neurodevelopmental effects, WDR26 haploinsufficiency disrupts craniofacial and skeletal morphogenesis, producing the recognisable facial gestalt, dental anomalies and minor skeletal anomalies.
Show evidence (2 references)
PMID:28686853 SUPPORT Human Clinical
"WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels."
Establishes that disease-associated LOF variants reduce WDR26 RNA and protein, the haploinsufficiency mechanism.
PMID:28686853 SUPPORT Human Clinical
"We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions."
Documents the de novo loss-of-function and missense variant spectrum underlying the disorder.
Impaired CTLH E3 Ubiquitin Ligase Complex Function
WDR26 is a structural scaffold and substrate-recognition subunit of the C-terminal to LisH (CTLH) E3 ubiquitin-ligase complex, which targets specific proteins for ubiquitin-proteasome degradation. Reduced WDR26 dosage impairs assembly and substrate targeting of the CTLH complex, lowering ubiquitination of its substrates.
protein ubiquitination GO:0016567 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein ubiquitination (GO:0016567). GO:0016567 is a biological process from the Gene Ontology. ↓ DECREASED
ubiquitin-protein transferase activity GO:0004842 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased ubiquitin-protein transferase activity (GO:0004842). GO:0004842 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
RUNX1T1 Stabilization Reduced CTLH-mediated ubiquitination stabilises the transcriptional coactivator RUNX1T1.
Show evidence (2 references)
PMID:42138082 SUPPORT Model Organism
"The WDR26 gene encodes a subunit of the E3 ubiquitin ligase multiprotein complex known as C-terminal to LisH (CTLH), targeting specific proteins for degradation"
Establishes WDR26 as a subunit of the CTLH E3 ubiquitin-ligase complex that degrades specific substrates.
PMID:42138082 SUPPORT Model Organism
"WDR26 serves as a structural scaffold for the CTLH E3 complex, facilitating the assembly of large, hollow, supramolecular CTLH E3 assemblies"
Identifies WDR26 as the scaffold subunit whose loss impairs CTLH complex assembly and function.
RUNX1T1 Stabilization
Mechanism confidence: Provisional
In Wdr26+/- mice and Wdr26-knockdown neuronal cells, reduced CTLH-mediated ubiquitination impairs proteasomal degradation of RUNX1T1 and stabilises the protein. RUNX1T1 is a transcriptional coactivator critical for neuronal differentiation. This stabilisation is demonstrated in mouse and cell models and has not yet been confirmed in human patient tissue, so the node is curated at provisional confidence.
proteasome-mediated ubiquitin-dependent protein catabolic process GO:0043161 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161). GO:0043161 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Neuronal Differentiation Dysregulation Stabilised RUNX1T1 raises MAP2, a regulator of dendritic architecture and synaptic plasticity, dysregulating neuronal differentiation.
Show evidence (1 reference)
PMID:42138082 SUPPORT Model Organism
"Wdr26 haploinsufficiency stabilized RUNX1 translocation partner 1 (RUNX1T1), a transcriptional coactivator critical for neuronal differentiation, by impairing its ubiquitination and proteasomal degradation"
Reports RUNX1T1 stabilization via impaired CTLH-dependent ubiquitination in the mouse model.
Neuronal Differentiation Dysregulation
Mechanism confidence: Provisional
Elevated RUNX1T1 raises MAP2, a regulator of dendritic architecture and synaptic plasticity, disrupting neuronal maturation. This WDR26/RUNX1T1/MAP2 axis is demonstrated in mouse and cell models and has not yet been confirmed in human patient tissue, so the node is curated at provisional confidence.
neuron differentiation GO:0030182 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated neuron differentiation (GO:0030182). GO:0030182 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Abnormal Neurodevelopment RUNX1T1/MAP2 dysregulation disrupts neuronal differentiation and dendritic architecture in the developing brain.
Show evidence (1 reference)
PMID:42138082 SUPPORT Model Organism
"consequently disrupting the level of microtubule-associated protein 2 (MAP2), a key regulator of dendritic architecture and synaptic plasticity."
Reports the RUNX1T1-driven MAP2 dysregulation that disrupts neuronal differentiation in the mouse model.
Abnormal Neurodevelopment
Disrupted neuronal differentiation and dendritic maturation in progenitors and neurons produces the neurodevelopmental phenotype. The Wdr26+/- mouse recapitulates core clinical features (learning/memory impairment, social dysfunction, heightened seizure susceptibility and motor deficits), supporting a causal path from WDR26 dosage to abnormal brain development.
neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology. neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Animal models
Wdr26 heterozygous-knockout mouse Mouse partially recapitulates Wdr26+/- mice reproduce core neurodevelopmental features (learning and memory impairment, social dysfunction, heightened seizure susceptibility, and motor deficits) and show an enlarged ventricular area paralleling patient ventriculomegaly. The heterozygous genotype matches the heterozygous human loss-of-function state.
Downstream
Intellectual Disability Impaired neuronal maturation underlies the cognitive impairment.
Global Developmental Delay Abnormal neurodevelopment produces global delay of motor and language milestones.
Delayed Speech Impaired neuronal maturation underlies delayed or absent speech.
Seizures Abnormal dendritic architecture and network excitability underlie the seizure susceptibility.
Abnormal Gait Impaired motor development underlies the wide-based gait.
Spastic Gait The spastic/stiff-legged component of the characteristic gait reflects corticospinal/motor involvement.
Hypotonia Central hypotonia is part of the neurodevelopmental phenotype.
Autistic Behavior Social dysfunction/autistic-like behaviour is a neurodevelopmental output.
Feeding Difficulties Oromotor/neurodevelopmental dysfunction underlies infant feeding difficulties.
Ventriculomegaly Enlarged cerebral ventricles are a structural correlate of the abnormal brain development.
Show evidence (1 reference)
PMID:42138082 SUPPORT Model Organism
"Wdr26 heterozygous-KO mice (Wdr26+/-) recapitulated core clinical features of the syndrome, including learning and memory impairments, social dysfunction, heightened seizure susceptibility, and motor deficits, alongside rare craniofacial and dental abnormalities."
