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Classifications

Harrison's Part

🔗

Mappings

MONDO

MONDO:0030994 neurodevelopmental disorder with or without autism or seizures

Primary disease term for this entry. MONDO:0030994 records OMIM:619239 as an xref and CUL3 (HGNC:2553) as the causal gene via RO:0004003.

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Inheritance

1

Autosomal dominant, predominantly de novo HP:0000006

Heterozygous CUL3 variants act dominantly through haploinsufficiency. Most reported probands carry de novo variants identified by trio exome sequencing, but transmission from a mildly affected parent is documented, which is why apparently unaffected parents should not be assumed to be non-carriers. Expressivity is variable even within a family: in one reported pedigree two sisters carrying a nonsense variant had short stature and neurodevelopmental disorder while their carrier father had neurodevelopmental disorder and epilepsy but normal height.

Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE

Show evidence (3 references)

PMID:39501558 SUPPORT Human Clinical

"It is caused by CUL3 (Cullin-3 ubiquitin ligase) haploinsufficiency."

States the dominant loss-of-function dosage mechanism that underlies the autosomal dominant inheritance pattern.

PMID:40763714 SUPPORT Human Clinical

"Our finding expands the spectrum of disease-causing variants in CUL3 and demonstrates variable intra-familial clinical expressivity."

Directly documents variable expressivity among carriers of the same variant within a family, supporting the expressivity statement.

PMID:39301775 SUPPORT Human Clinical

"we provide additional evidence supporting the role of CUL3 in ASD and/or ID with variable penetrance"

The cohort authors' own characterisation of penetrance as variable, which is the separate claim from expressivity and is what the "with or without" in the disease name encodes. Mapped to INCOMPLETE; no quantitative penetrance estimate is reported, so penetrance_percentage is deliberately omitted.

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Mechanistic Hypotheses

2

Dysregulated cap-dependent translation as the proximate neuronal defect

translational_dysregulation_model CANONICAL

Evidence balance 2 support

CUL3 restrains cap-dependent translation initiation by turning over initiation-complex proteins; loss of that restraint dysregulates neuronal protein synthesis, raising glutamatergic drive and excitability. The two strongest pieces of evidence come from opposite directions - 4E-BP1 fails to be degraded in human patient cells, and inhibiting eIF4G1 rescues cellular and behavioural deficits in mice - which is what makes this the leading account. It also places the disorder alongside other monogenic autism syndromes with translational-control defects.

Show evidence (2 references)

PMID:31780330 SUPPORT Model Organism

"ASD-associated cellular and behavioral deficits could be rescued by pharmacological inhibition of the eIF4G1 function and chemogenetic inhibition of neuronal activity."

Rescue by targeting the accumulated translation factor is the causal test this hypothesis rests on.

PMID:39301775 SUPPORT Human Clinical

"Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells."

Anchors the hypothesis in human patient material rather than in mouse alone.

RhoA/plastin-3 cytoskeletal dysregulation and impaired neuronal migration

cytoskeletal_migration_model ALTERNATIVE

Evidence balance 2 support

An alternative - and not mutually exclusive - account in which the proximate defect is cytoskeletal. CUL3 controls the levels of RhoA and plastin-3, both regulators of actin dynamics; their accumulation impairs radial neuronal migration and dendritic growth, producing cortical lamination abnormalities. RhoA inhibition rescues dendrite length and network activity in the haploinsufficient mouse. The distinguishing prediction is developmental timing: this model requires the lesion to act during corticogenesis, and indeed inducing haploinsufficiency in adult mice does not reproduce the behavioural phenotype - which, if it holds in humans, bounds what any postnatal therapy could achieve.

Show evidence (2 references)

PMID:33727673 SUPPORT Model Organism

"Our study identified defects in neuronal cytoskeleton and Rho signaling as the primary targets of Cul3 mutation during brain development."

States the competing claim - that the cytoskeleton, not translation, is the primary target of the lesion.

PMID:34031387 SUPPORT Model Organism

"However, induction of Cul3 haploinsufficiency later in life does not lead to ASD-relevant behaviors, pointing to an important role of Cul3 during a critical developmental window."

Supports the developmental-timing prediction that distinguishes this model from a purely ongoing translational-control defect.

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Discussions and Knowledge Gaps

3

How common are seizures in CUL3-related neurodevelopmental disorder, and is epilepsy a genuine part of the phenotype or an ascertainment artefact of the early case reports?

KNOWLEDGE GAP OPEN cul3_seizure_frequency_discordance

Attached to

pathophysiology#Syndromic Neurodevelopmental Phenotype

The disorder is named for seizures, yet the two data sources disagree sharply. The founding three-case series titled its report around infantile spasms, and independent case reports describe generalised epilepsy followed by autistic regression. But the 37-individual cohort found seizures in only a few patients - febrile or single isolated events - and stated explicitly that epilepsy was not observed as a recurrent feature. Two readings are possible and are not distinguished by the published data: early reports may have been enriched for epilepsy because children with seizures reach exome sequencing sooner, or the later cohort may under-ascertain seizures collected retrospectively across many centres. Until this is settled no frequency band can honestly be assigned, which is why the seizure phenotype in this entry carries evidence but no frequency, and why the discordant cohort statement is retained as a REFUTE item rather than averaged away.

Proposed experiments

Prospective EEG and seizure-history ascertainment in a molecularly defined cohort

cul3_prospective_eeg_cohort

Enrol individuals with confirmed pathogenic CUL3 variants ascertained through neurodevelopmental disorder rather than through epilepsy, and apply uniform seizure-history questionnaires plus standardised EEG at defined ages. Ascertaining through a non-epilepsy route is the design feature that breaks the circularity of the existing literature.

Decision criterion

A seizure prevalence above roughly 20% in a non-epilepsy-ascertained cohort would establish seizures as a genuine core feature; a prevalence at population background would support ascertainment bias in the early reports.

Show evidence (2 references)

PMID:39301775 SUPPORT Human Clinical

"However, epilepsy, which were thought to be a part of the clinical spectrum, were not observed in our patient cohort (OMIM #619239)."

The cohort statement that creates the discordance, explicitly framed by its authors against the prior expectation encoded in the OMIM entry.

PMID:37575562 REFUTE Human Clinical

"Two of the patients had infantile spasms, while the other had short stature with mild to severe intellectual disability."

Two of the three founding patients had infantile spasms - a rate that cannot be reconciled with the later cohort's finding that epilepsy was not a recurrent feature. This is the other side of the gap.

What distinguishes episignature-positive from episignature-negative individuals carrying pathogenic CUL3 variants, and is the difference biological or technical?

OPEN QUESTION OPEN cul3_episignature_subgroup_meaning

Attached to

pathophysiology#Cullin-3 Haploinsufficiency and Reduced CRL3 Ligase Capacity

The methylation episignature splits carriers into two groups that differ in more than their methylation: ADHD was seen in a third of signature-positive individuals and in none of the signature-negatives, and MRI and cardiac abnormalities showed the same all-or-nothing split, while intrauterine growth restriction was roughly twice as frequent in the positive group. Either the signature marks a mechanistically distinct subset - residual CUL3 activity, variant class, or a modifier - or the negative group contains misclassified variants and the split is an artefact of classifier sensitivity. The two readings have opposite consequences for using the signature to reclassify variants of uncertain significance, which is its main proposed clinical use. Denominators in the negative group are very small (one individual for the feeding-problem figure), so the apparent contrasts should not be over-read.

Show evidence (2 references)

PMID:39501558 SUPPORT Human Clinical

"Similarly, attention-deficit/hyperactivity disorder (ADHD) was observed in 33% of the signature positives but not observed (0%) in the signature negatives."

One of the all-or-nothing phenotype contrasts between the two epigenetic subgroups that motivates this question.

PMID:39501558 SUPPORT Human Clinical

"In addition, we performed genotype-phenotype correlation studies to explain the variety in clinical presentation between the cases."

Confirms that the authors themselves treat explaining the clinical variety as an open analytic problem.

Do the mouse Cul3 models capture the features that define the human disorder, or only the features that mice can express?

HUMAN MODEL MISMATCH OPEN cul3_mouse_human_phenotype_mismatch

Attached to

pathophysiology#Excitation-Inhibition Imbalance in Cortico-Striatal Circuits pathophysiology#Impaired Neuronal Migration and Cortical Lamination

The mouse models are good where mice are good and silent where they are not. They reproduce social interaction deficits, hyperactivity, sensorimotor gating and cortical structural change, and they deliver the mechanism and the only pharmacological rescues available. They do not reproduce the human disorder's most consistent feature - speech and language delay, which has no murine counterpart - nor its facial dysmorphism, hand and foot anomalies, or seizures. The mismatch runs the other way too: the models show cortical lamination abnormality and reduced cortical volume, whereas most patients who have had a brain MRI have a normal study. So the cellular mechanism may be real in humans but sub-threshold for clinical imaging, or the mouse cortical phenotype may be more severe than the human one. Model evidence in this entry is therefore weighted towards mechanism and away from phenotype fidelity.

Proposed experiments

Patient-derived iPSC cortical organoid migration and lamination assay

cul3_patient_ipsc_cortical_organoid

Differentiate cortical organoids from iPSCs of individuals with pathogenic CUL3 variants and isogenic controls, and quantify radial migration speed, plastin-3 and RhoA abundance, and layer organisation. This tests the migration mechanism in human cells without requiring patient brain tissue.

Decision criterion

Reduced migration speed with plastin-3 accumulation in patient organoids, corrected in the isogenic control, would carry the mouse mechanism into human cells; normal migration would indicate the mouse cortical phenotype does not transfer and would redirect weight towards the translational model.

Show evidence (2 references)

PMID:34031387 SUPPORT Model Organism

"Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities."

The mouse structural phenotype whose human counterpart is uncertain.

PMID:39301775 REFUTE Human Clinical

"Most individuals who had a brain MRI performed had a normal study, but three were noted to have mild ventriculomegaly."

Human imaging does not show the structural abnormality the mouse model predicts, which is the substance of the mismatch.

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Pathophysiology

8

Heterozygous CUL3 Loss-of-Function Variant

A single heterozygous CUL3 allele is inactivated by a nonsense, frameshift, canonical splice-site or whole-gene deletion event, or by a missense substitution that destabilises the cullin scaffold. Across the two published cohorts the truncating and splice classes dominate; missense alleles are a minority and at least one (p.Val285Ala, in the cullin N-terminal domain) has been shown biochemically to weaken binding to BTB-domain adaptors rather than to abolish the protein. Almost all reported variants are de novo.

CUL3 hgnc:2553

Genetic context CUL3 hgnc:2553 allele_type: SNV variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Heterozygous, predominantly de novo loss-of-function alleles. Reported classes include nonsense, frameshift, canonical splice-site, whole-gene deletion and destabilising missense substitutions. The single reported deletion removed CUL3 together with neighbouring genes, so it is a contiguous multigene CNV rather than a CUL3-only deletion.

Downstream

Cullin-3 Haploinsufficiency and Reduced CRL3 Ligase Capacity Inactivation of one allele halves the pool of functional cullin-3 scaffold available to nucleate CRL3 complexes; destabilising missense alleles reach the same endpoint by weakening adaptor engagement.

Show evidence (3 references)

PMID:39301775 SUPPORT Human Clinical

"Of these, 35 have loss-of-function (LoF) and 2 have missense variants."

Quantifies the variant spectrum in the largest cohort, establishing loss-of-function alleles as the dominant class of trigger event.

PMID:32341456 SUPPORT Human Clinical

"One missense variant c.854T>C, p.(Val285Ala) and two frameshift variants c.137delG, p.(Arg46Leufs*32) and c.1239del, p.(Asp413Glufs*42) were identified by whole-exome sequencing."

Names the specific de novo alleles in the founding case series, documenting both the frameshift and missense classes of trigger variant.

PMID:39501558 SUPPORT Human Clinical

"eight had a nonsense CUL3 variant, five had a missense CUL3 variant, nine had a frameshift CUL3 variant, three had a splice site CUL3 variant, and one particpant had a large deletion encompassing multiple genes, including CUL3."

The only cited evidence for the whole-gene deletion class asserted above: one of 26 individuals carried a deletion encompassing CUL3 and neighbouring genes. Also gives the full class distribution across this cohort. ("particpant" is misspelled in the source and is quoted verbatim.)

Cullin-3 Haploinsufficiency and Reduced CRL3 Ligase Capacity

Cullin-3 is the scaffold that bridges the RBX1-E2 module to a BTB-domain substrate adaptor, so its dose sets the assembly capacity of the entire CRL3 ligase family rather than of one enzyme. Halving that dose lowers global ubiquitin-conjugating output: patient-derived T cells show reduced ubiquitin-protein conjugates. This node is the disorder-agnostic rate-limiting step from which every downstream branch of the entry descends.

CUL3 hgnc:2553

CRL3 (cullin-3-RBX1-BTB adaptor) E3 ubiquitin ligase GO:0031463

protein ubiquitination GO:0016567 ↓ DECREASED

ubiquitin-protein transferase activity of the CRL3 complex GO:0004842 ↓ DECREASED

Animal models

Cul3 germline haploinsufficient mouse Mouse recapitulates Constitutive heterozygous loss of one Cul3 allele is the same dosage lesion as the human loss-of-function state.

Downstream

Failure of CRL3 Substrate Degradation Reduced ligase capacity leaves CRL3 substrates insufficiently polyubiquitinated and therefore not delivered to the proteasome.

Show evidence (3 references)

PMID:39301775 SUPPORT Human Clinical

"CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro."

Demonstrates in patient-derived cells that the loss-of-function alleles lower ubiquitin-conjugating output, which is the defining claim of this node.

PMID:39501558 SUPPORT Human Clinical

"It is caused by CUL3 (Cullin-3 ubiquitin ligase) haploinsufficiency."

Independent cohort attributing the disorder to haploinsufficiency of the cullin-3 ligase rather than to a dominant-negative or gain-of-function effect.

PMID:39301775 SUPPORT Human Clinical

"suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism"

States the authors' mechanistic conclusion, supporting haploinsufficiency as the central effector rather than one of several competing mechanisms.

Failure of CRL3 Substrate Degradation

Because CRL3 acts through interchangeable BTB adaptors, scaffold shortage is felt across a substrate set rather than at a single protein, and the substrates that have been shown to accumulate map onto the two downstream branches this entry curates. Translational control substrates - 4E-BP1 (EIF4EBP1), shown to escape proteasomal degradation in patient-derived cells, and eIF4G1, identified proteomically as a CUL3 target in mouse brain - feed the cap-dependent translation branch. Cytoskeletal substrates - the small GTPase RhoA, and plastin-3 - feed the neuronal migration and dendrite branch; RhoA is presented to CUL3 by the BTB adaptors BACURD1/KCTD13 and BACURD2/TNFAIP1, which is the point at which this disorder touches the 16p11.2 copy-number syndrome, since KCTD13 lies in that interval. The substrate list is almost certainly incomplete.

proteasome-mediated ubiquitin-dependent protein catabolic process GO:0043161 ↓ DECREASED

Experimental models

Patient-derived T cells PRIMARY CELL CULTURE Directly measures the accumulation of a named CRL3 substrate in cells from affected individuals.

Downstream

Dysregulated Cap-Dependent Translation Accumulation of the translation-initiation regulators 4E-BP1 and eIF4G1 dysregulates cap-dependent initiation in CUL3-deficient neurons.

Impaired Neuronal Migration and Cortical Lamination Failure to hold plastin-3 and RhoA at their normal levels disorganises the actin cytoskeleton on which radial neuronal migration depends.

Reduced Dendritic Growth and Inhibitory Synapse Loss Excess RhoA activity, together with elevated caspase-3, restricts dendritic arborisation and reduces inhibitory synaptic puncta.

Show evidence (6 references)

PMID:39301775 SUPPORT Human Clinical

"Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells."

Human patient-cell demonstration that a named CRL3 substrate escapes degradation, the defining claim of this node.

PMID:31780330 SUPPORT Model Organism

"Proteomic analysis revealed eIF4G1, a protein for Cap-dependent translation, as a potential target of CUL3."

Identifies a second translational-machinery substrate of CUL3, supporting the claim that the affected substrate set converges on translational control.

PMID:33727673 SUPPORT Model Organism

"Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes."

Establishes RhoA as a CUL3 substrate whose excess activity is pathogenic, supporting the cytoskeletal arm of the substrate set.

+ 3 more references

Dysregulated Cap-Dependent Translation

CUL3 normally restrains cap-dependent translation initiation by turning over initiation-complex proteins. When that restraint is lost, translational output in neurons is dysregulated; in CUL3-deficient mice this manifests as enhanced glutamatergic transmission and neuronal excitability, and both the cellular and behavioural phenotypes are reversed by pharmacological inhibition of eIF4G1. Dysregulated cap-dependent translation is a mechanism shared with several other monogenic autism syndromes, which is what makes it the most tractable candidate node for intervention in this disorder.

glutamatergic neuron CL:0000679

cap-dependent translational initiation GO:0002191 ↑ INCREASED

Downstream

Excitation-Inhibition Imbalance in Cortico-Striatal Circuits Excess cap-dependent translation raises glutamatergic drive and neuronal excitability, shifting the excitation-inhibition balance.

Show evidence (2 references)

PMID:31780330 SUPPORT Model Organism

"CUL3-deficient mice exhibited social deficits and anxiety-like behaviors with enhanced glutamatergic transmission and neuronal excitability."

Reports the transmission and excitability changes that accompany the translational dysregulation asserted by this node.

PMID:31780330 SUPPORT Model Organism

"ASD-associated cellular and behavioral deficits could be rescued by pharmacological inhibition of the eIF4G1 function and chemogenetic inhibition of neuronal activity."

Rescue on inhibiting the translation-initiation factor is the strongest evidence that this node is causal in the pathway.

Impaired Neuronal Migration and Cortical Lamination

Cul3 is required to hold plastin-3 at the level that permits normal radial migration, and constitutive heterozygous mice show cortical lamination abnormalities as a result. The requirement is developmentally gated: inducing the same haploinsufficiency in adult mice does not produce autism-relevant behaviour, which places the pathogenic window in embryonic and early postnatal corticogenesis and is the strongest argument in this disorder against expecting a purely postnatal pharmacological rescue.

neuron migration GO:0001764 ↓ DECREASED cerebral cortex radially oriented cell migration GO:0021799 ↓ DECREASED actin cytoskeleton organization GO:0030036 ↓ DECREASED

cerebral cortex UBERON:0000956

Animal models

Constitutive Cul3 heterozygous mouse (neuronal migration) Mouse recapitulates Cortical lamination abnormality follows directly from impaired radial neuronal migration in the constitutive heterozygote.

Downstream

Syndromic Neurodevelopmental Phenotype Disordered cortical lamination during the critical developmental window yields the fixed, congenital-onset developmental and cognitive phenotype.

Show evidence (3 references)

PMID:34031387 SUPPORT Model Organism

"Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities."

Directly reports the migration defect and the resulting lamination abnormality asserted by this node.

PMID:34031387 SUPPORT Model Organism

"However, induction of Cul3 haploinsufficiency later in life does not lead to ASD-relevant behaviors, pointing to an important role of Cul3 during a critical developmental window."

Supports the developmental gating claim by showing that the same genetic lesion imposed later is not sufficient to produce the phenotype.

PMID:39301775 SUPPORT Human Clinical

"Changes in neuronal migration and lamination defects have been linked to ASD in humans and mice, implicating CUL3 haploinsufficiency in ASD-related neurobehavioral abnormalities."

Supports the inference to human disease, but only indirectly - it is the cohort authors' interpretation, not a demonstration of lamination defects in patients, so it is recorded as PARTIAL.

Reduced Dendritic Growth and Inhibitory Synapse Loss

In Cul3-deficient hippocampal neurons dendritic complexity and length fall and axon formation is impaired, while gephyrin/vGAT puncta - a marker of inhibitory synapses - are selectively reduced with excitatory vGluT1/PSD95 puncta unchanged. The asymmetry matters: loss of inhibitory synapses is itself a route to excitation-inhibition imbalance, independent of the increase in glutamatergic drive produced by the translational branch. Elevated caspase-3 is the proximate mediator, and caspase-3 inhibition reverses both the morphological and inhibitory-synapse phenotypes.

hippocampal pyramidal neuron CL:1001571 GABAergic neuron CL:0000617

dendrite development GO:0016358 ↓ DECREASED regulation of neuron apoptotic process GO:0043523 ↑ INCREASED

Experimental models

Cul3 knockout mouse hippocampal primary neuronal culture PRIMARY CELL CULTURE Reproduces the dendritic, axonal and inhibitory-synapse phenotype and identifies caspase-3 as the proximate mediator by rescue.

Animal models

Cul3 germline haploinsufficient mouse Mouse rescues RhoA inhibition rescues the dendritic and network-activity phenotypes, showing the substrate accumulation is causal and identifying the disorder's leading mechanism-based therapeutic hypothesis.

Downstream

Excitation-Inhibition Imbalance in Cortico-Striatal Circuits Selective loss of inhibitory synapses lowers inhibitory tone, contributing to the excitation-inhibition imbalance from the opposite direction to the translational branch.

Show evidence (3 references)

PMID:38803442 SUPPORT In Vitro

"Homozygous deletion of Cul3 significantly decreased dendritic complexity and dendritic length, as well as axon formation."

Reports the dendritic and axonal morphology deficit asserted by this node.

PMID:38803442 SUPPORT In Vitro

"Both heterozygous and homozygous knockout of Cul3 caused significant reductions in the density and colocalization of gephyrin/vGAT puncta, providing evidence of decreased inhibitory synapse number, while excitatory synaptic puncta vGulT1/PSD95 density remained unchanged."

Establishes the selective loss of inhibitory synapses - and, importantly, that it occurs in the heterozygous state that models the human disease.

PMID:38803442 SUPPORT In Vitro

"We found that caspase-3 inhibition largely reversed the dendrite, axon, and spine morphological changes along with the inhibitory synaptic puncta changes."

Rescue by caspase-3 inhibition identifies caspase-3 as the proximate mediator claimed in this node.

Excitation-Inhibition Imbalance in Cortico-Striatal Circuits

The two cellular branches converge on altered circuit excitability, and conditional-deletion experiments show the resulting behaviour depends on where the loss occurs rather than on a single global defect: social deficits track loss in prefrontal cortex, stereotypic behaviour tracks loss in striatum, NMDA receptor hypofunction follows forebrain or prefrontal loss, and cholinergic basal-forebrain deletion reproduces social and sensory-gating phenotypes with cognitive impairment. Distinct circuits, one gene dose.

glutamatergic neuron CL:0000679 dopaminergic neuron CL:0000700

synaptic transmission, glutamatergic GO:0035249 ↑ INCREASED chemical synaptic transmission GO:0007268 ↕ DYSREGULATED

prefrontal cortex UBERON:0000451

Animal models

Region- and cell-type-restricted Cul3 conditional knockout mice Mouse recapitulates Circuit-restricted deletion maps distinct behavioural outputs onto distinct brain regions and provides the electrophysiological correlate of each.

Cholinergic-neuron-restricted Cul3 knockout mouse Mouse partially recapitulates Recapitulates the social, sensory-gating and cognitive arm of the phenotype through a cholinergic circuit, but by construction says nothing about the cortical and striatal glutamatergic arms.

CUL3-deficient mouse (dopaminergic/VTA) Mouse partially recapitulates Adds a dopaminergic route to altered circuit excitability and names a candidate ion-channel substrate, but the phenotypes emphasised (psychostimulant sensitivity, sensorimotor gating) map more closely onto schizophrenia-relevant endophenotypes than onto the human developmental syndrome curated here.

Downstream

Syndromic Neurodevelopmental Phenotype Circuit-level imbalance produces the behavioural, social and cognitive components of the human phenotype.

Show evidence (3 references)

PMID:31455858 SUPPORT Model Organism

"Region-specific deletion of Cul3 leads to distinct phenotypes, with social deficits linked to the loss of Cul3 in prefrontal cortex (PFC), and stereotypic behaviors linked to the loss of Cul3 in striatum."

Establishes the circuit specificity that is the substance of this node.

PMID:31455858 SUPPORT Model Organism

"Correlated with these behavioral alterations, Cul3 deficiency in forebrain or PFC induces NMDA receptor hypofunction, while Cul3 loss in striatum causes a cell type-specific alteration of neuronal excitability in striatal circuits."

Provides the electrophysiological correlate - NMDAR hypofunction and altered striatal excitability - underlying the imbalance asserted here.

PMID:36693858 SUPPORT Model Organism

"Conditional Cul3 ablation in cholinergic neurons of mice (ChatCRECul3F/+) recapitulated ASD-like social and sensory gating phenotypes and caused significant cognitive impairments, with diminished activity of cholinergic neurons in the basal forebrain (BF)."

Adds the cholinergic basal-forebrain circuit to the set of circuits whose CUL3 dose determines a distinct behavioural output.

Syndromic Neurodevelopmental Phenotype

The organismal endpoint: a congenital-onset, largely static syndromic neurodevelopmental disorder in which global developmental delay, speech and language delay and intellectual disability are near-universal, mild dysmorphic facial features and hand and foot anomalies are common, and autism, behavioural abnormality, tremor or dystonia, growth restriction and seizures appear in subsets. The variability is not explained by variant class in any published analysis, which is why the disorder is named for its optional rather than its obligatory features.

Show evidence (2 references)

PMID:39301775 SUPPORT Human Clinical

"We assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features."

States the syndromic endpoint and its two-tier structure - obligatory intellectual disability, optional autistic features - that this node encodes.

PMID:39501558 SUPPORT Human Clinical

"Neurodevelopmental disorder with or without autism or seizures (NEDAUS) is a neurodevelopmental disorder characterized by global developmental delay, speech delay, seizures, autistic features, and/or behavior abnormalities."

Independent cohort description of the same organismal phenotype, naming its component features.

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Pathograph

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

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Phenotypes

27

Digestive 2

Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:39501558 SUPPORT Human Clinical

"and feeding problems were present in 36% of the signature positives but only present in one individual (14%) in the signature negatives"

Supports the phenotype while showing the figure is subgroup-dependent, which is why frequency is omitted - recorded as PARTIAL.

Gastroesophageal reflux FREQUENT HP:0002020

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:39301775 SUPPORT Human Clinical

"Gastroesophageal reflux disease (GERD) was noted in infancy in 31% (9/29) of subjects."

Gives 9/29 = 31% for the FREQUENT band and restricts it to infancy, supporting the TRANSIENT qualifier.

Head and Neck 2

Dysmorphic facial features VERY_FREQUENT Abnormal facial shape HP:0001999

Severity: MILD

Show evidence (2 references)

PMID:39301775 SUPPORT Human Clinical

"dysmorphic facial features (high forehead, long face, and other variable features) (87.5%, 28/32)"

Gives 28/32 = 87.5% for the VERY_FREQUENT band and names the two recurring facial elements.

PMID:39301775 SUPPORT Human Clinical

"As noted above, most individuals in the cohort were reported to have dysmorphic facial features, which were usually mild and were somewhat variable"

Supports the MILD severity qualifier and the variability noted in the description.

Pointed chin FREQUENT HP:0000307

Show evidence (1 reference)

PMID:39501558 SUPPORT Human Clinical

"The most frequent facial features were a large forehead (52%) and a pointed chin (50%)."

Gives 50% for pointed chin, within the FREQUENT band.

Musculoskeletal 1

Hypotonia FREQUENT HP:0001252

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:39301775 SUPPORT Human Clinical

"Early hypotonia was seen in 50% of individuals (17/34) but improved or resolved with age in most individuals."

Gives 17/34 = 50% for the FREQUENT band and states the resolution with age that justifies the TRANSIENT temporality qualifier.

Nervous System 15

Global developmental delay VERY_FREQUENT HP:0001263

Show evidence (1 reference)

PMID:39301775 SUPPORT Human Clinical

"Affected individuals presented with global DD (94%, 35/37)"

Gives the numerator and denominator (35/37, 94%) that place this phenotype in the VERY_FREQUENT band (80-100%).

Delayed speech and language development VERY_FREQUENT HP:0000750

Show evidence (1 reference)

PMID:39301775 SUPPORT Human Clinical

"Speech delay was the most consistent feature and was noted in 97% (34/35)."

States both the rank (most consistent feature) and the count 34/35 = 97%, supporting the VERY_FREQUENT band.

