| Domain | Curated finding | Suggested ontology/identifier | Best evidence and date | Evidence gaps/caveats |
|---|---|---|---|---|
| Disease identity | Rare monogenic neurodevelopmental syndrome caused by CTNNB1 variation; commonly described as CTNNB1 syndrome / CTNNB1 neurodevelopmental syndrome / neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV) | MONDO:0100571; OMIM/MIM #615075; MeSH term used in trial browse: Neurodevelopmental Disorders | OpenTargets disease-target association for “CTNNB1-related neurodevelopmental disorder and/or vitreoretinopathy”; clinical-trial disease descriptions; 2025-2026 registry entries (pqac-00000015, pqac-00000008, pqac-00000013) | Naming is still heterogeneous across papers and trials; some legacy reports use MRD19 or emphasize vitreoretinopathy/visual defects rather than the broader syndrome |
| Evidence source type | Knowledge derives mainly from aggregated disease resources, published case reports/case series/systematic review, and prospective/retrospective observational registries rather than EHR-only datasets | Evidence type labels: primary human, review, registry, model organism | 24-patient cohort, 2-patient case series, systematic review, and interventional/observational registrations (pqac-00000001, pqac-00000003, pqac-00000005, pqac-00000008, pqac-00000011) | No large population-based EHR study identified in the available evidence |
| Causal gene | CTNNB1 encodes β-catenin, a 781-aa armadillo-family protein with 12 armadillo repeats | Gene: CTNNB1; approved symbol CTNNB1; target ENSG00000168036 | Mouse-model synthesis and OpenTargets association, 2025 and current database record (pqac-00000016, pqac-00000021, pqac-00000015) | HGNC ID not explicitly available in current context, so not asserted |
| Molecular mechanism | Predominant disease mechanism is heterozygous loss of function / haploinsufficiency affecting canonical Wnt/β-catenin signaling and cadherin-mediated cell adhesion; some variants may act via dominant-negative or gain-of-function effects and are excluded from current gene-replacement trial eligibility | Mechanism labels: haploinsufficiency; canonical Wnt signaling; cell-cell adhesion | Human cohort/case evidence and trial criteria, 2022-2026 (pqac-00000001, pqac-00000005, pqac-00000014, pqac-00000016) | Functional classification is variant-specific; only a subset of variants has direct functional evidence |
| Inheritance | Autosomal dominant, usually de novo | Autosomal dominant | 2022 Chinese cohort and 2025 mouse-model review (pqac-00000001, pqac-00000021) | Rare familial recurrence/sibling recurrence can occur; penetrance estimates not well quantified in available evidence |
| Prevalence | Estimated prevalence 2.6-3.2 per 100,000 births | Prevalence estimate (label only) | 2025 peer-reviewed mouse-model review summarizing human epidemiology (pqac-00000016) | Estimate appears review-derived rather than from a formal population registry in the provided evidence |
| Core quantitative phenotypes | In 24 mainland Chinese patients: developmental delay/intellectual disability 100%, motor delay 100%, speech impairment 100%, dystonia 87.5%, microcephaly 69.6%, visual defects 79.2%, behavioral abnormalities 83.3%, strabismus 62.5%, sleep disturbance 70.8% | HPO term labels: developmental delay; intellectual disability; motor delay; speech impairment; dystonia; microcephaly; visual impairment/strabismus; behavioral abnormality; sleep disturbance | Primary human cohort, 2022 (pqac-00000001, pqac-00000004) | Frequencies vary across ancestries, ascertainment strategies, and age distribution |
| Additional phenotype detail | Systematic review concluded a broad spectrum from normal to severe, with facial dysmorphism, motor disability, language/cognitive impairment, and autistic-like/aggressive behaviors common; C-terminal-region variants (exons 13-15) may trend milder | HPO labels: facial dysmorphism; autism spectrum traits; aggressive behavior | Systematic review, 2022 (pqac-00000005) | Genotype-phenotype correlation remains imperfect and not sufficiently predictive for individual prognosis |
| Onset / course | Typically early childhood/congenital neurodevelopmental presentation; motor features may be difficult to detect before age 1 year; available data do not suggest cognitive decline, but robust longitudinal data remain limited | Onset label: pediatric; chronic lifelong disorder | Levodopa pilot background and natural history rationale, 2025-2026 registry entries (pqac-00000009, pqac-00000008) | Natural history remains incompletely defined; formal longitudinal outcomes are still being collected |
| Anatomy affected | Central nervous system predominates; retina/visual system commonly involved; movement system/gait frequently impaired | UBERON/CL/GO labels only: brain, cerebral cortex, hippocampus, midbrain dopamine neurons, retina | Human cohorts and mouse models, 2022-2025 (pqac-00000001, pqac-00000016, pqac-00000020) | Cardiac involvement is being surveyed but frequency is not established in available evidence |
| Diagnostic approach | Genotype-first diagnosis: molecular confirmation of a pathogenic/likely pathogenic heterozygous CTNNB1 variant, commonly by exome sequencing; parental testing used to show de novo status; phenotyping often includes MRI, EEG, ophthalmology/OCT, motor/cognitive/behavioral testing | Diagnostic labels only: WES, WGS, gene panel, EEG, MRI, OCT | 23/24 patients diagnosed by exome in Chinese cohort; Dragonfly natural history assessments; case reports from WES, 2022-2026 (pqac-00000004, pqac-00000008, pqac-00000003) | No universally adopted disease-specific clinical diagnostic criteria identified; biomarker assays remain investigational |
| Differential diagnosis | Often overlaps clinically with cerebral palsy/genetic cerebral palsy, especially because of dystonic/spastic gait and early motor delay | Differential label: cerebral palsy | 2025-2026 trial descriptions and 2025 review (pqac-00000009, pqac-00000016) | Differential diagnosis list is broader in practice, but detailed comparative data were not available in the provided evidence |
| Established management | No curative standard therapy; management is supportive and multidisciplinary, emphasizing symptom management, physiotherapy/rehabilitation, developmental therapies, vision care, and monitoring of sleep/behavior/motor complications | NCIT labels only: supportive care; physical therapy; occupational therapy; speech therapy | Mouse-model review and Dragonfly protocol, 2025-2026 (pqac-00000016, pqac-00000008) | No evidence-based disease-specific treatment algorithm or response-rate meta-analysis available in current evidence |
| Quality of life / family impact | Family and patient quality of life are recognized outcomes and are being prospectively measured in ongoing studies | PedsQL Family Impact Module; PedsQL Core Module | Dragonfly natural history study and AAV9 trial outcome measures, 2025-2026 (pqac-00000008, pqac-00000014) | Published disease-specific QoL results were not available in the provided evidence |
| Natural history study | Dragonfly: international prospective longitudinal observational study of CTNNB1 neurodevelopmental syndrome; estimated enrollment 250; annual visits over 5 years; assesses neurology, motor/cognition, communication, behavior, vision, sleep, gait actimetry, EEG, MRI/OCT, blood biomarkers | NCT07167732 | ClinicalTrials.gov registry, first posted 2025-09-11; recruiting; study started 2024-06-14 (pqac-00000008) | Registry details may update; no results yet |
| Genotype-phenotype registry study | Completed cross-sectional observational study enrolling 100 participants to capture genotype/phenotype correlations and natural-course information | NCT04812119 | ClinicalTrials.gov registry, completed 2022-11-01 (pqac-00000011, pqac-00000012) | Results not included in current context |
| Hyperekplexia study | Completed observational cohort examining prevalence/clinical features of exaggerated startle/hyperekplexia in CTNNB1 syndrome; actual enrollment 10 | NCT05168969 | ClinicalTrials.gov registry, completed 2022-12-10; updated 2023-04-25 (pqac-00000007) | No posted results available in current evidence |
| Levodopa pilot | Prospective pilot of L-dopa/carbidopa for CTNNB1-related NDD in children with dystonia; estimated enrollment 7; primary endpoint GMFM-88 change at 6 months; secondary endpoints include cognition, Vineland, QoL, CGI, safety | NCT07614126; Drug label: Levodopa/carbidopa | ClinicalTrials.gov registry, first posted 2026-05-29; recruiting (pqac-00000009, pqac-00000010) | Very small, uncontrolled study; efficacy remains unproven |
| Gene-replacement trial | GAIN-CTNNB1 / Urbagen: first-in-human phase I/II open-label AAV9-based CTNNB1 gene addition therapy, single bilateral intracerebroventricular administration, pediatric participants, estimated enrollment 12; prophylactic sirolimus and methylprednisolone/prednisolone | NCT07270549; Biological: Urbagen gene addition therapy; AAV9/hCTNNB1 vector | ClinicalTrials.gov registry, first posted 2025-12-08; recruiting; orphan-drug note in registry (pqac-00000013, pqac-00000014) | No human efficacy/safety results yet; trial excludes predicted gain-of-function/dominant-negative variants |
| Model organisms | Extensive mouse models recapitulate embryonic lethality, cortical/hippocampal defects, reduced dendritic branching, autism-like behaviors, motor deficits, seizure phenotypes, hypothalamic abnormalities, and retinal exudative vitreoretinopathy features | Model labels only: mouse; retinal-specific model; conditional knockout; gain-of-function model | Peer-reviewed model synthesis, 2025 (pqac-00000017, pqac-00000018, pqac-00000020, pqac-00000021) | Mouse evidence is strongest in current context; zebrafish/cellular models are mentioned less directly and not richly detailed here |
| Pathophysiology chain | Reduced functional β-catenin disrupts destruction-complex-regulated Wnt transcription and cadherin-linked adhesion, impairing progenitor proliferation/survival, dendritic development, synaptic organization, and possibly dopaminergic neurogenesis, producing developmental, motor, cognitive, and visual phenotypes | GO labels only: canonical Wnt signaling pathway; cell adhesion; neuron projection development; synapse organization | Mechanistic synthesis from review and trial background with cited foundational PMIDs, 2025-2026 (pqac-00000016, pqac-00000017, pqac-00000009, pqac-00000010) | Human biomarker validation is limited; much mechanistic detail comes from model systems |
| Large cohort anchor | A 2022 Genet Med study of 404 individuals is referenced as a major phenotypic/genotypic characterization dataset | PMID 36083290 | Referenced in trial bibliography and mouse-model review, publication 2022-11 (pqac-00000010, pqac-00000019) | Full cohort details were not directly extractable from current context, so only anchored, not over-interpreted |
| Unavailable / not established | No robust incidence estimate, no validated protective factors, no confirmed environmental causes, no established gene-environment interaction, no disease-specific biochemical diagnostic biomarker, no survival/life-expectancy estimate, no standard prevention beyond genetic counseling and reproductive testing | “Not established in available evidence” | Across available cohorts, reviews, and trial registries (pqac-00000001, pqac-00000008, pqac-00000016) | Absence here reflects limits of available evidence/context, not proof of true absence in the wider literature |


*Table: This table condenses the most actionable disease-knowledge-base facts for CTNNB1 neurodevelopmental disorder, including identifiers, mechanism, quantitative phenotypes, diagnosis, management, and active clinical studies. It also flags where evidence remains preliminary or unavailable.*