Demonstrates that WDR26 haploinsufficiency produces the core neurodevelopmental phenotype in vivo.
Abnormal Craniofacial and Skeletal Development
In parallel with the neurodevelopmental arm, reduced WDR26 dosage disrupts craniofacial and skeletal morphogenesis. The Wdr26+/- mouse shows abnormal tooth growth and cranial misalignment, and reduced WDR26 expression is linked to craniofacial developmental abnormalities; RUNX1T1-mutation patients likewise show craniofacial defects, consistent with a shared developmental program. This node collects the recognisable facial gestalt, dental anomalies and minor skeletal anomalies of the syndrome.
Downstream
Prominent Maxilla Craniofacial dysmorphogenesis produces the prominent maxilla revealing the upper gingiva.
Widely Spaced Teeth Craniofacial/dental dysmorphogenesis produces widely spaced teeth.
Broad Nasal Tip Craniofacial dysmorphogenesis produces the broad nasal tip.
Anteverted Nares Craniofacial dysmorphogenesis produces anteverted nares.
Depressed Nasal Root Craniofacial dysmorphogenesis produces a depressed nasal root.
Abnormal Gums Craniofacial/gingival dysmorphogenesis produces abnormal gums.
Minor Skeletal Anomalies Skeletal dysmorphogenesis produces the minor skeletal anomalies of the disorder.
Show evidence (1 reference)
PMID:42138082 SUPPORT Model Organism
"motor deficits, alongside rare craniofacial and dental abnormalities."
The mouse model recapitulates craniofacial and dental abnormalities, supporting a WDR26-dosage-dependent craniofacial developmental node.
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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 Skraban-Deardorff 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.
●

Phenotypes

17
Digestive 1
Feeding Difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33675273 SUPPORT Human Clinical
"seizures, abnormal facial features, feeding difficulties, and minor skeletal anomalies."
Lists feeding difficulties among the defining clinical signs of the disorder.
Head and Neck 6
Prominent Maxilla FREQUENT Abnormal maxilla morphology HP:0000326 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent maxilla, annotated with Abnormal maxilla morphology (HP:0000326). HP:0000326 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28686853 SUPPORT Human Clinical
"These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip."
A prominent maxilla revealing the upper gingiva is part of the shared facial gestalt in the defining cohort.
Widely Spaced Teeth FREQUENT HP:0000687 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Widely spaced teeth (HP:0000687). HP:0000687 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28686853 SUPPORT Human Clinical
"a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip."
Widely spaced teeth are part of the shared facial gestalt in the defining cohort.
Broad Nasal Tip FREQUENT HP:0000455 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad nasal tip (HP:0000455). HP:0000455 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28686853 SUPPORT Human Clinical
"widely spaced teeth, and a broad nasal tip."
A broad nasal tip is part of the shared facial gestalt in the defining cohort.
Anteverted Nares FREQUENT HP:0000463 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anteverted nares (HP:0000463). HP:0000463 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42138082 SUPPORT Other
"More than half of the patients show anteverted nares, a depressed nasal root, widely spaced teeth, and abnormal gums"
Pooled clinical literature figure (secondary citation within the mouse paper) reporting anteverted nares in more than half of patients, supporting a FREQUENT band.
Depressed Nasal Root FREQUENT Depressed nasal bridge HP:0005280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Depressed nasal root, annotated with Depressed nasal bridge (HP:0005280). HP:0005280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42138082 SUPPORT Other
"More than half of the patients show anteverted nares, a depressed nasal root, widely spaced teeth, and abnormal gums"
Pooled clinical literature figure (secondary citation within the mouse paper) reporting a depressed nasal root in more than half of patients, supporting a FREQUENT band.
Abnormal Gums FREQUENT Abnormality of the gingiva HP:0000168 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal gums, annotated with Abnormality of the gingiva (HP:0000168). HP:0000168 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42138082 SUPPORT Other
"More than half of the patients show anteverted nares, a depressed nasal root, widely spaced teeth, and abnormal gums"
Pooled clinical literature figure (secondary citation within the mouse paper) reporting abnormal gums in more than half of patients, supporting a FREQUENT band.
Musculoskeletal 3
Spastic Gait VERY_FREQUENT HP:0002064 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spastic and/or stiff-legged gait, annotated with Spastic gait (HP:0002064). HP:0002064 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28686853 SUPPORT Human Clinical
"a wide-based, spastic, and/or stiff-legged gait."
The spastic/stiff-legged gait component was present in all individuals of the defining cohort.
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42138082 SUPPORT Other
"including intellectual disability, developmental delay, autistic tendencies, seizures, gait abnormalities, hypotonia, infant feeding difficulties, distinctive facial features, and skeletal abnormalities"
Literature-summary statement of the human syndrome's phenotypic features listing hypotonia; tagged OTHER because it is a review/background statement within a mouse-model study rather than a primary clinical observation.
Minor Skeletal Anomalies Abnormal skeletal morphology HP:0011842 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Minor skeletal anomalies, annotated with Abnormal skeletal morphology (HP:0011842). HP:0011842 is a phenotype from the Human Phenotype Ontology.
The generic HP:0011842 (Abnormal skeletal morphology) is retained because the cited sources describe only unspecified "minor skeletal anomalies" and do not name a specific skeletal feature that would support a more specific HPO term.
Show evidence (1 reference)
PMID:33675273 SUPPORT Human Clinical
"feeding difficulties, and minor skeletal anomalies."
Lists minor skeletal anomalies among the defining clinical signs; frequency omitted as no numerator is given.
Nervous System 7
Intellectual Disability OBLIGATE HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28686853 SUPPORT Human Clinical
"all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait."
All 15 individuals in the defining cohort had intellectual disability.
PMID:42138082 SUPPORT Other
"Consistent with the 30/30 incidence of patients with intellectual disability"
Pooled clinical literature figure (secondary citation within the mouse paper) reporting a 30/30 (100%) incidence of intellectual disability, supporting the OBLIGATE band.