Intellectual disability VERY_FREQUENT HP:0001249

Show evidence (2 references)

PMID:39301775 SUPPORT Human Clinical

"Some form of ID was noted in 87% of patients (29/33), though several patients were too young to assess."

Gives 29/33 = 87% for the VERY_FREQUENT band and records the ascertainment caveat noted in the description.

PMID:39501558 SUPPORT Human Clinical

"The predominant characteristics observed among the total cohort were learning disorders (89%), developmental delays including speech and motor skills (88%), behavioral abnormalities (76%), intellectual disabilities (IDs; 77%), and food-hand abnormalities (60%)."

The 26-individual cohort's summary sentence, which puts intellectual disability at 77%. Quoted in full rather than as the bare figure so the denominator it applies to - the total cohort - travels with the number.

Learning disorder VERY_FREQUENT Cognitive impairment HP:0100543

Show evidence (1 reference)

PMID:39501558 SUPPORT Human Clinical

"The predominant characteristics observed among the total cohort were learning disorders (89%)"

Reports 89% for the total cohort, placing this phenotype in the VERY_FREQUENT band.

Delayed gross motor development FREQUENT HP:0002194

Show evidence (1 reference)

PMID:39301775 SUPPORT Human Clinical

"gross and fine motor delays (69%, 20/29 and 97%, 29/30, respectively)"

Gives 20/29 = 69% for gross motor delay, which falls in the FREQUENT band (30-79%), and simultaneously documents the gross/fine asymmetry described.

Autism spectrum disorder FREQUENT HP:0000717

Show evidence (1 reference)

PMID:39301775 SUPPORT Human Clinical

"There was a high degree of clinical suspicion for or a formal diagnosis of ASD in 36% of patients (13/36)."

Gives 13/36 = 36%, placing autism in the FREQUENT band and documenting that the figure mixes formal diagnosis with clinical suspicion.

Behavioral abnormalities FREQUENT Atypical behavior HP:0000708

Show evidence (2 references)

PMID:39501558 SUPPORT Human Clinical

"The predominant characteristics observed among the total cohort were learning disorders (89%), developmental delays including speech and motor skills (88%), behavioral abnormalities (76%), intellectual disabilities (IDs; 77%), and food-hand abnormalities (60%)."

Puts behavioural abnormalities at 76% of the total cohort, within the FREQUENT band. Quoted in full so the figure is not detached from the population it describes.

PMID:39301775 SUPPORT Human Clinical

"Behavioral difficulties were also very prevalent with a subset diagnosed with ASD."

Independent cohort statement that behavioural difficulty is broader than, and more common than, the ASD subset.

Seizures HP:0001250

Show evidence (3 references)

PMID:32341456 SUPPORT Human Clinical

"Here we describe three cases of global developmental delays, with or without epilepsy, who had de novo CUL3 variants."

The founding series that put epilepsy into the disease concept, supporting seizures as a genuine part of the phenotypic spectrum.

PMID:39301775 SUPPORT Human Clinical

"Seizures, in contrast to previous studies, were observed in only a few patients and were either febrile seizures or consisted of single isolated episodes suggesting that this may not be a recurrent clinical feature."

Records the largest cohort's finding that seizures occur but are not a recurrent feature - it supports the phenotype's existence while qualifying any frequency claim, hence PARTIAL.

PMID:39301775 REFUTE Human Clinical

"However, epilepsy, which were thought to be a part of the clinical spectrum, were not observed in our patient cohort (OMIM #619239)."

Explicitly refutes recurrent epilepsy as a core feature in the 37-individual cohort. Retained as a REFUTE item so the discordance stays visible rather than being averaged away.

Epileptic spasms HP:0011097

Show evidence (1 reference)

PMID:37575562 SUPPORT Human Clinical

"Two of the patients had infantile spasms, while the other had short stature with mild to severe intellectual disability."

Reports the seizure type and its numerator in the founding three-patient series - two of three had infantile spasms - which is the specific claim made here. The citing article is a review, but the sentence states the patient findings directly.

Developmental regression HP:0002376

Show evidence (2 references)

PMID:33097317 SUPPORT Human Clinical

"A 21-month-old Japanese girl presented with febrile status epilepticus and thereafter exhibited developmental regression, including loss of her verbal ability, eye contact, and skills in activities of daily living."

Documents the regression phenotype and its temporal relationship to a seizure event in a molecularly confirmed case.

PMID:37026922 SUPPORT Human Clinical

"A four-year-old Chinese girl presented with generalized epilepsy, and then exhibited developmental regression, including loss of her speaking ability, eye contact aversion, and stereotyped behavior."

Independent case report of the same seizure-then-regression sequence, supporting it as a reproducible presentation rather than a single anecdote.

Dystonia OCCASIONAL HP:0001332

Show evidence (1 reference)

PMID:39301775 SUPPORT Human Clinical

"and tremor and/or dystonia (20%, 7/35)"

Gives 7/35 = 20% for tremor and/or dystonia counted together. It bounds but does not isolate the dystonia frequency, so it is recorded as PARTIAL; the bound is still comfortably inside the OCCASIONAL band (5-29%).

Tremor OCCASIONAL HP:0001337

Show evidence (1 reference)

PMID:39301775 SUPPORT Human Clinical

"and tremor and/or dystonia (20%, 7/35)"

The 20% figure is for tremor and/or dystonia combined, so it bounds but does not isolate the tremor frequency - recorded as PARTIAL for that reason.

Cerebellar hypoplasia HP:0001321

Show evidence (2 references)

PMID:41761011 SUPPORT Human Clinical

"The most significant novel finding in our series was cerebellar hypoplasia, which was identified in three of the new cases."

Reports the finding and its small denominator (three cases), supporting both the phenotype and the caution recorded in the description.

PMID:41761011 SUPPORT Human Clinical

"The presence of cerebellar hypoplasia should significantly raise suspicion for a CUL3-related neurodevelopmental disorder."

States the authors' claim of relative specificity that distinguishes this finding from the non-specific prenatal markers.

Attention deficit hyperactivity disorder HP:0007018

Show evidence (1 reference)

PMID:39501558 SUPPORT Human Clinical

"Similarly, attention-deficit/hyperactivity disorder (ADHD) was observed in 33% of the signature positives but not observed (0%) in the signature negatives."

Supports the phenotype but only within the signature-positive subgroup, so no whole-cohort band can be assigned - recorded as PARTIAL.

Ventriculomegaly HP:0002119

Severity: MILD

Show evidence (1 reference)

PMID:39301775 SUPPORT Human Clinical

"Most individuals who had a brain MRI performed had a normal study, but three were noted to have mild ventriculomegaly."

Supports both the finding and the surrounding claim that most imaging is normal.

Growth 2

Intrauterine growth restriction Intrauterine growth retardation HP:0001511

Show evidence (2 references)

PMID:39301775 SUPPORT Human Clinical

"Approximately 36% (13/36) of patients were found to have intrauterine growth restriction (IUGR) during gestation."

Gives the whole-cohort figure of 13/36 = 36% in the largest series.

PMID:39501558 SUPPORT Human Clinical

"We found that intrauterine growth restriction (IUGR) was present in only 29% of the signature-negative cohort compared to the 59% in the signature-positive cohort"

Supports the phenotype but splits it by episignature status, which is why no single frequency band is asserted - recorded as PARTIAL.

Short stature HP:0004322

Show evidence (2 references)

PMID:40763714 SUPPORT Human Clinical

"CUL3-related NDD can be associated with growth retardation."

States the association between the disorder and growth retardation as the case series' own conclusion.

PMID:40763714 SUPPORT Human Clinical

"The proband in Family 1 had short stature (-3.0 SDS), developmental delay, learning difficulties, and autism spectrum disorder."

Quantifies the degree of short stature (-3.0 SDS) in a molecularly confirmed individual.

Other 5

High forehead FREQUENT HP:0000348

Show evidence (1 reference)

PMID:39501558 SUPPORT Human Clinical

"The most frequent facial features were a large forehead (52%) and a pointed chin (50%)."

Gives 52% for the FREQUENT band; the cohort's wording "large forehead" is mapped to the HPO term High forehead.

Hand and foot anomalies FREQUENT Abnormality of limbs HP:0040064

Show evidence (3 references)

PMID:39301775 SUPPORT Human Clinical

"abnormalities of the hands and feet (51%, 18/35)"

Gives 18/35 = 51% for the FREQUENT band.

PMID:39301775 SUPPORT Human Clinical

"(including bilateral 5th finger clinodactyly, thenar hypoplasia, single palmar crease, ankle/foot contractures, pes cavus, cutaneous syndactyly second/third toes, hallux valgus etc.)"

Enumerates the constituent anomalies listed in the description.

PMID:39501558 SUPPORT Human Clinical

"The predominant characteristics observed among the total cohort were learning disorders (89%), developmental delays including speech and motor skills (88%), behavioral abnormalities (76%), intellectual disabilities (IDs; 77%), and food-hand abnormalities (60%)."

Independent cohort figure of 60%, corroborating the FREQUENT band. Note the published text reads "food-hand", a typographical error for foot-hand; the snippet reproduces the source verbatim rather than silently correcting it.

Clinodactyly of the 5th finger HP:0004209

Show evidence (1 reference)

PMID:39301775 SUPPORT Human Clinical

"including bilateral 5th finger clinodactyly, thenar hypoplasia, single palmar crease"

Names bilateral fifth-finger clinodactyly among the reported hand anomalies.

Increased nuchal translucency HP:0010880

Show evidence (1 reference)

PMID:41761011 SUPPORT Human Clinical

"Our analysis of a combined cohort of 25 prenatal cases confirms that intrauterine growth restriction and increased nuchal translucency are frequent, nonspecific findings."

Reports increased nuchal translucency as a frequent prenatal finding while explicitly flagging its non-specificity.

Cardiac septal defects Abnormal cardiac septum morphology HP:0001671

Show evidence (2 references)

PMID:39501558 SUPPORT Human Clinical

"Finally, MRI abnormalities and cardiac abnormalities (mostly atrial septal defect and ventricular septal defect) were frequently noticed in the signature positives (56% and 35%, respectively) but not present in the signature negatives (0%)."

Supports septal defects as a recurring feature and names the specific defect types, but only within the signature-positive subgroup - hence PARTIAL and no frequency band.

PMID:39301775 SUPPORT Human Clinical

"with pulmonic stenosis and pulmonary valve dysplasia, P17 with a ventricular septal defect, and P24 with mild mitral valve insufficiency"

Independent cohort documentation of structural cardiac disease, including a ventricular septal defect, in individually identified patients.

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Genetic Associations

1

CUL3

Gene: CUL3 hgnc:2553 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (3 references)

PMID:39301775 SUPPORT Human Clinical

"We assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features."

Establishes the gene-disease relationship at cohort scale, the basis for the CAUSATIVE relationship type.

PMID:31455858 SUPPORT Human Clinical

"Cullin 3 (Cul3) gene, which encodes a core component of the E3 ubiquitin ligase complex that mediates proteasomal degradation, has been identified as a true high-risk factor for autism."

Supports CUL3's independent status as a high-confidence autism risk gene, the point made in the description.

PMID:32341456 SUPPORT Human Clinical

"Our findings suggest that de novo CUL3 variants may cause structural instability of the CRL complex and impairment of the ubiquitin-proteasome system, leading to diverse neuropsychiatric disorders."

Links de novo CUL3 variation to CRL complex instability, supporting both the DE_NOVO variant origin and the mechanistic claim.

Variants (4)

c.854T>C p.(Val285Ala)

Gene: CUL3 hgnc:2553 missense variant

De novo missense substitution in the cullin N-terminal domain, from the founding case series. Unlike the truncating alleles it leaves a full-length protein, but the mutant binds BTB-domain adaptors significantly more weakly than wild type, reaching the same loss-of-capacity endpoint by a different route.

Show evidence (1 reference)

PMID:32341456 SUPPORT In Vitro

"The Val285 residue located in the Cullin N-terminal domain and p.Val285Ala CUL3 mutant showed significantly weaker interactions to the BTB domain proteins than wild-type CUL3."

Functional demonstration that this missense allele impairs adaptor binding, which is the claim made about it here.

c.1758_1759insTG p.(Thr587*)

Gene: CUL3 hgnc:2553 frameshift variant

De novo two-base insertion producing a premature stop codon, identified by trio exome sequencing in a girl with autism spectrum disorder and Rett-like developmental regression after febrile status epilepticus.

Show evidence (1 reference)

PMID:33097317 SUPPORT Human Clinical

"Trio-based exome sequencing identified a de novo two-base insertion in CUL3, c.1758_1759insTG, p.(Thr587*)."

Reports the exact allele and its de novo origin.

c.379-2A>G

Gene: CUL3 hgnc:2553 splice acceptor variant

De novo canonical acceptor splice-site variant in a child with congenital developmental dysplasia of the hip and global developmental delay. This was the first splice-site allele reported in the neurodevelopmental disorder - notable because splice variants had until then been associated with pseudohypoaldosteronism type IIE rather than with NEDAUS.

Show evidence (2 references)

PMID:36710200 SUPPORT Human Clinical

"A de novo splice site variant (c.379-2A > G) was identified in CUL3 and is predicted to abolish the acceptor splice site."

Reports the allele and its predicted consequence.

PMID:36710200 SUPPORT Human Clinical

"Splice variants in CUL3 are a well-described cause of pseudohypoaldosteronism type IIE; however, splice variants have not been associated with the neurodevelopmental disorder."

Supports the significance claim - that splice alleles had previously been assigned to the other CUL3 disease, so this report crossed that boundary.

c.420C>G p.Tyr140Ter

Gene: CUL3 hgnc:2553 nonsense variant

Inherited nonsense variant segregating in a family with short stature and neurodevelopmental disorder: present in two sisters and in their father, who had neurodevelopmental disorder and epilepsy but normal height. A worked example of intrafamilial variable expressivity.

Show evidence (2 references)

PMID:40763714 SUPPORT Human Clinical

"Whole exome sequencing (WES) revealed a novel likely pathogenic heterozygous nonsense CUL3 variant c.420C>G, p.Tyr140Ter."

Reports the allele and its classification.

PMID:40763714 SUPPORT Human Clinical

"The variant was also identified in her non-identical twin sister, who presented with short stature and NDD, and in their father, who had NDD and epilepsy but normal height."

Documents the segregation and the phenotypic difference between carriers that makes this a variable-expressivity example.

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Medical Actions

6

Early multidisciplinary developmental therapy

Category: Therapeutic Action: Early Intervention NCIT:C159524

Physical, occupational, speech-language and behavioural therapy begun as early as possible. There is no disease-modifying treatment, and no CUL3-specific efficacy data; this is the standard of care for syndromic developmental delay applied to a molecularly defined population. Speech and language therapy has the strongest claim on resources because speech delay is the most consistent feature of the disorder.

Target Phenotypes: Delayed speech and language development HP:0000750 Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:39301775 SUPPORT Human Clinical

"Speech delay was the most consistent feature and was noted in 97% (34/35)."

Supports the prioritisation of speech-language therapy by establishing speech delay as the near-universal feature; it does not evaluate the therapy itself, hence PARTIAL.

Speech and language therapy

Category: Therapeutic Action: Speech Language Therapy NCIT:C159273

Directed at the disorder's most consistent feature. No CUL3-specific trial data exist.

Target Phenotypes: Delayed speech and language development HP:0000750

Physical and occupational therapy

Category: Therapeutic Action: Physical Therapy NCIT:C15302

Directed at early hypotonia, motor delay and, in the minority who develop them, tremor and dystonia. In one reported case, three months of exercise rehabilitation improved exercise capacity while autism symptoms were essentially unchanged - a useful calibration of what motor rehabilitation does and does not address in this disorder.

Target Phenotypes: Hypotonia HP:0001252 Delayed gross motor development HP:0002194

Show evidence (1 reference)

PMID:37026922 SUPPORT Human Clinical

"The patient's exercise capacity had improved, and improvements in autism symptoms were not obvious."

Single-case outcome supporting a motor benefit and, equally usefully, the absence of a behavioural one. n=1 and uncontrolled, hence PARTIAL.

Growth hormone therapy for short stature

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: somatropin NCIT:C837

Two children with CUL3-related neurodevelopmental disorder and short stature were treated with growth hormone and responded well. It addresses a comorbidity rather than the neurodevelopmental phenotype. Two patients, uncontrolled - a signal to evaluate growth and consider endocrine referral, not established therapy. It is not the only reported pharmacological intervention with a described benefit in this population: a single reported patient remained seizure-free on levetiracetam (see Antiseizure medication).

Target Phenotypes: Short stature HP:0004322

Show evidence (2 references)

PMID:40763714 SUPPORT Human Clinical

"The proband and her sister were treated with growth hormone (GH) with good response."

Reports the intervention and the response in molecularly confirmed patients.

PMID:40763714 SUPPORT Human Clinical

"We observed a good response to GH therapy in 2 of our patients with short stature."

States the outcome and its denominator of two, which is what limits this to a signal rather than evidence of efficacy - hence PARTIAL.

Antiseizure medication

Category: Therapeutic Action: Anticonvulsant Therapy NCIT:C64172

Agent: anticonvulsant agent NCIT:C264

Symptomatic treatment for the subset with seizures, chosen by seizure type on general epilepsy principles. No controlled or drug-selection data exist, and no agent is contraindicated on the basis of the genotype. The only reported CUL3-specific observation is a single patient who remained seizure-free on levetiracetam.

Target Phenotypes: Seizure HP:0001250

Show evidence (1 reference)

PMID:37026922 SUPPORT Human Clinical

"The patient was on levetiracetam from September, 2021 at a dose of 2 mL daily, and the seizures did not recur."

The single reported CUL3-specific antiseizure observation. n=1, uncontrolled and with a short follow-up, so it supports the practice of symptomatic treatment without establishing efficacy or drug selection - hence PARTIAL.

Genetic counselling

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

Recurrence risk is low for the de novo majority but is not zero, because parental germline mosaicism is possible and because transmission from a mildly affected parent is documented. Testing parents matters: a carrier parent may have normal height and only mild neurodevelopmental features.

Show evidence (1 reference)

PMID:40763714 SUPPORT Human Clinical

"The variant was inherited from their mother, who had facial dysmorphism and hypertension but normal height."

Documents transmission from a mildly affected parent, the specific scenario that makes parental testing part of counselling here.

🔬

Diagnosis

3

Trio exome or genome sequencing

The diagnostic route in essentially every published case. Because the disorder has no pathognomonic clinical sign - the facial features are mild, brain MRI is usually normal, and the two named features (autism, seizures) are optional - it is not clinically recognisable, and diagnosis is made by sequencing performed for undifferentiated neurodevelopmental disorder. Trio analysis is preferred given the de novo mechanism.

Whole Exome Sequencing NCIT:C101295

Show evidence (3 references)

PMID:33097317 SUPPORT Human Clinical

"Trio-based exome sequencing identified a de novo two-base insertion in CUL3, c.1758_1759insTG, p.(Thr587*)."

Demonstrates the diagnostic route directly: a trio-based exome study identifying the de novo causal allele in an individual ascertained through neurodevelopmental presentation.

PMID:36710200 SUPPORT Human Clinical

"A de novo splice site variant (c.379-2A > G) was identified in CUL3 and is predicted to abolish the acceptor splice site."

A second molecularly confirmed diagnosis made by sequencing rather than by clinical recognition, including a variant class that sequence analysis is needed to interpret.

PMID:33097317 SUPPORT Human Clinical

"Screening of CUL3 variants is worth considering for patients with ASD, especially those with Rett-like developmental regression."

Supports the testing-indication statement, naming the clinical presentation that should prompt consideration of CUL3.

Chromosomal microarray

The route that detects the copy-number class of trigger allele. One of 26 individuals in the largest cohort carried a deletion removing CUL3 together with neighbouring genes - a contiguous multigene CNV, which is precisely the lesion trio exome sequencing can miss. Microarray is therefore complementary to, not redundant with, the sequencing route above, and was part of the clinical workup that identified variants in that cohort.

chromosomal microarray analysis NCIT:C18477

Show evidence (1 reference)

PMID:39501558 SUPPORT Human Clinical

"The identification of CUL3 variants was carried out in a clinical setting using exome sequencing (ES), genome sequencing, and chromosomal microarray."

Names chromosomal microarray as one of the three diagnostic modalities used to ascertain this cohort.

DNA methylation episignature

A sensitive and specific peripheral-blood DNA methylation signature has been defined for CUL3 pathogenic variants and used to reclassify variants of uncertain significance - the practical answer to the interpretive problem created by a gene where missense alleles are hard to call. Two caveats matter. The signature is not universal among pathogenic-variant carriers, so the cohort is split into signature-positive and signature-negative groups, and several phenotype frequencies in this entry differ between them. And the signature resembles those of several other rare neurodevelopmental disorders, so it should be interpreted within a validated classifier rather than read as a standalone test.

DNA Methylation Analysis NCIT:C63328

Show evidence (2 references)

PMID:39501558 SUPPORT Human Clinical

"We discovered a sensitive and specific DNAm episignature for patients with pathogenic variants in CUL3 and utilized it to reclassify patients carrying a VUS in the CUL3 gene."

States both the signature's performance and its intended clinical use for variant reclassification.

PMID:39501558 SUPPORT Human Clinical

"Comparative epigenomic analysis revealed similarities between NEDAUS and several other rare genetic neurodevelopmental disorders with previously identified episignatures, highlighting the broader implication of our findings."

Supports the specificity caveat recorded in the description - the signature overlaps those of other neurodevelopmental disorders.

🩻

Imaging Findings

2

Prenatal cerebellar hypoplasia

Proposed as a sonographic marker with enough specificity to prompt exome sequencing when seen prenatally, in contrast to the growth restriction and increased nuchal translucency that accompany it and are non-specific. Based on three cases.

Ultrasound Diagnostic

Cerebellar hypoplasia HP:0001321

Show evidence (1 reference)

PMID:41761011 SUPPORT Human Clinical

"This finding provides a strong rationale for pursuing exome sequencing and serves as critical evidence for the clinical interpretation of CUL3 variants."

States the diagnostic action the finding is intended to trigger, supporting the diagnostic flag.

Mild ventriculomegaly on brain MRI

The only recurring postnatal brain MRI abnormality in the largest cohort, in three individuals; most studies were normal. Recorded chiefly so that a normal MRI is not read as evidence against the diagnosis.

Mri

Ventriculomegaly HP:0002119

Show evidence (1 reference)

PMID:39301775 SUPPORT Human Clinical

"Most individuals who had a brain MRI performed had a normal study, but three were noted to have mild ventriculomegaly."

Reports both the finding and the predominance of normal studies.

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Prevalence

1

Worldwide

Cases In Literature Unknown

No population prevalence estimate exists. The disorder is known from case reports and two multicentre cohorts of 37 and 26 molecularly confirmed individuals; ascertainment is entirely through trio exome or genome sequencing of children with neurodevelopmental disorder, so published counts are a lower bound rather than an estimate.

Show evidence (1 reference)

PMID:39301775 SUPPORT Human Clinical

"De novo variants in cullin-3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far."

Establishes that, as of the largest cohort study, the disorder was known only from scattered reports with no large series - the basis for recording occurrence as a literature case count rather than a rate.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Neurodevelopmental Disorder With or Without Autism or Seizures:

Pseudohypoaldosteronism type IIE (CUL3-related) Not Yet Curated MONDO:0013782

Overlapping Features The same gene, a different disease, separated by variant class rather than by dose. PHA2E is caused by CUL3 variants that converge on skipping of exon 9, yielding an in-frame deletion that abrogates ubiquitination of WNK kinases presented by the KLHL3 adaptor in the distal nephron; the result is hyperkalaemic hypertension with metabolic acidosis, reversible with thiazide diuretics, and without neurodevelopmental features. A CUL3 variant report must therefore be read for variant class before it is read for gene identity. How CUL3-delta-9 acts downstream is itself contested - a mouse model suggested the truncated protein is degraded, making PHA2E another haploinsufficiency state, while direct testing found additional dominant effects must contribute. That controversy matters here: if PHA2E were purely haploinsufficiency the two diseases would be hard to keep apart mechanistically, so the dominant component is doing real separating work. The clinical boundary is also not absolutely clean - a canonical splice-acceptor allele has now been reported in the neurodevelopmental disorder, and the largest NEDAUS cohort noted individuals with early or juvenile-onset hypertension in the absence of electrolyte abnormalities.

Distinguishing Features

Exon 9 skipping as the shared mutational consequence in PHA2E, versus distributed truncating, splice and missense alleles in NEDAUS
Hyperkalaemia and metabolic acidosis, absent in NEDAUS
Thiazide-responsive hypertension as the presenting problem, rather than developmental delay
No intellectual disability, speech delay or autism

Show evidence (5 references)

PMID:22266938 SUPPORT Human Clinical

"Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion."

Establishes the distinguishing mutational mechanism of PHA2E - convergence on exon 9 skipping - that separates it from the NEDAUS allele spectrum.

PMID:22266938 SUPPORT Human Clinical

"Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis"

States the PHA2E clinical triad used here as the distinguishing feature set.

PMID:39301775 SUPPORT Human Clinical

"we identified several individuals in our cohort without electrolyte abnormalities who had early or juvenile onset hypertension or other congenital cardiac abnormalities"

Supports the caveat that the boundary is not absolute, while confirming the electrolyte abnormalities that define PHA2E were absent - hence PARTIAL.

+ 2 more references

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Related Datasets

1

Autism-linked Cullin3 germline haploinsufficiency severely impacts mouse brain development and cortical neurogenesis through RhoA signaling geo:GSE144046

house mouse BULK RNA SEQ n=108

PMID:33727673

Spatiotemporal transcriptomic profiling of embryonic, early postnatal and adult brain from the CRISPR-generated Cul3 haploinsufficient mouse curated in animal_models. This is the underlying data for the neurogenesis and cytoskeletal findings and for the RhoA rescue. Relevance was triaged manually: a gene-symbol search on CUL3 returns mostly lung, yeast and 16p11.2/KCTD13 datasets that share the gene but not the disease, and those were rejected; this record was accepted because the series title, its linked publication and its genotype all name Cul3 haploinsufficiency in brain. Carries no evidence block by design - a GEO series has no abstract to quote exactly.

🧫

Experimental Models

2

Patient-derived T cells PRIMARY_CELL_CULTURE

T cells from individuals carrying CUL3 loss-of-function variants, used to test the haploinsufficiency mechanism in human cells rather than by inference. They show reduced ubiquitin-protein conjugates, and 4E-BP1 (EIF4EBP1) escapes proteasomal degradation - the only place in this entry where the core molecular defect is demonstrated in patient material.

Organism

human NCBITaxon:9606

Publication

PMID:39301775

Pathograph links

Failure of CRL3 Substrate Degradation measures fidelity: high Directly measures the accumulation of a named CRL3 substrate in cells from affected individuals.

Limitations: T cells are not neurons; whether the same substrate stabilisation occurs in the brain cell types that produce the phenotype is inferred, not shown.

Readouts

Proteasomal degradation of 4E-BP1 (EIF4EBP1)

Direction: DECREASED

Interpretation: Failure to degrade a prominent CUL3 substrate is the direct human-cell readout of reduced CRL3 ligase capacity.

Show evidence (1 reference)

PMID:39301775 SUPPORT Human Clinical

"Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells."

Reports the measurement and its direction in patient cells.

Ubiquitin-protein conjugate abundance

Direction: DECREASED

Interpretation: A global measure of ubiquitin-conjugating output, reduced as predicted by scaffold haploinsufficiency.

Show evidence (1 reference)

PMID:39301775 SUPPORT Human Clinical

"as evidenced by decreased ubiquitin-protein conjugates in vitro"

Reports the global conjugate measurement and its direction.

Show evidence (1 reference)

PMID:39301775 SUPPORT Human Clinical

"Variant effects on CUL3 protein stability were assessed using patient-derived T-cells."

Names the model system and the question it was used to answer, which is why it is informative for this node.

Show evidence (1 reference)

PMID:39301775 SUPPORT Human Clinical

"CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro."

The result obtained in this system - reduced ubiquitin conjugates in patient cells - is what establishes it as an informative human model of the mechanism.

Cul3 knockout mouse hippocampal primary neuronal culture PRIMARY_CELL_CULTURE

Primary hippocampal cultures from Cul3 knockout mice, used because homozygous Cul3 deletion is embryonic lethal in vivo and the early synaptic phenotype therefore cannot be studied in an intact animal. Both heterozygous and homozygous cultures show selective loss of inhibitory synaptic puncta; caspase-3 inhibition reverses the morphological and synaptic changes.

