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:

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:

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:

1. RhoA (via BACURD/KCTD13/TNFAIP1 adaptors) — actin cytoskeleton, neuronal migration, dendrite growth (PMID: 33727673; PMID: 26969432).
2. 4E-BP1/EIF4EBP1 — cap-dependent translation / mTOR–eIF4E (PMID: 39301775).
3. KEAP1–NRF2 (NFE2L2) — antioxidant / oxidative-stress response (PMID: 42446772; PMID: 37328017).
4. 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

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

1. 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).
2. 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.
3. Two missense variants in the cohort are not fully mechanistically resolved versus LoF — the contribution of non-null alleles to NEDAUS remains uncertain.
4. 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.
5. No therapeutic trials. RhoA and mTOR–eIF4E rescue data are preclinical only; translational safety/efficacy in humans is unknown.
6. Biomarkers (4E-BP1 accumulation, ubiquitin-conjugate levels) are research assays, not validated clinical diagnostics.

Proposed Follow-up Experiments / Actions

1. Establish an international NEDAUS registry to define prevalence, natural history, epilepsy trajectories, sex ratio, and genotype–phenotype correlations at scale.
2. 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.
3. 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.
4. Deep phenotyping of the CRL3 substrate/adaptor network (KCTD13, KLHL family, NRF2/KEAP1) in patient cells to identify secondary biomarkers and additional therapeutic nodes.
5. Systematic reclassification of ClinVar VUS (of the 727 records, ~500 non-P/LP) using functional 4E-BP1/ubiquitin-conjugate assays to improve diagnostic yield.
6. 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

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Reference Validation

Checked with linkml-reference-validator 0.2.1.

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.