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.
Show evidence (1 reference)
PMID:33675273 SUPPORT Human Clinical
"including intellectual disability (ID), developmental delay (DD), seizures, abnormal facial features, feeding difficulties, and minor skeletal anomalies."
Lists developmental delay among the defining clinical signs of the disorder.
Delayed Speech VERY_FREQUENT 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.
Show evidence (1 reference)
PMID:28686853 SUPPORT Human Clinical
"all have intellectual disability with delayed speech"
Delayed speech was present in all individuals of the defining cohort.
Seizures VERY_FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28686853 SUPPORT Human Clinical
"a history of febrile and/or non-febrile seizures"
Febrile and/or non-febrile seizures were present in all individuals of the defining cohort.
PMID:42138082 SUPPORT Other
"Eighty percent of patients (24 of 30) exhibit either clinical seizures or electroencephalographic abnormalities"
Pooled clinical literature figure (secondary citation within the mouse paper, not its own cohort) quantifying seizures/EEG abnormalities at 80%, supporting the VERY_FREQUENT band.
Abnormal Gait VERY_FREQUENT Broad-based gait HP:0002136 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide-based, spastic, and/or stiff-legged gait, annotated with Broad-based gait (HP:0002136). HP:0002136 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28686853 SUPPORT Human Clinical
"a wide-based, spastic, and/or stiff-legged gait."
A wide-based/spastic/stiff-legged gait was present in all individuals of the defining cohort.
Autistic Behavior FREQUENT HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42138082 SUPPORT Other
"social impairments resembling autistic-like behaviors in 65% of patients (15 of 23)"
Pooled clinical literature figure (secondary citation within the mouse paper, not its own cohort) quantifying autistic-like social impairment at 65%, supporting a FREQUENT band.
Ventriculomegaly HP:0002119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42138082 SUPPORT Model Organism
"an enlarged ventricular area was observed in the brains of Wdr26+/- mice"
The mouse model shows an enlarged ventricular area paralleling patient ventriculomegaly; no patient numerator is reported, so frequency is omitted.
🧬

Genetic Associations

1
WDR26 (Causative)
Gene: WDR26 hgnc:21208 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is WDR26 (hgnc:21208). hgnc:21208 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Show evidence (2 references)
PMID:28686853 SUPPORT Human Clinical
"We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions."
Establishes WDR26 de novo pathogenic variants (predominantly loss of function) as causative.
PMID:28686853 SUPPORT Human Clinical
"We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein."
Documents that missense variants affect conserved residues of the WD40-repeat protein.
💊

Medical Actions

4
Antiseizure Medication
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: anticonvulsant agent NCIT:C264 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses anticonvulsant agent (NCIT:C264). NCIT:C264 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Symptomatic pharmacological control of febrile and non-febrile seizures with antiseizure medication.
Physical Therapy
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
Physical therapy to address hypotonia, gait abnormality and motor delay.
Speech and Language Therapy
Action: speech language therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is speech language therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. Ontology label: Speech Language Therapy NCIT:C159273
Platform: Behavioral / lifestyle
Speech and language therapy, including augmentative and alternative communication, for delayed or absent speech.
Occupational Therapy
Action: occupational therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is occupational therapy (NCIT:C121351). NCIT:C121351 is a clinical intervention from the NCI Thesaurus. Ontology label: Occupational Therapy NCIT:C121351
Platform: Behavioral / lifestyle
Occupational therapy to support adaptive skills and daily functioning.
📊

Prevalence

1
Published individuals worldwide
Cases In Literature Ultra Rare
An ultra-rare disorder; 18 clinically reported cases by 2021 and roughly 33 documented in the literature by 2026. WDR26 may be poorly annotated in exome interpretation pipelines, so the disorder is likely underdiagnosed.
Show evidence (1 reference)
PMID:33675273 SUPPORT Human Clinical
"Currently, 18 cases have been reported in the literature and for only 15 of them a clinical description is available."
Quantifies the small number of reported cases, supporting the ultra-rare class.
🐁

Animal Models

1
Wdr26 heterozygous-knockout mouse
Heterozygous Wdr26-knockout mouse, matching the heterozygous loss-of-function genotype of human WDR26 haploinsufficiency, which recapitulates core neurodevelopmental features of Skraban-Deardorff syndrome.
Species
Mouse
Genotype
Wdr26+/- (heterozygous knockout)
Publication
PMID:42138082
Pathograph links
Abnormal Neurodevelopment partially recapitulates fidelity: moderate Wdr26+/- mice reproduce core neurodevelopmental features (learning and memory impairment, social dysfunction, heightened seizure susceptibility, and motor deficits) and show an enlarged ventricular area paralleling patient ventriculomegaly. The heterozygous genotype matches the heterozygous human loss-of-function state.
Limitations: Murine models cannot capture the human speech/language and higher-cognitive phenotype directly, and the craniofacial and dental abnormalities occur in only ~6% of heterozygous mice, far below their frequency in affected individuals.
Readouts
Ventricular area on brain imaging/histology
Direction: INCREASED
Interpretation: Enlarged ventricular area is the structural correlate of patient ventriculomegaly.
Show evidence (1 reference)
PMID:42138082 SUPPORT Model Organism
"an enlarged ventricular area was observed in the brains of Wdr26+/- mice"
Reports the enlarged ventricular area measured in the heterozygous mouse brain.
Show evidence (1 reference)
PMID:42138082 SUPPORT Model Organism
"Wdr26 heterozygous-KO mice (Wdr26+/-) recapitulated core clinical features of the syndrome, including learning and memory impairments, social dysfunction, heightened seizure susceptibility, and motor deficits, alongside rare craniofacial and dental abnormalities."
Establishes the Wdr26+/- mouse as recapitulating the core neurodevelopmental features of the syndrome, supporting its use as a model for this node.