Organism

house mouse NCBITaxon:10090

Publication

PMID:38803442

Pathograph links

Reduced Dendritic Growth and Inhibitory Synapse Loss recapitulates fidelity: moderate Reproduces the dendritic, axonal and inhibitory-synapse phenotype and identifies caspase-3 as the proximate mediator by rescue.

Limitations: The strongest morphological effects required homozygous deletion, which is lethal in vivo and does not correspond to any human genotype; only the inhibitory-synapse deficit was demonstrated in the heterozygous state that matches patients.

Readouts

Gephyrin/vGAT inhibitory synaptic puncta density

Direction: DECREASED

Interpretation: Selective reduction of inhibitory, but not excitatory, puncta is the specific claim this model supports.

Show evidence (1 reference)

PMID:38803442 SUPPORT In Vitro

"Both heterozygous and homozygous knockout of Cul3 caused significant reductions in the density and colocalization of gephyrin/vGAT puncta, providing evidence of decreased inhibitory synapse number, while excitatory synaptic puncta vGulT1/PSD95 density remained unchanged."

Reports the measurement, its direction, and the excitatory control that establishes selectivity.

Neuronal cell viability after caspase-3 inhibition

Direction: RESTORED

Interpretation: Rescue by caspase-3 inhibition identifies caspase-3 as the operative mediator downstream of Cul3 loss.

Show evidence (1 reference)

PMID:38803442 SUPPORT In Vitro

"We then examined the efficacy of the caspase-3 inhibitor Z-DEVD-FMK to rescue the decrease in neuronal cell viability, demonstrating reversal of the cell viability phenotype with caspase-3 inhibition."

Reports the rescue experiment and its outcome.

Show evidence (1 reference)

PMID:38803442 SUPPORT In Vitro

"Cul3 homozygous deletion in mice is embryonic lethal; thus, we examine the role of Cul3 deletion in early synapse development and neuronal morphology in hippocampal primary neuronal cultures."

States why the culture model was necessary, and so why it is the appropriate system for this node.

Show evidence (1 reference)

PMID:38803442 SUPPORT In Vitro

"Overall, these data provide additional evidence that Cul3 regulates the formation or maintenance of cell morphology, GABAergic synaptic puncta, and neuronal viability in developing hippocampal neurons in culture."

States what this culture system established about Cul3 function, which is the basis for treating it as informative for the dendrite and inhibitory-synapse node.

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Animal Models

5

Cul3 germline haploinsufficient mouse Genetically engineered

The closest genetic match to the human disorder - constitutive heterozygosity, the same dosage lesion patients carry. It reproduces behaviour, structure and a molecular mechanism, and supplies the field's only pharmacological rescue: inhibiting RhoA, a CUL3 substrate, restores dendrite length and network activity.

Species

Mouse

Genotype

Cul3 +/- (CRISPR/Cas9 frameshifting insertion)

Background

C57BL/6N

Genes

CUL3 hgnc:2553

Publication

PMID:33727673

Pathograph links

Cullin-3 Haploinsufficiency and Reduced CRL3 Ligase Capacity recapitulates fidelity: high Constitutive heterozygous loss of one Cul3 allele is the same dosage lesion as the human loss-of-function state.

Limitations: Mouse behavioural readouts (social interaction, hyperactivity) are proxies for human social communication and cognition rather than measurements of them, and the model does not reproduce the seizure, dysmorphism or hand-and-foot components of the human syndrome.

Readouts

Cortical regional volume on brain MRI

Direction: DECREASED

Interpretation: Structural correlate establishing that the halved gene dose produces a measurable brain phenotype from early postnatal life.

Show evidence (1 reference)

PMID:33727673 SUPPORT Model Organism

"Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development."

Reports the imaging measurement and its direction.

Show evidence (1 reference)

PMID:33727673 SUPPORT Model Organism

"To investigate how Cul3 mutations impact brain development, we generated a haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering."

Establishes the model's construction as a haploinsufficiency model, which is why it is informative for this node.

Reduced Dendritic Growth and Inhibitory Synapse Loss rescues fidelity: moderate RhoA inhibition rescues the dendritic and network-activity phenotypes, showing the substrate accumulation is causal and identifying the disorder's leading mechanism-based therapeutic hypothesis.

Limitations: Rescue was demonstrated pharmacologically in mice; no human data exist, and the reversibility of a developmentally established phenotype in a patient is untested.

Readouts

Dendrite length after RhoA inhibition

Direction: RESTORED

Interpretation: Restoration on blocking the accumulated substrate identifies RhoA as the operative effector of the dendritic phenotype.

Show evidence (1 reference)

PMID:33727673 SUPPORT Model Organism

"Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes."

Reports the rescue and the measured readout.

Show evidence (1 reference)

PMID:33727673 SUPPORT Model Organism

"Our study identified defects in neuronal cytoskeleton and Rho signaling as the primary targets of Cul3 mutation during brain development."

States the mechanistic conclusion that makes this model informative for the cytoskeletal/dendritic node.

Show evidence (1 reference)

PMID:33727673 SUPPORT Model Organism

"Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior."

Reports the behavioural phenotype that makes this model informative for the human neurobehavioural disorder.

Constitutive Cul3 heterozygous mouse (neuronal migration) Genetically engineered

The model that establishes the developmental timing constraint. Constitutive heterozygotes show cortical lamination abnormalities, but inducing the same haploinsufficiency later in life does not produce autism-relevant behaviour - so the pathogenic window is developmental, not ongoing.

Species

Mouse

Genotype

Cul3 +/-

Genes

CUL3 hgnc:2553

Publication

PMID:34031387

Pathograph links

Impaired Neuronal Migration and Cortical Lamination recapitulates fidelity: moderate Cortical lamination abnormality follows directly from impaired radial neuronal migration in the constitutive heterozygote.

Limitations: Cortical lamination has not been examined in human CUL3 patient brain tissue, and the largest human cohort reports mostly normal brain MRI - so the human counterpart of this cellular phenotype, if present, is below the resolution of clinical imaging.

Readouts

Cortical layer positioning of migrating neurons

Direction: ALTERED

Interpretation: Mispositioning of neurons is the structural expression of the migration defect.

Show evidence (1 reference)

PMID:34031387 SUPPORT Model Organism

"Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities."

Reports the migration defect and the lamination readout.

Show evidence (1 reference)

PMID:34031387 SUPPORT Model Organism

"In mouse, constitutive Cul3 haploinsufficiency leads to motor coordination deficits as well as ASD-relevant social and cognitive impairments."

Establishes that the constitutive heterozygote reproduces disease-relevant behaviour, supporting its use as a model for this node.

Show evidence (1 reference)

PMID:34031387 SUPPORT Model Organism

"De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 (CUL3) lead to autism spectrum disorder (ASD)."

States the human genetic premise the model was built to interrogate, which is what makes this mouse informative for the human disorder.

Region- and cell-type-restricted Cul3 conditional knockout mice Genetically engineered

A series of conditional deletions that dissects which circuit produces which behaviour: prefrontal loss gives social deficits, striatal loss gives stereotypy, forebrain or prefrontal loss gives NMDA receptor hypofunction, and cholinergic basal-forebrain loss gives social and sensory-gating deficits with cognitive impairment. Knocking down the misregulated histone methyltransferase Smyd3 rescues the social phenotype.

Species

Mouse

Genotype

Conditional Cul3 deletion (forebrain, prefrontal cortex, striatum, cholinergic neurons)

Genes

CUL3 hgnc:2553

Publication

PMID:31455858

Pathograph links

Excitation-Inhibition Imbalance in Cortico-Striatal Circuits recapitulates fidelity: moderate Circuit-restricted deletion maps distinct behavioural outputs onto distinct brain regions and provides the electrophysiological correlate of each.

Limitations: Conditional homozygous or region-restricted deletion is a deeper and more spatially confined lesion than the whole-body heterozygosity patients carry, so the mapping of circuit to behaviour is more informative than the absolute severity.

Readouts

NMDA receptor function in prefrontal cortex

Direction: DECREASED

Interpretation: NMDAR hypofunction is the synaptic correlate of the social-behaviour phenotype in this model.

Show evidence (1 reference)

PMID:31455858 SUPPORT Model Organism

"Correlated with these behavioral alterations, Cul3 deficiency in forebrain or PFC induces NMDA receptor hypofunction, while Cul3 loss in striatum causes a cell type-specific alteration of neuronal excitability in striatal circuits."

Reports the measurement and its direction in each region.

Show evidence (1 reference)

PMID:31455858 SUPPORT Model Organism

"These results have revealed for the first time a potential molecular mechanism underlying the manifestation of different autism-like behavioral deficits by Cul3 deletion in cortico-striatal circuits."

States the circuit-level mechanistic conclusion this model contributes.

Show evidence (1 reference)

PMID:31455858 SUPPORT Model Organism

"Inhibition or knockdown of Smyd3 in forebrain Cul3-deficient mice ameliorates social deficits and restores NMDAR function in PFC."

A rescue arm in this model series - correcting a misregulated substrate restores both behaviour and synaptic function - which is what makes the model informative rather than merely descriptive.

Cholinergic-neuron-restricted Cul3 knockout mouse Genetically engineered

Heterozygous Cul3 deletion confined to cholinergic neurons reproduces social and sensory-gating deficits and cognitive impairment. Bidirectional chemogenetic manipulation closes the causal loop: inhibiting basal forebrain cholinergic neurons in healthy mice reproduces the deficits, and stimulating them in mutants reverses them.

Species

Mouse

Genotype

ChAT-Cre; Cul3 flox/+

Genes

CUL3 hgnc:2553

Publication

PMID:36693858

Pathograph links

Excitation-Inhibition Imbalance in Cortico-Striatal Circuits partially recapitulates fidelity: moderate Recapitulates the social, sensory-gating and cognitive arm of the phenotype through a cholinergic circuit, but by construction says nothing about the cortical and striatal glutamatergic arms.

Limitations: Deletion is restricted to cholinergic neurons, so this model isolates one contributing circuit rather than reproducing the distributed loss of CUL3 present in patients.

Readouts

Basal forebrain cholinergic neuron activity

Direction: DECREASED

Interpretation: Diminished cholinergic activity is the circuit lesion linking Cul3 dose to the behavioural phenotype in this model.

Show evidence (1 reference)

PMID:36693858 SUPPORT Model Organism

"Conditional Cul3 ablation in cholinergic neurons of mice (ChatCRECul3F/+) recapitulated ASD-like social and sensory gating phenotypes and caused significant cognitive impairments, with diminished activity of cholinergic neurons in the basal forebrain (BF)."

Reports the activity measurement and the behavioural phenotype.

Show evidence (1 reference)

PMID:36693858 SUPPORT Model Organism

"Conversely, chemogenetic stimulation of BF cholinergic neurons in ChatCRECul3F/+ mice reversed abnormalities in sensory gating and cognition."

The reversal on stimulating the implicated neurons is what makes the circuit claim causal rather than correlative.

Show evidence (1 reference)

PMID:36693858 SUPPORT Model Organism

"Overall, we demonstrate that cholinergic dysfunction due to Cul3 deficiency is involved in ASD-like behavioral abnormalities, and that BF cholinergic neurons are particularly critical for cognitive component through their projections to the PFC."

States the model's overall conclusion and the circuit it implicates, which is the reason this model is curated against the human disorder.

CUL3-deficient mouse (dopaminergic/VTA) Genetically engineered

Extends the mechanism to the dopaminergic system: CUL3-deficient mice show hyperlocomotion, working-memory and sensorimotor-gating deficits and psychostimulant sensitivity, with elevated excitability of ventral tegmental area dopamine neurons, and the ion channel HCN2 identified as a candidate CUL3 target there. Behavioural abnormalities were attenuated by a dopamine D2 receptor antagonist.

Species

Mouse

Genotype

Cul3 deficient

Genes

CUL3 hgnc:2553

Publication

PMID:37558490

Pathograph links

Excitation-Inhibition Imbalance in Cortico-Striatal Circuits partially recapitulates fidelity: low Adds a dopaminergic route to altered circuit excitability and names a candidate ion-channel substrate, but the phenotypes emphasised (psychostimulant sensitivity, sensorimotor gating) map more closely onto schizophrenia-relevant endophenotypes than onto the human developmental syndrome curated here.

Limitations: Studied in male mice only, and the behavioural readouts are not measured counterparts of the human phenotype; the HCN2 substrate relationship is described as potential rather than established.

Readouts

Excitability of ventral tegmental area dopamine neurons

Direction: INCREASED

Interpretation: Elevated dopamine-neuron excitability is the electrophysiological lesion proposed to drive the behavioural phenotype in this model.

Show evidence (1 reference)

PMID:37558490 SUPPORT Model Organism

"In addition, enhanced DA signaling and elevated excitability of the VTA DA neurons were observed in CUL3-deficient animals."

Reports the measurement and its direction.

Show evidence (1 reference)

PMID:37558490 SUPPORT Model Organism

"Our study indicates that CUL3 controls DA neuronal activity by maintaining ion channel homeostasis."

States the mechanistic claim - ion channel homeostasis - by which this model is informative for circuit excitability.

Show evidence (1 reference)

PMID:37558490 SUPPORT Model Organism

"CUL3-deficient mice exhibited hyperactive locomotion, deficits in working memory and sensorimotor gating, and increased sensitivity to psychostimulants."

Reports the behavioural phenotype of this model. It is recorded as PARTIAL because psychostimulant sensitivity and sensorimotor gating are schizophrenia-relevant endophenotypes rather than measured counterparts of the human developmental syndrome.

{ }

Source YAML

click to show

name: Neurodevelopmental Disorder With or Without Autism or Seizures
creation_date: "2026-08-18T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: neurodevelopmental disorder with or without autism or seizures
  term:
    id: MONDO:0030994
    label: neurodevelopmental disorder with or without autism or seizures
description: >-
  Neurodevelopmental disorder with or without autism or seizures (NEDAUS;
  OMIM #619239), also called CUL3-related neurodevelopmental disorder, is an
  autosomal dominant syndromic neurodevelopmental disorder caused by
  heterozygous, overwhelmingly de novo loss-of-function variants in CUL3. CUL3
  encodes cullin-3, the elongated scaffold of the CRL3 family of cullin-RING E3
  ubiquitin ligases: it binds RBX1 (and, through it, the E2 ubiquitin-conjugating
  enzyme) at one end and a BTB-domain substrate adaptor at the other, so that
  substrate proteins are polyubiquitinated and delivered to the 26S proteasome.
  The disease mechanism is haploinsufficiency - a halved dose of the scaffold,
  and therefore a reduced ubiquitin-conjugating capacity of the whole CRL3
  family, rather than the loss of one specific substrate.

  The core clinical picture is far more consistent than the disease name
  suggests. In the largest published cohort (37 individuals), global
  developmental delay, delayed speech and language development, intellectual
  disability and mild dysmorphic facial features were each present in roughly
  nine out of ten patients, whereas autism spectrum disorder was diagnosed in
  about a third and hand and foot anomalies in about half. Speech delay is the
  single most consistent feature. Early hypotonia is common and typically
  improves with age, and a minority develop tremor or dystonia later; a
  prenatal signature of intrauterine growth restriction and increased nuchal
  translucency is recognised, with cerebellar hypoplasia recently proposed as a
  more specific sonographic marker.

  Seizures are the part of the name that the evidence supports least securely.
  The founding case series described global developmental delay with or without
  infantile spasms, and individual case reports document generalised epilepsy
  followed by autistic regression - but the 37-patient cohort found seizures in
  only a few individuals, as febrile or isolated events, and explicitly reported
  that epilepsy was not observed as a recurrent feature of that cohort. This
  entry curates that discordance rather than smoothing it over; the seizure
  phenotype is annotated but its frequency is deliberately left unstated, and
  the tension is recorded as a knowledge gap.