{ }

Source YAML

click to show 
name: Skraban-Deardorff Syndrome
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Skraban-Deardorff syndrome (SKDEAS; WDR26-related neurodevelopmental disorder;
  intellectual developmental disorder, autosomal dominant 47, OMIM 617616) is an
  ultra-rare autosomal dominant neurodevelopmental disorder caused by
  heterozygous, typically de novo, loss-of-function variants (and 1q42.12
  microdeletions) in WDR26, producing WDR26 haploinsufficiency. WDR26 encodes a
  WD40-repeat scaffold/substrate-recognition subunit of the C-terminal to LisH
  (CTLH) E3 ubiquitin-ligase complex. Affected individuals show intellectual
  disability with delayed or absent speech, developmental delay, febrile and
  non-febrile seizures, a wide-based/spastic/stiff-legged gait, hypotonia,
  feeding difficulties, autistic-like behaviour, minor skeletal anomalies, and a
  recognisable facial gestalt (a prominent maxilla and upper lip revealing the
  upper gingiva, widely spaced teeth, and a broad nasal tip).
disease_term:
  preferred_term: Skraban-Deardorff syndrome
  term:
    id: MONDO:0054636
    label: Skraban-Deardorff syndrome
parents:
- Neurodevelopmental Disorder
- Syndromic Intellectual Disability
synonyms:
- SKDEAS
- WDR26-related neurodevelopmental disorder
- WDR26 haploinsufficiency syndrome
- intellectual developmental disorder, autosomal dominant 47
- MRD47
notes: >-
  Scope and mechanism confidence. The molecular link from WDR26 haploinsufficiency
  to the neurodevelopmental phenotype is best established in the Wdr26+/- mouse
  (PMID:42138082), which recapitulates the core clinical features and identifies a
  WDR26/RUNX1T1/MAP2 axis: reduced CTLH-complex ubiquitination stabilises the
  transcriptional coactivator RUNX1T1, which in turn dysregulates MAP2 and neuronal
  differentiation. Because this mechanistic chain is currently demonstrated in mouse
  and cell models rather than in human patient tissue, the RUNX1T1/MAP2 node is
  curated at PROVISIONAL confidence. The same study reported that the antipsychotic
  risperidone raised WDR26 levels and ameliorated cognitive and social deficits in
  Wdr26+/- mice; this is a preclinical model-organism finding and is deliberately
  NOT curated as an established human treatment.
review_notes: >-
  GeneReviews check (2026-08-29): a PubMed search of the GeneReviews Bookshelf
  (query "(WDR26 OR Skraban-Deardorff) AND GeneReviews[Book]") returned one
  chapter — "WDR26-Related Intellectual Disability" (PMID:31021590, GeneReviews,
  Skraban & Deardorff) — the authoritative expert-reviewed summary for this
  disorder. It is available as a lead for future phenotype/management enrichment;
  it is not cited as an evidence snippet here because GeneReviews chapters cache as
  Bookshelf metadata rather than a quotable abstract.
inheritance:
- name: Autosomal dominant, typically de novo
  expressivity: VARIABLE
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Skraban-Deardorff syndrome is autosomal dominant and in nearly all reported
    individuals arises from a de novo heterozygous loss-of-function variant or a
    1q42.12 microdeletion encompassing WDR26.
  evidence:
  - reference: PMID:33675273
    reference_title: "Expanding the clinical phenotype of the ultra-rare Skraban-Deardorff syndrome: Two novel individuals with WDR26 loss-of-function variants and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This condition is an ultra-rare autosomal dominant neurodevelopmental disorder characterized by a broad range of clinical signs"
    explanation: States the autosomal dominant inheritance of the disorder.
prevalence:
- population: Published individuals worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    An ultra-rare disorder; 18 clinically reported cases by 2021 and roughly 33
    documented in the literature by 2026. WDR26 may be poorly annotated in exome
    interpretation pipelines, so the disorder is likely underdiagnosed.
  evidence:
  - reference: PMID:33675273
    reference_title: "Expanding the clinical phenotype of the ultra-rare Skraban-Deardorff syndrome: Two novel individuals with WDR26 loss-of-function variants and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, 18 cases have been reported in the literature and for only 15 of them a clinical description is available."
    explanation: Quantifies the small number of reported cases, supporting the ultra-rare class.
pathophysiology:
- name: WDR26 Haploinsufficiency
  biological_scale: MOLECULAR
  description: >-
    Heterozygous nonsense, frameshift and splice-site variants, and 1q42.12
    microdeletions, reduce the functional dosage of WDR26. Loss-of-function
    single-nucleotide variants trigger nonsense-mediated decay, reducing WDR26 RNA
    and protein levels; missense variants localise to highly conserved residues of
    the WD40-repeat protein. The single-gene dosage reduction is the core lesion.
  genes:
  - preferred_term: WDR26
    term:
      id: hgnc:21208
      label: WDR26
  downstream:
  - target: Impaired CTLH E3 Ubiquitin Ligase Complex Function
    causal_link_type: DIRECT
    description: >-
      Reduced WDR26 protein depletes the scaffold/substrate-recognition subunit of
      the CTLH E3 ubiquitin-ligase complex.
  - target: Abnormal Craniofacial and Skeletal Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      In parallel with its neurodevelopmental effects, WDR26 haploinsufficiency
      disrupts craniofacial and skeletal morphogenesis, producing the recognisable
      facial gestalt, dental anomalies and minor skeletal anomalies.
    evidence:
    - reference: PMID:42138082
      reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "reduced WDR26 expression was linked to abnormalities of the craniofacial, tectum, and ventricular areas"
      explanation: The mouse model links reduced WDR26 dosage to craniofacial (and tectal/ventricular) developmental abnormalities.
  evidence:
  - reference: PMID:28686853
    reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels."
    explanation: Establishes that disease-associated LOF variants reduce WDR26 RNA and protein, the haploinsufficiency mechanism.
  - reference: PMID:28686853
    reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions."
    explanation: Documents the de novo loss-of-function and missense variant spectrum underlying the disorder.
- name: Impaired CTLH E3 Ubiquitin Ligase Complex Function
  biological_scale: MOLECULAR
  description: >-
    WDR26 is a structural scaffold and substrate-recognition subunit of the
    C-terminal to LisH (CTLH) E3 ubiquitin-ligase complex, which targets specific
    proteins for ubiquitin-proteasome degradation. Reduced WDR26 dosage impairs
    assembly and substrate targeting of the CTLH complex, lowering ubiquitination
    of its substrates.
  biological_processes:
  - preferred_term: protein ubiquitination
    term:
      id: GO:0016567
      label: protein ubiquitination
    modifier: DECREASED
  molecular_functions:
  - preferred_term: ubiquitin-protein transferase activity
    term:
      id: GO:0004842
      label: ubiquitin-protein transferase activity
    modifier: DECREASED
  downstream:
  - target: RUNX1T1 Stabilization
    causal_link_type: DIRECT
    description: >-
      Reduced CTLH-mediated ubiquitination stabilises the transcriptional
      coactivator RUNX1T1.
  evidence:
  - reference: PMID:42138082
    reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The WDR26 gene encodes a subunit of the E3 ubiquitin ligase multiprotein complex known as C-terminal to LisH (CTLH), targeting specific proteins for degradation"
    explanation: Establishes WDR26 as a subunit of the CTLH E3 ubiquitin-ligase complex that degrades specific substrates.
  - reference: PMID:42138082
    reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "WDR26 serves as a structural scaffold for the CTLH E3 complex, facilitating the assembly of large, hollow, supramolecular CTLH E3 assemblies"
    explanation: Identifies WDR26 as the scaffold subunit whose loss impairs CTLH complex assembly and function.
- name: RUNX1T1 Stabilization
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    In Wdr26+/- mice and Wdr26-knockdown neuronal cells, reduced CTLH-mediated
    ubiquitination impairs proteasomal degradation of RUNX1T1 and stabilises the
    protein. RUNX1T1 is a transcriptional coactivator critical for neuronal
    differentiation. This stabilisation is demonstrated in mouse and cell models and
    has not yet been confirmed in human patient tissue, so the node is curated at
    provisional confidence.
  biological_processes:
  - preferred_term: proteasome-mediated ubiquitin-dependent protein catabolic process
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    modifier: DECREASED
  downstream:
  - target: Neuronal Differentiation Dysregulation
    causal_link_type: DIRECT
    description: >-
      Stabilised RUNX1T1 raises MAP2, a regulator of dendritic architecture and
      synaptic plasticity, dysregulating neuronal differentiation.
    evidence:
    - reference: PMID:42138082
      reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "consequently disrupting the level of microtubule-associated protein 2 (MAP2), a key regulator of dendritic architecture and synaptic plasticity."
      explanation: Links stabilised RUNX1T1 to MAP2 dysregulation, the step from the molecular node to the cellular differentiation node.
  evidence:
  - reference: PMID:42138082
    reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Wdr26 haploinsufficiency stabilized RUNX1 translocation partner 1 (RUNX1T1), a transcriptional coactivator critical for neuronal differentiation, by impairing its ubiquitination and proteasomal degradation"
    explanation: Reports RUNX1T1 stabilization via impaired CTLH-dependent ubiquitination in the mouse model.
- name: Neuronal Differentiation Dysregulation
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Elevated RUNX1T1 raises MAP2, a regulator of dendritic architecture and synaptic
    plasticity, disrupting neuronal maturation. This WDR26/RUNX1T1/MAP2 axis is
    demonstrated in mouse and cell models and has not yet been confirmed in human
    patient tissue, so the node is curated at provisional confidence.
  biological_processes:
  - preferred_term: neuron differentiation
    term:
      id: GO:0030182
      label: neuron differentiation
    modifier: DYSREGULATED
  downstream:
  - target: Abnormal Neurodevelopment
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      RUNX1T1/MAP2 dysregulation disrupts neuronal differentiation and dendritic
      architecture in the developing brain.
    evidence:
    - reference: PMID:42138082
      reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "a key regulator of dendritic architecture and synaptic plasticity."
      explanation: MAP2-mediated disruption of dendritic architecture bridges the axis node to abnormal neurodevelopment.
  evidence:
  - reference: PMID:42138082
    reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "consequently disrupting the level of microtubule-associated protein 2 (MAP2), a key regulator of dendritic architecture and synaptic plasticity."
    explanation: Reports the RUNX1T1-driven MAP2 dysregulation that disrupts neuronal differentiation in the mouse model.
- name: Abnormal Neurodevelopment
  biological_scale: CELLULAR
  description: >-
    Disrupted neuronal differentiation and dendritic maturation in progenitors and
    neurons produces the neurodevelopmental phenotype. The Wdr26+/- mouse
    recapitulates core clinical features (learning/memory impairment, social
    dysfunction, heightened seizure susceptibility and motor deficits), supporting
    a causal path from WDR26 dosage to abnormal brain development.
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Impaired neuronal maturation underlies the cognitive impairment.
    evidence:
    - reference: PMID:28686853
      reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "all have intellectual disability with delayed speech"
      explanation: Intellectual disability was present in all individuals of the defining cohort, the neurodevelopmental output of this node.
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Abnormal neurodevelopment produces global delay of motor and language milestones.
    evidence:
    - reference: PMID:33675273
      reference_title: "Expanding the clinical phenotype of the ultra-rare Skraban-Deardorff syndrome: Two novel individuals with WDR26 loss-of-function variants and a literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "including intellectual disability (ID), developmental delay (DD), seizures, abnormal facial features, feeding difficulties, and minor skeletal anomalies."
      explanation: Developmental delay is a defining clinical sign, the neurodevelopmental output of this node.
  - target: Delayed Speech
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Impaired neuronal maturation underlies delayed or absent speech.
    evidence:
    - reference: PMID:28686853
      reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "all have intellectual disability with delayed speech"
      explanation: Delayed speech was present in all individuals of the defining cohort.
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal dendritic architecture and network excitability underlie the seizure
      susceptibility.
    evidence:
    - reference: PMID:28686853
      reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a history of febrile and/or non-febrile seizures"
      explanation: Febrile and/or non-febrile seizures were present in all individuals of the defining cohort.