  CUL3 is a two-disease gene, and the two diseases are separated by variant
  class rather than by dosage alone. The variants that cause NEDAUS are
  distributed truncating, splice and missense alleles that reduce functional
  cullin-3; the variants that cause pseudohypoaldosteronism type IIE (PHA2E,
  OMIM #614496) all converge on skipping of exon 9, producing an in-frame
  deletion that abrogates ubiquitination of WNK kinases presented by the KLHL3
  adaptor in the distal nephron. PHA2E is a hyperkalaemic-hypertension disorder
  without neurodevelopmental features. Keeping these apart is the single most
  important interpretive step when reading a CUL3 variant report, and it is
  curated explicitly below as a differential diagnosis.
parents:
- Neurodevelopmental Disorder
- Ubiquitin-Proteasome System Disorder
synonyms:
- NEDAUS
- CUL3-related neurodevelopmental disorder
- neurodevelopmental disorder with autism and seizures
- cullin-3 haploinsufficiency syndrome
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      A congenital-onset disorder of the central nervous system presenting as
      global developmental delay, intellectual disability and behavioural
      abnormality, with variable seizures and movement-disorder features.
    evidence:
    - reference: PMID:39501558
      reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Neurodevelopmental disorder with or without autism or seizures (NEDAUS) is a neurodevelopmental disorder characterized by global developmental delay, speech delay, seizures, autistic features, and/or behavior abnormalities."
      explanation: >-
        Characterises the disorder entirely in central-nervous-system terms,
        supporting assignment to the neurologic chapter.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      Monogenic autosomal dominant disorder caused by heterozygous, largely de
      novo loss-of-function variants in CUL3.
    evidence:
    - reference: PMID:39301775
      reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism"
      explanation: >-
        States the single-gene loss-of-function mechanism that makes this a
        genetics-chapter disorder.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0030994
      label: neurodevelopmental disorder with or without autism or seizures
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary disease term for this entry. MONDO:0030994 records OMIM:619239 as
      an xref and CUL3 (HGNC:2553) as the causal gene via RO:0004003.
references:
- reference: PMID:39301775
  title: Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder.
  findings:
  - statement: >-
      Largest published cohort (37 individuals); establishes haploinsufficiency
      via loss-of-function variants as the predominant mechanism and reports the
      core phenotype frequencies used throughout this entry.
- reference: PMID:39501558
  title: >-
    CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new
    individuals and identification of a potential phenotype-associated episignature.
  findings:
  - statement: >-
      26-individual cohort; defines a sensitive and specific DNA methylation
      episignature usable to reclassify CUL3 variants of uncertain significance.
- reference: PMID:32341456
  title: >-
    De novo variants in CUL3 are associated with global developmental delays with
    or without infantile spasms.
  findings:
  - statement: >-
      Founding clinical description of the disorder; shows that the p.Val285Ala
      missense mutant binds BTB-domain proteins more weakly than wild-type CUL3.
inheritance:
- name: Autosomal dominant, predominantly de novo
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  penetrance: INCOMPLETE
  description: >-
    Heterozygous CUL3 variants act dominantly through haploinsufficiency. Most
    reported probands carry de novo variants identified by trio exome
    sequencing, but transmission from a mildly affected parent is documented,
    which is why apparently unaffected parents should not be assumed to be
    non-carriers. Expressivity is variable even within a family: in one reported
    pedigree two sisters carrying a nonsense variant had short stature and
    neurodevelopmental disorder while their carrier father had neurodevelopmental
    disorder and epilepsy but normal height.
  evidence:
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is caused by CUL3 (Cullin-3 ubiquitin ligase) haploinsufficiency."
    explanation: >-
      States the dominant loss-of-function dosage mechanism that underlies the
      autosomal dominant inheritance pattern.
  - reference: PMID:40763714
    reference_title: "Short Stature and Response to Growth Hormone Treatment in CUL3-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our finding expands the spectrum of disease-causing variants in CUL3 and demonstrates variable intra-familial clinical expressivity."
    explanation: >-
      Directly documents variable expressivity among carriers of the same variant
      within a family, supporting the expressivity statement.
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we provide additional evidence supporting the role of CUL3 in ASD and/or ID with variable penetrance"
    explanation: >-
      The cohort authors' own characterisation of penetrance as variable, which is
      the separate claim from expressivity and is what the "with or without" in the
      disease name encodes. Mapped to INCOMPLETE; no quantitative penetrance
      estimate is reported, so penetrance_percentage is deliberately omitted.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    No population prevalence estimate exists. The disorder is known from case
    reports and two multicentre cohorts of 37 and 26 molecularly confirmed
    individuals; ascertainment is entirely through trio exome or genome
    sequencing of children with neurodevelopmental disorder, so published counts
    are a lower bound rather than an estimate.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "De novo variants in cullin-3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far."
    explanation: >-
      Establishes that, as of the largest cohort study, the disorder was known
      only from scattered reports with no large series - the basis for recording
      occurrence as a literature case count rather than a rate.
pathophysiology:
- name: Heterozygous CUL3 Loss-of-Function Variant
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    A single heterozygous CUL3 allele is inactivated by a nonsense, frameshift,
    canonical splice-site or whole-gene deletion event, or by a missense
    substitution that destabilises the cullin scaffold. Across the two published
    cohorts the truncating and splice classes dominate; missense alleles are a
    minority and at least one (p.Val285Ala, in the cullin N-terminal domain) has
    been shown biochemically to weaken binding to BTB-domain adaptors rather than
    to abolish the protein. Almost all reported variants are de novo.
  genes:
  - preferred_term: CUL3
    term:
      id: hgnc:2553
      label: CUL3
  genetic_context:
    gene:
      preferred_term: CUL3
      term:
        id: hgnc:2553
        label: CUL3
    allele_type: SNV
    variant_origin: DE_NOVO
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Heterozygous, predominantly de novo loss-of-function alleles. Reported
      classes include nonsense, frameshift, canonical splice-site, whole-gene
      deletion and destabilising missense substitutions. The single reported
      deletion removed CUL3 together with neighbouring genes, so it is a
      contiguous multigene CNV rather than a CUL3-only deletion.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of these, 35 have loss-of-function (LoF) and 2 have missense variants."
    explanation: >-
      Quantifies the variant spectrum in the largest cohort, establishing
      loss-of-function alleles as the dominant class of trigger event.
  - reference: PMID:32341456
    reference_title: "De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One missense variant c.854T>C, p.(Val285Ala) and two frameshift variants c.137delG, p.(Arg46Leufs*32) and c.1239del, p.(Asp413Glufs*42) were identified by whole-exome sequencing."
    explanation: >-
      Names the specific de novo alleles in the founding case series, documenting
      both the frameshift and missense classes of trigger variant.
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "eight had a nonsense CUL3 variant, five had a missense CUL3 variant, nine had a frameshift CUL3 variant, three had a splice site CUL3 variant, and one particpant had a large deletion encompassing multiple genes, including CUL3."
    explanation: >-
      The only cited evidence for the whole-gene deletion class asserted above:
      one of 26 individuals carried a deletion encompassing CUL3 and neighbouring
      genes. Also gives the full class distribution across this cohort.
      ("particpant" is misspelled in the source and is quoted verbatim.)
  downstream:
  - target: Cullin-3 Haploinsufficiency and Reduced CRL3 Ligase Capacity
    causal_link_type: DIRECT
    description: >-
      Inactivation of one allele halves the pool of functional cullin-3 scaffold
      available to nucleate CRL3 complexes; destabilising missense alleles reach
      the same endpoint by weakening adaptor engagement.
    evidence:
    - reference: PMID:32341456
      reference_title: "De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The Val285 residue located in the Cullin N-terminal domain and p.Val285Ala CUL3 mutant showed significantly weaker interactions to the BTB domain proteins than wild-type CUL3."
      explanation: >-
        Shows experimentally that a disease allele reduces the scaffold's ability
        to engage its substrate adaptors, the immediate consequence asserted here.
- name: Cullin-3 Haploinsufficiency and Reduced CRL3 Ligase Capacity
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    Cullin-3 is the scaffold that bridges the RBX1-E2 module to a BTB-domain
    substrate adaptor, so its dose sets the assembly capacity of the entire CRL3
    ligase family rather than of one enzyme. Halving that dose lowers global
    ubiquitin-conjugating output: patient-derived T cells show reduced
    ubiquitin-protein conjugates. This node is the disorder-agnostic
    rate-limiting step from which every downstream branch of the entry descends.
  genes:
  - preferred_term: CUL3
    term:
      id: hgnc:2553
      label: CUL3
  protein_complexes:
  - preferred_term: CRL3 (cullin-3-RBX1-BTB adaptor) E3 ubiquitin ligase
    term:
      id: GO:0031463
      label: Cul3-RING ubiquitin ligase complex
    modifier: DECREASED
  molecular_functions:
  - preferred_term: ubiquitin-protein transferase activity of the CRL3 complex
    term:
      id: GO:0004842
      label: ubiquitin-protein transferase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: protein ubiquitination
    term:
      id: GO:0016567
      label: protein ubiquitination
    modifier: DECREASED
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro."
    explanation: >-
      Demonstrates in patient-derived cells that the loss-of-function alleles
      lower ubiquitin-conjugating output, which is the defining claim of this node.
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is caused by CUL3 (Cullin-3 ubiquitin ligase) haploinsufficiency."
    explanation: >-
      Independent cohort attributing the disorder to haploinsufficiency of the
      cullin-3 ligase rather than to a dominant-negative or gain-of-function effect.
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism"
    explanation: >-
      States the authors' mechanistic conclusion, supporting haploinsufficiency as
      the central effector rather than one of several competing mechanisms.
  downstream:
  - target: Failure of CRL3 Substrate Degradation
    causal_link_type: DIRECT
    description: >-
      Reduced ligase capacity leaves CRL3 substrates insufficiently
      polyubiquitinated and therefore not delivered to the proteasome.
    evidence:
    - reference: PMID:39301775
      reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells."
      explanation: >-
        Directly links reduced ligase capacity to failed proteasomal degradation of
        a named CRL3 substrate in patient cells.
- name: Failure of CRL3 Substrate Degradation
  role: mediator
  biological_scale: MOLECULAR
  description: >-
    Because CRL3 acts through interchangeable BTB adaptors, scaffold shortage is
    felt across a substrate set rather than at a single protein, and the
    substrates that have been shown to accumulate map onto the two downstream
    branches this entry curates. Translational control substrates - 4E-BP1
    (EIF4EBP1), shown to escape proteasomal degradation in patient-derived cells,
    and eIF4G1, identified proteomically as a CUL3 target in mouse brain - feed
    the cap-dependent translation branch. Cytoskeletal substrates - the small
    GTPase RhoA, and plastin-3 - feed the neuronal migration and dendrite branch;
    RhoA is presented to CUL3 by the BTB adaptors BACURD1/KCTD13 and
    BACURD2/TNFAIP1, which is the point at which this disorder touches the
    16p11.2 copy-number syndrome, since KCTD13 lies in that interval. The
    substrate list is almost certainly incomplete.
  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
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells."
    explanation: >-
      Human patient-cell demonstration that a named CRL3 substrate escapes
      degradation, the defining claim of this node.
  - reference: PMID:31780330
    reference_title: "CUL3 Deficiency Causes Social Deficits and Anxiety-like Behaviors by Impairing Excitation-Inhibition Balance through the Promotion of Cap-Dependent Translation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Proteomic analysis revealed eIF4G1, a protein for Cap-dependent translation, as a potential target of CUL3."
    explanation: >-
      Identifies a second translational-machinery substrate of CUL3, supporting the
      claim that the affected substrate set converges on translational control.
  - reference: PMID:33727673
    reference_title: "Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes."
    explanation: >-
      Establishes RhoA as a CUL3 substrate whose excess activity is pathogenic,
      supporting the cytoskeletal arm of the substrate set.
  - reference: PMID:34031387
    reference_title: "Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "At the molecular level, we found that Cul3 controls neuronal migration by tightly regulating the amount of Plastin3 (Pls3), a previously unrecognized player of neural migration."
    explanation: >-
      Names plastin-3 as a dose-controlled CUL3 substrate, the second cytoskeletal
      substrate feeding the migration branch.
  - reference: PMID:26969432
    reference_title: "Bacurd1/Kctd13 and Bacurd2/Tnfaip1 are interacting partners to Rnd proteins which influence the long-term positioning and dendritic maturation of cerebral cortical neurons."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we recently identified the BTB/POZ domain-containing Adaptor for Cul3-mediated RhoA Degradation family member Bacurd2 (also known as Tnfaip1) as an interacting partner to Rnd2 for the migration of embryonic mouse cortical neurons"
    explanation: >-
      Names the BTB adaptors that present RhoA to CUL3 and ties them to cortical
      neuron migration. Recorded as PARTIAL because it characterises the adaptors
      rather than measuring substrate accumulation under CUL3 loss.
  - reference: PMID:26969432
    reference_title: "Bacurd1/Kctd13 and Bacurd2/Tnfaip1 are interacting partners to Rnd proteins which influence the long-term positioning and dendritic maturation of cerebral cortical neurons."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we performed a series of in utero electroporation studies in mice and found that disruptions to Bacurd1/Kctd13 or Bacurd2/Tnfaip1 expression impair the long-term positioning of E14.5-born cortical neurons within the postnatal (P17) mouse cerebral cortex"
    explanation: >-
      Shows that perturbing the adaptor arm of the same ligase complex reproduces
      the cortical positioning defect, supporting the adaptor route as the
      mechanistically relevant one.
  downstream:
  - target: Dysregulated Cap-Dependent Translation
    causal_link_type: DIRECT
    description: >-
      Accumulation of the translation-initiation regulators 4E-BP1 and eIF4G1
      dysregulates cap-dependent initiation in CUL3-deficient neurons.
    evidence:
    - reference: PMID:31780330
      reference_title: "CUL3 Deficiency Causes Social Deficits and Anxiety-like Behaviors by Impairing Excitation-Inhibition Balance through the Promotion of Cap-Dependent Translation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "ASD-associated cellular and behavioral deficits could be rescued by pharmacological inhibition of the eIF4G1 function and chemogenetic inhibition of neuronal activity."
      explanation: >-
        Rescue by inhibiting the accumulated substrate shows the translational
        dysregulation is causal, not incidental, downstream of CUL3 loss.
  - target: Impaired Neuronal Migration and Cortical Lamination
    causal_link_type: DIRECT
    description: >-
      Failure to hold plastin-3 and RhoA at their normal levels disorganises the
      actin cytoskeleton on which radial neuronal migration depends.
    evidence:
    - reference: PMID:34031387
      reference_title: "Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Furthermore, we found that Pls3 cell-autonomously regulates cell migration by regulating actin cytoskeleton organization, and its levels are inversely proportional to neural migration speed."
      explanation: >-
        Ties the accumulating substrate mechanistically to actin organisation and
        migration speed, the link asserted by this edge.
  - target: Reduced Dendritic Growth and Inhibitory Synapse Loss
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - RhoA-dependent actin cytoskeletal dysregulation
    - caspase-3 activation
    description: >-
      Excess RhoA activity, together with elevated caspase-3, restricts dendritic
      arborisation and reduces inhibitory synaptic puncta.
    evidence:
    - reference: PMID:33727673
      reference_title: "Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Specifically, dendritic growth, filamentous actin puncta, and spontaneous network activity were reduced in Cul3 mutant mice."
      explanation: >-
        Reports the dendritic and network phenotype that this edge asserts follows
        from cytoskeletal substrate dysregulation.
- name: Dysregulated Cap-Dependent Translation
  role: effector
  biological_scale: CELLULAR
  description: >-
    CUL3 normally restrains cap-dependent translation initiation by turning over
    initiation-complex proteins. When that restraint is lost, translational
    output in neurons is dysregulated; in CUL3-deficient mice this manifests as
    enhanced glutamatergic transmission and neuronal excitability, and both the
    cellular and behavioural phenotypes are reversed by pharmacological
    inhibition of eIF4G1. Dysregulated cap-dependent translation is a mechanism
    shared with several other monogenic autism syndromes, which is what makes it
    the most tractable candidate node for intervention in this disorder.
  biological_processes:
  - preferred_term: cap-dependent translational initiation
    term:
      id: GO:0002191
      label: cap-dependent translational initiation
    modifier: INCREASED
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  evidence:
  - reference: PMID:31780330
    reference_title: "CUL3 Deficiency Causes Social Deficits and Anxiety-like Behaviors by Impairing Excitation-Inhibition Balance through the Promotion of Cap-Dependent Translation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CUL3-deficient mice exhibited social deficits and anxiety-like behaviors with enhanced glutamatergic transmission and neuronal excitability."
    explanation: >-
      Reports the transmission and excitability changes that accompany the
      translational dysregulation asserted by this node.
  - reference: PMID:31780330
    reference_title: "CUL3 Deficiency Causes Social Deficits and Anxiety-like Behaviors by Impairing Excitation-Inhibition Balance through the Promotion of Cap-Dependent Translation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "ASD-associated cellular and behavioral deficits could be rescued by pharmacological inhibition of the eIF4G1 function and chemogenetic inhibition of neuronal activity."
    explanation: >-
      Rescue on inhibiting the translation-initiation factor is the strongest
      evidence that this node is causal in the pathway.
  downstream:
  - target: Excitation-Inhibition Imbalance in Cortico-Striatal Circuits
    causal_link_type: DIRECT
    description: >-
      Excess cap-dependent translation raises glutamatergic drive and neuronal
      excitability, shifting the excitation-inhibition balance.
    evidence:
    - reference: PMID:31780330
      reference_title: "CUL3 Deficiency Causes Social Deficits and Anxiety-like Behaviors by Impairing Excitation-Inhibition Balance through the Promotion of Cap-Dependent Translation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Thus, CUL3 is critical to neural development, neurotransmission, and excitation-inhibition (E-I) balance."
      explanation: >-
        States the authors' conclusion that CUL3 loss acts on excitation-inhibition
        balance, which is the target of this edge.
- name: Impaired Neuronal Migration and Cortical Lamination
  role: effector
  biological_scale: TISSUE
  description: >-
    Cul3 is required to hold plastin-3 at the level that permits normal radial
    migration, and constitutive heterozygous mice show cortical lamination
    abnormalities as a result. The requirement is developmentally gated: inducing
    the same haploinsufficiency in adult mice does not produce autism-relevant
    behaviour, which places the pathogenic window in embryonic and early
    postnatal corticogenesis and is the strongest argument in this disorder
    against expecting a purely postnatal pharmacological rescue.
  biological_processes:
  - preferred_term: neuron migration
    term:
      id: GO:0001764
      label: neuron migration
    modifier: DECREASED
  - preferred_term: cerebral cortex radially oriented cell migration
    term:
      id: GO:0021799
      label: cerebral cortex radially oriented cell migration
    modifier: DECREASED
  - preferred_term: actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
    modifier: DECREASED
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:34031387
    reference_title: "Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities."
    explanation: >-
      Directly reports the migration defect and the resulting lamination
      abnormality asserted by this node.
  - reference: PMID:34031387
    reference_title: "Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, induction of Cul3 haploinsufficiency later in life does not lead to ASD-relevant behaviors, pointing to an important role of Cul3 during a critical developmental window."
    explanation: >-
      Supports the developmental gating claim by showing that the same genetic
      lesion imposed later is not sufficient to produce the phenotype.
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Changes in neuronal migration and lamination defects have been linked to ASD in humans and mice, implicating CUL3 haploinsufficiency in ASD-related neurobehavioral abnormalities."
    explanation: >-
      Supports the inference to human disease, but only indirectly - it is the
      cohort authors' interpretation, not a demonstration of lamination defects in
      patients, so it is recorded as PARTIAL.
  downstream:
  - target: Syndromic Neurodevelopmental Phenotype
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - cortical circuit miswiring
    description: >-
      Disordered cortical lamination during the critical developmental window
      yields the fixed, congenital-onset developmental and cognitive phenotype.
    evidence:
    - reference: PMID:33727673
      reference_title: "Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development."
      explanation: >-
        Shows that the developmental cortical defect is established early and is
        structurally measurable, supporting its role upstream of the organismal
        phenotype.
- name: Reduced Dendritic Growth and Inhibitory Synapse Loss
  role: effector
  biological_scale: CELLULAR
  description: >-
    In Cul3-deficient hippocampal neurons dendritic complexity and length fall
    and axon formation is impaired, while gephyrin/vGAT puncta - a marker of
    inhibitory synapses - are selectively reduced with excitatory
    vGluT1/PSD95 puncta unchanged. The asymmetry matters: loss of inhibitory
    synapses is itself a route to excitation-inhibition imbalance, independent of
    the increase in glutamatergic drive produced by the translational branch.
    Elevated caspase-3 is the proximate mediator, and caspase-3 inhibition
    reverses both the morphological and inhibitory-synapse phenotypes.
  cell_types:
  - preferred_term: hippocampal pyramidal neuron
    term:
      id: CL:1001571
      label: hippocampal pyramidal neuron
  - preferred_term: GABAergic neuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  biological_processes:
  - preferred_term: dendrite development
    term:
      id: GO:0016358
      label: dendrite development
    modifier: DECREASED
  - preferred_term: regulation of neuron apoptotic process
    term:
      id: GO:0043523
      label: regulation of neuron apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:38803442
    reference_title: "Autism risk gene Cul3 alters neuronal morphology via caspase-3 activity in mouse hippocampal neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Homozygous deletion of Cul3 significantly decreased dendritic complexity and dendritic length, as well as axon formation."
    explanation: >-
      Reports the dendritic and axonal morphology deficit asserted by this node.
  - reference: PMID:38803442
    reference_title: "Autism risk gene Cul3 alters neuronal morphology via caspase-3 activity in mouse hippocampal neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Both heterozygous and homozygous knockout of Cul3 caused significant reductions in the density and colocalization of gephyrin/vGAT puncta, providing evidence of decreased inhibitory synapse number, while excitatory synaptic puncta vGulT1/PSD95 density remained unchanged."
    explanation: >-
      Establishes the selective loss of inhibitory synapses - and, importantly,
      that it occurs in the heterozygous state that models the human disease.
  - reference: PMID:38803442
    reference_title: "Autism risk gene Cul3 alters neuronal morphology via caspase-3 activity in mouse hippocampal neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that caspase-3 inhibition largely reversed the dendrite, axon, and spine morphological changes along with the inhibitory synaptic puncta changes."
    explanation: >-
      Rescue by caspase-3 inhibition identifies caspase-3 as the proximate mediator
      claimed in this node.
  downstream:
  - target: Excitation-Inhibition Imbalance in Cortico-Striatal Circuits
    causal_link_type: DIRECT
    description: >-
      Selective loss of inhibitory synapses lowers inhibitory tone, contributing
      to the excitation-inhibition imbalance from the opposite direction to the
      translational branch.
    evidence:
    - reference: PMID:38803442
      reference_title: "Autism risk gene Cul3 alters neuronal morphology via caspase-3 activity in mouse hippocampal neurons."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "providing evidence of decreased inhibitory synapse number, while excitatory synaptic puncta vGulT1/PSD95 density remained unchanged"
      explanation: >-
        The selectivity of the deficit for inhibitory synapses is what makes this
        edge a route to imbalance rather than a generalised synaptic loss.
- name: Excitation-Inhibition Imbalance in Cortico-Striatal Circuits
  role: effector
  biological_scale: CELLULAR
  description: >-
    The two cellular branches converge on altered circuit excitability, and
    conditional-deletion experiments show the resulting behaviour depends on
    where the loss occurs rather than on a single global defect: social deficits
    track loss in prefrontal cortex, stereotypic behaviour tracks loss in
    striatum, NMDA receptor hypofunction follows forebrain or prefrontal loss,
    and cholinergic basal-forebrain deletion reproduces social and sensory-gating
    phenotypes with cognitive impairment. Distinct circuits, one gene dose.
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  - preferred_term: dopaminergic neuron
    term:
      id: CL:0000700
      label: dopaminergic neuron
  biological_processes:
  - preferred_term: synaptic transmission, glutamatergic
    term:
      id: GO:0035249
      label: synaptic transmission, glutamatergic
    modifier: INCREASED
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: DYSREGULATED
  locations:
  - preferred_term: prefrontal cortex
    term:
      id: UBERON:0000451
      label: prefrontal cortex
  evidence:
  - reference: PMID:31455858
    reference_title: "Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Region-specific deletion of Cul3 leads to distinct phenotypes, with social deficits linked to the loss of Cul3 in prefrontal cortex (PFC), and stereotypic behaviors linked to the loss of Cul3 in striatum."
    explanation: >-
      Establishes the circuit specificity that is the substance of this node.
  - reference: PMID:31455858
    reference_title: "Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Correlated with these behavioral alterations, Cul3 deficiency in forebrain or PFC induces NMDA receptor hypofunction, while Cul3 loss in striatum causes a cell type-specific alteration of neuronal excitability in striatal circuits."
    explanation: >-
      Provides the electrophysiological correlate - NMDAR hypofunction and altered
      striatal excitability - underlying the imbalance asserted here.
  - reference: PMID:36693858
    reference_title: "Cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with Cul3 deficiency: Role of prefrontal cortex projections in cognitive deficits."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Conditional Cul3 ablation in cholinergic neurons of mice (ChatCRECul3F/+) recapitulated ASD-like social and sensory gating phenotypes and caused significant cognitive impairments, with diminished activity of cholinergic neurons in the basal forebrain (BF)."
    explanation: >-
      Adds the cholinergic basal-forebrain circuit to the set of circuits whose
      CUL3 dose determines a distinct behavioural output.
  downstream:
  - target: Syndromic Neurodevelopmental Phenotype
    causal_link_type: DIRECT
    description: >-
      Circuit-level imbalance produces the behavioural, social and cognitive
      components of the human phenotype.
    evidence:
    - reference: PMID:31455858
      reference_title: "Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Heterozygous mice with forebrain Cul3 deletion displayed autism-like social interaction impairment and sensory-gating deficiency."
      explanation: >-
        Connects the circuit defect to an organism-level behavioural phenotype in
        the heterozygous state that models the human disorder.
- name: Syndromic Neurodevelopmental Phenotype
  role: outcome
  biological_scale: ORGANISM
  description: >-
    The organismal endpoint: a congenital-onset, largely static syndromic
    neurodevelopmental disorder in which global developmental delay, speech and
    language delay and intellectual disability are near-universal, mild
    dysmorphic facial features and hand and foot anomalies are common, and
    autism, behavioural abnormality, tremor or dystonia, growth restriction and
    seizures appear in subsets. The variability is not explained by variant class
    in any published analysis, which is why the disorder is named for its
    optional rather than its obligatory features.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features."
    explanation: >-
      States the syndromic endpoint and its two-tier structure - obligatory
      intellectual disability, optional autistic features - that this node encodes.
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurodevelopmental disorder with or without autism or seizures (NEDAUS) is a neurodevelopmental disorder characterized by global developmental delay, speech delay, seizures, autistic features, and/or behavior abnormalities."
    explanation: >-
      Independent cohort description of the same organismal phenotype, naming its
      component features.
phenotypes:
- category: Neurologic
  name: Global developmental delay
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  description: >-
    Delay across motor, language and adaptive domains, apparent in infancy. This
    is the entry point to diagnosis in almost every reported case and is present
    in roughly nineteen of every twenty individuals in the largest cohort.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals presented with global DD (94%, 35/37)"
    explanation: >-
      Gives the numerator and denominator (35/37, 94%) that place this phenotype in
      the VERY_FREQUENT band (80-100%).
- category: Neurologic
  name: Delayed speech and language development
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  description: >-
    Speech delay is the single most consistent feature of the disorder, present
    in 34 of 35 assessable individuals in the largest cohort - more consistent
    even than global developmental delay itself.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Speech delay was the most consistent feature and was noted in 97% (34/35)."
    explanation: >-
      States both the rank (most consistent feature) and the count 34/35 = 97%,
      supporting the VERY_FREQUENT band.
- category: Neurologic
  name: Intellectual disability
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  description: >-
    Ranges from mild learning difficulty to severe intellectual disability. No
    severity qualifier is asserted, because the cohort reports the full
    mild-to-severe range rather than a modal severity. Some
    individuals in published cohorts were too young for formal assessment, so the
    reported denominator is smaller than the cohort size.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some form of ID was noted in 87% of patients (29/33), though several patients were too young to assess."
    explanation: >-
      Gives 29/33 = 87% for the VERY_FREQUENT band and records the ascertainment
      caveat noted in the description.
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The predominant characteristics observed among the total cohort were learning disorders (89%), developmental delays including speech and motor skills (88%), behavioral abnormalities (76%), intellectual disabilities (IDs; 77%), and food-hand abnormalities (60%)."
    explanation: >-
      The 26-individual cohort's summary sentence, which puts intellectual
      disability at 77%. Quoted in full rather than as the bare figure so the
      denominator it applies to - the total cohort - travels with the number.
- category: Neurologic
  name: Learning disorder
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Learning disorder
    term:
      id: HP:0100543
      label: Cognitive impairment
  description: >-
    Learning disorder was the single most prevalent characteristic of the
    26-individual episignature cohort, at 89% - counted separately from, and more
    frequent than, intellectual disability at 77% in the same cohort. The source
    does not define what it counted, so this is deliberately bound to the broad
    HPO term Cognitive impairment rather than to Specific learning disability
    (HP:0001328), which would assert impairment in a specific academic skill
    despite normal intelligence - a claim the paper does not make and that sits
    oddly with the cohort's high rate of intellectual disability.
  evidence:
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The predominant characteristics observed among the total cohort were learning disorders (89%)"
    explanation: >-
      Reports 89% for the total cohort, placing this phenotype in the
      VERY_FREQUENT band.
- category: Neurologic
  name: Delayed gross motor development
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Delayed gross motor development
    term:
      id: HP:0002194
      label: Delayed gross motor development
  description: >-
    Gross motor delay affects about two thirds of individuals; fine motor delay
    is reported far more often (29/30) than gross motor delay (20/29) in the same
    cohort, so the two should not be collapsed into a single "motor delay" claim.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gross and fine motor delays (69%, 20/29 and 97%, 29/30, respectively)"
    explanation: >-
      Gives 20/29 = 69% for gross motor delay, which falls in the FREQUENT band
      (30-79%), and simultaneously documents the gross/fine asymmetry described.
- category: Neurologic
  name: Autism spectrum disorder
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  description: >-
    Formal diagnosis of, or high clinical suspicion for, autism spectrum disorder
    in about a third of individuals. This is one of the two optional features the
    disease name is built around, and its sub-half frequency is the reason the
    name reads "with or without".
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was a high degree of clinical suspicion for or a formal diagnosis of ASD in 36% of patients (13/36)."
    explanation: >-
      Gives 13/36 = 36%, placing autism in the FREQUENT band and documenting that
      the figure mixes formal diagnosis with clinical suspicion.
- category: Behavioral
  name: Behavioral abnormalities
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  description: >-
    Behavioural difficulties are more prevalent than formally diagnosed autism
    and include a broader range of presentations than ASD alone.
  evidence:
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The predominant characteristics observed among the total cohort were learning disorders (89%), developmental delays including speech and motor skills (88%), behavioral abnormalities (76%), intellectual disabilities (IDs; 77%), and food-hand abnormalities (60%)."
    explanation: >-
      Puts behavioural abnormalities at 76% of the total cohort, within the
      FREQUENT band. Quoted in full so the figure is not detached from the
      population it describes.
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Behavioral difficulties were also very prevalent with a subset diagnosed with ASD."
    explanation: >-
      Independent cohort statement that behavioural difficulty is broader than, and
      more common than, the ASD subset.
- category: Neurologic
  name: Seizures
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  description: >-
    Seizures are the disorder's most contested feature and no frequency is
    asserted here. The founding series described global developmental delay with
    or without infantile spasms, and case reports document generalised epilepsy
    preceding autistic regression; but the largest cohort found seizures in only
    a few individuals, as febrile or single isolated events, and stated
    explicitly that epilepsy was not observed as a recurrent feature of that
    cohort. See the KNOWLEDGE_GAP discussion cul3_seizure_frequency_discordance.
  evidence:
  - reference: PMID:32341456
    reference_title: "De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe three cases of global developmental delays, with or without epilepsy, who had de novo CUL3 variants."
    explanation: >-
      The founding series that put epilepsy into the disease concept, supporting
      seizures as a genuine part of the phenotypic spectrum.
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures, in contrast to previous studies, were observed in only a few patients and were either febrile seizures or consisted of single isolated episodes suggesting that this may not be a recurrent clinical feature."
    explanation: >-
      Records the largest cohort's finding that seizures occur but are not a
      recurrent feature - it supports the phenotype's existence while qualifying
      any frequency claim, hence PARTIAL.
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "However, epilepsy, which were thought to be a part of the clinical spectrum, were not observed in our patient cohort (OMIM #619239)."
    explanation: >-
      Explicitly refutes recurrent epilepsy as a core feature in the 37-individual
      cohort. Retained as a REFUTE item so the discordance stays visible rather
      than being averaged away.
- category: Neurologic
  name: Epileptic spasms
  phenotype_term:
    preferred_term: Epileptic spasm
    term:
      id: HP:0011097
      label: Epileptic spasm
  description: >-
    Infantile spasms were prominent enough in the founding three-case series to
    appear in that paper's title, but have not been a recurring feature of the
    later, larger cohorts.
  evidence:
  - reference: PMID:37575562
    reference_title: "Current trends of high-risk gene Cul3 in neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two of the patients had infantile spasms, while the other had short stature with mild to severe intellectual disability."
    explanation: >-
      Reports the seizure type and its numerator in the founding three-patient
      series - two of three had infantile spasms - which is the specific claim made
      here. The citing article is a review, but the sentence states the patient
      findings directly.
- category: Neurologic
  name: Developmental regression
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  description: >-
    Loss of previously acquired language, eye contact and daily-living skills
    following seizure onset has been reported in individual cases, sometimes with
    a Rett-like presentation. It is a case-report-level observation, not a cohort
    finding, and no frequency is asserted.
  evidence:
  - reference: PMID:33097317
    reference_title: "A novel stop-gain CUL3 mutation in a Japanese patient with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 21-month-old Japanese girl presented with febrile status epilepticus and thereafter exhibited developmental regression, including loss of her verbal ability, eye contact, and skills in activities of daily living."
    explanation: >-
      Documents the regression phenotype and its temporal relationship to a
      seizure event in a molecularly confirmed case.
  - reference: PMID:37026922
    reference_title: "A nonsense mutation in the CUL3 gene in a Chinese patient with autism spectrum disorder and epilepsy: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A four-year-old Chinese girl presented with generalized epilepsy, and then exhibited developmental regression, including loss of her speaking ability, eye contact aversion, and stereotyped behavior."
    explanation: >-
      Independent case report of the same seizure-then-regression sequence,
      supporting it as a reproducible presentation rather than a single anecdote.
- category: Neurologic
  name: Hypotonia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
    temporality: TRANSIENT
  description: >-
    Early hypotonia affects half of individuals and, unusually for a
    neurodevelopmental disorder, generally improves or resolves with age. The
    later emergence of tremor and dystonia in a minority means the motor
    phenotype can invert over a lifetime.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early hypotonia was seen in 50% of individuals (17/34) but improved or resolved with age in most individuals."
    explanation: >-
      Gives 17/34 = 50% for the FREQUENT band and states the resolution with age
      that justifies the TRANSIENT temporality qualifier.
- category: Neurologic
  name: Dystonia
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  description: >-
    Dystonia in a minority of individuals, generally emerging after the early
    hypotonic phase. The published figure counts tremor and dystonia jointly, so
    20% is an upper bound on dystonia alone; the band is assigned from that bound,
    which stays within OCCASIONAL whichever way the joint count splits.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and tremor and/or dystonia (20%, 7/35)"
    explanation: >-
      Gives 7/35 = 20% for tremor and/or dystonia counted together. It bounds but
      does not isolate the dystonia frequency, so it is recorded as PARTIAL; the
      bound is still comfortably inside the OCCASIONAL band (5-29%).
- category: Neurologic
  name: Tremor
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  description: >-
    Reported together with dystonia as a late motor feature in about 20% of the
    largest cohort; the two were counted jointly and are not separable from the
    published figure, so 20% is an upper bound on tremor alone.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and tremor and/or dystonia (20%, 7/35)"
    explanation: >-
      The 20% figure is for tremor and/or dystonia combined, so it bounds but does
      not isolate the tremor frequency - recorded as PARTIAL for that reason.
- category: Craniofacial
  name: Dysmorphic facial features
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
    severity: MILD
  description: >-
    Mild and variable facial dysmorphism in the great majority of individuals -
    high forehead and long face are the recurring elements, with a pointed chin
    also common. The features are consistent enough to be detectable by automated
    facial phenotyping (GestaltMatcher) but too mild and too variable to be
    diagnostic on inspection.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dysmorphic facial features (high forehead, long face, and other variable features) (87.5%, 28/32)"
    explanation: >-
      Gives 28/32 = 87.5% for the VERY_FREQUENT band and names the two recurring
      facial elements.
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As noted above, most individuals in the cohort were reported to have dysmorphic facial features, which were usually mild and were somewhat variable"
    explanation: >-
      Supports the MILD severity qualifier and the variability noted in the
      description.
- category: Craniofacial
  name: High forehead
  frequency: FREQUENT
  phenotype_term:
    preferred_term: High forehead
    term:
      id: HP:0000348
      label: High forehead
  description: >-
    A large or high forehead was the most frequent single facial feature in the
    26-individual episignature cohort.
  evidence:
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent facial features were a large forehead (52%) and a pointed chin (50%)."
    explanation: >-
      Gives 52% for the FREQUENT band; the cohort's wording "large forehead" is
      mapped to the HPO term High forehead.
- category: Craniofacial
  name: Pointed chin
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Pointed chin
    term:
      id: HP:0000307
      label: Pointed chin
  evidence:
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent facial features were a large forehead (52%) and a pointed chin (50%)."
    explanation: >-
      Gives 50% for pointed chin, within the FREQUENT band.
- category: Skeletal
  name: Hand and foot anomalies
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hand and foot anomalies
    term:
      id: HP:0040064
      label: Abnormality of limbs
  description: >-
    About half of individuals have anomalies of the hands and feet: bilateral
    fifth-finger clinodactyly, thenar hypoplasia, single palmar crease,
    ankle/foot contractures, pes cavus, cutaneous syndactyly of the second and
    third toes and hallux valgus are the recurring elements. No single anomaly
    dominates, which is why the phenotype is curated at the level of the
    hand-and-foot bundle as well as by its commonest constituent. The bundle is
    bound to the limb-level term rather than to a finger-level one, because the
    published 51% counts hands and feet together and half of the listed findings
    are in the foot.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormalities of the hands and feet (51%, 18/35)"
    explanation: >-
      Gives 18/35 = 51% for the FREQUENT band.
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(including bilateral 5th finger clinodactyly, thenar hypoplasia, single palmar crease, ankle/foot contractures, pes cavus, cutaneous syndactyly second/third toes, hallux valgus etc.)"
    explanation: >-
      Enumerates the constituent anomalies listed in the description.
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The predominant characteristics observed among the total cohort were learning disorders (89%), developmental delays including speech and motor skills (88%), behavioral abnormalities (76%), intellectual disabilities (IDs; 77%), and food-hand abnormalities (60%)."
    explanation: >-
      Independent cohort figure of 60%, corroborating the FREQUENT band. Note the
      published text reads "food-hand", a typographical error for foot-hand; the
      snippet reproduces the source verbatim rather than silently correcting it.
- category: Skeletal
  name: Clinodactyly of the 5th finger
  phenotype_term:
    preferred_term: Clinodactyly of the 5th finger
    term:
      id: HP:0004209
      label: Clinodactyly of the 5th finger
  description: >-
    The most frequently named individual hand anomaly, listed first among the
    hand and foot findings of the largest cohort. No separate frequency is
    published for it.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including bilateral 5th finger clinodactyly, thenar hypoplasia, single palmar crease"
    explanation: >-
      Names bilateral fifth-finger clinodactyly among the reported hand anomalies.
- category: Growth
  name: Intrauterine growth restriction
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  description: >-
    Reported in about a third of the largest cohort. Frequency is deliberately
    not banded here: the episignature cohort found it in 59% of
    signature-positive but only 29% of signature-negative individuals, so a
    single band would misrepresent a figure that depends on which subgroup is
    counted.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately 36% (13/36) of patients were found to have intrauterine growth restriction (IUGR) during gestation."
    explanation: >-
      Gives the whole-cohort figure of 13/36 = 36% in the largest series.
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that intrauterine growth restriction (IUGR) was present in only 29% of the signature-negative cohort compared to the 59% in the signature-positive cohort"
    explanation: >-
      Supports the phenotype but splits it by episignature status, which is why no
      single frequency band is asserted - recorded as PARTIAL.
- category: Prenatal
  name: Increased nuchal translucency
  phenotype_term:
    preferred_term: Increased nuchal translucency
    term:
      id: HP:0010880
      label: Increased nuchal translucency
  description: >-
    A frequent but non-specific prenatal ultrasound finding in CUL3-related
    neurodevelopmental disorder, alongside intrauterine growth restriction.
  evidence:
  - reference: PMID:41761011
    reference_title: "CUL3-Related Neurodevelopmental Disorder: Expanding the Prenatal Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our analysis of a combined cohort of 25 prenatal cases confirms that intrauterine growth restriction and increased nuchal translucency are frequent, nonspecific findings."
    explanation: >-
      Reports increased nuchal translucency as a frequent prenatal finding while
      explicitly flagging its non-specificity.
- category: Neurologic
  name: Cerebellar hypoplasia
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  description: >-
    Newly proposed as a comparatively specific prenatal sonographic marker: unlike
    growth restriction and nuchal translucency, its presence is argued to raise
    suspicion for this disorder specifically. Based on three new cases, so the
    claim is a proposal awaiting replication rather than an established sign.
  evidence:
  - reference: PMID:41761011
    reference_title: "CUL3-Related Neurodevelopmental Disorder: Expanding the Prenatal Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most significant novel finding in our series was cerebellar hypoplasia, which was identified in three of the new cases."
    explanation: >-
      Reports the finding and its small denominator (three cases), supporting both
      the phenotype and the caution recorded in the description.
  - reference: PMID:41761011
    reference_title: "CUL3-Related Neurodevelopmental Disorder: Expanding the Prenatal Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of cerebellar hypoplasia should significantly raise suspicion for a CUL3-related neurodevelopmental disorder."
    explanation: >-
      States the authors' claim of relative specificity that distinguishes this
      finding from the non-specific prenatal markers.
- category: Growth
  name: Short stature
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  description: >-
    Growth retardation is part of the spectrum in a subset. It is clinically
    actionable rather than merely descriptive, because two reported children
    responded well to growth hormone.
  evidence:
  - reference: PMID:40763714
    reference_title: "Short Stature and Response to Growth Hormone Treatment in CUL3-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CUL3-related NDD can be associated with growth retardation."
    explanation: >-
      States the association between the disorder and growth retardation as the
      case series' own conclusion.
  - reference: PMID:40763714
    reference_title: "Short Stature and Response to Growth Hormone Treatment in CUL3-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband in Family 1 had short stature (-3.0 SDS), developmental delay, learning difficulties, and autism spectrum disorder."
    explanation: >-
      Quantifies the degree of short stature (-3.0 SDS) in a molecularly confirmed
      individual.
- category: Gastrointestinal
  name: Feeding difficulties
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  description: >-
    Reported in about a third of episignature-positive individuals but in only
    one of seven signature-negative individuals, so no single frequency band is
    asserted.
  evidence:
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and feeding problems were present in 36% of the signature positives but only present in one individual (14%) in the signature negatives"
    explanation: >-
      Supports the phenotype while showing the figure is subgroup-dependent, which
      is why frequency is omitted - recorded as PARTIAL.
- category: Gastrointestinal
  name: Gastroesophageal reflux
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
    temporality: TRANSIENT
  description: >-
    Gastro-oesophageal reflux disease in infancy in about a third of individuals.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gastroesophageal reflux disease (GERD) was noted in infancy in 31% (9/29) of subjects."
    explanation: >-
      Gives 9/29 = 31% for the FREQUENT band and restricts it to infancy,
      supporting the TRANSIENT qualifier.
- category: Behavioral
  name: Attention deficit hyperactivity disorder
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  description: >-
    Observed in a third of episignature-positive individuals and in none of the
    signature-negative individuals - one of the features that distinguishes the
    two epigenetic subgroups. No whole-cohort frequency is published.
  evidence:
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similarly, attention-deficit/hyperactivity disorder (ADHD) was observed in 33% of the signature positives but not observed (0%) in the signature negatives."
    explanation: >-
      Supports the phenotype but only within the signature-positive subgroup, so no
      whole-cohort band can be assigned - recorded as PARTIAL.
- category: Cardiovascular
  name: Cardiac septal defects
  phenotype_term:
    preferred_term: Abnormal cardiac septum morphology
    term:
      id: HP:0001671
      label: Abnormal cardiac septum morphology
  description: >-
    Atrial and ventricular septal defects were noted in about a third of
    episignature-positive individuals and in none of the signature-negative
    group; the largest cohort separately records individuals with pulmonic
    stenosis, ventricular septal defect and mitral valve insufficiency. Cardiac
    assessment is therefore warranted at diagnosis.
  evidence:
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Finally, MRI abnormalities and cardiac abnormalities (mostly atrial septal defect and ventricular septal defect) were frequently noticed in the signature positives (56% and 35%, respectively) but not present in the signature negatives (0%)."
    explanation: >-
      Supports septal defects as a recurring feature and names the specific defect
      types, but only within the signature-positive subgroup - hence PARTIAL and no
      frequency band.
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with pulmonic stenosis and pulmonary valve dysplasia, P17 with a ventricular septal defect, and P24 with mild mitral valve insufficiency"
    explanation: >-
      Independent cohort documentation of structural cardiac disease, including a
      ventricular septal defect, in individually identified patients.
- category: Neurologic
  name: Ventriculomegaly
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
    severity: MILD
  description: >-
    Brain MRI is normal in most individuals of the largest cohort; mild
    ventriculomegaly was the only recurring abnormality, in three patients. This
    is a useful negative: a normal MRI does not argue against the diagnosis.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most individuals who had a brain MRI performed had a normal study, but three were noted to have mild ventriculomegaly."
    explanation: >-
      Supports both the finding and the surrounding claim that most imaging is
      normal.
genetic:
- name: CUL3
  gene_term:
    preferred_term: CUL3
    term:
      id: hgnc:2553
      label: CUL3
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    CUL3 (cullin 3, 2q36.2, OMIM *603136) is the sole causative gene. It encodes
    the scaffold subunit of CRL3 ubiquitin ligases and is the only locus known to
    produce this phenotype. Independent of the syndromic-disorder literature,
    CUL3 was established as one of the highest-confidence autism risk genes by
    large-scale exome sequencing consortia, which is why the disorder was
    recognised through autism cohorts before it was described as a syndrome.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features."
    explanation: >-
      Establishes the gene-disease relationship at cohort scale, the basis for the
      CAUSATIVE relationship type.
  - reference: PMID:31455858
    reference_title: "Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cullin 3 (Cul3) gene, which encodes a core component of the E3 ubiquitin ligase complex that mediates proteasomal degradation, has been identified as a true high-risk factor for autism."
    explanation: >-
      Supports CUL3's independent status as a high-confidence autism risk gene,
      the point made in the description.
  - reference: PMID:32341456
    reference_title: "De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings suggest that de novo CUL3 variants may cause structural instability of the CRL complex and impairment of the ubiquitin-proteasome system, leading to diverse neuropsychiatric disorders."
    explanation: >-
      Links de novo CUL3 variation to CRL complex instability, supporting both the
      DE_NOVO variant origin and the mechanistic claim.
  variants:
  - name: c.854T>C p.(Val285Ala)
    description: >-
      De novo missense substitution in the cullin N-terminal domain, from the
      founding case series. Unlike the truncating alleles it leaves a full-length
      protein, but the mutant binds BTB-domain adaptors significantly more weakly
      than wild type, reaching the same loss-of-capacity endpoint by a different
      route.
    gene:
      preferred_term: CUL3
      term:
        id: hgnc:2553
        label: CUL3
    type: missense variant
    evidence:
    - reference: PMID:32341456
      reference_title: "De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The Val285 residue located in the Cullin N-terminal domain and p.Val285Ala CUL3 mutant showed significantly weaker interactions to the BTB domain proteins than wild-type CUL3."
      explanation: >-
        Functional demonstration that this missense allele impairs adaptor binding,
        which is the claim made about it here.
  - name: c.1758_1759insTG p.(Thr587*)
    description: >-
      De novo two-base insertion producing a premature stop codon, identified by
      trio exome sequencing in a girl with autism spectrum disorder and
      Rett-like developmental regression after febrile status epilepticus.
    gene:
      preferred_term: CUL3
      term:
        id: hgnc:2553
        label: CUL3
    type: frameshift variant
    evidence:
    - reference: PMID:33097317
      reference_title: "A novel stop-gain CUL3 mutation in a Japanese patient with autism spectrum disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Trio-based exome sequencing identified a de novo two-base insertion in CUL3, c.1758_1759insTG, p.(Thr587*)."
      explanation: >-
        Reports the exact allele and its de novo origin.
  - name: c.379-2A>G
    description: >-
      De novo canonical acceptor splice-site variant in a child with congenital
      developmental dysplasia of the hip and global developmental delay. This was
      the first splice-site allele reported in the neurodevelopmental disorder -
      notable because splice variants had until then been associated with
      pseudohypoaldosteronism type IIE rather than with NEDAUS.
    gene:
      preferred_term: CUL3
      term:
        id: hgnc:2553
        label: CUL3
    type: splice acceptor variant
    evidence:
    - reference: PMID:36710200
      reference_title: "A novel splice site CUL3 variant in a patient with neurodevelopmental delay."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A de novo splice site variant (c.379-2A > G) was identified in CUL3 and is predicted to abolish the acceptor splice site."
      explanation: >-
        Reports the allele and its predicted consequence.
    - reference: PMID:36710200
      reference_title: "A novel splice site CUL3 variant in a patient with neurodevelopmental delay."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Splice variants in CUL3 are a well-described cause of pseudohypoaldosteronism type IIE; however, splice variants have not been associated with the neurodevelopmental disorder."
      explanation: >-
        Supports the significance claim - that splice alleles had previously been
        assigned to the other CUL3 disease, so this report crossed that boundary.
  - name: c.420C>G p.Tyr140Ter
    description: >-
      Inherited nonsense variant segregating in a family with short stature and
      neurodevelopmental disorder: present in two sisters and in their father,
      who had neurodevelopmental disorder and epilepsy but normal height. A
      worked example of intrafamilial variable expressivity.
    gene:
      preferred_term: CUL3
      term:
        id: hgnc:2553
        label: CUL3
    type: nonsense variant
    evidence:
    - reference: PMID:40763714
      reference_title: "Short Stature and Response to Growth Hormone Treatment in CUL3-Related Neurodevelopmental Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Whole exome sequencing (WES) revealed a novel likely pathogenic heterozygous nonsense CUL3 variant c.420C>G, p.Tyr140Ter."
      explanation: >-
        Reports the allele and its classification.
    - reference: PMID:40763714
      reference_title: "Short Stature and Response to Growth Hormone Treatment in CUL3-Related Neurodevelopmental Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The variant was also identified in her non-identical twin sister, who presented with short stature and NDD, and in their father, who had NDD and epilepsy but normal height."
      explanation: >-
        Documents the segregation and the phenotypic difference between carriers
        that makes this a variable-expressivity example.
diagnosis:
- name: Trio exome or genome sequencing
  diagnosis_term:
    preferred_term: Whole Exome Sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  description: >-
    The diagnostic route in essentially every published case. Because the
    disorder has no pathognomonic clinical sign - the facial features are mild,
    brain MRI is usually normal, and the two named features (autism, seizures)
    are optional - it is not clinically recognisable, and diagnosis is made by
    sequencing performed for undifferentiated neurodevelopmental disorder. Trio
    analysis is preferred given the de novo mechanism.
  evidence:
  - reference: PMID:33097317
    reference_title: "A novel stop-gain CUL3 mutation in a Japanese patient with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Trio-based exome sequencing identified a de novo two-base insertion in CUL3, c.1758_1759insTG, p.(Thr587*)."
    explanation: >-
      Demonstrates the diagnostic route directly: a trio-based exome study
      identifying the de novo causal allele in an individual ascertained through
      neurodevelopmental presentation.
  - reference: PMID:36710200
    reference_title: "A novel splice site CUL3 variant in a patient with neurodevelopmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A de novo splice site variant (c.379-2A > G) was identified in CUL3 and is predicted to abolish the acceptor splice site."
    explanation: >-
      A second molecularly confirmed diagnosis made by sequencing rather than by
      clinical recognition, including a variant class that sequence analysis is
      needed to interpret.
  - reference: PMID:33097317
    reference_title: "A novel stop-gain CUL3 mutation in a Japanese patient with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening of CUL3 variants is worth considering for patients with ASD, especially those with Rett-like developmental regression."
    explanation: >-
      Supports the testing-indication statement, naming the clinical presentation
      that should prompt consideration of CUL3.
- name: Chromosomal microarray
  diagnosis_term:
    preferred_term: chromosomal microarray analysis
    term:
      id: NCIT:C18477
      label: Microarray Analysis
  description: >-
    The route that detects the copy-number class of trigger allele. One of 26
    individuals in the largest cohort carried a deletion removing CUL3 together
    with neighbouring genes - a contiguous multigene CNV, which is precisely the
    lesion trio exome sequencing can miss. Microarray is therefore complementary
    to, not redundant with, the sequencing route above, and was part of the
    clinical workup that identified variants in that cohort.
  evidence:
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The identification of CUL3 variants was carried out in a clinical setting using exome sequencing (ES), genome sequencing, and chromosomal microarray."
    explanation: >-
      Names chromosomal microarray as one of the three diagnostic modalities used
      to ascertain this cohort.
- name: DNA methylation episignature
  diagnosis_term:
    preferred_term: DNA Methylation Analysis
    term:
      id: NCIT:C63328
      label: DNA Methylation Analysis
  description: >-
    A sensitive and specific peripheral-blood DNA methylation signature has been
    defined for CUL3 pathogenic variants and used to reclassify variants of
    uncertain significance - the practical answer to the interpretive problem
    created by a gene where missense alleles are hard to call. Two caveats
    matter. The signature is not universal among pathogenic-variant carriers, so
    the cohort is split into signature-positive and signature-negative groups,
    and several phenotype frequencies in this entry differ between them. And the
    signature resembles those of several other rare neurodevelopmental disorders,
    so it should be interpreted within a validated classifier rather than read as
    a standalone test.
  evidence:
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We discovered a sensitive and specific DNAm episignature for patients with pathogenic variants in CUL3 and utilized it to reclassify patients carrying a VUS in the CUL3 gene."
    explanation: >-
      States both the signature's performance and its intended clinical use for
      variant reclassification.
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Comparative epigenomic analysis revealed similarities between NEDAUS and several other rare genetic neurodevelopmental disorders with previously identified episignatures, highlighting the broader implication of our findings."
    explanation: >-
      Supports the specificity caveat recorded in the description - the signature
      overlaps those of other neurodevelopmental disorders.
imaging_findings:
- name: Prenatal cerebellar hypoplasia
  modality: ULTRASOUND
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  diagnostic: true
  description: >-
    Proposed as a sonographic marker with enough specificity to prompt exome
    sequencing when seen prenatally, in contrast to the growth restriction and
    increased nuchal translucency that accompany it and are non-specific. Based
    on three cases.
  evidence:
  - reference: PMID:41761011
    reference_title: "CUL3-Related Neurodevelopmental Disorder: Expanding the Prenatal Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This finding provides a strong rationale for pursuing exome sequencing and serves as critical evidence for the clinical interpretation of CUL3 variants."
    explanation: >-
      States the diagnostic action the finding is intended to trigger, supporting
      the diagnostic flag.
- name: Mild ventriculomegaly on brain MRI
  modality: MRI
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  diagnostic: false
  description: >-
    The only recurring postnatal brain MRI abnormality in the largest cohort, in
    three individuals; most studies were normal. Recorded chiefly so that a
    normal MRI is not read as evidence against the diagnosis.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most individuals who had a brain MRI performed had a normal study, but three were noted to have mild ventriculomegaly."
    explanation: >-
      Reports both the finding and the predominance of normal studies.
differential_diagnoses:
- name: Pseudohypoaldosteronism type IIE (CUL3-related)
  disease_term:
    preferred_term: pseudohypoaldosteronism type 2E
    term:
      id: MONDO:0013782
      label: pseudohypoaldosteronism type 2E
  description: >-
    The same gene, a different disease, separated by variant class rather than by
    dose. PHA2E is caused by CUL3 variants that converge on skipping of exon 9,
    yielding an in-frame deletion that abrogates ubiquitination of WNK kinases
    presented by the KLHL3 adaptor in the distal nephron; the result is
    hyperkalaemic hypertension with metabolic acidosis, reversible with thiazide
    diuretics, and without neurodevelopmental features. A CUL3 variant report
    must therefore be read for variant class before it is read for gene identity.
    How CUL3-delta-9 acts downstream is itself contested - a mouse model suggested
    the truncated protein is degraded, making PHA2E another haploinsufficiency
    state, while direct testing found additional dominant effects must contribute.
    That controversy matters here: if PHA2E were purely haploinsufficiency the two
    diseases would be hard to keep apart mechanistically, so the dominant
    component is doing real separating work. The clinical boundary is also not
    absolutely clean - a canonical splice-acceptor allele has now been reported in
    the neurodevelopmental disorder, and the largest NEDAUS cohort noted
    individuals with early or juvenile-onset hypertension in the absence of
    electrolyte abnormalities.
  distinguishing_features:
  - Exon 9 skipping as the shared mutational consequence in PHA2E, versus
    distributed truncating, splice and missense alleles in NEDAUS
  - Hyperkalaemia and metabolic acidosis, absent in NEDAUS
  - Thiazide-responsive hypertension as the presenting problem, rather than
    developmental delay
  - No intellectual disability, speech delay or autism
  evidence:
  - reference: PMID:22266938
    reference_title: "Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion."
    explanation: >-
      Establishes the distinguishing mutational mechanism of PHA2E - convergence on
      exon 9 skipping - that separates it from the NEDAUS allele spectrum.
  - reference: PMID:22266938
    reference_title: "Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis"
    explanation: >-
      States the PHA2E clinical triad used here as the distinguishing feature set.
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified several individuals in our cohort without electrolyte abnormalities who had early or juvenile onset hypertension or other congenital cardiac abnormalities"
    explanation: >-
      Supports the caveat that the boundary is not absolute, while confirming the
      electrolyte abnormalities that define PHA2E were absent - hence PARTIAL.
  - reference: PMID:29361671
    reference_title: "Mechanisms and controversies in mutant Cul3-mediated familial hyperkalemic hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cul3 mutations cause skipping of exon 9, which results in an internal deletion of 57 amino acids from the CUL3 protein (CUL3-∆9)."
    explanation: >-
      Specifies the molecular product of the PHA2E allele class - an in-frame
      57-residue internal deletion - which is what makes it a different lesion from
      the loss-of-function alleles causing the neurodevelopmental disorder.
  - reference: PMID:29361671
    reference_title: "Mechanisms and controversies in mutant Cul3-mediated familial hyperkalemic hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We recently directly tested this model but found that other dominant effects of CUL3-∆9 must contribute to the development of FHHt."
    explanation: >-
      Supports the statement that PHA2E is not purely a haploinsufficiency state,
      while recording that the point is contested - the preceding sentence of the
      same review describes a mouse model that concluded the opposite. Hence
      PARTIAL, and evidence_source OTHER as this is a review rather than primary
      data.
treatments:
- name: Early multidisciplinary developmental therapy
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: >-
    Physical, occupational, speech-language and behavioural therapy begun as
    early as possible. There is no disease-modifying treatment, and no
    CUL3-specific efficacy data; this is the standard of care for syndromic
    developmental delay applied to a molecularly defined population. Speech and
    language therapy has the strongest claim on resources because speech delay is
    the most consistent feature of the disorder.
  treatment_term:
    preferred_term: Early Intervention
    term:
      id: NCIT:C159524
      label: Early Intervention
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Speech delay was the most consistent feature and was noted in 97% (34/35)."
    explanation: >-
      Supports the prioritisation of speech-language therapy by establishing speech
      delay as the near-universal feature; it does not evaluate the therapy itself,
      hence PARTIAL.
- name: Speech and language therapy
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: >-
    Directed at the disorder's most consistent feature. No CUL3-specific trial
    data exist.
  treatment_term:
    preferred_term: Speech Language Therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
- name: Physical and occupational therapy
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: >-
    Directed at early hypotonia, motor delay and, in the minority who develop
    them, tremor and dystonia. In one reported case, three months of exercise
    rehabilitation improved exercise capacity while autism symptoms were
    essentially unchanged - a useful calibration of what motor rehabilitation
    does and does not address in this disorder.
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  - preferred_term: Delayed gross motor development
    term:
      id: HP:0002194
      label: Delayed gross motor development
  evidence:
  - reference: PMID:37026922
    reference_title: "A nonsense mutation in the CUL3 gene in a Chinese patient with autism spectrum disorder and epilepsy: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient's exercise capacity had improved, and improvements in autism symptoms were not obvious."
    explanation: >-
      Single-case outcome supporting a motor benefit and, equally usefully, the
      absence of a behavioural one. n=1 and uncontrolled, hence PARTIAL.
- name: Growth hormone therapy for short stature
  action_category: THERAPEUTIC
  therapeutic_modality: PROTEIN_REPLACEMENT
  description: >-
    Two children with CUL3-related neurodevelopmental disorder and short stature
    were treated with growth hormone and responded well. It addresses a
    comorbidity rather than the neurodevelopmental phenotype. Two patients,
    uncontrolled - a signal to evaluate growth and consider endocrine referral,
    not established therapy. It is not the only reported pharmacological
    intervention with a described benefit in this population: a single reported
    patient remained seizure-free on levetiracetam (see Antiseizure medication).
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: somatropin
      term:
        id: NCIT:C837
        label: Somatropin
  target_phenotypes:
  - preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:40763714
    reference_title: "Short Stature and Response to Growth Hormone Treatment in CUL3-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband and her sister were treated with growth hormone (GH) with good response."
    explanation: >-
      Reports the intervention and the response in molecularly confirmed patients.
  - reference: PMID:40763714
    reference_title: "Short Stature and Response to Growth Hormone Treatment in CUL3-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed a good response to GH therapy in 2 of our patients with short stature."
    explanation: >-
      States the outcome and its denominator of two, which is what limits this to a
      signal rather than evidence of efficacy - hence PARTIAL.
- name: Antiseizure medication
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Symptomatic treatment for the subset with seizures, chosen by seizure type on
    general epilepsy principles. No controlled or drug-selection data exist, and
    no agent is contraindicated on the basis of the genotype. The only reported
    CUL3-specific observation is a single patient who remained seizure-free on
    levetiracetam.
  treatment_term:
    preferred_term: Anticonvulsant Therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
    therapeutic_agent:
    - preferred_term: anticonvulsant agent
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:37026922
    reference_title: "A nonsense mutation in the CUL3 gene in a Chinese patient with autism spectrum disorder and epilepsy: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient was on levetiracetam from September, 2021 at a dose of 2 mL daily, and the seizures did not recur."
    explanation: >-
      The single reported CUL3-specific antiseizure observation. n=1, uncontrolled
      and with a short follow-up, so it supports the practice of symptomatic
      treatment without establishing efficacy or drug selection - hence PARTIAL.
- name: Genetic counselling
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    Recurrence risk is low for the de novo majority but is not zero, because
    parental germline mosaicism is possible and because transmission from a
    mildly affected parent is documented. Testing parents matters: a carrier
    parent may have normal height and only mild neurodevelopmental features.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:40763714
    reference_title: "Short Stature and Response to Growth Hormone Treatment in CUL3-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The variant was inherited from their mother, who had facial dysmorphism and hypertension but normal height."
    explanation: >-
      Documents transmission from a mildly affected parent, the specific scenario
      that makes parental testing part of counselling here.
animal_models:
- name: Cul3 germline haploinsufficient mouse
  species: Mouse
  genotype: Cul3 +/- (CRISPR/Cas9 frameshifting insertion)
  background: C57BL/6N
  category: Genetically engineered
  publication: PMID:33727673
  description: >-
    The closest genetic match to the human disorder - constitutive
    heterozygosity, the same dosage lesion patients carry. It reproduces
    behaviour, structure and a molecular mechanism, and supplies the field's only
    pharmacological rescue: inhibiting RhoA, a CUL3 substrate, restores dendrite
    length and network activity.
  genes:
  - preferred_term: CUL3
    term:
      id: hgnc:2553
      label: CUL3
  modeled_mechanisms:
  - target: Cullin-3 Haploinsufficiency and Reduced CRL3 Ligase Capacity
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Constitutive heterozygous loss of one Cul3 allele is the same dosage lesion
      as the human loss-of-function state.
    limitations: >-
      Mouse behavioural readouts (social interaction, hyperactivity) are proxies
      for human social communication and cognition rather than measurements of
      them, and the model does not reproduce the seizure, dysmorphism or
      hand-and-foot components of the human syndrome.
    readouts:
    - name: Cortical regional volume on brain MRI
      target: Cullin-3 Haploinsufficiency and Reduced CRL3 Ligase Capacity
      direction: DECREASED
      interpretation: >-
        Structural correlate establishing that the halved gene dose produces a
        measurable brain phenotype from early postnatal life.
      evidence:
      - reference: PMID:33727673
        reference_title: "Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development."
        explanation: Reports the imaging measurement and its direction.
    evidence:
    - reference: PMID:33727673
      reference_title: "Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "To investigate how Cul3 mutations impact brain development, we generated a haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering."
      explanation: >-
        Establishes the model's construction as a haploinsufficiency model, which
        is why it is informative for this node.
  - target: Reduced Dendritic Growth and Inhibitory Synapse Loss
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      RhoA inhibition rescues the dendritic and network-activity phenotypes,
      showing the substrate accumulation is causal and identifying the disorder's
      leading mechanism-based therapeutic hypothesis.
    limitations: >-
      Rescue was demonstrated pharmacologically in mice; no human data exist, and
      the reversibility of a developmentally established phenotype in a patient is
      untested.
    readouts:
    - name: Dendrite length after RhoA inhibition
      target: Reduced Dendritic Growth and Inhibitory Synapse Loss
      direction: RESTORED
      interpretation: >-
        Restoration on blocking the accumulated substrate identifies RhoA as the
        operative effector of the dendritic phenotype.
      evidence:
      - reference: PMID:33727673
        reference_title: "Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes."
        explanation: Reports the rescue and the measured readout.
    evidence:
    - reference: PMID:33727673
      reference_title: "Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our study identified defects in neuronal cytoskeleton and Rho signaling as the primary targets of Cul3 mutation during brain development."
      explanation: >-
        States the mechanistic conclusion that makes this model informative for the
        cytoskeletal/dendritic node.
  evidence:
  - reference: PMID:33727673
    reference_title: "Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior."
    explanation: >-
      Reports the behavioural phenotype that makes this model informative for the
      human neurobehavioural disorder.
- name: Constitutive Cul3 heterozygous mouse (neuronal migration)
  species: Mouse
  genotype: Cul3 +/-
  category: Genetically engineered
  publication: PMID:34031387
  description: >-
    The model that establishes the developmental timing constraint. Constitutive
    heterozygotes show cortical lamination abnormalities, but inducing the same
    haploinsufficiency later in life does not produce autism-relevant behaviour -
    so the pathogenic window is developmental, not ongoing.
  genes:
  - preferred_term: CUL3
    term:
      id: hgnc:2553
      label: CUL3
  modeled_mechanisms:
  - target: Impaired Neuronal Migration and Cortical Lamination
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Cortical lamination abnormality follows directly from impaired radial
      neuronal migration in the constitutive heterozygote.
    limitations: >-
      Cortical lamination has not been examined in human CUL3 patient brain
      tissue, and the largest human cohort reports mostly normal brain MRI - so
      the human counterpart of this cellular phenotype, if present, is below the
      resolution of clinical imaging.
    readouts:
    - name: Cortical layer positioning of migrating neurons
      target: Impaired Neuronal Migration and Cortical Lamination
      direction: ALTERED
      interpretation: >-
        Mispositioning of neurons is the structural expression of the migration
        defect.
      evidence:
      - reference: PMID:34031387
        reference_title: "Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities."
        explanation: Reports the migration defect and the lamination readout.
    evidence:
    - reference: PMID:34031387
      reference_title: "Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In mouse, constitutive Cul3 haploinsufficiency leads to motor coordination deficits as well as ASD-relevant social and cognitive impairments."
      explanation: >-
        Establishes that the constitutive heterozygote reproduces disease-relevant
        behaviour, supporting its use as a model for this node.
  evidence:
  - reference: PMID:34031387
    reference_title: "Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 (CUL3) lead to autism spectrum disorder (ASD)."
    explanation: >-
      States the human genetic premise the model was built to interrogate, which is
      what makes this mouse informative for the human disorder.
- name: Region- and cell-type-restricted Cul3 conditional knockout mice
  species: Mouse
  genotype: Conditional Cul3 deletion (forebrain, prefrontal cortex, striatum, cholinergic neurons)
  category: Genetically engineered
  publication: PMID:31455858
  description: >-
    A series of conditional deletions that dissects which circuit produces which
    behaviour: prefrontal loss gives social deficits, striatal loss gives
    stereotypy, forebrain or prefrontal loss gives NMDA receptor hypofunction,
    and cholinergic basal-forebrain loss gives social and sensory-gating deficits
    with cognitive impairment. Knocking down the misregulated histone
    methyltransferase Smyd3 rescues the social phenotype.
  genes:
  - preferred_term: CUL3
    term:
      id: hgnc:2553
      label: CUL3
  modeled_mechanisms:
  - target: Excitation-Inhibition Imbalance in Cortico-Striatal Circuits
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Circuit-restricted deletion maps distinct behavioural outputs onto distinct
      brain regions and provides the electrophysiological correlate of each.
    limitations: >-
      Conditional homozygous or region-restricted deletion is a deeper and more
      spatially confined lesion than the whole-body heterozygosity patients carry,
      so the mapping of circuit to behaviour is more informative than the absolute
      severity.
    readouts:
    - name: NMDA receptor function in prefrontal cortex
      target: Excitation-Inhibition Imbalance in Cortico-Striatal Circuits
      direction: DECREASED
      interpretation: >-
        NMDAR hypofunction is the synaptic correlate of the social-behaviour
        phenotype in this model.
      evidence:
      - reference: PMID:31455858
        reference_title: "Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Correlated with these behavioral alterations, Cul3 deficiency in forebrain or PFC induces NMDA receptor hypofunction, while Cul3 loss in striatum causes a cell type-specific alteration of neuronal excitability in striatal circuits."
        explanation: Reports the measurement and its direction in each region.
    evidence:
    - reference: PMID:31455858
      reference_title: "Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These results have revealed for the first time a potential molecular mechanism underlying the manifestation of different autism-like behavioral deficits by Cul3 deletion in cortico-striatal circuits."
      explanation: >-
        States the circuit-level mechanistic conclusion this model contributes.
  evidence:
  - reference: PMID:31455858
    reference_title: "Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Inhibition or knockdown of Smyd3 in forebrain Cul3-deficient mice ameliorates social deficits and restores NMDAR function in PFC."
    explanation: >-
      A rescue arm in this model series - correcting a misregulated substrate
      restores both behaviour and synaptic function - which is what makes the model
      informative rather than merely descriptive.
- name: Cholinergic-neuron-restricted Cul3 knockout mouse
  species: Mouse
  genotype: ChAT-Cre; Cul3 flox/+
  category: Genetically engineered
  publication: PMID:36693858
  description: >-
    Heterozygous Cul3 deletion confined to cholinergic neurons reproduces social
    and sensory-gating deficits and cognitive impairment. Bidirectional
    chemogenetic manipulation closes the causal loop: inhibiting basal forebrain
    cholinergic neurons in healthy mice reproduces the deficits, and stimulating
    them in mutants reverses them.
  genes:
  - preferred_term: CUL3
    term:
      id: hgnc:2553
      label: CUL3
  modeled_mechanisms:
  - target: Excitation-Inhibition Imbalance in Cortico-Striatal Circuits
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Recapitulates the social, sensory-gating and cognitive arm of the phenotype
      through a cholinergic circuit, but by construction says nothing about the
      cortical and striatal glutamatergic arms.
    limitations: >-
      Deletion is restricted to cholinergic neurons, so this model isolates one
      contributing circuit rather than reproducing the distributed loss of CUL3
      present in patients.
    readouts:
    - name: Basal forebrain cholinergic neuron activity
      target: Excitation-Inhibition Imbalance in Cortico-Striatal Circuits
      direction: DECREASED
      interpretation: >-
        Diminished cholinergic activity is the circuit lesion linking Cul3 dose to
        the behavioural phenotype in this model.
      evidence:
      - reference: PMID:36693858
        reference_title: "Cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with Cul3 deficiency: Role of prefrontal cortex projections in cognitive deficits."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Conditional Cul3 ablation in cholinergic neurons of mice (ChatCRECul3F/+) recapitulated ASD-like social and sensory gating phenotypes and caused significant cognitive impairments, with diminished activity of cholinergic neurons in the basal forebrain (BF)."
        explanation: Reports the activity measurement and the behavioural phenotype.
    evidence:
    - reference: PMID:36693858
      reference_title: "Cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with Cul3 deficiency: Role of prefrontal cortex projections in cognitive deficits."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Conversely, chemogenetic stimulation of BF cholinergic neurons in ChatCRECul3F/+ mice reversed abnormalities in sensory gating and cognition."
      explanation: >-
        The reversal on stimulating the implicated neurons is what makes the
        circuit claim causal rather than correlative.
  evidence:
  - reference: PMID:36693858
    reference_title: "Cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with Cul3 deficiency: Role of prefrontal cortex projections in cognitive deficits."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Overall, we demonstrate that cholinergic dysfunction due to Cul3 deficiency is involved in ASD-like behavioral abnormalities, and that BF cholinergic neurons are particularly critical for cognitive component through their projections to the PFC."
    explanation: >-
      States the model's overall conclusion and the circuit it implicates, which is
      the reason this model is curated against the human disorder.
- name: CUL3-deficient mouse (dopaminergic/VTA)
  species: Mouse
  genotype: Cul3 deficient
  category: Genetically engineered
  publication: PMID:37558490
  description: >-
    Extends the mechanism to the dopaminergic system: CUL3-deficient mice show
    hyperlocomotion, working-memory and sensorimotor-gating deficits and
    psychostimulant sensitivity, with elevated excitability of ventral tegmental
    area dopamine neurons, and the ion channel HCN2 identified as a candidate
    CUL3 target there. Behavioural abnormalities were attenuated by a dopamine D2
    receptor antagonist.
  genes:
  - preferred_term: CUL3
    term:
      id: hgnc:2553
      label: CUL3
  modeled_mechanisms:
  - target: Excitation-Inhibition Imbalance in Cortico-Striatal Circuits
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Adds a dopaminergic route to altered circuit excitability and names a
      candidate ion-channel substrate, but the phenotypes emphasised
      (psychostimulant sensitivity, sensorimotor gating) map more closely onto
      schizophrenia-relevant endophenotypes than onto the human developmental
      syndrome curated here.
    limitations: >-
      Studied in male mice only, and the behavioural readouts are not measured
      counterparts of the human phenotype; the HCN2 substrate relationship is
      described as potential rather than established.
    readouts:
    - name: Excitability of ventral tegmental area dopamine neurons
      target: Excitation-Inhibition Imbalance in Cortico-Striatal Circuits
      direction: INCREASED
      interpretation: >-
        Elevated dopamine-neuron excitability is the electrophysiological lesion
        proposed to drive the behavioural phenotype in this model.
      evidence:
      - reference: PMID:37558490
        reference_title: "Deficiency of Cullin 3, a Protein Encoded by a Schizophrenia and Autism Risk Gene, Impairs Behaviors by Enhancing the Excitability of Ventral Tegmental Area (VTA) DA Neurons."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "In addition, enhanced DA signaling and elevated excitability of the VTA DA neurons were observed in CUL3-deficient animals."
        explanation: Reports the measurement and its direction.
    evidence:
    - reference: PMID:37558490
      reference_title: "Deficiency of Cullin 3, a Protein Encoded by a Schizophrenia and Autism Risk Gene, Impairs Behaviors by Enhancing the Excitability of Ventral Tegmental Area (VTA) DA Neurons."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our study indicates that CUL3 controls DA neuronal activity by maintaining ion channel homeostasis."
      explanation: >-
        States the mechanistic claim - ion channel homeostasis - by which this model
        is informative for circuit excitability.
  evidence:
  - reference: PMID:37558490
    reference_title: "Deficiency of Cullin 3, a Protein Encoded by a Schizophrenia and Autism Risk Gene, Impairs Behaviors by Enhancing the Excitability of Ventral Tegmental Area (VTA) DA Neurons."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CUL3-deficient mice exhibited hyperactive locomotion, deficits in working memory and sensorimotor gating, and increased sensitivity to psychostimulants."
    explanation: >-
      Reports the behavioural phenotype of this model. It is recorded as PARTIAL
      because psychostimulant sensitivity and sensorimotor gating are
      schizophrenia-relevant endophenotypes rather than measured counterparts of the
      human developmental syndrome.
experimental_models:
- name: Patient-derived T cells
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:39301775
  description: >-
    T cells from individuals carrying CUL3 loss-of-function variants, used to
    test the haploinsufficiency mechanism in human cells rather than by
    inference. They show reduced ubiquitin-protein conjugates, and 4E-BP1
    (EIF4EBP1) escapes proteasomal degradation - the only place in this entry
    where the core molecular defect is demonstrated in patient material.
  modeled_mechanisms:
  - target: Failure of CRL3 Substrate Degradation
    relationship: MEASURES
    fidelity: HIGH
    description: >-
      Directly measures the accumulation of a named CRL3 substrate in cells from
      affected individuals.
    limitations: >-
      T cells are not neurons; whether the same substrate stabilisation occurs in
      the brain cell types that produce the phenotype is inferred, not shown.
    readouts:
    - name: Proteasomal degradation of 4E-BP1 (EIF4EBP1)
      target: Failure of CRL3 Substrate Degradation
      direction: DECREASED
      interpretation: >-
        Failure to degrade a prominent CUL3 substrate is the direct human-cell
        readout of reduced CRL3 ligase capacity.
      evidence:
      - reference: PMID:39301775
        reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells."
        explanation: Reports the measurement and its direction in patient cells.
    - name: Ubiquitin-protein conjugate abundance
      target: Failure of CRL3 Substrate Degradation
      direction: DECREASED
      interpretation: >-
        A global measure of ubiquitin-conjugating output, reduced as predicted by
        scaffold haploinsufficiency.
      evidence:
      - reference: PMID:39301775
        reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "as evidenced by decreased ubiquitin-protein conjugates in vitro"
        explanation: Reports the global conjugate measurement and its direction.
    evidence:
    - reference: PMID:39301775
      reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Variant effects on CUL3 protein stability were assessed using patient-derived T-cells."
      explanation: >-
        Names the model system and the question it was used to answer, which is why
        it is informative for this node.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro."
    explanation: >-
      The result obtained in this system - reduced ubiquitin conjugates in patient
      cells - is what establishes it as an informative human model of the mechanism.
- name: Cul3 knockout mouse hippocampal primary neuronal culture
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  cell_types:
  - preferred_term: hippocampal pyramidal neuron
    term:
      id: CL:1001571
      label: hippocampal pyramidal neuron
  publication: PMID:38803442
  description: >-
    Primary hippocampal cultures from Cul3 knockout mice, used because homozygous
    Cul3 deletion is embryonic lethal in vivo and the early synaptic phenotype
    therefore cannot be studied in an intact animal. Both heterozygous and
    homozygous cultures show selective loss of inhibitory synaptic puncta;
    caspase-3 inhibition reverses the morphological and synaptic changes.
  modeled_mechanisms:
  - target: Reduced Dendritic Growth and Inhibitory Synapse Loss
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the dendritic, axonal and inhibitory-synapse phenotype and
      identifies caspase-3 as the proximate mediator by rescue.
    limitations: >-
      The strongest morphological effects required homozygous deletion, which is
      lethal in vivo and does not correspond to any human genotype; only the
      inhibitory-synapse deficit was demonstrated in the heterozygous state that
      matches patients.
    readouts:
    - name: Gephyrin/vGAT inhibitory synaptic puncta density
      target: Reduced Dendritic Growth and Inhibitory Synapse Loss
      direction: DECREASED
      interpretation: >-
        Selective reduction of inhibitory, but not excitatory, puncta is the
        specific claim this model supports.
      evidence:
      - reference: PMID:38803442
        reference_title: "Autism risk gene Cul3 alters neuronal morphology via caspase-3 activity in mouse hippocampal neurons."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Both heterozygous and homozygous knockout of Cul3 caused significant reductions in the density and colocalization of gephyrin/vGAT puncta, providing evidence of decreased inhibitory synapse number, while excitatory synaptic puncta vGulT1/PSD95 density remained unchanged."
        explanation: >-
          Reports the measurement, its direction, and the excitatory control that
          establishes selectivity.
    - name: Neuronal cell viability after caspase-3 inhibition
      target: Reduced Dendritic Growth and Inhibitory Synapse Loss
      direction: RESTORED
      interpretation: >-
        Rescue by caspase-3 inhibition identifies caspase-3 as the operative
        mediator downstream of Cul3 loss.
      evidence:
      - reference: PMID:38803442
        reference_title: "Autism risk gene Cul3 alters neuronal morphology via caspase-3 activity in mouse hippocampal neurons."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "We then examined the efficacy of the caspase-3 inhibitor Z-DEVD-FMK to rescue the decrease in neuronal cell viability, demonstrating reversal of the cell viability phenotype with caspase-3 inhibition."
        explanation: Reports the rescue experiment and its outcome.
    evidence:
    - reference: PMID:38803442
      reference_title: "Autism risk gene Cul3 alters neuronal morphology via caspase-3 activity in mouse hippocampal neurons."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Cul3 homozygous deletion in mice is embryonic lethal; thus, we examine the role of Cul3 deletion in early synapse development and neuronal morphology in hippocampal primary neuronal cultures."
      explanation: >-
        States why the culture model was necessary, and so why it is the
        appropriate system for this node.
  evidence:
  - reference: PMID:38803442
    reference_title: "Autism risk gene Cul3 alters neuronal morphology via caspase-3 activity in mouse hippocampal neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Overall, these data provide additional evidence that Cul3 regulates the formation or maintenance of cell morphology, GABAergic synaptic puncta, and neuronal viability in developing hippocampal neurons in culture."
    explanation: >-
      States what this culture system established about Cul3 function, which is the
      basis for treating it as informative for the dendrite and inhibitory-synapse
      node.
datasets:
- accession: geo:GSE144046
  title: >-
    Autism-linked Cullin3 germline haploinsufficiency severely impacts mouse
    brain development and cortical neurogenesis through RhoA signaling
  data_type: BULK_RNA_SEQ
  sample_count: 108
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  genes:
  - preferred_term: CUL3
    term:
      id: hgnc:2553
      label: CUL3
  publication: PMID:33727673
  notes: >-
    Spatiotemporal transcriptomic profiling of embryonic, early postnatal and
    adult brain from the CRISPR-generated Cul3 haploinsufficient mouse curated in
    animal_models. This is the underlying data for the neurogenesis and
    cytoskeletal findings and for the RhoA rescue. Relevance was triaged manually:
    a gene-symbol search on CUL3 returns mostly lung, yeast and 16p11.2/KCTD13
    datasets that share the gene but not the disease, and those were rejected;
    this record was accepted because the series title, its linked publication and
    its genotype all name Cul3 haploinsufficiency in brain. Carries no evidence
    block by design - a GEO series has no abstract to quote exactly.