  - target: Abnormal Gait
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Impaired motor development underlies the wide-based gait.
    evidence:
    - reference: PMID:28686853
      reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a wide-based, spastic, and/or stiff-legged gait."
      explanation: A wide-based/spastic/stiff-legged gait was present in all individuals of the defining cohort.
  - target: Spastic Gait
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The spastic/stiff-legged component of the characteristic gait reflects corticospinal/motor involvement.
    evidence:
    - reference: PMID:28686853
      reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a wide-based, spastic, and/or stiff-legged gait."
      explanation: The spastic/stiff-legged gait component was present in the defining cohort.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Central hypotonia is part of the neurodevelopmental phenotype.
    evidence:
    - reference: PMID:42138082
      reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "including intellectual disability, developmental delay, autistic tendencies, seizures, gait abnormalities, hypotonia, infant feeding difficulties, distinctive facial features, and skeletal abnormalities"
      explanation: Literature-summary statement of the human syndrome's features listing hypotonia; tagged OTHER as a review/background statement within the mouse-model study.
  - target: Autistic Behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Social dysfunction/autistic-like behaviour is a neurodevelopmental output.
    evidence:
    - reference: PMID:42138082
      reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "social impairments resembling autistic-like behaviors in 65% of patients (15 of 23)"
      explanation: Pooled clinical literature figure (secondary citation within the mouse paper) quantifying autistic-like social impairment.
  - target: Feeding Difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Oromotor/neurodevelopmental dysfunction underlies infant feeding difficulties.
    evidence:
    - reference: PMID:33675273
      reference_title: "Expanding the clinical phenotype of the ultra-rare Skraban-Deardorff syndrome: Two novel individuals with WDR26 loss-of-function variants and a literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "seizures, abnormal facial features, feeding difficulties, and minor skeletal anomalies."
      explanation: Feeding difficulties are a defining clinical sign of the disorder.
  - target: Ventriculomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Enlarged cerebral ventricles are a structural correlate of the abnormal brain development.
    evidence:
    - reference: PMID:42138082
      reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "an enlarged ventricular area was observed in the brains of Wdr26+/- mice"
      explanation: The mouse model shows enlarged ventricular area, paralleling patient ventriculomegaly, as a structural correlate of this node.
  evidence:
  - reference: PMID:42138082
    reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Wdr26 heterozygous-KO mice (Wdr26+/-) recapitulated core clinical features of the syndrome, including learning and memory impairments, social dysfunction, heightened seizure susceptibility, and motor deficits, alongside rare craniofacial and dental abnormalities."
    explanation: Demonstrates that WDR26 haploinsufficiency produces the core neurodevelopmental phenotype in vivo.
- name: Abnormal Craniofacial and Skeletal Development
  biological_scale: TISSUE
  description: >-
    In parallel with the neurodevelopmental arm, reduced WDR26 dosage disrupts
    craniofacial and skeletal morphogenesis. The Wdr26+/- mouse shows abnormal tooth
    growth and cranial misalignment, and reduced WDR26 expression is linked to
    craniofacial developmental abnormalities; RUNX1T1-mutation patients likewise show
    craniofacial defects, consistent with a shared developmental program. This node
    collects the recognisable facial gestalt, dental anomalies and minor skeletal
    anomalies of the syndrome.
  downstream:
  - target: Prominent Maxilla
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Craniofacial dysmorphogenesis produces the prominent maxilla revealing the upper gingiva.
    evidence:
    - reference: PMID:28686853
      reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip."
      explanation: A prominent maxilla is part of the shared facial gestalt in the defining cohort.
  - target: Widely Spaced Teeth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Craniofacial/dental dysmorphogenesis produces widely spaced teeth.
    evidence:
    - reference: PMID:28686853
      reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "widely spaced teeth, and a broad nasal tip."
      explanation: Widely spaced teeth are part of the shared facial gestalt in the defining cohort.
  - target: Broad Nasal Tip
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Craniofacial dysmorphogenesis produces the broad nasal tip.
    evidence:
    - reference: PMID:28686853
      reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "widely spaced teeth, and a broad nasal tip."
      explanation: A broad nasal tip is part of the shared facial gestalt in the defining cohort.
  - target: Anteverted Nares
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Craniofacial dysmorphogenesis produces anteverted nares.
    evidence:
    - reference: PMID:42138082
      reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "More than half of the patients show anteverted nares, a depressed nasal root, widely spaced teeth, and abnormal gums"
      explanation: Pooled clinical literature figure (secondary citation within the mouse paper) reporting anteverted nares in more than half of patients.
  - target: Depressed Nasal Root
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Craniofacial dysmorphogenesis produces a depressed nasal root.
    evidence:
    - reference: PMID:42138082
      reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "More than half of the patients show anteverted nares, a depressed nasal root, widely spaced teeth, and abnormal gums"
      explanation: Pooled clinical literature figure (secondary citation within the mouse paper) reporting a depressed nasal root in more than half of patients.
  - target: Abnormal Gums
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Craniofacial/gingival dysmorphogenesis produces abnormal gums.
    evidence:
    - reference: PMID:42138082
      reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "More than half of the patients show anteverted nares, a depressed nasal root, widely spaced teeth, and abnormal gums"
      explanation: Pooled clinical literature figure (secondary citation within the mouse paper) reporting abnormal gums in more than half of patients.
  - target: Minor Skeletal Anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Skeletal dysmorphogenesis produces the minor skeletal anomalies of the disorder.
    evidence:
    - reference: PMID:33675273
      reference_title: "Expanding the clinical phenotype of the ultra-rare Skraban-Deardorff syndrome: Two novel individuals with WDR26 loss-of-function variants and a literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "feeding difficulties, and minor skeletal anomalies."
      explanation: Minor skeletal anomalies are a defining clinical sign of the disorder.
  evidence:
  - reference: PMID:42138082
    reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "motor deficits, alongside rare craniofacial and dental abnormalities."
    explanation: The mouse model recapitulates craniofacial and dental abnormalities, supporting a WDR26-dosage-dependent craniofacial developmental node.
phenotypes:
- category: Cognitive
  name: Intellectual Disability
  description: >-
    Intellectual disability is present in all reported individuals and is
    accompanied by delayed or absent speech.
  frequency: OBLIGATE
  diagnostic: true
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:28686853
    reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait."
    explanation: All 15 individuals in the defining cohort had intellectual disability.
  - reference: PMID:42138082
    reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Consistent with the 30/30 incidence of patients with intellectual disability"
    explanation: Pooled clinical literature figure (secondary citation within the mouse paper) reporting a 30/30 (100%) incidence of intellectual disability, supporting the OBLIGATE band.
- category: Developmental
  name: Global Developmental Delay
  description: >-
    Developmental delay is a defining feature, affecting motor and language
    milestones from infancy.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:33675273
    reference_title: "Expanding the clinical phenotype of the ultra-rare Skraban-Deardorff syndrome: Two novel individuals with WDR26 loss-of-function variants and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including intellectual disability (ID), developmental delay (DD), seizures, abnormal facial features, feeding difficulties, and minor skeletal anomalies."
    explanation: Lists developmental delay among the defining clinical signs of the disorder.
- category: Neurological
  name: Delayed Speech
  description: >-
    Speech is delayed or absent; expressive language is severely limited in most
    individuals.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:28686853
    reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all have intellectual disability with delayed speech"
    explanation: Delayed speech was present in all individuals of the defining cohort.
- category: Neurological
  name: Seizures
  description: >-
    Febrile and non-febrile seizures are characteristic; a majority of individuals
    have clinical seizures or electroencephalographic abnormalities.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:28686853
    reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a history of febrile and/or non-febrile seizures"
    explanation: Febrile and/or non-febrile seizures were present in all individuals of the defining cohort.
  - reference: PMID:42138082
    reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Eighty percent of patients (24 of 30) exhibit either clinical seizures or electroencephalographic abnormalities"
    explanation: Pooled clinical literature figure (secondary citation within the mouse paper, not its own cohort) quantifying seizures/EEG abnormalities at 80%, supporting the VERY_FREQUENT band.
- category: Neurological
  name: Abnormal Gait
  description: >-
    A characteristic wide-based, spastic and/or stiff-legged gait is present in
    affected individuals.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Wide-based, spastic, and/or stiff-legged gait
    term:
      id: HP:0002136
      label: Broad-based gait
  evidence:
  - reference: PMID:28686853
    reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a wide-based, spastic, and/or stiff-legged gait."
    explanation: A wide-based/spastic/stiff-legged gait was present in all individuals of the defining cohort.
- category: Neurological
  name: Spastic Gait
  description: >-
    The spastic and/or stiff-legged component of the characteristic gait; captured
    separately from the wide-based component because the two facets map to distinct
    HPO terms.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Spastic and/or stiff-legged gait
    term:
      id: HP:0002064
      label: Spastic gait
  evidence:
  - reference: PMID:28686853
    reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a wide-based, spastic, and/or stiff-legged gait."
    explanation: The spastic/stiff-legged gait component was present in all individuals of the defining cohort.
- category: Neurological
  name: Hypotonia
  description: >-
    Hypotonia is part of the recognised neurological phenotype of the syndrome.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:42138082
    reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "including intellectual disability, developmental delay, autistic tendencies, seizures, gait abnormalities, hypotonia, infant feeding difficulties, distinctive facial features, and skeletal abnormalities"
    explanation: Literature-summary statement of the human syndrome's phenotypic features listing hypotonia; tagged OTHER because it is a review/background statement within a mouse-model study rather than a primary clinical observation.
- category: Behavioral
  name: Autistic Behavior
  description: >-
    Autistic-like behaviour and social impairment are common and individuals are
    frequently given an autism diagnosis.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:42138082
    reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "social impairments resembling autistic-like behaviors in 65% of patients (15 of 23)"
    explanation: Pooled clinical literature figure (secondary citation within the mouse paper, not its own cohort) quantifying autistic-like social impairment at 65%, supporting a FREQUENT band.
- category: Gastrointestinal
  name: Feeding Difficulties
  description: >-
    Feeding difficulties, often in infancy, are part of the clinical spectrum.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:33675273
    reference_title: "Expanding the clinical phenotype of the ultra-rare Skraban-Deardorff syndrome: Two novel individuals with WDR26 loss-of-function variants and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "seizures, abnormal facial features, feeding difficulties, and minor skeletal anomalies."
    explanation: Lists feeding difficulties among the defining clinical signs of the disorder.
- category: Craniofacial
  name: Prominent Maxilla
  description: >-
    A prominent maxilla with an upper lip that readily reveals the upper gingiva is
    part of the recognisable facial gestalt.
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Prominent maxilla
    term:
      id: HP:0000326
      label: Abnormal maxilla morphology
  evidence:
  - reference: PMID:28686853
    reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip."
    explanation: A prominent maxilla revealing the upper gingiva is part of the shared facial gestalt in the defining cohort.
- category: Craniofacial
  name: Widely Spaced Teeth
  description: >-
    Widely spaced teeth are a consistent component of the facial and dental
    gestalt.
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Widely spaced teeth
    term:
      id: HP:0000687
      label: Widely spaced teeth
  evidence:
  - reference: PMID:28686853
    reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip."
    explanation: Widely spaced teeth are part of the shared facial gestalt in the defining cohort.
- category: Craniofacial
  name: Broad Nasal Tip
  description: >-
    A broad nasal tip completes the recognisable facial gestalt.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Broad nasal tip
    term:
      id: HP:0000455
      label: Broad nasal tip
  evidence:
  - reference: PMID:28686853
    reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "widely spaced teeth, and a broad nasal tip."
    explanation: A broad nasal tip is part of the shared facial gestalt in the defining cohort.