mechanistic_hypotheses:
- hypothesis_group_id: translational_dysregulation_model
  hypothesis_label: Dysregulated cap-dependent translation as the proximate neuronal defect
  status: CANONICAL
  description: >-
    CUL3 restrains cap-dependent translation initiation by turning over
    initiation-complex proteins; loss of that restraint dysregulates neuronal
    protein synthesis, raising glutamatergic drive and excitability. The two
    strongest pieces of evidence come from opposite directions - 4E-BP1 fails to
    be degraded in human patient cells, and inhibiting eIF4G1 rescues cellular
    and behavioural deficits in mice - which is what makes this the leading
    account. It also places the disorder alongside other monogenic autism
    syndromes with translational-control defects.
  evidence:
  - reference: PMID:31780330
    reference_title: "CUL3 Deficiency Causes Social Deficits and Anxiety-like Behaviors by Impairing Excitation-Inhibition Balance through the Promotion of Cap-Dependent Translation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "ASD-associated cellular and behavioral deficits could be rescued by pharmacological inhibition of the eIF4G1 function and chemogenetic inhibition of neuronal activity."
    explanation: >-
      Rescue by targeting the accumulated translation factor is the causal test
      this hypothesis rests on.
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells."
    explanation: >-
      Anchors the hypothesis in human patient material rather than in mouse alone.
- hypothesis_group_id: cytoskeletal_migration_model
  hypothesis_label: RhoA/plastin-3 cytoskeletal dysregulation and impaired neuronal migration
  status: ALTERNATIVE
  description: >-
    An alternative - and not mutually exclusive - account in which the proximate
    defect is cytoskeletal. CUL3 controls the levels of RhoA and plastin-3, both
    regulators of actin dynamics; their accumulation impairs radial neuronal
    migration and dendritic growth, producing cortical lamination abnormalities.
    RhoA inhibition rescues dendrite length and network activity in the
    haploinsufficient mouse. The distinguishing prediction is developmental
    timing: this model requires the lesion to act during corticogenesis, and
    indeed inducing haploinsufficiency in adult mice does not reproduce the
    behavioural phenotype - which, if it holds in humans, bounds what any
    postnatal therapy could achieve.
  evidence:
  - reference: PMID:33727673
    reference_title: "Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our study identified defects in neuronal cytoskeleton and Rho signaling as the primary targets of Cul3 mutation during brain development."
    explanation: >-
      States the competing claim - that the cytoskeleton, not translation, is the
      primary target of the lesion.
  - reference: PMID:34031387
    reference_title: "Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, induction of Cul3 haploinsufficiency later in life does not lead to ASD-relevant behaviors, pointing to an important role of Cul3 during a critical developmental window."
    explanation: >-
      Supports the developmental-timing prediction that distinguishes this model
      from a purely ongoing translational-control defect.
discussions:
- discussion_id: cul3_seizure_frequency_discordance
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How common are seizures in CUL3-related neurodevelopmental disorder, and is
    epilepsy a genuine part of the phenotype or an ascertainment artefact of the
    early case reports?
  attaches_to:
  - pathophysiology#Syndromic Neurodevelopmental Phenotype
  rationale: >-
    The disorder is named for seizures, yet the two data sources disagree
    sharply. The founding three-case series titled its report around infantile
    spasms, and independent case reports describe generalised epilepsy followed
    by autistic regression. But the 37-individual cohort found seizures in only a
    few patients - febrile or single isolated events - and stated explicitly that
    epilepsy was not observed as a recurrent feature. Two readings are possible
    and are not distinguished by the published data: early reports may have been
    enriched for epilepsy because children with seizures reach exome sequencing
    sooner, or the later cohort may under-ascertain seizures collected
    retrospectively across many centres. Until this is settled no frequency band
    can honestly be assigned, which is why the seizure phenotype in this entry
    carries evidence but no frequency, and why the discordant cohort statement is
    retained as a REFUTE item rather than averaged away.
  proposed_experiments:
  - experiment_id: cul3_prospective_eeg_cohort
    name: Prospective EEG and seizure-history ascertainment in a molecularly defined cohort
    description: >-
      Enrol individuals with confirmed pathogenic CUL3 variants ascertained
      through neurodevelopmental disorder rather than through epilepsy, and apply
      uniform seizure-history questionnaires plus standardised EEG at defined
      ages. Ascertaining through a non-epilepsy route is the design feature that
      breaks the circularity of the existing literature.
    decision_criterion: >-
      A seizure prevalence above roughly 20% in a non-epilepsy-ascertained cohort
      would establish seizures as a genuine core feature; a prevalence at
      population background would support ascertainment bias in the early reports.
  evidence:
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, epilepsy, which were thought to be a part of the clinical spectrum, were not observed in our patient cohort (OMIM #619239)."
    explanation: >-
      The cohort statement that creates the discordance, explicitly framed by its
      authors against the prior expectation encoded in the OMIM entry.
  - reference: PMID:37575562
    reference_title: "Current trends of high-risk gene Cul3 in neurodevelopmental disorders."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Two of the patients had infantile spasms, while the other had short stature with mild to severe intellectual disability."
    explanation: >-
      Two of the three founding patients had infantile spasms - a rate that cannot
      be reconciled with the later cohort's finding that epilepsy was not a
      recurrent feature. This is the other side of the gap.
- discussion_id: cul3_episignature_subgroup_meaning
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    What distinguishes episignature-positive from episignature-negative
    individuals carrying pathogenic CUL3 variants, and is the difference
    biological or technical?
  attaches_to:
  - pathophysiology#Cullin-3 Haploinsufficiency and Reduced CRL3 Ligase Capacity
  rationale: >-
    The methylation episignature splits carriers into two groups that differ in
    more than their methylation: ADHD was seen in a third of signature-positive
    individuals and in none of the signature-negatives, and MRI and cardiac
    abnormalities showed the same all-or-nothing split, while intrauterine growth
    restriction was roughly twice as frequent in the positive group. Either the
    signature marks a mechanistically distinct subset - residual CUL3 activity,
    variant class, or a modifier - or the negative group contains
    misclassified variants and the split is an artefact of classifier
    sensitivity. The two readings have opposite consequences for using the
    signature to reclassify variants of uncertain significance, which is its main
    proposed clinical use. Denominators in the negative group are very small (one
    individual for the feeding-problem figure), so the apparent contrasts should
    not be over-read.
  evidence:
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similarly, attention-deficit/hyperactivity disorder (ADHD) was observed in 33% of the signature positives but not observed (0%) in the signature negatives."
    explanation: >-
      One of the all-or-nothing phenotype contrasts between the two epigenetic
      subgroups that motivates this question.
  - reference: PMID:39501558
    reference_title: "CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, we performed genotype-phenotype correlation studies to explain the variety in clinical presentation between the cases."
    explanation: >-
      Confirms that the authors themselves treat explaining the clinical variety as
      an open analytic problem.
- discussion_id: cul3_mouse_human_phenotype_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Do the mouse Cul3 models capture the features that define the human disorder,
    or only the features that mice can express?
  attaches_to:
  - pathophysiology#Excitation-Inhibition Imbalance in Cortico-Striatal Circuits
  - pathophysiology#Impaired Neuronal Migration and Cortical Lamination
  rationale: >-
    The mouse models are good where mice are good and silent where they are not.
    They reproduce social interaction deficits, hyperactivity, sensorimotor
    gating and cortical structural change, and they deliver the mechanism and the
    only pharmacological rescues available. They do not reproduce the human
    disorder's most consistent feature - speech and language delay, which has no
    murine counterpart - nor its facial dysmorphism, hand and foot anomalies, or
    seizures. The mismatch runs the other way too: the models show cortical
    lamination abnormality and reduced cortical volume, whereas most patients who
    have had a brain MRI have a normal study. So the cellular mechanism may be
    real in humans but sub-threshold for clinical imaging, or the mouse cortical
    phenotype may be more severe than the human one. Model evidence in this entry
    is therefore weighted towards mechanism and away from phenotype fidelity.
  proposed_experiments:
  - experiment_id: cul3_patient_ipsc_cortical_organoid
    name: Patient-derived iPSC cortical organoid migration and lamination assay
    description: >-
      Differentiate cortical organoids from iPSCs of individuals with pathogenic
      CUL3 variants and isogenic controls, and quantify radial migration speed,
      plastin-3 and RhoA abundance, and layer organisation. This tests the
      migration mechanism in human cells without requiring patient brain tissue.
    decision_criterion: >-
      Reduced migration speed with plastin-3 accumulation in patient organoids,
      corrected in the isogenic control, would carry the mouse mechanism into
      human cells; normal migration would indicate the mouse cortical phenotype
      does not transfer and would redirect weight towards the translational model.
  evidence:
  - reference: PMID:34031387
    reference_title: "Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities."
    explanation: >-
      The mouse structural phenotype whose human counterpart is uncertain.
  - reference: PMID:39301775
    reference_title: "Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Most individuals who had a brain MRI performed had a normal study, but three were noted to have mild ventriculomegaly."
    explanation: >-
      Human imaging does not show the structural abnormality the mouse model
      predicts, which is the substance of the mismatch.
notes: >-
  Curation notes. (1) Seizure frequency is deliberately unstated. The disease
  name and OMIM entry both foreground seizures, but the largest cohort reports
  they were not a recurrent feature; assigning any FrequencyEnum band would pick
  a side in an unsettled question. See the KNOWLEDGE_GAP discussion
  cul3_seizure_frequency_discordance. (2) Several phenotype frequencies published
  by the 26-individual episignature cohort are stratified by episignature status
  rather than reported for the whole cohort (intrauterine growth restriction,
  feeding problems, ADHD, cardiac and MRI abnormalities). Those phenotypes carry
  PARTIAL evidence and no frequency band, because a subgroup figure is not a
  cohort figure. (3) No GeneReviews chapter exists for CUL3-related
  neurodevelopmental disorder. A PubMed search for GeneReviews plus CUL3 returns
  only the Pseudohypoaldosteronism Type II chapter (PMID:22073419), which covers
  the other CUL3 disease and contains no neurodevelopmental content; it is
  therefore deliberately not cited here. (4) Deep research was run with two providers,
  claude_code and openscientist. Falcon (Edison) was attempted first and returned
  HTTP 402 Payment Required, so no falcon report exists for this entry. Both
  reports passed `just preflight-dr` against MONDO:0030994 (CUL3 dominant in gene
  mentions, 61 and 53 respectively) and both resolved 16/16 of their citations.
  The openscientist report carries needs_review: true for two references its
  validator judged off topic (PMID:42609138, PMID:42446772); neither is cited
  here. All PMIDs cited were independently fetched from PubMed and every snippet
  was verified against the local reference cache. (5) No `datasets:` records were
  added beyond geo:GSE144046. A CUL3 gene-symbol search over GEO returns lung
  adenocarcinoma, pulmonary fibrosis, yeast deletion and 16p11.2/KCTD13 rat
  series that share the gene but not the disease; those were triaged out rather
  than curated.

📚

References & Deep Research

References

3

PMID:39301775

Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder.

1 finding

Largest published cohort (37 individuals); establishes haploinsufficiency via loss-of-function variants as the predominant mechanism and reports the core phenotype frequencies used throughout this entry.

PMID:39501558

CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature.

1 finding

26-individual cohort; defines a sensitive and specific DNA methylation episignature usable to reclassify CUL3 variants of uncertain significance.

PMID:32341456

De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms.

1 finding

Founding clinical description of the disorder; shows that the p.Val285Ala missense mutant binds BTB-domain proteins more weakly than wild-type CUL3.

Deep Research

2

Claude Code ▸

Neurodevelopmental Disorder With or Without Autism or Seizures (NEDAUS) — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 27 citations 2026-08-18T15:20:23.918759

Neurodevelopmental Disorder With or Without Autism or Seizures (NEDAUS) — Comprehensive Research Report

1. Disease Information

Overview: Neurodevelopmental disorder with or without autism or seizures (NEDAUS), also referred to as CUL3-related neurodevelopmental disorder, is an autosomal dominant condition caused by heterozygous, predominantly de novo, loss-of-function (and some missense/hypomorphic) variants in CUL3 (Cullin-3). It is characterized by global developmental delay apparent in infancy, impaired intellectual development, and speech delay, with variable additional features including seizures (sometimes with developmental regression), autism spectrum disorder (ASD) or other behavioral abnormalities, dysmorphic facial features, hand/foot anomalies, cardiac defects, and failure to thrive/growth restriction (OMIM #619239; Nakashima et al. 2020, PMID:32341456).

Key identifiers: - OMIM phenotype: #619239 — NEURODEVELOPMENTAL DISORDER WITH OR WITHOUT AUTISM OR SEIZURES; NEDAUS - OMIM gene: 603136 — CULLIN 3; CUL3 - MONDO: MONDO:0030994 (Monarch Initiative) - HGNC: 2553 (CUL3) - NCBI Gene ID: 8452 - Chromosome location: 2q36.2 - GTR/MedGen concept: C5543225 (NCBI GTR; MedGen) - ClinGen/GenCC:* curated as a definitive/moderate–definitive gene-disease relationship by multiple Intellectual Disability/Autism and Syndromic Disorders GCEPs (ClinGen; GenCC)

Synonyms/related terms: CUL3-related neurodevelopmental disorder; Cullin-3 haploinsufficiency syndrome; NEDAUS. Note: CUL3 is a dual-disease gene — distinct, mechanistically unrelated pathogenic variants (specifically those disrupting exon 9 splicing) cause pseudohypoaldosteronism type IIE (PHA2E; OMIM #614496), a renal salt-wasting/hypertension disorder acting through the WNK-kinase pathway, not through the neurodevelopmental mechanism described here (PMC4604684; OMIM #614496). This distinction is important for curation — NEDAUS and PHA2E are separate MONDO/OMIM entities despite sharing a gene.

Source of information: Data are derived from aggregated case series and cohort studies (clinical genetics case reports, exome-sequencing cohorts, and multi-center collaborations), not from a single large EHR/registry-based dataset. The largest published cohorts to date are ~26 individuals (Sadler et al. 2024/2025, PMID:39501558) and 37 families (Blackburn et al. 2025, Ann Neurol, DOI:10.1002/ana.27077), supplemented by numerous smaller case reports. Exact population prevalence is unknown; the disease is considered rare (MedlinePlus Genetics).

2. Etiology

Disease causal factor: NEDAUS is a monogenic Mendelian disorder caused by heterozygous pathogenic variants in CUL3, encoding Cullin-3, the scaffold protein of Cullin-RING E3 ubiquitin ligase (CRL3) complexes. The overwhelming majority of reported cases arise from de novo variants; germline mosaicism and rare familial transmission (autosomal dominant, presumably with variable expressivity) have been reported but are uncommon.

Genetic risk factors: - Heterozygous loss-of-function (nonsense, frameshift, canonical splice-site) variants are the most common mechanism, consistent with a haploinsufficiency model. - Missense variants also occur and, in a subset, have been shown to impair CRL3 complex assembly or substrate ubiquitination. - A large-deletion (CNV) encompassing CUL3 has also been reported (Sadler et al., PMID:39501558). - CUL3 is independently established as one of the highest-confidence autism spectrum disorder risk genes by two landmark exome sequencing consortia: - De Rubeis et al. 2014 (Autism Sequencing Consortium, PMID:25363760) — CUL3 met genome-wide significance (FDR ≈0.01) among de novo/rare damaging variant enrichment in ASD. - Satterstrom et al. 2020 (Cell, PMID:31981491) — large-scale exome sequencing of 35,584 samples (11,986 with ASD) identified 102 ASD-associated genes at FDR ≤0.1; CUL3 was among the top-ranked, high-confidence genes. - SFARI Gene database assigns CUL3 a Category 1 ("high confidence") ASD gene score (gene.sfari.org/database/human-gene/CUL3). - Analysis of published mutations found approximately 20 CUL3 variants (13 protein-truncating, 7 missense) across ASD/developmental-delay/schizophrenia cohorts, with essentially no comparable variants found in unaffected controls.

Environmental risk factors: None specifically established; as a monogenic de novo disorder, standard advanced-paternal-age associations with de novo mutation rate may apply generally but are not specifically quantified for CUL3.

Protective factors: None established in the literature.

Gene-environment interactions: Not reported; the disorder's penetrance and expressivity appear driven primarily by variant type/location and possibly genetic background/modifiers rather than documented environmental modifiers.

3. Phenotypes

Phenotype frequencies below are drawn primarily from the largest published cohort (Sadler et al. 2024/2025, n=26, PMID:39501558; full text) and the Blackburn et al. 2025 cohort (n=37 families, Ann Neurol), supplemented by MedlinePlus Genetics and OMIM.

Phenotype	Frequency (approx.)	Suggested HPO term
Global developmental delay	Near-universal	HP:0001263
Speech/motor developmental delay	88%	HP:0000750 / HP:0001270
Intellectual disability	77%	HP:0001249
Learning disorder	89%	HP:0002194
Behavioral abnormalities	76%	HP:0000708
Autism spectrum disorder / autistic features	~33–36%	HP:0000717
Seizures (variable types incl. infantile spasms)	Subset (reported in original 3-case series, ~67% had infantile spasms; overall cohort seizure rate lower, estimated in the range of a fifth to a third of cases)	HP:0001250; infantile spasms HP:0011097
ADHD	33% (signature-positive subgroup)	HP:0007018
Hand/foot abnormalities (curved 5th finger, high foot arches, toe webbing)	51–60%	HP:0001167 (camptodactyly of finger); HP:0001762 (talipes); HP:0001777 (syndactyly of toes)
Dysmorphic facial features (long triangular face, large forehead, pointed chin, deep-set eyes)	50–52%	HP:0000275 (narrow face); HP:0000341 (prominent forehead); HP:0000307 (pointed chin); HP:0000490 (deeply set eye)
Cardiac/septal defects	35%	HP:0001671
Brain MRI abnormalities	56%	HP:0012443
Fetal/intrauterine growth restriction	35–59%	HP:0001511
Feeding problems / poor feeding	36%	HP:0011968
Failure to thrive	Present in subset	HP:0001508
Hypotonia (childhood) progressing to dystonia/tremor/spasms (adulthood)	Reported in a subset	HP:0001252 (hypotonia); HP:0001332 (dystonia); HP:0001337 (tremor)
Microcephaly	Subset	HP:0000252
Poor visual contact	Subset	HP:0000618-adjacent
GERD	Reported	HP:0002020
Genitourinary anomalies	Reported in subset	HP:0000119

Phenotype characteristics: - Onset: Congenital/infantile — developmental delay is apparent from infancy in essentially all cases. - Progression: Variable — most features are static/developmental rather than progressive, but adult-onset movement disorder (dystonia, tremor, spasms) has been described, and seizure onset can be accompanied by developmental regression in some patients. - Severity: Highly variable, ranging from mild learning difficulties to profound intellectual disability with epilepsy; some carriers have neither seizures nor autism despite pathogenic variants (variable expressivity/incomplete penetrance for specific features). - Quality of life impact: Not systematically quantified with standardized instruments (EQ-5D/SF-36) in the literature to date; impact is inferred to be substantial given the combination of intellectual disability, behavioral, and motor involvement, with early multidisciplinary therapy recommended.

4. Genetic/Molecular Information

Causal gene: CUL3 (Cullin 3), OMIM *603136, chromosome 2q36.2, HGNC:2553, NCBI Gene ID 8452, UniProt Q13618.

Variant classes reported (cohort of 26, PMID:39501558): - Nonsense: 8 cases - Frameshift: 9 cases - Missense: 5 cases - Splice-site: 3 cases - Copy number variant (large deletion encompassing CUL3): 1 case

Functional consequence: Predominantly loss of function via haploinsufficiency — truncating and splice-disrupting variants are the majority class, consistent with a dosage-sensitive gene. Missense variants have been shown in functional studies (e.g., Gao et al. 2023, PMID:37558490) to impair Cullin-3 scaffolding activity within CRL3 complexes.

Allele frequency: CUL3 loss-of-function variants are under strong purifying selection in population databases (gnomAD), consistent with high intolerance to loss-of-function variation (pLI ≈1), supporting pathogenicity of de novo truncating variants; no NEDAUS-causing variants are expected/observed at appreciable frequency in gnomAD.

Origin: Overwhelmingly germline de novo; distinguish from CUL3 somatic involvement, which is not a recognized feature of NEDAUS (unlike some cancer contexts where CUL3 substrate adaptors are somatically altered).

Modifier genes/epigenetics: A robust DNA methylation episignature comprising 213 differentially methylated probes has been identified in a subset of CUL3 pathogenic-variant carriers ("signature-positive" cases), with high sensitivity/specificity for distinguishing affected individuals from controls, and predominant hypomethylation changes (Sadler et al. 2024/2025, PMID:39501558). This episignature may aid reclassification of variants of uncertain significance and suggests a downstream epigenetic mechanism (potentially via disrupted CRL3-mediated turnover of chromatin-modifying enzymes).

Chromosomal abnormalities: A large deletion encompassing the CUL3 locus has been reported causing the phenotype (contiguous gene/whole-gene deletion mechanism), reinforcing haploinsufficiency as the operative mechanism.

Gene-disease validity: CUL3 is recognized by ClinGen-affiliated expert panels (Intellectual Disability and Autism GCEP) with substantial published evidence (at least seven unrelated cases in the literature meeting curation criteria per Genomics England PanelApp) and is a definitive gene-disease relationship in Gen2Phen/PanelApp curation for intellectual disability (PanelApp).

5. Environmental Information

No specific environmental, lifestyle, or infectious causal factors have been established for NEDAUS; it is understood as a purely monogenic disorder driven by de novo germline CUL3 variation. No CTD (Comparative Toxicogenomics Database) gene-environment interaction records specific to CUL3-associated neurodevelopmental disease were identified in this search.

6. Mechanism / Pathophysiology

Molecular function of CUL3: CUL3 encodes Cullin-3, the elongated scaffold protein that "orchestrates the assembly" of Cullin-RING E3 ubiquitin ligase 3 (CRL3/BCR complexes) — Cullin-3 binds RBX1 at one end (recruiting an E2 ubiquitin-conjugating enzyme) and a BTB-domain-containing substrate adaptor protein at the other, bridging E2 enzyme and substrate to catalyze substrate ubiquitination, typically targeting proteins for 26S proteasomal degradation (reviewed in PMC10416632, PMID:37575562).

Causal chain (molecular → cellular → organismal): 1. Trigger: Heterozygous de novo loss-of-function (or damaging missense) CUL3 variant → CUL3 haploinsufficiency. 2. Molecular consequence: Reduced/impaired CRL3 ubiquitin ligase complex assembly and activity → disrupted ubiquitin-proteasome-mediated protein turnover of CRL3 substrates, including small GTPase RhoA (via BACURD1/2 [KCTD adaptors]), with downstream evidence also implicating altered turnover of chromatin-modifying enzymes (proposed mechanism for the observed methylation episignature). 3. Cellular consequence: In Cul3-haploinsufficient mouse models, elevated/dysregulated RhoA signaling disrupts actin cytoskeletal dynamics, impairing cortical neurogenesis, dendritic growth, filamentous actin puncta formation, and spontaneous neuronal network activity (Amar/Dong et al. 2021, Mol Psychiatry, PMID:33727673). Pharmacological RhoA inhibition rescued dendrite length and network activity phenotypes in this model, directly demonstrating RhoA as a key downstream effector. 4. Circuit/systems consequence: Conditional Cul3 ablation restricted to cholinergic neurons of the basal forebrain recapitulates ASD-like social and sensory-gating deficits and cognitive impairment, implicating prefrontal cortex cholinergic projections in the behavioral phenotype (PMID:36693858). Postnatal, forebrain-restricted excitatory-neuron Cul3 deletion (CaMKIIα-Cre model) produces repetitive jumping, reduced marble burying, hyperlocomotion, impaired motor coordination, and hindlimb clasping (Sekar et al. 2025, Genes Brain Behav, PMC12536218). 5. Organismal consequence: Global developmental delay, intellectual disability, autistic features/behavioral abnormalities, and in a subset, seizures (with occasional regression) and dysmorphic/structural features.

Cell types/processes implicated: - Cortical neural progenitor cells / radial glia (neurogenesis defect) - Excitatory forebrain (pyramidal) neurons (dendritic/synaptic defects) - Cholinergic basal forebrain neurons (behavioral/cognitive circuit) - Suggested GO terms: GO:0016567 (protein ubiquitination), GO:0031461 (cullin-RING ubiquitin ligase complex), GO:0007399 (nervous system development), GO:0021987 (cerebral cortex development), GO:0035556 (intracellular signal transduction, RhoA-related) - Suggested CL terms: CL:0000030 (neuroblast, generic — for cortical neural progenitor), CL:0000598 (pyramidal neuron), CL:0002453 (oligodendrocyte precursor cell — not specifically implicated, included only if relevant), CL:0011005 (GABAergic neuron — not primary), cholinergic neuron (CL:0000108)

Distinct mechanism for PHA2E (differential note): Exon-9-disrupting CUL3 variants (a structurally distinct mutational class from the truncating/missense variants causing NEDAUS) impair CRL3-mediated ubiquitination of WNK kinases (via the KLHL3 adaptor) in the distal nephron, causing familial hyperkalemic hypertension (PHA2E) — a completely separate clinical entity that curators should not conflate with NEDAUS despite the shared gene (PMC4604684).

Molecular profiling: DNA methylation array (episignature) data support pathway-level evidence of altered epigenetic regulation in CUL3 haploinsufficiency (Sadler et al., PMID:39501558). No large-scale transcriptomic/proteomic human patient datasets were identified; mouse model studies provide transcriptomic/proteomic profiling of embryonic through adult brain (Amar et al. 2021, PMID:33727673).

7. Anatomical Structures Affected

Organ level (primary): Central nervous system (brain — cerebral cortex specifically implicated in animal models).
Secondary/associated organ involvement: Cardiovascular system (septal defects), gastrointestinal system (feeding difficulties, GERD), musculoskeletal system (hand/foot anomalies), genitourinary system (anomalies in a subset), growth (failure to thrive, IUGR).
Tissue/cell level: Cerebral cortex — neural progenitor cells, pyramidal (excitatory) neurons; basal forebrain cholinergic neurons; prefrontal cortex circuitry.
Subcellular level: Cytoskeleton (actin dynamics via RhoA), ubiquitin-proteasome system components (CRL3 complex assembly), and by extension chromatin/epigenetic machinery (implicated by the methylation episignature).
Suggested UBERON terms: UBERON:0000955 (brain), UBERON:0000956 (cerebral cortex), UBERON:0001890 (forebrain), UBERON:0002037 (cerebellum — not specifically implicated but sometimes assessed on MRI), UBERON:0000948 (heart, for septal defects).
Suggested GO Cellular Component terms: GO:0031461 (cullin-RING ubiquitin ligase complex), GO:0015629 (actin cytoskeleton), GO:0005634 (nucleus, for epigenetic effects).
Laterality: Not applicable — a diffuse neurodevelopmental process rather than a lateralized structural lesion, though individual brain MRI anomalies (reported in 56% of signature-positive cases) may show focal or global findings.

8. Temporal Development

Onset: Congenital/infantile onset; global developmental delay is apparent from infancy in essentially all reported patients. Seizures, when present, are often infantile-onset (infantile spasms reported in the original Nakashima et al. 2020 case series).
Progression: Largely a static/developmental disorder rather than degenerative, though:
Developmental regression can follow seizure onset in a subset.
Movement-disorder features (dystonia, tremor, spasms) have been reported to emerge or become more prominent in adulthood, following childhood hypotonia — suggesting an evolving, age-dependent motor phenotype.
Disease course: Chronic, lifelong neurodevelopmental condition; no reports of spontaneous resolution of the core intellectual/developmental features.
Critical periods: Early childhood is emphasized as the critical window for intervention — specialist guidance (e.g., CUL3 Foundation/family advocacy resources) recommends initiating physical, occupational, speech, and behavioral therapies "as early as possible, ideally before a child begins school" (cul3.org).

9. Inheritance and Population

Epidemiology: Prevalence and incidence are unknown/not established; the condition is rare, with only several dozen molecularly confirmed cases published to date (aggregate across case reports and the two largest cohorts of 26 and 37 individuals). The CUL3 patient advocacy organization states there is no reliable estimate of the number of individuals living with the condition worldwide, and likely substantial underascertainment (cul3.org).
Inheritance pattern: Autosomal dominant (OMIM #619239); the great majority of cases are de novo; rare parent-to-child transmission and germline mosaicism are possible but not well-quantified.
Penetrance: Appears high for the core developmental delay/intellectual disability phenotype but incomplete/variable for specific features — seizures and autism are present in only a subset of variant carriers ("with or without" nomenclature reflects this variable expressivity), and some individuals show neither.
Expressivity: Highly variable across affected individuals, even among those with similar variant classes.
Genetic anticipation: Not reported/applicable (not a repeat-expansion disorder).
Founder effects: None specifically reported.
Consanguinity: Not a relevant risk factor, given the dominant de novo mechanism.
Carrier frequency: Not applicable (de novo dominant disorder, not a recessive carrier-screening condition).
Population demographics: No ethnic, geographic, or sex-based enrichment has been specifically reported; the Sadler et al. cohort included 15 males and 11 females, without strong sex skew noted. Cases have been reported from multiple countries (Japan, Malaysia, Netherlands, USA, Turkey, China, and others), consistent with a pan-ethnic de novo disorder.

10. Diagnostics

Genetic testing (primary diagnostic modality):
Whole exome sequencing (WES) or whole genome sequencing (WGS) with trio (parent-child) analysis is the standard approach, given the de novo, genetically heterogeneous nature of neurodevelopmental disorders; this is how essentially all published cases have been identified.
Multi-gene neurodevelopmental disorder / intellectual disability / autism gene panels that include CUL3 are also used clinically (e.g., Genomics England PanelApp intellectual disability panel lists CUL3 as a "green"/definitive gene).
Chromosomal microarray (CMA) can detect the large-deletion CNV mechanism encompassing CUL3.
Single-gene Sanger confirmation is used once a candidate variant is identified.
Emerging diagnostic tool — DNA methylation episignature: A CUL3-specific episignature (213 differentially methylated CpG probes, predominantly hypomethylated in "signature-positive" cases) has been validated as a functional classifier that can help resolve variants of uncertain significance (Sadler et al. 2024/2025, PMID:39501558) — an approach paralleling episignature testing used for other chromatin/ubiquitin-pathway neurodevelopmental disorders.
Clinical/phenotypic criteria: No formal consensus clinical diagnostic criteria exist (as for a purely molecularly defined disorder); diagnosis rests on genetic confirmation plus compatible phenotype.
Differential diagnosis: Other monogenic neurodevelopmental disorders with overlapping developmental delay/autism/seizure phenotype, particularly other ubiquitin-proteasome pathway or chromatin-regulator disorders; and, importantly, must be distinguished from PHA2E (exon-9 splice-region CUL3 variants) which is a distinct renal/endocrine phenotype without neurodevelopmental features.
Supportive/monitoring investigations (per patient advocacy clinical guidance, cul3.org): cardiac echocardiogram, EEG, brain MRI, growth monitoring, and referrals to developmental pediatrics, cardiology, neurology, endocrinology, gastroenterology, and psychology as indicated by individual presentation.
Screening: No population or newborn screening program exists (rare, de novo, molecularly heterogeneous disorder); prenatal detection is occurring increasingly via prenatal exome/genome sequencing when structural anomalies (e.g., growth restriction) are noted on ultrasound (Gofin et al. 2026, Prenatal Diagnosis, "CUL3-Related Neurodevelopmental Disorder: Expanding the Prenatal Phenotype").

11. Outcome/Prognosis

Survival/mortality: No specific mortality data or life-expectancy reduction has been reported in the literature reviewed; the disorder is not classically associated with early mortality, though cardiac defects and severe epilepsy in a subset of patients could theoretically affect morbidity.
Morbidity/function: Variable functional impairment ranging from mild learning disability to significant intellectual disability with motor and behavioral involvement; adult-onset movement disorder (dystonia/tremor/spasms) may add to long-term morbidity in some patients.
Quality of life: Not formally measured with standardized QOL instruments in published literature to date.
Complications: Seizures (with possible regression), cardiac septal defects, feeding difficulties/failure to thrive, and orthopedic/limb anomalies are recurring complications.
Recovery potential: Developmental gains are achievable with early, sustained multidisciplinary therapy (physical, occupational, speech, behavioral), per current expert/family-advocacy guidance, though the underlying intellectual disability and neurodevelopmental features are lifelong.
Prognostic factors: Presence/absence of seizures and autism are the major axes of clinical heterogeneity noted in the disorder's name and clinical descriptions; whether specific variant type (truncating vs. missense) or "episignature-positive" status correlates with a more severe/distinct phenotype is an active area of study (the episignature-positive subgroup in Sadler et al. showed higher rates of ADHD, MRI abnormalities, cardiac defects, and feeding problems, suggesting a possible phenotype-genotype/epigenotype correlation).

12. Treatment

There is no disease-modifying or curative treatment; management is entirely supportive/symptomatic, consistent with the current understanding stated by the patient advocacy organization: "There is currently no cure or drug treatment" (cul3.org).

Supportive/rehabilitative care:
Physical therapy — NCIT:C15302 (Physical Therapy)
Occupational therapy — NCIT:C121351 (Occupational Therapy)
Speech-language therapy — NCIT:C159273 (Speech Therapy)
Behavioral therapy/counseling (for autism-spectrum features) — NCIT:C181743 (Behavioral Counseling) or a therapeutic-procedure equivalent
Early intervention services are specifically emphasized as most effective when initiated before school age.
Pharmacotherapy: Symptomatic only — e.g., antiseizure medications for the subset with epilepsy (agent selection driven by seizure type, not CUL3-specific; infantile spasms historically treated per standard protocols such as ACTH/vigabatrin in the general infantile-spasms population, though no CUL3-specific efficacy data were identified) — NCIT:C15986 (Pharmacotherapy).
Surgical/interventional: Cardiac surgical correction for septal defects when clinically indicated — NCIT:C15329 (Surgical Procedure).
Genetic counseling: NCIT:C15240 (Genetic Counseling) — recommended for all families given the (usually de novo) inheritance, to discuss recurrence risk (low but nonzero due to possible germline mosaicism) and reproductive options.
Experimental/research directions: Mechanistic mouse-model work (Amar et al. 2021, PMID:33727673) demonstrating that pharmacological RhoA inhibition rescues dendritic and network activity phenotypes identifies RhoA/actin-cytoskeleton signaling as a plausible future therapeutic target, though this remains preclinical and has not translated to human trials.
Clinical trials: No CUL3/NEDAUS-specific interventional trials were identified in this search (ClinicalTrials.gov was not directly queried in this pass but no trial was surfaced via general search).

13. Prevention

No primary prevention exists for this de novo genetic disorder.
Secondary prevention/early detection: Prenatal diagnosis via exome/genome sequencing is increasingly reported, especially when fetal growth restriction or structural anomalies are noted on ultrasound (Gofin et al. 2026, Prenatal Diagnosis); this enables early postnatal surveillance and early-intervention referral.
Genetic counseling: Central preventive/risk-management tool for families, addressing recurrence risk (low, given predominant de novo origin, but genetic counselors should discuss the possibility of parental germline mosaicism).
Tertiary prevention: Early multidisciplinary surveillance (cardiac, neurologic/EEG, growth, GI) to detect and manage complications early, as recommended by patient advocacy/clinical guidance.

14. Other Species / Natural Disease

No naturally occurring CUL3-related neurodevelopmental disease has been reported in companion animals or wildlife (OMIA search not specifically performed, but no evidence surfaced).
Comparative biology: CUL3 is highly evolutionarily conserved; the Drosophila melanogaster ortholog Cullin-3 and the murine ortholog Cul3 (MGI:1347360) are used extensively in mechanistic modeling (see Model Organisms below), reflecting deep conservation of the CRL3 ubiquitin-ligase pathway across metazoans.
Zoonotic potential: Not applicable (a genetic, non-infectious disorder).

15. Model Organisms

Multiple genetically engineered animal and invertebrate models recapitulate aspects of CUL3 haploinsufficiency:

Mouse models: 1. Germline haploinsufficient Cul3 mouse (Amar/Dong et al. 2021, Mol Psychiatry, PMID:33727673): CRISPR/Cas9-generated 1-bp frameshifting insertion in exon 6 of Cul3 (C57BL/6N background). Phenotypes: reduced cortical volume from early postnatal development (on brain MRI), social and cognitive deficits, hyperactive behavior, reduced dendritic growth and filamentous actin puncta, reduced spontaneous neuronal network activity — rescued by pharmacological RhoA inhibition, directly implicating RhoA as the key downstream mechanistic substrate. Access: PMC8443683 / bioRxiv preprint. 2. Cholinergic-neuron-restricted Cul3 knockout (2023, Translational Psychiatry, PMID:36693858): Conditional ablation of Cul3 in cholinergic neurons recapitulates ASD-like social and sensory-gating deficits and cognitive impairment, with diminished basal-forebrain cholinergic neuron activity and implication of prefrontal cortex cholinergic projections in the cognitive phenotype. 3. Postnatal forebrain-restricted conditional knockout (Sekar et al. 2025, Genes Brain Behav, PMC12536218): CaMKIIα-Cre x floxed-Cul3 mice with delayed postnatal deletion in predominantly forebrain excitatory neurons. Phenotypes: repetitive jumping, reduced marble burying, increased locomotion, impaired motor coordination, and increased hindlimb clasping — demonstrating that even postnatal, cell-type-restricted loss of Cul3 (not just developmental/germline loss) is sufficient to cause robust behavioral abnormalities, relevant to therapeutic-window considerations. 4. Cul3 gene resource: MGI:1347360 (Mouse Genome Informatics).

Drosophila model: - Neuronal knockdown of Cullin3 in flies (2024, Scientific Reports, PMC10794434) reproduces multiple ASD-relevant phenotypes: short sleep, reduced courtship behavior, impaired courtship-suppression learning/memory, faster starvation and lower triacylglyceride levels (metabolic/lipid dysregulation), heightened hyperoxia sensitivity (oxidative stress), and severe mushroom-body neuroanatomical defects (93% of knockdown brains missing at least one lobe; ~36% lacking αβ projections) — establishing an invertebrate model of both behavioral and structural neurodevelopmental phenotypes.

Applications: These models collectively support study of (a) cortical neurogenesis and dendritic/cytoskeletal defects, (b) circuit-specific (cholinergic/prefrontal) contributions to cognitive and social phenotypes, (c) postnatal reversibility/rescue windows, and (d) conserved metabolic/sleep phenotypes — and provide the RhoA-pathway rescue data that constitute the field's leading candidate mechanism-based therapeutic hypothesis.

Limitations: No model fully recapitulates the human seizure phenotype or the specific dysmorphic/growth features reported clinically; cross-species translational fidelity for the epilepsy and craniofacial/limb components remains an open question (a candidate HUMAN_MODEL_MISMATCH-type gap for curation purposes).

Summary of Key Primary Literature (PMID-anchored)

Citation	PMID/DOI	Contribution
De Rubeis et al. 2014, Nature	PMID:25363760	CUL3 identified as high-confidence ASD gene (Autism Sequencing Consortium)
Nakashima et al. 2020, J Hum Genet	PMID:32341456	First clinical description establishing NEDAUS (3 patients, de novo CUL3 variants)
Satterstrom et al. 2020, Cell	PMID:31981491	Large-scale exome sequencing confirms CUL3 among 102 high-confidence ASD genes
Amar/Dong et al. 2021, Mol Psychiatry	PMID:33727673	Haploinsufficient Cul3 mouse model; RhoA-dependent cortical/synaptic mechanism
Cholinergic Cul3 KO, 2023, Transl Psychiatry	PMID:36693858	Basal-forebrain cholinergic circuit mechanism for behavioral phenotype
Review, 2023, Front Psychiatry	PMID:37575562	"Current trends of high-risk gene Cul3 in neurodevelopmental disorders"
Nonsense mutation case report, 2023, Medicine	—	ASD + epilepsy phenotype, Chinese cohort
Sadler et al. 2024/2025, HGG Advances (ScienceDirect)	PMID:39501558	Largest cohort to date (n=26); episignature discovery; detailed phenotype frequencies
Blackburn et al. 2025, Ann Neurol	DOI:10.1002/ana.27077	37-family cohort establishing loss-of-function CUL3 as cause of syndromic NDD
Sekar et al. 2025, Genes Brain Behav	PMC12536218	Postnatal forebrain conditional knockout mouse model
Gofin et al. 2026, Prenatal Diagnosis	DOI:10.1002/pd.70106	Expanded prenatal phenotype (fetal growth restriction)

Sources

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Neurodevelopmental Disorder With or Without Autism or Seizures (NEDAUS): A Comprehensive Disease Characteristics Report

openscientist-autonomous 14 citations 2026-08-18T15:32:06.454925

Neurodevelopmental Disorder With or Without Autism or Seizures (NEDAUS): A Comprehensive Disease Characteristics Report

Disease: Neurodevelopmental Disorder With or Without Autism or Seizures (NEDAUS) MONDO ID: MONDO:0030994 · OMIM: #619239 · Causal gene: CUL3 (HGNC:2553) Category: Mendelian (autosomal dominant, syndromic neurodevelopmental disorder)

Summary

Neurodevelopmental disorder with or without autism or seizures (NEDAUS) is a rare, autosomal-dominant, syndromic neurodevelopmental disorder caused by heterozygous — and predominantly de novo — loss-of-function (LoF) variants in CUL3, the gene encoding Cullin-3, the scaffold subunit of the Cullin-3 RING E3 ubiquitin-ligase (CRL3) complexes. The disorder maps to MONDO:0030994 / OMIM #619239 and is classified as a Mendelian neurodevelopmental disorder. Its clinical hallmark is global developmental delay and intellectual disability (nearly constant), accompanied by variable autism spectrum features and epilepsy — frequently infantile spasms with hypsarrhythmia — hence the descriptive name "with or without autism or seizures."

The mechanistic basis is haploinsufficiency. A single functional CUL3 allele produces roughly half the normal amount of Cullin-3 scaffold, reducing the ubiquitin-ligase activity of the ~180 CRL3 complexes that depend on it. This was demonstrated directly in patient-derived cells: reduced ubiquitin–protein conjugates and failure to degrade the canonical CRL3 substrate 4E-BP1 (EIF4EBP1), a regulator of mTOR–eIF4E cap-dependent translation (PMID: 39301775). A parallel substrate axis — RhoA, controlled via KCTD13/BACURD adaptors — governs actin cytoskeletal dynamics, neuronal migration, and dendritic growth; a Cul3-haploinsufficient mouse recapitulates social/cognitive deficits and reduced cortical volume, and pharmacologic RhoA inhibition rescues the dendritic and network-activity phenotypes (PMID: 33727673). CUL3 is one of the most loss-of-function-intolerant genes in the human genome (gnomAD pLI ≈ 1.0, LOEUF 0.31), fully consistent with a haploinsufficiency disease model.

There is currently no disease-specific therapy; management is symptomatic and supportive (antiseizure medication, developmental/behavioral therapies, and management of feeding and structural anomalies). The mechanistic work does, however, nominate RhoA and the mTOR–eIF4E translational axis as rational future therapeutic targets. Notably, a mechanistically distinct allelic disorder — pseudohypoaldosteronism type IIE / familial hyperkalemic hypertension (OMIM #614496) — is caused by CUL3 exon-9-skipping variants acting through a dominant-negative mechanism, and must be distinguished from the LoF-driven neurodevelopmental disorder.

Key Findings

Finding 1 — Disease identity and identifiers (F001)

NEDAUS is a CUL3-related autosomal-dominant neurodevelopmental disorder. The Monarch/MONDO graph maps MONDO:0030994 (synonym NEDAUS) to OMIM:619239, DOID:0061147, GARD:0018540, UMLS:C5543225, and MedGen:1784023. The disease is associated causally with HGNC:2553 (CUL3) and mode of inheritance HP:0000006 (autosomal dominant), and is a subclass of MONDO:0100500 (Mendelian disease). Core HPO annotations returned for the disease include:

Phenotype	HPO term
Seizure	HP:0001250
Autistic behavior	HP:0000729
Delayed speech and language development	HP:0000750
Motor delay	HP:0001270
Intellectual disability, mild → severe	HP:0001256 / HP:0010864
Infantile spasms	HP:0012469
Hypsarrhythmia	HP:0002521
Microcephaly	HP:0000252
Failure to thrive	HP:0001508

Synonyms / alternative names: Neurodevelopmental disorder with or without autism or seizures; NEDAUS; CUL3-related neurodevelopmental disorder; CUL3 haploinsufficiency syndrome. Information is derived from aggregated, disease-level resources (OMIM, MONDO, HPO curation) plus published multi-center patient cohorts — not from a single EHR system.

Finding 2 — CUL3 loss-of-function causes syndromic NDD via haploinsufficiency; 4E-BP1 accumulates (F002)

The largest cohort assembled to date comprised 37 individuals with heterozygous CUL3 variants — 35 with LoF variants and 2 with missense variants — presenting a syndromic NDD characterized by intellectual disability with or without autistic features (PMID: 39301775). The authors verified the mechanism in patient-derived T-cells:

"We assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss-of-function (LoF) and 2 have missense variants." (PMID: 39301775)

"Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells." (PMID: 39301775)

Patient cells showed decreased ubiquitin–protein conjugates, confirming that reduced CUL3 dosage translates into reduced global CRL3 E3-ligase output, with the substrate 4E-BP1 accumulating rather than being degraded. Haploinsufficiency via LoF is therefore the predominant pathogenic mechanism.

Finding 3 — Mouse model: RhoA/cytoskeletal signaling and cortical neurogenesis (F003)

A CRISPR-engineered Cul3-haploinsufficient mouse recapitulates the human phenotype and pinpoints a causal substrate (PMID: 33727673):

"Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior. Brain MRI found decreased volume of cortical regions." (PMID: 33727673)

Multi-omic profiling implicated neurogenesis and cytoskeletal defects; dendritic growth, filamentous-actin puncta, and spontaneous network activity were all reduced. Critically, the phenotype was pharmacologically reversible:

"Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes." (PMID: 33727673)

This establishes RhoA as a mechanistically causal, druggable node downstream of CUL3 loss.

Finding 4 — Extreme LoF intolerance and the distinct allelic hypertension disorder (F004)

gnomAD constraint metrics for CUL3 (ENSG00000036257, chromosome 2) place it among the most intolerant genes in the genome: pLI = 1.0, observed/expected LoF (oe_lof) = 0.213 (95% CI 0.149–0.313; LOEUF = 0.31), observed LoF 19 vs expected 89.1, LoF Z = 6.30, and strong missense constraint (missense Z = 6.58). This severe intolerance is exactly what a haploinsufficiency model predicts and provides the population-genetic underpinning for ACMG PVS1-level pathogenicity of null variants.

Importantly, a mechanistically distinct allelic disorder exists: pseudohypoaldosteronism type IIE / familial hyperkalemic hypertension (OMIM #614496) is caused by CUL3 exon-9-skipping variants producing an internal deletion of residues 403–459 (CUL3-Δ9):

"Cul3 mutations cause skipping of exon 9, which results in an internal deletion of 57 amino acids from the CUL3 protein (CUL3-∆9)." (PMID: 29361671)

CUL3-Δ9 acts by a dominant-negative mechanism on the renal KLHL3–WNK-kinase degradation axis — not haploinsufficiency — and produces hypertension/hyperkalemia rather than neurodevelopmental disease. This dichotomy is essential for correct variant interpretation.

Finding 5 — Phenotype spectrum and HPO frequencies (F005)

Curated HPO annotations for OMIM:619239 (source PMIDs 30311385, 32341456, 31696658) plus the Blackburn 2024 cohort (n = 37) yield a frequency-stratified phenotype profile:

Frequency tier	Phenotype (HPO)
Constant / near-constant	Global developmental delay incl. delayed speech/language (HP:0000750, 5/5); delayed sitting (HP:0025336, 3/3) and walking (HP:0031936, 3/3); motor delay (HP:0001270); intellectual disability, mild→severe (HP:0001256 / HP:0010864); infantile onset (HP:0003593, 3/3)
Frequent	Autistic behavior (HP:0000729); seizures (HP:0001250, 2/3) incl. infantile spasms (HP:0012469, 2/3) with hypsarrhythmia (HP:0002521) and EEG burst suppression (HP:0010851); tonic seizures (HP:0032792); hyperactivity/ADHD (HP:0000752); delayed CNS myelination (HP:0002188); feeding difficulties (HP:0011968); failure to thrive (HP:0001508)
Variable / less common	Microcephaly (HP:0000252); dysmorphic facial features (GestaltMatcher-analyzed); submucous cleft palate (HP:0000176); bifid uvula (HP:0000193); atrial septal defect (HP:0001631); pulmonic stenosis (HP:0001642); absent thumb (HP:0009777)

The quality-of-life impact is substantial and lifelong, driven principally by intellectual disability, communication impairment, epilepsy, and feeding difficulty — features that require multidisciplinary developmental, educational, and medical support. Autism-associated motor and feeding difficulties (well documented in the broader ASD literature, e.g. PMID: 42608985, PMID: 42609138) compound daily-functioning burden.

Finding 6 — CUL3/CRL3 substrate-adaptor network links NEDAUS to multiple neuronal pathways (F006)

CUL3 is the scaffold of Cullin-3 RING E3 ligases (CRL3s), which use ~180 BTB/Kelch (KLHL/KCTD) substrate adaptors to recognize hundreds of substrates. The brain-relevant CRL3 axes documented in the literature are:

RhoA (via BACURD/KCTD13/TNFAIP1 adaptors) — actin cytoskeleton, neuronal migration, dendrite growth (PMID: 33727673; PMID: 26969432).
4E-BP1/EIF4EBP1 — cap-dependent translation / mTOR–eIF4E (PMID: 39301775).
KEAP1–NRF2 (NFE2L2) — antioxidant / oxidative-stress response (PMID: 42446772; PMID: 37328017).
KLHL3–WNK kinase — renal ion homeostasis, relevant to the allelic hypertension disorder (PMID: 29361671).

The 16p11.2 CNV adaptor KCTD13 converges on the CUL3–RhoA axis (PMID: 37465586), tying NEDAUS mechanistically to one of the most common autism-associated copy-number syndromes.

Finding 7 — ClinVar variant landscape (F007)

ClinVar returns 727 total CUL3 variant records, of which 226 are classified pathogenic or likely-pathogenic. These P/LP records encompass both (a) the NDD-associated whole-gene loss-of-function alleles (nonsense, frameshift, splice-site, and larger deletions; germline, typically de novo) and (b) the mechanistically distinct exon-9-skipping alleles causing familial hyperkalemic hypertension (OMIM #614496). Variant interpretation follows ACMG/AMP guidelines; null variants readily meet PVS1 given CUL3's strong LoF intolerance.

Finding 8 — Cross-species conservation of the CUL3/KCTD13 social-behavior axis (F008)

Outbred rat models of the 16p11.2 deletion and duplication (Sprague-Dawley and Long-Evans backgrounds) display convergent social-behavior and novel-object deficits, with altered MAPK1 and CUL3 pathways and male-biased sexual dimorphism (PMID: 37465586):

"Altogether, the consequences of the 16p11.2 genetic region dosage on social behavior are now found in three different species: humans, mice and rats." (PMID: 37465586)

"Interestingly major pathways affecting MAPK1 and CUL3 were found altered in the rat 16p11.2 models with additional changes in males compared to females." (PMID: 37465586)

Together with the Cul3-haploinsufficient mouse (PMID: 33727673) and the human cohort (PMID: 39301775), this demonstrates conservation of the CUL3/KCTD13–RhoA social-behavior circuit across humans, mice, and rats.

Finding 9 — Consolidated causal chain (F009)

Integrating all findings, the causal chain runs from a single germline variant to the clinical syndrome (detailed in the Mechanistic Model below): heterozygous de novo CUL3 LoF → ~50% reduced CUL3 → decreased CRL3 activity → accumulation of substrates 4E-BP1 and RhoA → impaired neurogenesis, migration, dendritic growth, and network activity → reduced cortical volume and delayed myelination → developmental delay/intellectual disability with variable autism and epilepsy. Inheritance is autosomal dominant with essentially complete penetrance but highly variable expressivity; the disorder is ultra-rare, and management is symptomatic only.

Mechanistic Model / Interpretation

   Heterozygous de novo CUL3 loss-of-function variant
   (nonsense / frameshift / splice / deletion; 35/37 LoF)
   gnomAD pLI ≈ 1.0, LOEUF 0.31  →  no tolerance for haploinsufficiency
     │
     ▼
~50% reduction in CUL3 scaffold protein
     │
     ▼
   Reduced Cullin-3 RING E3 ligase (CRL3) activity
   (↓ ubiquitin–protein conjugates in patient T-cells)
     │
┌────────────┴─────────────┐
▼                          ▼
  4E-BP1 (EIF4EBP1)            RhoA  (via KCTD13/
  fails to be degraded         BACURD/TNFAIP1 adaptors)
│                          │
▼                          ▼
  Dysregulated mTOR–eIF4E      Disrupted actin cytoskeleton,
  cap-dependent translation    neuronal migration, dendrite growth
└────────────┬─────────────┘
     ▼
   Impaired cortical neurogenesis & neuronal network activity
     ▼
   ↓ Cortical volume · delayed CNS myelination (mouse MRI + human)
     ▼
   Global developmental delay / intellectual disability
   + variable autism (HP:0000729) + epilepsy / infantile spasms (HP:0012469)

Upstream vs downstream. The initiating (upstream) event is CUL3 dosage reduction and consequent global loss of CRL3 ubiquitination capacity. The substrate-accumulation steps (4E-BP1, RhoA) are proximate downstream effectors; cytoskeletal/translational dysregulation and impaired neurogenesis are intermediate; reduced cortical volume and the clinical neurodevelopmental phenotype are the most distal outputs.

Cell types and processes. Affected cell types include cortical projection neurons (CL:0000598), neural progenitor/radial-glia populations (CL:0000047), and layer II/III pyramidal neurons whose positioning and dendritic maturation depend on KCTD13/TNFAIP1–Rnd signaling (PMID: 26969432). Relevant GO biological processes: protein polyubiquitination (GO:0000209), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), neuron migration (GO:0001764), dendrite development (GO:0016358), cerebral cortex development (GO:0021987), and regulation of Rho protein signal transduction (GO:0035023). Subcellular compartments: cytosol (GO:0005829), Cul3-RING ubiquitin ligase complex (GO:0031463), and the actin cytoskeleton. Primary anatomy: cerebral cortex (UBERON:0000956), with brain (UBERON:0000955) and the nervous system broadly affected.

Section-by-Section Report

1. Disease Information

NEDAUS is a rare Mendelian syndromic neurodevelopmental disorder defined by developmental delay/intellectual disability with variable autism and seizures. Identifiers: MONDO:0030994; OMIM #619239; DOID:0061147; GARD:0018540; UMLS:C5543225; MedGen:1784023. No dedicated Orphanet code or ICD-10/11 code is specific to NEDAUS; it is captured under broad NDD/intellectual-disability categories. Synonyms: CUL3-related NDD; CUL3 haploinsufficiency syndrome. Data are from disease-level curation and published cohorts.

2. Etiology

Primary cause: genetic — heterozygous, mostly de novo loss-of-function variants in CUL3. Genetic risk: the causal LoF variant itself; CUL3 is a defined haploinsufficient gene (pLI ≈ 1.0). No confirmed environmental risk, protective, or gene–environment-interaction factors are established for this Mendelian disorder; disease is essentially fully determined by the causal variant with variable expressivity. Sex may modulate expression (male-biased effects seen in rat 16p11.2/CUL3-pathway models, PMID: 37465586), but this is not established in humans for NEDAUS specifically.

3. Phenotypes

See Finding 5 for the full frequency-stratified table and HPO terms. Phenotype types span behavioral changes (autism HP:0000729, hyperactivity HP:0000752), neurological signs (seizures HP:0001250, infantile spasms HP:0012469, hypotonia), cognitive/developmental (intellectual disability HP:0001256/HP:0010864, delayed speech HP:0000750), structural/physical (microcephaly HP:0000252, palatal anomalies HP:0000176/HP:0000193, congenital heart defects HP:0001631/HP:0001642), and EEG laboratory abnormalities (hypsarrhythmia HP:0002521, burst suppression HP:0010851). Onset is infantile/congenital; severity is variable (mild to severe); course is generally stable/non-progressive (a static encephalopathy) with epilepsy that may be episodic.

4. Genetic / Molecular Information

Causal gene: CUL3 (HGNC:2553; OMIM 603136; Ensembl ENSG00000036257; chromosome 2q36.2). Variant classes: predominantly nonsense, frameshift, canonical splice-site, and gene/exon deletions (LoF); rare missense. In the largest cohort, 35/37 were LoF (PMID: 39301775). ClinVar: 226 P/LP of 727 records (Finding 7). Allele frequency: causal alleles are absent/ultra-rare in gnomAD, consistent with strong constraint. Origin: germline, typically de novo. Functional consequence: loss of function → haploinsufficiency. Distinct allelic mechanism: exon-9-skipping CUL3-Δ9 → dominant-negative → hypertension disorder (PMID: 29361671, PMID: 32619053, PMID: 35563538). Modifier genes / epigenetics: not specifically defined for NEDAUS; substrate-adaptor genes (KCTD13, KLHL family) are mechanistic partners. Chromosomal abnormalities:* 16p11.2 CNVs (containing KCTD13) converge on the same CUL3–RhoA pathway (PMID: 37465586).

5. Environmental Information

No environmental, lifestyle, or infectious agents are established as causes or triggers. This is a monogenic disorder.

6. Mechanism / Pathophysiology

Detailed in the Mechanistic Model section and Findings 2, 3, 6, 9. Molecular pathways: ubiquitin–proteasome system (CRL3), mTOR–eIF4E cap-dependent translation (via 4E-BP1), Rho-GTPase/actin signaling (via RhoA/KCTD13), and KEAP1–NRF2 oxidative-stress response. Cellular processes: cortical neurogenesis, neuronal migration, dendritic maturation, network-activity formation. Protein dysfunction: loss of scaffold function → reduced substrate ubiquitination → substrate accumulation. Transcriptomic/multi-omic dysregulation of neurogenesis and cytoskeletal programs is documented in the mouse model (PMID: 33727673).

7. Anatomical Structures Affected

Primary organ: brain (UBERON:0000955), specifically cerebral cortex (UBERON:0000956) with reduced volume and delayed myelination (HP:0002188). Body system: central nervous system (nervous). Secondary involvement: cardiovascular (septal defects), craniofacial/palate, and occasionally limb. Cell types (CL): cortical projection neurons (CL:0000598), neural progenitors (CL:0000047), pyramidal neurons. Subcellular (GO CC): cytosol (GO:0005829), Cul3-RING ligase complex (GO:0031463). Lateralization: bilateral/generalized CNS involvement.

8. Temporal Development

Onset: congenital/infantile (HP:0003593). Course: static (non-progressive) neurodevelopmental encephalopathy; epilepsy may be episodic and infantile spasms have a characteristic early-infancy window. Critical period: early cortical development (fetal/early postnatal neurogenesis and migration) is the mechanistically vulnerable window, consistent with the mouse MRI finding of decreased cortical volume from early postnatal development. Duration: chronic, lifelong.

9. Inheritance and Population

Inheritance: autosomal dominant (HP:0000006), predominantly de novo. Penetrance: essentially complete for the neurodevelopmental phenotype; expressivity highly variable. Epidemiology: ultra-rare; precise prevalence/incidence not established (fewer than ~50 published patients). Sex ratio: not firmly established; model organisms suggest possible male-biased severity. Founder effects/consanguinity: not applicable (dominant, de novo). Recurrence risk to siblings is low (germline mosaicism possible but not quantified); risk to offspring of an affected individual is 50%.

10. Diagnostics

Genetic testing is definitive. Recommended approach: trio whole-exome sequencing (WES) or whole-genome sequencing (WGS), or a broad intellectual-disability/autism/epilepsy gene panel that includes CUL3; chromosomal microarray (CMA) detects gene/exon-level and 16p11.2 CNVs. Variant interpretation by ACMG/AMP (PVS1 for null variants). Supportive tests: EEG (may show hypsarrhythmia/burst suppression), brain MRI (reduced cortical volume, delayed myelination). No specific biochemical biomarker exists, though patient cells show reduced ubiquitin conjugates and elevated 4E-BP1 (research assays). Differential diagnosis: other monogenic syndromic NDD/DEE genes (e.g., STXBP1 PMID: 42609058, SCN2A, MED13L, SHANK3, KCNB1, PTEN, CDKL5 — several co-identified in ASD/NDD cohorts, PMID: 25969726, PMID: 31696658) and 16p11.2 deletion/duplication syndrome.

11. Outcome / Prognosis

NEDAUS is a chronic, lifelong disorder. It is not typically life-limiting on its own, but severe epilepsy (infantile spasms/DEE), feeding difficulty/failure to thrive, and structural anomalies contribute morbidity. Prognostic factors: severity of intellectual disability, presence and control of epilepsy, and structural comorbidities. Long-term outcomes reflect the degree of developmental impairment; recovery is limited (static encephalopathy) but developmental gains occur with intervention.

12. Treatment

No disease-specific therapy exists — management is symptomatic and supportive: - Antiseizure medications for epilepsy/infantile spasms (standard infantile-spasms therapy: ACTH, vigabatrin, corticosteroids as clinically indicated). - Developmental/behavioral therapies: early intervention, special education, applied behavioral therapy for autism, speech and occupational therapy. - Feeding support for feeding difficulty/failure to thrive; surgical repair of palatal/cardiac anomalies as needed. - Emerging mechanistic targets (preclinical): RhoA inhibition rescued dendritic and network phenotypes in the mouse model (PMID: 33727673); the mTOR–eIF4E/4E-BP1 translational axis is a rational second target (PMID: 39301775). Neither is an approved therapy for NEDAUS. No pharmacogenomic or gene/RNA-based therapy is established.

13. Prevention

No primary prevention exists for a de novo dominant disorder. Genetic counseling is central: an affected individual has a 50% transmission risk; sibling recurrence risk is low but germline mosaicism cannot be excluded. Prenatal/preimplantation genetic testing is available for families with a known pathogenic variant. Secondary/tertiary prevention focuses on early epilepsy control and developmental intervention to limit complications.

14. Other Species / Natural Disease

Cul3 orthologs are conserved: mouse Cul3 (NCBI Gene 26554) and rat Cul3 (NCBI Gene 292630). Model species: Mus musculus (NCBI:txid10090), Rattus norvegicus (NCBI:txid10116). No naturally occurring companion-animal disease is catalogued in OMIA for CUL3, but the pathway is evolutionarily conserved and disease mechanisms recapitulate across humans, mice, and rats (PMID: 37465586). No zoonotic relevance (non-infectious genetic disease).

15. Model Organisms

Mouse (Cul3 germline haploinsufficient, CRISPR): recapitulates social/cognitive deficits, hyperactivity, reduced cortical volume, and dendritic/network deficits; RhoA inhibition rescues key phenotypes — strong construct and face validity (PMID: 33727673). Databases: MGI, IMPC.
Rat (16p11.2 deletion/duplication, outbred SD & LE): altered MAPK1/CUL3 pathways, social-behavior deficits, sexual dimorphism (PMID: 37465586). Database: RGD.
In vitro / patient-derived cells: patient T-cells demonstrate reduced ubiquitin conjugates and 4E-BP1 accumulation, providing a cellular readout of the mechanism (PMID: 39301775).
In utero electroporation (mouse): KCTD13/TNFAIP1 manipulation alters cortical neuron positioning and dendritic maturation (PMID: 26969432).
Limitations: models capture cytoskeletal/neurogenesis phenotypes but incompletely model the full human cognitive/autistic/epileptic spectrum; iPSC-derived neuron/organoid models of NEDAUS are not yet established in the reviewed literature.

Evidence Base

PMID	Title (abbrev.)	Role in this report
39301775	Loss-of-function variants in CUL3 cause a syndromic NDD	Landmark human cohort (n=37, 35 LoF); defines phenotype + 4E-BP1 mechanism (F002, F009)
33727673	Autism-linked Cullin3 germline haploinsufficiency…RhoA signaling	Key mouse model; cortical volume ↓, RhoA rescue (F003)
37465586	…16p11.2 rat models…MAPK2 and KCTD13/CUL3	Cross-species conservation; CUL3-pathway alteration (F008)
29361671	Mutant Cul3-mediated familial hyperkalemic hypertension	Defines distinct CUL3-Δ9 dominant-negative allelic disorder (F004)
26969432	Bacurd1/Kctd13 and Bacurd2/Tnfaip1…Rnd proteins	Adaptor→RhoA/cortical positioning mechanism (F006)
32619053, 35563538, 27378813	PHA II / CUL3-Δ9 papers	Support the distinct hypertension mechanism
42446772, 37328017	KEAP1–NRF2 / Cul3 antioxidant papers	Supporting CRL3 substrate network (F006)
31696658, 25969726	ASD/NDD WES cohorts	Independent identification of de novo CUL3 LoF in ASD; differential-diagnosis context
31279627	Structural basis…KLHL20 E3 ligase	Structural context for BTB-Kelch CRL3 substrate recruitment

Evidence-source types: human clinical cohorts (39301775, 31696658, 25969726); model organism (33727673, 37465586, 26969432, 27378813); in vitro/patient-derived cells (39301775, 35563538, 37328017); population genetics/computational (gnomAD constraint, ClinVar).

Limitations and Knowledge Gaps

Small case numbers. The largest cohort is n=37; precise prevalence, incidence, sex ratio, and natural-history milestones are not established. Phenotype frequencies for several HPO terms rest on small denominators (e.g., 2/3, 3/3).
Genotype–phenotype correlation is underpowered. The basis for highly variable expressivity (why some individuals have autism, others seizures, others neither) is unexplained; no confirmed human modifier genes or epigenetic modifiers.
Two missense variants in the cohort are not fully mechanistically resolved versus LoF — the contribution of non-null alleles to NEDAUS remains uncertain.
No human neuronal disease models (iPSC-derived neurons/organoids) were identified in the reviewed literature; mechanistic inferences rest on mouse/rat and patient blood cells.
No therapeutic trials. RhoA and mTOR–eIF4E rescue data are preclinical only; translational safety/efficacy in humans is unknown.
Biomarkers (4E-BP1 accumulation, ubiquitin-conjugate levels) are research assays, not validated clinical diagnostics.

Proposed Follow-up Experiments / Actions

Establish an international NEDAUS registry to define prevalence, natural history, epilepsy trajectories, sex ratio, and genotype–phenotype correlations at scale.
Generate patient iPSC-derived cortical neurons/organoids to test whether 4E-BP1 accumulation and RhoA-dependent cytoskeletal/network phenotypes reproduce in human neurons, and to screen rescue compounds.
Preclinical target validation: test RhoA inhibitors (e.g., ROCK-pathway or direct RhoA modulators) and mTOR–eIF4E/4E-BP1-axis modulators in the Cul3⁺/⁻ mouse for behavioral/cognitive rescue and therapeutic window.
Deep phenotyping of the CRL3 substrate/adaptor network (KCTD13, KLHL family, NRF2/KEAP1) in patient cells to identify secondary biomarkers and additional therapeutic nodes.
Systematic reclassification of ClinVar VUS (of the 727 records, ~500 non-P/LP) using functional 4E-BP1/ubiquitin-conjugate assays to improve diagnostic yield.
Distinguish allelic disorders diagnostically: ensure clinical pipelines flag exon-9-skipping CUL3-Δ9 variants (hypertension) separately from whole-gene LoF (NEDAUS), given opposite mechanisms and management.

Report compiled from 9 confirmed findings and 27 reviewed papers over 5 iterations. Evidence is strongest for the core identity (F001), haploinsufficiency mechanism with 4E-BP1 accumulation (F002), and RhoA-dependent cortical/behavioral phenotypes with pharmacologic rescue in mouse (F003).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	16
Resolved	16
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	7
Quoted claims found in source	7
Quoted claims not found in source	0
References weighed for topical relevance	16
On topic	6
Off topic	2

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

PMID:42609138 (3 mentions) - Feeding Behaviours in Families With Children or Young People With Autism: A Systematic Review.
shared terms: reduced, autism
PMID:42446772 (4 mentions) - Neuroprotective Potential of Nardostachys jatamansi Extract via Keap1-Nrf2 Pathway Regulation in Parkinson's Disease.
shared terms: mechanism

Weighed against this report's own most characteristic terms: cul3, disorder, model, rhoa, variant, phenotype, nedaus, e-bp1, cortical, mouse, lof, epilepsy, gene, human, reduced, cohort, kctd13, mechanism, autism, cell.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

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Classifications

Mappings

Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Imaging Findings

Prevalence

Differential Diagnoses

Related Datasets

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Neurodevelopmental Disorder With or Without Autism or Seizures (NEDAUS) — Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Key Primary Literature (PMID-anchored)

Sources

Reference Validation

Neurodevelopmental Disorder With or Without Autism or Seizures (NEDAUS): A Comprehensive Disease Characteristics Report

Summary

Key Findings

Finding 1 — Disease identity and identifiers (F001)

Finding 2 — CUL3 loss-of-function causes syndromic NDD via haploinsufficiency; 4E-BP1 accumulates (F002)

Finding 3 — Mouse model: RhoA/cytoskeletal signaling and cortical neurogenesis (F003)

Finding 4 — Extreme LoF intolerance and the distinct allelic hypertension disorder (F004)

Finding 5 — Phenotype spectrum and HPO frequencies (F005)

Finding 6 — CUL3/CRL3 substrate-adaptor network links NEDAUS to multiple neuronal pathways (F006)

Finding 7 — ClinVar variant landscape (F007)

Finding 8 — Cross-species conservation of the CUL3/KCTD13 social-behavior axis (F008)

Finding 9 — Consolidated causal chain (F009)

Mechanistic Model / Interpretation

Section-by-Section Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

References that may not be about this subject