- category: Craniofacial
  name: Anteverted Nares
  description: >-
    Anteverted nares are reported in more than half of individuals with the syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Anteverted nares
    term:
      id: HP:0000463
      label: Anteverted nares
  evidence:
  - reference: PMID:42138082
    reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "More than half of the patients show anteverted nares, a depressed nasal root, widely spaced teeth, and abnormal gums"
    explanation: Pooled clinical literature figure (secondary citation within the mouse paper) reporting anteverted nares in more than half of patients, supporting a FREQUENT band.
- category: Craniofacial
  name: Depressed Nasal Root
  description: >-
    A depressed nasal root is reported in more than half of individuals with the
    syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Depressed nasal root
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: PMID:42138082
    reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "More than half of the patients show anteverted nares, a depressed nasal root, widely spaced teeth, and abnormal gums"
    explanation: Pooled clinical literature figure (secondary citation within the mouse paper) reporting a depressed nasal root in more than half of patients, supporting a FREQUENT band.
- category: Craniofacial
  name: Abnormal Gums
  description: >-
    Abnormal gums are reported in more than half of individuals with the syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal gums
    term:
      id: HP:0000168
      label: Abnormality of the gingiva
  evidence:
  - reference: PMID:42138082
    reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "More than half of the patients show anteverted nares, a depressed nasal root, widely spaced teeth, and abnormal gums"
    explanation: Pooled clinical literature figure (secondary citation within the mouse paper) reporting abnormal gums in more than half of patients, supporting a FREQUENT band.
- category: Neurological
  name: Ventriculomegaly
  description: >-
    Enlarged cerebral ventricles are reported in patients and are recapitulated in
    the Wdr26+/- mouse.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:42138082
    reference_title: "Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "an enlarged ventricular area was observed in the brains of Wdr26+/- mice"
    explanation: The mouse model shows an enlarged ventricular area paralleling patient ventriculomegaly; no patient numerator is reported, so frequency is omitted.
- category: Musculoskeletal
  name: Minor Skeletal Anomalies
  description: >-
    Minor skeletal anomalies are part of the clinical spectrum of the disorder.
  notes: >-
    The generic HP:0011842 (Abnormal skeletal morphology) is retained because the
    cited sources describe only unspecified "minor skeletal anomalies" and do not
    name a specific skeletal feature that would support a more specific HPO term.
  phenotype_term:
    preferred_term: Minor skeletal anomalies
    term:
      id: HP:0011842
      label: Abnormal skeletal morphology
  evidence:
  - reference: PMID:33675273
    reference_title: "Expanding the clinical phenotype of the ultra-rare Skraban-Deardorff syndrome: Two novel individuals with WDR26 loss-of-function variants and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "feeding difficulties, and minor skeletal anomalies."
    explanation: Lists minor skeletal anomalies among the defining clinical signs; frequency omitted as no numerator is given.
animal_models:
- name: Wdr26 heterozygous-knockout mouse
  species: Mouse
  genotype: Wdr26+/- (heterozygous knockout)
  publication: PMID:42138082
  description: >-
    Heterozygous Wdr26-knockout mouse, matching the heterozygous loss-of-function
    genotype of human WDR26 haploinsufficiency, which recapitulates core
    neurodevelopmental features of Skraban-Deardorff syndrome.
  modeled_mechanisms:
  - target: Abnormal Neurodevelopment
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Wdr26+/- mice reproduce core neurodevelopmental features (learning and
      memory impairment, social dysfunction, heightened seizure susceptibility,
      and motor deficits) and show an enlarged ventricular area paralleling
      patient ventriculomegaly. The heterozygous genotype matches the
      heterozygous human loss-of-function state.
    limitations: >-
      Murine models cannot capture the human speech/language and higher-cognitive
      phenotype directly, and the craniofacial and dental abnormalities occur in
      only ~6% of heterozygous mice, far below their frequency in affected
      individuals.
    readouts:
    - name: Ventricular area on brain imaging/histology
      target: Abnormal Neurodevelopment
      direction: INCREASED
      interpretation: Enlarged ventricular area is the structural correlate of patient ventriculomegaly.
      evidence:
      - reference: PMID:42138082
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "an enlarged ventricular area was observed in the brains of Wdr26+/- mice"
        explanation: Reports the enlarged ventricular area measured in the heterozygous mouse brain.
    evidence:
    - reference: PMID:42138082
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Wdr26 heterozygous-KO mice (Wdr26+/-) recapitulated core clinical features of the syndrome, including learning and memory impairments, social dysfunction, heightened seizure susceptibility, and motor deficits, alongside rare craniofacial and dental abnormalities."
      explanation: Establishes the Wdr26+/- mouse as recapitulating the core neurodevelopmental features of the syndrome, supporting its use as a model for this node.
genetic:
- name: WDR26
  gene_term:
    preferred_term: WDR26
    term:
      id: hgnc:21208
      label: WDR26
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    Heterozygous de novo loss-of-function variants (nonsense, frameshift,
    splice-site) and 1q42.12 microdeletions in WDR26 cause the disorder through
    haploinsufficiency; LOF single-nucleotide variants trigger nonsense-mediated
    decay with reduced WDR26 RNA and protein. A minority of pathogenic variants are
    missense substitutions at highly conserved WD40-repeat residues.
  evidence:
  - reference: PMID:28686853
    reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions."
    explanation: Establishes WDR26 de novo pathogenic variants (predominantly loss of function) as causative.
  - reference: PMID:28686853
    reference_title: "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein."
    explanation: Documents that missense variants affect conserved residues of the WD40-repeat protein.
treatments:
- name: Antiseizure Medication
  description: >-
    Symptomatic pharmacological control of febrile and non-febrile seizures with
    antiseizure medication.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticonvulsant agent
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
- name: Physical Therapy
  description: >-
    Physical therapy to address hypotonia, gait abnormality and motor delay.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
- name: Speech and Language Therapy
  description: >-
    Speech and language therapy, including augmentative and alternative
    communication, for delayed or absent speech.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
- name: Occupational Therapy
  description: >-
    Occupational therapy to support adaptive skills and daily functioning.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: occupational therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy