CTNNB1 Neurodevelopmental Disorder

Mendelian MONDO:0014035 Pathograph 43 Show in embeddings browser Neurodevelopmental Disorder Syndromic Intellectual Disability

CTNNB1 neurodevelopmental disorder (CTNNB1-NDD; CTNNB1 syndrome; NEDSDV; MRD19) is an autosomal dominant disorder usually caused by a de novo heterozygous loss-of-function variant in CTNNB1, encoding beta-catenin. Beta-catenin mediates canonical Wnt transcription and cadherin-dependent cell adhesion. Developmental and speech delay, variable cognitive impairment, axial hypotonia, limb hypertonia, dystonia, microcephaly, behavioral difficulties and visual abnormalities characterize the disorder. Motor impairment can meet clinical criteria for cerebral palsy; its course varies between individuals. Retinal vascular disease may remain undetected on routine ophthalmoscopy. Most pathogenic alleles reduce beta-catenin function, but selected variants have dominant-negative or assay-dependent activating effects. This entry covers the germline neurodevelopmental disorder, including its ocular manifestations.

Ask OpenScientist

Ask a research question about CTNNB1 Neurodevelopmental Disorder. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

🏷

Classifications

Harrison's Part

👪

Inheritance

Autosomal dominant, typically de novo HP:0000006

CTNNB1-NDD is autosomal dominant and usually results from a de novo heterozygous pathogenic variant. Familial transmission and presumed parental germline mosaicism are documented. Apparently unaffected relatives can have subtle retinal vascular findings, so absence of reported symptoms does not establish absence of disease. Parental testing informs recurrence counseling; disease severity cannot be predicted reliably from that of another family member.

Autosomal dominant inheritance Expressivity: VARIABLE

Show evidence (3 references)

PMID:35593792 SUPPORT Human Clinical

"CTNNB1-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with CTNNB1-NDD inherited a CTNNB1 pathogenic variant from a parent."

GeneReviews states the autosomal dominant, predominantly de novo inheritance and the rare inherited exception.

PMID:36790797 SUPPORT Human Clinical

"Among the eight families with CTNNB1 mutations, seven were de novo mutations, and one proband inherited the mutation from his asymptomatic mother."

Seven of eight probands had de novo variants. The transmitting mother and sister in the remaining family had no visual complaints but showed mild retinal vascular abnormalities on detailed examination, demonstrating variable expressivity.

PMID:36790797 SUPPORT Human Clinical

"His mother and elder sister were asymptomatic with bilateral best corrected visual acuity of 20/20; however, supernumerary branches were detected in scanning laser ophthalmoscope (SLO) and fundus fluorescein angiography (FFA)."

Detailed examination detected retinal findings despite normal visual acuity and no reported symptoms.

Discussions and Knowledge Gaps

Does the reduced midbrain dopaminergic neurogenesis seen in Ctnnb1 knockout mouse models translate into a dopaminergic deficit in human CTNNB1-NDD that is sufficient to make levodopa a rational therapy?

HUMAN MODEL MISMATCH OPEN ctnnb1_dopaminergic_deficit

Attached to

pathophysiology#Developmental Motor Circuit Dysfunction

Conditional Ctnnb1 mouse models motivate a dopaminergic hypothesis, but a specific presynaptic deficit has not been established by the cited human studies. In a selected movement-disorder series levodopa helped 1/4 treated patients and botulinum toxin 5/6. These uncontrolled responses cannot determine which neuronal pathway causes the motor phenotype.

Proposed experiments

Presynaptic dopaminergic imaging in CTNNB1-NDD

ctnnb1_dopaminergic_imaging

DaTscan or FDOPA PET in individuals with molecularly confirmed CTNNB1-NDD and dystonia, compared with age-matched reference data, to test whether a presynaptic nigrostriatal dopaminergic deficit is present in humans.

Decision criterion

Reduced tracer measures would support a presynaptic abnormality. Normal measures would weaken that specific hypothesis without excluding altered dopamine signaling or a symptomatic levodopa benefit.

CSF neurotransmitter metabolite profiling in CTNNB1-NDD

ctnnb1_csf_neurotransmitters

Measurement of CSF homovanillic acid and 5-hydroxyindoleacetic acid in a CTNNB1-NDD cohort to detect a biochemical dopaminergic deficiency.

Decision criterion

Low CSF homovanillic acid would provide biochemical support for the dopaminergic-deficit model.

Completion of the NCT07614126 levodopa pilot

ctnnb1_levodopa_pilot

Completion and prespecified analysis of the open-label levodopa/carbidopa pilot, with GMFM-88 as the primary motor endpoint. The registered study is unblinded.

Decision criterion

Improvement would support symptomatic benefit for further controlled testing; either response or nonresponse is insufficient by itself to establish or refute a specific dopaminergic mechanism.

Show evidence (1 reference)

PMID:39067319 SUPPORT Human Clinical

"Treatment efficacy was variable: botulinum toxin was (at least partially) effective in 5/6, levodopa in 1 of 4 treated patients."

Human treatment-response data are weak for levodopa relative to botulinum toxin, tempering the model-derived dopaminergic hypothesis.

⚙

Pathophysiology

CTNNB1 Loss-of-Function and Beta-Catenin Haploinsufficiency

Heterozygous truncating, splice-disrupting and deletion alleles commonly reduce functional beta-catenin dosage. Nonsense-mediated RNA decay was demonstrated in lymphocyte-derived cells from two patients; it must not be assumed for every truncation. Missense variants and some expressed truncations can instead alter specific functions or inhibit wild-type protein. The 2025 cohort contained 88 distinct variants, 87 predicted to reduce function, but prediction, protein abundance and reporter activity are different measurements.

CTNNB1 hgnc:2514

Genetic context CTNNB1 hgnc:2514 zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Heterozygous loss-of-function alleles are usually de novo; transmitted alleles and presumed parental mosaicism also occur. Nonsense-mediated decay is experimentally established for selected alleles.

Downstream

Canonical Wnt/Beta-Catenin Transcriptional Deficit Reduced functional beta-catenin can lower Wnt-responsive transcription; the effect depends on allele and tissue.

Impaired Cadherin-Catenin Adherens Junction Adhesion Lower beta-catenin abundance reduces N-cadherin association in a germline heterozygous mouse.

Reduced Neural Progenitor Expansion Conditional knockout models support a developmental consequence of beta-catenin loss; the magnitude in human heterozygotes remains uncertain.

Reduced Brain Sodium-Potassium ATPase Abundance Germline heterozygous mice have lower ATPase alpha2 and alpha3 protein levels; the intervening regulatory mechanism remains unresolved.

Disorganization of Callosal Midline Guidance Cells Midline-restricted biallelic loss disrupts guidance populations in mice; translation to human heterozygosity is provisional.

Cardiac Developmental Wnt Signalling Disruption A developmental cardiac contribution is proposed from the clinical association, not established by a disease-specific experiment.

Retinal Vascular Norrin/Beta-Catenin Signalling Failure Endothelial beta-catenin deficiency reduces Norrin-responsive transcription.

Compromised Retinal Endothelial Junction Integrity CTNNB1 knockdown produces junctional defects in human retinal endothelial cells.

Show evidence (4 references)

PMID:25326669 SUPPORT Human Clinical

"We report on 16 additional individuals from 15 families in whom we newly identified de novo loss-of-function CTNNB1 mutations (six nonsense, five frameshift, one missense, two splice mutation, and one whole gene deletion)."

Documents the loss-of-function variant spectrum (nonsense, frameshift, splice, missense and whole-gene deletion) underlying the haploinsufficiency mechanism.

PMID:24668549 SUPPORT Human Clinical

"Array CGH karyotyping showed a 333 kb de novo microdeletion on 3p22 covering the entire genomic sequence of a single gene, CTNNB1, which codes for β-catenin."

The deletion encompasses the entire CTNNB1 gene and supports dosage sensitivity. The abstract describes a single complete gene; this does not exclude partial neighboring-gene involvement.

PMID:40684264 SUPPORT Human Clinical

"we identified 88 different variants of the CTNNB1 gene, 87 of which were predicted to lead to loss of CTNNB1 function"

The 2025 cohort reports 88 distinct variants and predicts loss of function for 87. This prediction does not establish an identical molecular mechanism for every allele.

+ 1 more reference

Variant-Specific Dominant-Negative Wnt Inhibition

Selected variants inhibit Wnt reporter activity when coexpressed with wild-type CTNNB1. HEK293T experiments identified Leu388Pro and Leu424Arg missense alleles; SK-N-MC experiments identified four truncating protein variants in eleven participants: Tyr333*, Gln193*, Ala317Valfs8* and Ser352fs*. The 2025 abstract refers to eleven variants, whereas the body distinguishes four protein variants. Overexpressed cDNA does not demonstrate escape from endogenous nonsense-mediated decay. These assays do not define a clinically validated subtype.

Downstream

Canonical Wnt/Beta-Catenin Transcriptional Deficit Wild-type cotransfection assays demonstrate reduced reporter output for this subset.

Show evidence (2 references)

PMID:36083290 SUPPORT In Vitro

"Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants."

TOPFlash reporter assays demonstrate reduced/dominant-negative WNT signalling output for disease-associated CTNNB1 missense variants.

PMID:40684264 SUPPORT In Vitro

"However, four variants (p.Y333∗, p.Q193∗, p.A317Vfs8∗, and p.S352fs∗) showed reduced levels of TOPFlash-luciferase activity suggesting a dominant negative mechanism"

The full-text cotransfection experiment identifies four truncating variants, rather than eleven distinct dominant-negative protein variants.

Canonical Wnt/Beta-Catenin Transcriptional Deficit

Reduced beta-catenin-mediated transcription is demonstrated by Wnt-responsive reporter assays for many patient variants and by lower DKK1 and EN2 protein levels in a germline heterozygous mouse. It is not universal across every variant or assay: Gly575Arg had normal, reduced or increased reporter activity in three experimental contexts. Reporter activity alone cannot classify an allele or predict clinical severity.

canonical Wnt signaling pathway GO:0060070 ↓ DECREASED

Downstream

Reduced Neural Progenitor Expansion Wnt-dependent progenitor regulation is implicated by conditional mouse experiments; human developmental intermediates remain incompletely established.

Show evidence (3 references)

PMID:25326669 SUPPORT Other

"Beta-catenin is a key downstream component of the canonical Wnt signaling pathway."

Background statement establishing beta-catenin as the downstream effector of canonical Wnt signalling; the substantive functional claims for this node rest on the two IN_VITRO items below.

PMID:36083290 SUPPORT In Vitro

"Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants."

TOPFlash reporter assays demonstrate reduced/dominant-negative WNT signalling output for disease-associated CTNNB1 missense variants.

DOI:10.1038/s44321-024-00110-5 SUPPORT Model Organism

"Protein expression levels of two canonical Wnt target genes, DKK1 and EN2, are reduced in the β-cat het hippocampus"

The germline heterozygous mouse supplies in vivo evidence of reduced Wnt target proteins. LEF1 abundance was unchanged.

Impaired Cadherin-Catenin Adherens Junction Adhesion

Beta-catenin participates in cadherin-associated adhesion complexes. The batface Thr653Lys allele reduces cadherin binding despite normal beta-catenin abundance and enhanced Wnt activity; it is not a simple dosage-loss model. A separate germline heterozygous deletion model also shows reduced beta-catenin association with N-cadherin. These results support an adhesion contribution while leaving its relative importance in individual human alleles unresolved.

adherens junction organization GO:0034332 ↓ DECREASED

cadherin binding GO:0045296 ↓ DECREASED

adherens junction GO:0005912

Downstream

Impaired Dendritic Arborization Reduced adhesion and abnormal dendritic maturation coexist in batface neurons; a contribution is supported, but exclusive mediation is not established.

Show evidence (2 references)

PMID:24614104 SUPPORT Model Organism

"The mouse mutant, designated batface (Bfc), carries a Thr653Lys substitution in the C-terminal armadillo repeat of β-catenin and displayed a reduced affinity for membrane-associated cadherins."

Demonstrates in vivo that a disease-modelling beta-catenin substitution reduces binding to membrane cadherins, the adhesion arm of the mechanism.

DOI:10.1038/s44321-024-00110-5 SUPPORT Model Organism

"β-cat association with N-cadherin is reduced in β-cat het mice, relative to littermate controls"

Co-immunoprecipitation demonstrates reduced association in the germline haploinsufficient mouse independently of the batface allele.

Reduced Neural Progenitor Expansion

Mechanism confidence: Provisional

Conditional neural beta-catenin knockout models show reduced progenitor proliferation and increased apoptosis. These severe tissue-specific perturbations suggest a developmental route to reduced brain growth but do not demonstrate neuronal loss in living patients. Human microcephaly can be congenital or acquired, and no single timing or mechanism explains every case.

neural progenitor cell CL:0011020

Downstream

Microcephaly Reduced developmental brain growth is a plausible contributor; congenital and postnatal microcephaly both occur.

Show evidence (1 reference)

PMID:39833474 SUPPORT Other

"Lower proliferation and increased apoptosis"

The mouse-model review describes neural conditional knockout experiments. The evidence is a secondary summary of models, not direct human histology.

Impaired Dendritic Arborization

Batface cortical cultures develop reduced dendritic branching at later culture stages, despite initially increased neurite outgrowth. Separately, siRNA reduction of Ctnnb1 in wild-type mouse cortical cultures reduces neurite extension. These model observations support impaired neuronal maturation; they do not establish an identical defect in every human neuron.

dendrite morphogenesis GO:0048813 ↓ DECREASED

Downstream

Intellectual Disability Altered dendritic development offers a model-supported contribution to cognitive impairment; the intervening human circuit effects are unresolved.

Show evidence (2 references)

PMID:24614104 SUPPORT Model Organism

"In association with this decreased cadherin interaction, we found that the mutation results in decreased intrahemispheric connections, with deficits in dendritic branching, long-term potentiation, and cognitive function."

The batface model links reduced cadherin interaction with dendritic, connectivity and plasticity deficits; it does not establish those defects in human neurons.

PMID:24614104 SUPPORT In Vitro

"Transfection of this siRNA decreased β-catenin expression by 54% in WT cultures"

A separate knockdown experiment in wild-type mouse cultures approximates a dosage reduction. The measurement was gene expression; it should not be described as a protein assay.

Impaired Hippocampal Synaptic Potentiation

Hippocampal slices from batface heterozygous mice show reduced long-term potentiation after tetanic or theta-burst stimulation. Basal transmission and paired-pulse measures were not significantly changed. This supports a selective plasticity defect in an adhesion-impaired, Wnt-activating mouse allele, rather than a direct measurement of human cognition.

Downstream

Intellectual Disability The mouse plasticity deficit provides a possible contribution to learning impairment, without proving its prevalence or magnitude in humans.

Show evidence (1 reference)

PMID:24614104 SUPPORT Model Organism

"long-term potentiation (LTP) induced by either tetanic (Figure 8F) or θ-burst (Figure 8G) stimulation was significantly reduced in slices from Bfc/+ animals"

Direct ex vivo electrophysiology in batface mice demonstrates impaired potentiation.

Reduced Brain Sodium-Potassium ATPase Abundance

Mechanism confidence: Provisional

In germline Ctnnb1 heterozygous mice, hippocampal and frontal cortical ATPase alpha2 and alpha3 protein levels are reduced, whereas alpha1 is unchanged. Their role in the excitability phenotype is plausible but not isolated by a pump-specific rescue, and this molecular finding has not been established in patients.

Downstream

Altered Hippocampal Neuronal Excitability Reduced activity-dependent ion-gradient regulation is proposed to contribute to the electrophysiological changes; parallel rescue by GSK3 inhibition is not proof of exclusive mediation.

Show evidence (1 reference)

DOI:10.1038/s44321-024-00110-5 SUPPORT Model Organism

"Na/K ATPases α2 and α3 catalytic subunit levels are reduced, whereas Na/K ATPase α1 catalytic subunit levels are not altered in the β-cat het hippocampus and frontal cortex, compared to wild-type littermates"

The primary mouse study directly reports reduced alpha2 and alpha3 abundance; alpha1 is unchanged in the full figure legend.

Altered Hippocampal Neuronal Excitability

Dentate gyrus granule cells in germline heterozygous mice have a depolarized resting potential and lower firing threshold, but lower maximal firing rates under strong current injection. This mixed phenotype should not be summarized as uniformly increased or decreased excitability. Dual GSK3 inhibition improves several measures without normalizing the resting potential. Equivalent electrophysiological changes have not been established in patients.

Downstream

Intellectual Disability The mouse functional changes offer a potential route to altered learning and memory; the human intermediates remain unresolved.

Show evidence (1 reference)

DOI:10.1038/s44321-024-00110-5 SUPPORT Model Organism

"Taken together, the functional changes suggest reduced threshold for excitability and potential depolarization block."

The authors interpret patch-clamp recordings as a reduced threshold with possible depolarization block, not a simple global hyperexcitability state.

Disorganization of Callosal Midline Guidance Cells

Mechanism confidence: Provisional

In Lmx1a-lineage mouse models, biallelic beta-catenin loss or constitutive stabilization disrupts the glial wedge, indusium griseum glia and midline guidance-neuron organization. The similar gain- and loss-of-function phenotypes leave the relative roles of transcription and adhesion unresolved. Midline heterozygous deletion did not produce a callosal defect, limiting direct extrapolation to human haploinsufficiency.

Downstream

Failure of Callosal Axon Midline Crossing Disorganized midline guidance populations contribute to failed crossing and Probst bundles in the conditional mouse models.

Show evidence (2 references)

PMID:40894864 SUPPORT Model Organism

"These results suggest that misoriented and dysmorphic midline glial cells impair axonal guidance across the midline in Ctnnb1 LOF and GOF brains."

Cell-type-specific mouse experiments identify the midline guidance population as a mechanistic contributor.

PMID:40894864 SUPPORT Model Organism

"We do not find a CC phenotype in Lmx1aCre; Ctnnb1 loxP/+ mice, indicating that the threshold requirement for CTNNB1 for CC crossing is met in heterozygote mice."

The negative heterozygote result limits the match between this model and human CTNNB1-NDD.

Failure of Callosal Axon Midline Crossing

Mechanism confidence: Provisional

Conditional Lmx1a-lineage gain- and biallelic loss-of-function models show near-complete failure of callosal crossing and Probst bundles while the anterior commissure remains intact. Five patients from the GenPhe cohort had abnormal callosal MRI morphology, but equivalent cellular defects were not demonstrated in them.

Downstream

Hypoplasia of the Corpus Callosum The mouse crossing defect supplies a candidate developmental explanation for human callosal abnormalities, with an explicit genotype and severity gap.

Show evidence (1 reference)

PMID:40894864 SUPPORT Model Organism

"Immunostaining for L1CAM, an adhesion molecule enriched in axonal tracts, reveals a near-complete failure of CC crossing at the midline in both Ctnnb1 LOF and GOF brains"

Axonal staining directly demonstrates failed crossing in the conditional mouse models.

Developmental Motor Circuit Dysfunction

Mechanism confidence: Provisional

A developmental motor-circuit contribution is inferred from the combined spasticity, dystonia and weakness phenotype, but the responsible human pathways and lesion sites have not been established. Clinical progression varies; a selected movement-disorder series reported later cervical dystonia in three patients, whereas a broader cohort already showed dystonia across ages. The clinical diagnosis of cerebral palsy can coexist with CTNNB1-NDD. Specific corticospinal, basal-ganglia or brainstem pathology must not be inferred from these signs alone.

Downstream

Spastic Diplegia Developmental motor-network dysfunction is a proposed basis for the lower-limb tone abnormality.

Dystonia An altered motor-network contribution is plausible; the precise human circuit mechanism is unresolved.

Show evidence (3 references)

PMID:39067319 SUPPORT Human Clinical

"13 patients presented progressive lower limbs hypertonia without overt pyramidal signs. Five patients reported exaggerated startle, three developed upper body (prominently cervical) dystonia in the second decade, with or without bradykinesia (2/13)."

Systematic movement-disorder phenotyping of 14 patients establishing the progressive lower-limb hypertonia, startle and later dystonia/bradykinesia components.

PMID:39067319 SUPPORT Human Clinical

"CTNNB1-syndrome is associated with a peculiar, but recognizable movement disorder phenotype, encompassing complex gait disorders with progressive lower limb hypertonia, exaggerated startle, and possible occurrence in the second decade of life of upper body dystonia with or without bradykinesia."

The clinical series establishes a movement-disorder pattern; it does not demonstrate an anatomical lesion or dopaminergic deficiency.

PMID:36083290 SUPPORT Human Clinical

"Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP)."

Establishes that the CTNNB1 motor phenotype is the commonest recurrent monogenic cause of a cerebral palsy diagnosis.

Retinal Vascular Norrin/Beta-Catenin Signalling Failure

In retinal endothelial experimental systems, CTNNB1 knockdown reduces Norrin-responsive target transcripts. Truncating variants reduce reporter activity. This is one mechanistic arm of retinal disease and does not establish that every CTNNB1 allele has identical activity across assays.

retinal blood vessel endothelial cell CL:0002585

canonical Wnt signaling pathway GO:0060070 ↓ DECREASED

Downstream

Reduced Retinal Endothelial Proliferation Reduced beta-catenin transcriptional output is accompanied by impaired proliferation in knockdown cells; the full target-gene chain is unresolved.

Show evidence (1 reference)

PMID:35361685 SUPPORT In Vitro

"These variants caused truncation and degradation of β-catenin that reduced Norrin/β-catenin signalling activity. Additionally, knockdown (KD) of CTNNB1 in HRECs led to diminished mRNA levels of Norrin/β-catenin targeted genes, reduced cell proliferation and compromised junctional integrity."

Mechanistically links CTNNB1 truncating variants to reduced Norrin/beta-catenin signalling, endothelial proliferation and junctional integrity in human retinal microvascular endothelial cells.

Reduced Retinal Endothelial Proliferation

CTNNB1 knockdown in primary human retinal microvascular endothelial cells reduces proliferation. Endothelial heterozygous deletion in mice produces FEVR-like disease, supporting a retinal vascular role while not isolating proliferation from other endothelial effects.

retinal blood vessel endothelial cell CL:0002585

Downstream

Exudative Vitreoretinopathy Reduced endothelial expansion contributes to incomplete retinal vascular development; additional junctional effects may contribute.

Show evidence (1 reference)

PMID:35361685 SUPPORT In Vitro

Mechanistically links CTNNB1 truncating variants to reduced Norrin/beta-catenin signalling, endothelial proliferation and junctional integrity in human retinal microvascular endothelial cells.

Compromised Retinal Endothelial Junction Integrity

CTNNB1 knockdown compromises junctional integrity in primary human retinal microvascular endothelial cells. This cellular phenotype provides an adhesion-related contribution to retinal vascular dysfunction distinct from proliferation; the relative contributions to human FEVR remain unresolved.

retinal blood vessel endothelial cell CL:0002585

Downstream

Exudative Vitreoretinopathy Defective endothelial junctions offer an additional route to retinal vascular dysfunction.

Show evidence (1 reference)

PMID:35361685 SUPPORT In Vitro

Mechanistically links CTNNB1 truncating variants to reduced Norrin/beta-catenin signalling, endothelial proliferation and junctional integrity in human retinal microvascular endothelial cells.

Cardiac Developmental Wnt Signalling Disruption

Mechanism confidence: Provisional

Congenital cardiac anomalies are reported in CTNNB1-NDD, and beta-catenin is expressed in the heart. A developmental Wnt contribution is plausible, but the cited clinical series does not establish a specific second-heart-field, valve or outflow-tract mechanism.

Downstream

Congenital Heart Defect A beta-catenin-dependent cardiac developmental contribution is proposed from the clinical association; its molecular intermediates remain unestablished.

Show evidence (2 references)

PMID:37455656 SUPPORT Other

"CTNNB1 is highly expressed in brain as well as in other tissues, including heart."

Background statement of cardiac CTNNB1 expression; it makes a heart-development contribution plausible but does not demonstrate it, consistent with the PROVISIONAL mechanism confidence of this node.

PMID:37455656 SUPPORT Human Clinical

"Notably, five patients showed congenital heart anomalies including absent pulmonary valve with intact ventricular septum, atrioventricular canal with hypoplastic aortic arch, tetralogy of Fallot, and mitral valve prolapse."

Documents the spectrum of congenital heart defects observed in a dedicated CTNNB1 cardiac series.

⬡

Pathograph

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

●

Phenotypes

Cardiovascular 1

Congenital Heart Defect OCCASIONAL Abnormal heart morphology HP:0001627

Show evidence (2 references)

PMID:37455656 SUPPORT Human Clinical

"We report on a new series of 19 NEDSDV patients (mean age 10.3 years), nine of whom bearing novel CTNNB1 variants. Notably, five patients showed congenital heart anomalies"

Five of 19 patients (26%) had congenital heart anomalies, consistent with an OCCASIONAL (5-29%) band.

PMID:37455656 SUPPORT Human Clinical

"While congenital heart defects had occasionally been reported so far, the present findings configure a higher rate of cardiac anomalies, suggesting dedicated heart examination to NEDSDV clinical management."

Supports the recommendation for dedicated cardiac examination and the higher-than-expected rate.

Digestive 3

Feeding Difficulties FREQUENT HP:0011968

Show evidence (2 references)

PMID:35593792 SUPPORT Human Clinical

"Less common features include intrauterine growth restriction, feeding difficulties, and scoliosis."

GeneReviews classifies feeding difficulties among the less common features.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf SUPPORT Human Clinical

"Short stature 8/39 (20.5%) Feeding difficulties 14/35 (40%) Scoliosis 6/30 (20%)"

The GeneReviews table reports 14/35 (40%), supporting FREQUENT. Its abstract wording less common is relative to the core manifestations.

Constipation FREQUENT HP:0002019

Show evidence (1 reference)

PMID:38247296 SUPPORT Human Clinical

"Gastrointestinal problems were common and included constipation in 50% and gastroesophageal reflux disease in 18.8%."

The medical history of the 32 conference participants records constipation in 50%, supporting FREQUENT.

Gastroesophageal Reflux OCCASIONAL HP:0002020

Show evidence (1 reference)

PMID:38247296 SUPPORT Human Clinical

"gastroesophageal reflux disease in 18.8%"

The 32-person conference cohort reports gastroesophageal reflux disease in 18.8%, supporting OCCASIONAL.

Ear 1

Large Ears FREQUENT Macrotia HP:0000400

Show evidence (1 reference)

PMID:40684264 SUPPORT Human Clinical

"large ears (78.7%; 95% CI, 70.8%–85.0%)"

The remote study of 127 participants reports large ears in 78.7%; caregiver reporting and recruitment limit generalizability.

Eye 6

Exudative Vitreoretinopathy FREQUENT HP:0030490

Show evidence (2 references)

PMID:35593792 SUPPORT Human Clinical

"in up to 39% of reported individuals by exudative vitreoretinopathy, an ophthalmologic finding consistent with familial exudative vitreoretinopathy (FEVR)"

GeneReviews reports exudative vitreoretinopathy in up to 39% of individuals, placing the frequency in the FREQUENT (30-79%) band.

PMID:39145965 SUPPORT Human Clinical

"FEVR was present in 5 of 11 patients and in 9 eyes. The presence of disease requiring treatment was identified in 6 eyes, including 1 retinal detachment."

In children with previously normal office retinal examinations, angiography detected FEVR in 5 of 11, including treatment-requiring disease and a retinal detachment.

Strabismus VERY_FREQUENT HP:0000486

Show evidence (2 references)

PMID:39145965 SUPPORT Human Clinical

"A total of 9 patients had a diagnosis of strabismus, and 5 patients had undergone strabismus surgery."

The abstract reports strabismus in 9/11. The full-text body gives a different surgery count; no uniform surgical-treatment rate is inferred.

PMID:38247296 SUPPORT Human Clinical

"Visual problems included strabismus, hyperopia, and familial exudative vitreoretinopathy."

Confirms strabismus among the visual problems in a deeply phenotyped cohort.

Refractive Error Abnormality of refraction HP:0000539

Show evidence (2 references)

PMID:39145965 SUPPORT Human Clinical

"nearly all patients with CTNNB1 syndrome required ophthalmic care for refractive error and strabismus"

This combined care statement supports ophthalmic involvement, but does not supply a separate frequency for refractive error.

PMID:38247296 SUPPORT Human Clinical

"Visual problems included strabismus, hyperopia, and familial exudative vitreoretinopathy."

Identifies hyperopia as the characteristic refractive error in this disorder.

Hyperopia FREQUENT Hypermetropia HP:0000540

Show evidence (1 reference)

PMID:40684264 SUPPORT Human Clinical

"47.2% had farsightedness (95% CI, 38.7%–55.9%)"

The remote study of 127 participants reports farsightedness in 47.2%, supporting FREQUENT in this caregiver-assessed cohort.

Myopia OCCASIONAL HP:0000545

Show evidence (1 reference)

PMID:40684264 SUPPORT Human Clinical

"near-sightedness (16.5%; 95% CI, 11.1%–24.0%)"

The remote study of 127 participants reports nearsightedness in 16.5%, supporting OCCASIONAL in this caregiver-assessed cohort.

Astigmatism OCCASIONAL HP:0000483

Show evidence (1 reference)

PMID:36153650 SUPPORT Human Clinical

"Astigmatism | 3 | 24 | 12.5"

The Chinese cohort table reports astigmatism in 3/24 individuals (12.5%), supporting OCCASIONAL.

Genitourinary 1

Cryptorchidism OCCASIONAL HP:0000028

Show evidence (1 reference)

PMID:38247296 SUPPORT Human Clinical

"Cryptorchidism was noted in 3 males (17%) and two males required orchiopexy (11%)."

The conference cohort included 18 males; cryptorchidism in three gives a male-specific frequency of 17%, with orchiopexy in two.

Head and Neck 7

Microcephaly FREQUENT HP:0000252

Show evidence (5 references)

PMID:25326669 SUPPORT Human Clinical

"The craniofacial phenotype comprised microcephaly (typically -2 to -4 SD) in 12 of 16"

Quantifies microcephaly in 12 of 16 individuals (75%) with the typical severity range, supporting a FREQUENT band.

PMID:24668549 SUPPORT Human Clinical

"Postnatal microcephaly and progressive ataxia and spasticity appeared later."

This individual developed postnatal microcephaly. Other patients have congenital microcephaly, so this case does not define universal onset.

PMID:36153650 SUPPORT Human Clinical

"dystonia (87.5%) and microcephaly (69.6%)"

Independently quantifies microcephaly at 69.6% in a 24-patient cohort, within the FREQUENT (30-79%) band.

+ 2 more references

Thin Upper Lip Vermilion FREQUENT HP:0000219

Show evidence (2 references)

PMID:40684264 SUPPORT Human Clinical

"a thin upper lip (78.0%; 95% CI, 70.0%–84.3%)"

The remote study of 127 participants reports thin upper lip in 78.0%, within FREQUENT; caregiver ascertainment limits generalizability.

PMID:36153650 SUPPORT Human Clinical

"long philtrum (45.8%) and thin upper lip (45.8%)"

Thin upper lip occurred in 11/24 individuals (45.8%) in the Chinese cohort, also within FREQUENT; the two cohorts are not pooled.

Broad Nasal Tip VERY_FREQUENT HP:0000455

Show evidence (1 reference)

PMID:40684264 SUPPORT Human Clinical

"a broad nasal tip (96.1%; 95% CI, 91.1%–98.3%)"

The 2025 caregiver cohort reports this specifically defined facial feature; frequencies from differently defined nasal findings are not pooled.

Long Philtrum FREQUENT HP:0000343

Show evidence (1 reference)

PMID:36153650 SUPPORT Human Clinical

"Characteristic facial phenotype included long eyelashes (10/24), wide nasal bridge (14/24), bulbous nasal tip (11/24), long philtrum (11/24), and thin upper lip (11/24)."

The Chinese cohort documents a long philtrum in 11/24 individuals, supporting FREQUENT without pooling with the differently ascertained remote cohort.

Long Eyelashes FREQUENT HP:0000527

Show evidence (1 reference)

PMID:36153650 SUPPORT Human Clinical

"Characteristic facial phenotype included long eyelashes (10/24), wide nasal bridge (14/24), bulbous nasal tip (11/24), long philtrum (11/24), and thin upper lip (11/24)."

Long eyelashes were observed in 10/24 individuals in the Chinese cohort, supporting FREQUENT.

Underdeveloped Nasal Alae FREQUENT HP:0000430

Show evidence (1 reference)

PMID:40684264 SUPPORT Human Clinical

"small alae nasi (77.2%; 95% CI, 69.1%–83.6%)"

The remote study of 127 participants reports small alae nasi in 77.2%; this specifically defined finding is distinct from a broad nasal tip.

Sparse Eyebrows FREQUENT HP:0045075

Show evidence (1 reference)

PMID:36153650 SUPPORT Human Clinical

"One affected individual was found to have narrowed forehead and nine with sparse eyebrows."

Nine of 24 individuals in the Chinese cohort had sparse eyebrows, supporting FREQUENT.

Integument 1

Sparse Fair Hair Sparse hair HP:0008070

Show evidence (2 references)

PMID:24668549 SUPPORT Human Clinical

"Initial clinical evaluation revealed an overall developmental delay, mildly dysmorphic features, thin, sparse fair hair, and fair skin."

Documents the thin, sparse, fair hair phenotype in the index CTNNB1 whole-gene-deletion patient.

PMID:40684264 SUPPORT Human Clinical

"thin hair (66.9%; 95% CI, 58.4%–74.5%)"

Thin hair was common in the remote cohort; this does not establish the frequency of fair pigmentation or identically defined sparse hair.

Limbs 1

Pes Planus FREQUENT HP:0001763

Show evidence (1 reference)

PMID:38247296 SUPPORT Human Clinical

"Musculoskeletal abnormalities included pes planus in 71.9%"

The examination of 32 conference participants identified pes planus in 71.9%, supporting FREQUENT in this selected cohort.

Musculoskeletal 5

Truncal Hypotonia VERY_FREQUENT Axial hypotonia HP:0008936

Show evidence (3 references)

PMID:35593792 SUPPORT Human Clinical

"Other common findings include truncal hypotonia, peripheral spasticity, dystonia, behavior problems, microcephaly, and refractive errors and strabismus."

The abstract describes a common feature; the direct 96.9% cohort measurement below supplies the assigned frequency band.

PMID:38247296 SUPPORT Human Clinical

"Most individuals had truncal hypotonia, muscle weakness, hypertonia, dystonia, microcephaly, and many had a history of tethered cord."

Deep phenotyping of 32 individuals confirms truncal hypotonia in most.

PMID:38247296 SUPPORT Human Clinical

"| - Truncal hypotonic | 96.9 |"

Table 1 reports axial hypotonia on examination in 96.9% of the 32 conference participants, supporting VERY_FREQUENT in this selected cohort.

Spastic Diplegia VERY_FREQUENT HP:0001264

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:39067319 SUPPORT Human Clinical

"13 patients presented progressive lower limbs hypertonia without overt pyramidal signs."

13 of 14 systematically assessed patients had progressive lower-limb hypertonia, supporting a very frequent, progressive spastic diplegia.

Muscle Weakness VERY_FREQUENT HP:0001324

Show evidence (2 references)

PMID:38247296 SUPPORT Human Clinical

"Most individuals had truncal hypotonia, muscle weakness, hypertonia, dystonia, microcephaly, and many had a history of tethered cord."

This qualitative summary describes weakness in most of the 32 conference participants; the 90.6% table measurement supplies the VERY_FREQUENT band.

PMID:38247296 SUPPORT Human Clinical

"| - Muscle weakness | 90.6 |"

Table 1 reports weakness in 90.6% of 32 examined participants, supporting VERY_FREQUENT in this selected cohort.

Scoliosis OCCASIONAL HP:0002650

Show evidence (2 references)

PMID:35593792 SUPPORT Human Clinical

"Less common features include intrauterine growth restriction, feeding difficulties, and scoliosis."

GeneReviews lists scoliosis among the less common features.

PMID:38247296 SUPPORT Human Clinical

"- Scoliosis | 15.6"

The conference cohort table reports scoliosis in 15.6%.

Appendicular Hypotonia OCCASIONAL HP:0012389

Show evidence (1 reference)

PMID:38247296 SUPPORT Human Clinical

"- Peripheral hypotonia | 12.5"

Table 1 reports peripheral hypotonia in 12.5% of the 32 conference participants; it is distinct from the much more common axial hypotonia.

Nervous System 21

Intellectual Disability HP:0001249

Show evidence (3 references)

PMID:35593792 SUPPORT Human Clinical

"CTNNB1 neurodevelopmental disorder (CTNNB1-NDD) is characterized in all individuals by mild-to-profound cognitive impairment"

The earlier GeneReviews synthesis describes cognitive impairment in all reported individuals; newer direct assessments show wider variation, so this is not used to assert an obligatory formal ID diagnosis.

PMID:40145647 SUPPORT Human Clinical

"No cognitive differences were found among verbal tasks between groups, even though CTNNB1 syndrome patients obtained significantly lower scores in visuospatial and logical tasks."

Characterises the cognitive profile, with disproportionate visuospatial and logical-reasoning weakness.

PMID:38247296 SUPPORT Human Clinical

"These data suggest that cognitive functioning within this population is more variable than previously appreciated, and it is important to understand individual strengths and weaknesses to maximize cognitive and learning interventions."

The in-person study qualifies older descriptions of universal intellectual disability; no single frequency band is assigned to formally measured intellectual disability.

Global Developmental Delay VERY_FREQUENT HP:0001263

Show evidence (3 references)

PMID:25326669 SUPPORT Human Clinical

"All patients have ID, motor delay and speech impairment (both mostly severe) and abnormal muscle tone (truncal hypotonia and distal hypertonia/spasticity)."

The 16-person cohort reports motor delay and speech impairment in all individuals; small ascertained cohorts do not establish universality.

PMID:36153650 SUPPORT Human Clinical

"developmental delay/intellectual disability (100%), motor delay (100%), speech impairment (100%)"

The full-text denominators vary by assessment: developmental delay/ID was recorded in 18 assessed individuals, and speech was assessed in five age-eligible children. These percentages must not be applied to all 24 participants.

PMID:38247296 SUPPORT Human Clinical

"Half of individuals walked without an assistive device."

Quantifies gross-motor outcome in a deeply phenotyped cohort of 32 individuals.

Severe Speech Impairment VERY_FREQUENT Delayed speech and language development HP:0000750

Show evidence (3 references)

PMID:25326669 SUPPORT Human Clinical

"All patients have ID, motor delay and speech impairment (both mostly severe)"

Speech impairment, mostly severe, was present in all 16 individuals of this cohort. The band is held at VERY_FREQUENT rather than OBLIGATE given the modest cohort sizes underlying the 100% figures.

PMID:36153650 SUPPORT Human Clinical

"speech impairment (100%)"

The full text reports speech impairment in all five children assessed at age three years or older, not all 24 participants.

PMID:36293418 SUPPORT Human Clinical

"The CTNNB1 Syndrome is a rare neurodevelopmental disorder associated with developmental delay, intellectual disability, and delayed or absent speech."

A systematic review of the published literature lists delayed or absent speech as a defining feature.

Dystonia FREQUENT HP:0001332

Show evidence (3 references)

PMID:35593792 SUPPORT Human Clinical

"Other common findings include truncal hypotonia, peripheral spasticity, dystonia, behavior problems, microcephaly, and refractive errors and strabismus."

GeneReviews lists dystonia among the common findings, supporting a FREQUENT band.

PMID:39067319 SUPPORT Human Clinical

"three developed upper body (prominently cervical) dystonia in the second decade, with or without bradykinesia (2/13)"

Characterises the anatomical distribution and second-decade onset of dystonia. The low cross-sectional fraction here (3/14) reflects the age-dependence of the upper-body form specifically; overall dystonia frequency across cohorts is higher (see the 87.5% figure below), so the band is set from the pooled picture.

PMID:36153650 SUPPORT Human Clinical

"dystonia (87.5%) and microcephaly (69.6%)"

In a 24-patient Chinese cohort dystonia was present in 87.5%; together with the 3/14 upper-body figure from Garone and the GeneReviews "common findings" wording, a FREQUENT band is the conservative pooled estimate.

Bradykinesia OCCASIONAL HP:0002067

Show evidence (1 reference)

PMID:39067319 SUPPORT Human Clinical

"three developed upper body (prominently cervical) dystonia in the second decade, with or without bradykinesia (2/13)"

Bradykinesia was documented in 2 of 13 patients with motor disorders, consistent with an OCCASIONAL (5-29%) band.

Exaggerated Startle Response FREQUENT HP:0002267

Show evidence (3 references)

PMID:36419413 SUPPORT Human Clinical

"All 12 patients presented exaggerated startle responses to an unexpected stimulus. They provoked falls in 8 patients, causing injuries in 3, and 3 patients were afraid to walk. This startle disorder corresponds to atypic hyperekplexia."

Case series characterising the startle phenotype as atypical hyperekplexia with injurious falls.

PMID:39067319 SUPPORT Human Clinical

"Five patients reported exaggerated startle"

Exaggerated startle in 5 of 14 systematically assessed patients (approximately 36%), supporting a FREQUENT band.

PMID:38247296 SUPPORT Human Clinical

"| - Startle | 59.4 |"

Startle was elicited on examination in 59.4% of the 32-person cohort, supporting FREQUENT without deriving a prevalence estimate from the startle-selected case series.

Behavioral Problems FREQUENT Atypical behavior HP:0000708

Show evidence (3 references)

PMID:38247296 SUPPORT Human Clinical

"Based upon the Child Behavior Checklist total problems score, the majority (65%) of individuals had behavioral challenges."

The 65% estimate concerns the 17 participants with a completed Child Behavior Checklist, not all 32 enrolled individuals.

PMID:40145647 SUPPORT Human Clinical

"Externalizing problems were more prevalent in the CTNNB1 syndrome group compared with the control groups."

Characterises the behavioural profile as disproportionately externalising relative to ASD and cerebral palsy comparison groups.

PMID:36153650 SUPPORT Human Clinical

"we discovered that 20 patients (83.3%) exhibited various behavioral abnormalities"

The Chinese cohort reports behavioral abnormalities in 20/24; its broad assessment differs from the Child Behavior Checklist and the estimates are not pooled.

Autistic Behavior FREQUENT HP:0000729

Show evidence (2 references)

PMID:36293418 SUPPORT Human Clinical

"behavioral abnormalities (e.g., autistic-like or aggressive behavior)"

The systematic review establishes autistic-like behavior in the clinical spectrum; a direct cohort supplies a formal diagnosis frequency separately.

PMID:38247296 SUPPORT Human Clinical

"- Autism spectrum disorder | 34.4"

The conference cohort table reports a prior ASD diagnosis in 34.4%; this is not interchangeable with screening traits.

Tethered Cord OCCASIONAL HP:0002144

Show evidence (2 references)

PMID:38247296 SUPPORT Human Clinical

"Most individuals had truncal hypotonia, muscle weakness, hypertonia, dystonia, microcephaly, and many had a history of tethered cord."

Documents a history of tethered cord in many of 32 individuals.

PMID:38247296 SUPPORT Human Clinical

"Tethered cord was reported in 25% of participants, which is higher than other studies"

The 32-person conference cohort reports 25%, within OCCASIONAL; the authors explicitly note possible ascertainment bias.

Sleep Disturbance FREQUENT HP:0002360

Show evidence (1 reference)

PMID:40684264 SUPPORT Human Clinical

"Parents also reported that 56.3% of children living with the CTNNB1 syndrome (95% CI, 47.6%–64.7%) had sleeping problems."

The 127-participant remote caregiver study supports FREQUENT. Recruitment and parent reporting limit generalizability.

Gait Ataxia FREQUENT HP:0002066

Show evidence (1 reference)

PMID:38247296 SUPPORT Human Clinical

"- Ataxic gait | 43.8"

Table 1 of the 32-person conference cohort reports ataxic gait in 43.8%; mixed gait abnormalities were assessed in person.

Attention Deficit Hyperactivity Disorder OCCASIONAL HP:0007018

Show evidence (1 reference)

PMID:38247296 SUPPORT Human Clinical

"- Attention-deficit/hyperactivity disorder | 25"

Table 1 records a prior ADHD diagnosis in 25% of the 32 conference participants; this is a diagnosis history rather than a symptom-screening estimate.

Anxiety OCCASIONAL HP:0000739

Show evidence (1 reference)

PMID:38247296 SUPPORT Human Clinical

"- Anxiety | 15.6"

Table 1 records an anxiety diagnosis in 15.6% of the 32 conference participants; the broader internalizing-symptom screen is a different measure.

Motor Stereotypies FREQUENT Motor stereotypy HP:0000733

Show evidence (1 reference)

PMID:38247296 SUPPORT Human Clinical

"- Stereotypies | 40.6"

Table 1 reports stereotypies in 40.6% of the 32 conference participants, supporting FREQUENT.

Developmental Regression FREQUENT HP:0002376

Show evidence (1 reference)

PMID:40684264 SUPPORT Human Clinical

"A substantial proportion (35.1%; 95% CI, 26.9%–44.4%) of respondents reported signs of developmental regression"

In the remote study of 127 participants, 35.1% of respondents reported regression. This retrospective caregiver report does not demonstrate progressive neurodegeneration.

Hypoplasia of the Corpus Callosum HP:0002079

Show evidence (1 reference)

PMID:40684264 SUPPORT Human Clinical

"Of these 26 participants, 5 also had an abnormal corpus callosum (CC) morphology, accompanied with a smaller CC volume in 4 participants."

Among 121 participants with imaging, 26 had abnormal findings, five had abnormal callosal morphology and four had smaller callosal volume. The related mechanistic paper draws from the same cohort.

Seizures HP:0001250

Show evidence (1 reference)

PMID:40684264 SUPPORT Human Clinical

"seizures (3.9%; 95% CI, 1.7%–8.9%)"

The 127-person remote caregiver cohort reports seizures in 3.9%; ascertainment differs from earlier selected clinical series, so a pooled frequency band is not assigned.

Toe Walking FREQUENT Tip-toe gait HP:0030051

Show evidence (1 reference)

PMID:38247296 SUPPORT Human Clinical

"- Toe walking | 37.5"

Table 1 reports toe walking in 37.5% of the 32 conference participants; this can overlap with other gait findings.

Cerebral White Matter Abnormalities OCCASIONAL Abnormal cerebral white matter morphology HP:0002500

Show evidence (1 reference)

PMID:40684264 SUPPORT Human Clinical

"White matter abnormalities were reported in 26 of these 34 participants (76.5%). Among these, 15 participants were reported to have white matter volume loss, 11 participants had abnormal signal intensity, and 8 had delayed myelinization."

The imaging categories overlap and are kept as a variable spectrum; the frequency among all 121 imaged participants is about 21.5%.

Self-Injurious Behavior OCCASIONAL HP:0100716

Show evidence (1 reference)

PMID:36153650 SUPPORT Human Clinical

"Self‐injury | 2 | 24 | 8.3"

The Chinese cohort table records self-injury in 2/24 individuals (8.3%); combined aggression/self-mutilation estimates are not used for this specific feature.

Aggressive Behavior HP:0000718

Show evidence (1 reference)

PMID:38247296 SUPPORT Human Clinical

"we documented frequent externalizing behaviors (delinquent and aggressive behaviors)"

The conference study describes aggressive externalizing behavior. Child Behavior Checklist data were available for 17 of 32 participants, and the quoted summary does not supply a separate aggression frequency.

Growth 2

Intrauterine Growth Restriction OCCASIONAL Intrauterine growth retardation HP:0001511

Show evidence (2 references)

PMID:35593792 SUPPORT Human Clinical

"Less common features include intrauterine growth restriction, feeding difficulties, and scoliosis."

GeneReviews lists intrauterine growth restriction among the less common features.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf SUPPORT Human Clinical

"IUGR 10/44 (22.7%) Short stature 8/39 (20.5%)"

The GeneReviews full-text table supplies the denominator for prenatal growth restriction.

Short Stature OCCASIONAL HP:0004322

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf SUPPORT Human Clinical

"IUGR 10/44 (22.7%) Short stature 8/39 (20.5%)"

The full-text GeneReviews synthesis reports short stature in 8/39 assessed individuals (20.5%), supporting OCCASIONAL.

🧬

Genetic Associations

CTNNB1 (Causal - heterozygous germline variants, predominantly loss of function)

Gene: CTNNB1 hgnc:2514 gene page relationship_type: CAUSATIVE

Show evidence (5 references)

PMID:36083290 SUPPORT Human Clinical

"Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075)"

Establishes germline CTNNB1 loss of function as the cause of the disorder and confirms the OMIM identity (615075) matching the MONDO xref.

PMID:40684264 SUPPORT Human Clinical

"those with missense variants presented a milder phenotype, including earlier achievement of independent walking, fewer motor impairments, better conceptual and social skills, improved communication, and fewer feeding difficulties"

This exploratory association concerns only four individuals with missense variants and is not a general prediction for future patients.

PMID:36293418 SUPPORT Human Clinical

"While mutations cannot be more generally categorized by location, it is generally observed that the C-terminal protein region (exons 13, 14, 15) correlates with a milder phenotype."

The systematic review used a small, heterogeneous subset including isolated FEVR; the positional association is exploratory and not sufficient to assign a clinical subtype.

+ 2 more references

Variants (11)

p.Leu388Pro

A missense allele with a dominant-negative Wnt reporter effect in HEK293T cotransfection experiments.

Show evidence (1 reference)

PMID:36083290 SUPPORT In Vitro

"We were able to resolve p.Leu388Pro and p.Leu424Arg as likely dominant negative variants affecting the WNT signalling pathway"

The experiment supports an allele-specific reporter effect, not a universal missense mechanism.

p.Leu424Arg

A missense allele with a dominant-negative Wnt reporter effect in HEK293T cotransfection experiments.

Show evidence (1 reference)

PMID:36083290 SUPPORT In Vitro

"We were able to resolve p.Leu388Pro and p.Leu424Arg as likely dominant negative variants affecting the WNT signalling pathway"

The experiment supports an allele-specific reporter effect, not a universal missense mechanism.

p.Tyr333Ter

One of four truncating protein variants showing dominant-negative reporter effects with wild-type cotransfection in the 2025 study. Protein shorthand follows the publication; cDNA expression does not prove endogenous transcript stability.

Show evidence (1 reference)

PMID:40684264 SUPPORT In Vitro

"However, four variants (p.Y333∗, p.Q193∗, p.A317Vfs8∗, and p.S352fs∗) showed reduced levels of TOPFlash-luciferase activity suggesting a dominant negative mechanism"

The body identifies four truncating protein variants found in eleven participants.

p.Gln193Ter

Show evidence (1 reference)

PMID:40684264 SUPPORT In Vitro

"However, four variants (p.Y333∗, p.Q193∗, p.A317Vfs8∗, and p.S352fs∗) showed reduced levels of TOPFlash-luciferase activity suggesting a dominant negative mechanism"

The body identifies four truncating protein variants found in eleven participants.

p.Ala317ValfsTer8

Show evidence (1 reference)

PMID:40684264 SUPPORT In Vitro

"However, four variants (p.Y333∗, p.Q193∗, p.A317Vfs8∗, and p.S352fs∗) showed reduced levels of TOPFlash-luciferase activity suggesting a dominant negative mechanism"

The body identifies four truncating protein variants found in eleven participants.

p.Ser352fsTer

Show evidence (1 reference)

PMID:40684264 SUPPORT In Vitro

"However, four variants (p.Y333∗, p.Q193∗, p.A317Vfs8∗, and p.S352fs∗) showed reduced levels of TOPFlash-luciferase activity suggesting a dominant negative mechanism"

The body identifies four truncating protein variants found in eleven participants.

p.Gly575Arg

An assay-dependent allele: normal reporter output in the 2022 HEK293T study, reduced output in 2023 SuperTopFlash cells, and increased activity and thermal stability in 2025 SK-N-MC cells. The gene-addition trial excludes it under its predicted gain-of-function criterion.

Show evidence (3 references)

PMID:40684264 SUPPORT In Vitro

"For p.G575R, the Tm was shifted to 55.32 ± 0.51°C, indicating that the p.G575R mutant protein is more stable than the WT protein"

Thermal shift experiments support greater stability in this system. Degradation-complex resistance was proposed, not directly measured.

PMID:36083290 SUPPORT In Vitro

"The functional impact of p.Gly575Arg was not evident using this assay; however, given that this variant is recurrent, there is already sufficient evidence to determine that it is pathogenic."

The 2022 functional assay did not resolve an abnormal effect; this conflicts with the later reporter results.

PMID:36790797 SUPPORT In Vitro

"Compared to wild-type CTNNB1, the CTNNB1 mutants failed to induce luciferase reporter activity in SuperTopFlash (STF) cells."

The tested set included Gly575Arg; the full text reports reduced reporter activity in this experimental context.

p.Leu577Arg

A nearby missense allele with reduced reporter activity and lower thermal stability in SK-N-MC cells.

Show evidence (1 reference)

PMID:40684264 SUPPORT In Vitro

"the Tm of p.L577R was 46.02 ± 0.84°C, suggesting that the p.L577R mutant protein was less stable"

Contrasting effects of nearby Gly575Arg and Leu577Arg caution against predicting mechanism from position alone.

c.2137+5G>T

A transmitted intronic variant in a FEVR family; the mother and sister had subtle retinal vascular abnormalities despite normal acuity. Splice disruption was predicted, without a reported patient RNA assay.

Show evidence (1 reference)

PMID:36790797 SUPPORT Human Clinical

"Five of the 7 CTNNB1 mutations were found to be novel, namely, c.888_889dup (p.Thr297Ilefs*9), c.1707del (p.Ile569Metfs*12), c.2138-4_2140del, c.1543C>T (p.Arg515*), and c.2137+5G>T."

The full-text variant list and pedigree identify the allele; its functional splice consequence remains a prediction.

CTNNB1 exons 2-6 deletion

An intragenic deletion reported in the conference cohort.

Show evidence (1 reference)

PMID:38247296 SUPPORT Human Clinical

"included exons 2-6 of CTNNB1."

Direct clinical copy-number evidence supports the deletion class.

Inv(3)(p24.3p22.1)

A chromosomal inversion involving CTNNB1 exons 1-9 in the conference cohort.

Show evidence (1 reference)

PMID:38247296 SUPPORT Human Clinical

"involved exon 1-9 of the CTNNB1 gene"

The rearrangement expands the diagnostic variant spectrum beyond coding substitutions.

💊

Medical Actions

Multidisciplinary Supportive Care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

No established curative or disease-modifying treatment is supported by the cited clinical literature. Multidisciplinary care addresses motor, communication, feeding, visual, behavioral and family needs. Gene addition is in early clinical testing; GSK3 inhibition has preclinical mouse evidence. Neither constitutes proven human disease modification.

Show evidence (2 references)

PMID:35593792 SUPPORT Human Clinical

"There is no curative treatment. Supportive care by a multidisciplinary team often includes a neurologist, speech-language pathologist, physiatrist, occupational therapist, physical therapist, feeding team, pediatric ophthalmologist, audiologist, and developmental pediatrician."

GeneReviews defines the standard of care as multidisciplinary supportive management in the absence of curative treatment.

PMID:39833474 SUPPORT Other

"There is currently no effective treatment option available for patients with CTNNB1 syndrome, with support largely focused on the management of symptoms and physiotherapy"

Confirms the absence of disease-modifying therapy and the symptom-management/physiotherapy focus of current care.

Physical Therapy and Motor Rehabilitation

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Physical therapy, stretching, positioning and individualized mobility aids address hypotonia, weakness, spasticity and gait limitations. Occupational therapy addresses fine motor and adaptive tasks. These are expert supportive-care recommendations rather than CTNNB1-specific controlled efficacy results.

Target Phenotypes: Spastic diplegia HP:0001264 Muscle weakness HP:0001324

Show evidence (3 references)

PMID:39833474 SUPPORT Other

"with support largely focused on the management of symptoms and physiotherapy"

Identifies physiotherapy as a core component of current supportive management.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf SUPPORT Human Clinical

"wheelchairs, walkers, bath chairs, orthotics, adaptive strollers"

GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), full text. GeneReviews lists individualized assistive equipment.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf SUPPORT Human Clinical

"Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing."

GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), full text. GeneReviews provides explicit occupational-therapy guidance.

Speech and Language Therapy

Action: speech and language therapy Ontology label: Speech Language Therapy NCIT:C159273

Platform: Behavioral / lifestyle

Speech-language therapy including augmentative and alternative communication addresses the severe expressive speech impairment that is near-universal in the disorder.

Target Phenotypes: Delayed speech and language development HP:0000750

Show evidence (2 references)

PMID:35593792 SUPPORT Human Clinical

"Supportive care by a multidisciplinary team often includes a neurologist, speech-language pathologist"

GeneReviews includes speech-language pathology in the standard multidisciplinary care team.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf SUPPORT Human Clinical

"Consider evaluation for alternative means of communication"

GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), full text. GeneReviews specifically recommends considering augmentative and alternative communication.

Botulinum Toxin for Spasticity and Dystonia

Action: Pharmacotherapy NCIT:C15986

Agent: botulinum toxin type A CHEBI:3160

Platform: Other

Botulinum toxin injection was at least partially effective for the movement disorder in most treated patients in a systematically assessed cohort; levodopa was much less consistently helpful.

Target Phenotypes: Spastic diplegia HP:0001264 Dystonia HP:0001332

Show evidence (1 reference)

PMID:39067319 SUPPORT Human Clinical

"Treatment efficacy was variable: botulinum toxin was (at least partially) effective in 5/6, levodopa in 1 of 4 treated patients."

Reports partial or better response to botulinum toxin in 5 of 6 treated patients and limited levodopa benefit.

Ophthalmological Surveillance and FEVR Treatment

Action: laser photocoagulation Ontology label: Laser Photocoagulation NCIT:C217424

Platform: Surgery

Regular paediatric ophthalmology review with refractive correction and strabismus management, plus ultra-widefield fluorescein angiography to detect occult vitreoretinopathy; treatment-requiring peripheral retinal non-perfusion is managed with laser photocoagulation and, when detachment occurs, vitreoretinal surgery.

Target Phenotypes: Exudative vitreoretinopathy HP:0030490

Show evidence (3 references)

PMID:39145965 SUPPORT Human Clinical

"The presence of disease requiring treatment was identified in 6 eyes, including 1 retinal detachment."

Establishes that a meaningful proportion of eyes harbour treatment-requiring retinal disease, justifying active ophthalmological management.

PMID:35593792 SUPPORT Human Clinical

"Surveillance: Monitor neurologic findings for response to supportive interventions and emergence of new findings or concerns regarding developmental/educational progress, behavior issues, ophthalmologic findings and vision, and family support."

GeneReviews specifies ophthalmological findings and vision as a required surveillance domain.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf SUPPORT Human Clinical

"For significant retinal findings: argon laser photocoagulation, scleral buckling &/or pars plana vitrectomy to attempt to halt progressive changes & ↓ complications"

The full-text GeneReviews treatment table explicitly lists laser photocoagulation and vitreoretinal procedures for significant retinal findings.

AAV9-Mediated CTNNB1 Gene Replacement (Investigational)

Action: gene therapy Ontology label: Gene Therapy NCIT:C15238

Platform: Gene therapy

Urbagen is an investigational single-stranded AAV9 vector carrying human CTNNB1, administered once by bilateral intracerebroventricular infusion in the open-label phase I/II GAIN study (NCT07270549). Twelve participants aged 2-12 years are planned, with part A restricted to 6-12 years. Prophylaxis includes methylprednisolone followed by prednisolone and sirolimus. The registry excludes selected predicted gain-of-function and dominant-negative alleles, including Gly575Arg and four truncating variants. Gene addition aims to increase functional dosage; no human safety or efficacy results are posted. Its benefit and long-term safety remain unestablished.

Mechanism Target:

ACTIVATES CTNNB1 Loss-of-Function and Beta-Catenin Haploinsufficiency — The vector is intended to increase functional CTNNB1 expression in eligible loss-of-function genotypes. Restoration of dosage or clinical benefit has not yet been demonstrated in trial results.

Show evidence (2 references)

clinicaltrials:NCT07270549 SUPPORT Human Clinical

"gene therapy via bilateral intracerebroventricular administration."

Describes the route and dosing of the investigational AAV9 CTNNB1 gene replacement therapy.

url:https://clinicaltrials.gov/api/v2/studies/NCT07270549 SUPPORT Human Clinical

"* Participant has a mutation in the CTNNB1 gene which is predicted to result in a gain-of-function effect (e.g. p.G575R) or dominant negative effect (e.g. p.Y333\\*, p.Q193\\*, p.A317Vfs8\\* and p.S352fs\\*) on the Wnt/β-catenin pathway, or any variant that, in the opinion of the PI, is..."

The GAIN registry specifies allele-related exclusions; this criterion does not resolve discordant experimental results for Gly575Arg.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counseling covers autosomal dominant inheritance, parental testing, variable expressivity and possible germline mosaicism. GeneReviews gives a 50% transmission risk when a parent carries the variant and an empirical approximately 1% sibling recurrence estimate when it is absent from both parents’ leukocyte DNA. These estimates require family-specific interpretation; phenotype severity cannot be reliably predicted. Prenatal and preimplantation testing are possible after identifying the familial pathogenic variant.

Show evidence (3 references)

PMID:35593792 SUPPORT Human Clinical

"Once the CTNNB1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."

GeneReviews states the reproductive-testing options that genetic counselling addresses.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf SUPPORT Human Clinical

"the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism"

GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), full text. GeneReviews supplies the empirical estimate when parental leukocyte testing is negative.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf SUPPORT Human Clinical

"Each child of an individual with CTNNB1-NDD has a 50% chance of inheriting the CTNNB1 pathogenic variant."

The full-text GeneReviews genetic counseling section states the transmission risk for an affected individual; this differs from sibling recurrence when both parents test negative.

Baclofen and Tizanidine for Tone Abnormalities

Action: Pharmacotherapy NCIT:C15986

Agent: baclofen CHEBI:2972 tizanidine CHEBI:63629

Platform: Other

GeneReviews lists baclofen, including intrathecal delivery in selected cases, and tizanidine as specialist-directed symptomatic options. Controlled CTNNB1-specific efficacy is not established.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf SUPPORT Human Clinical

"For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of Levodopa, baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures."

GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), full text. The full-text motor-care section lists these symptomatic options.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf SUPPORT Human Clinical

"Botulinum toxin & intrathecal baclofen injection may be considered."

GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), full text. The treatment table includes consideration of intrathecal baclofen.

Levodopa for Dystonia (Limited Evidence)

Action: Pharmacotherapy NCIT:C15986

Agent: L-dopa CHEBI:15765 carbidopa CHEBI:3395

Platform: Other

A selected movement-disorder series reported benefit in only one of four treated patients. The open-label levodopa/carbidopa pilot is testing motor outcomes; a response does not itself prove presynaptic dopamine deficiency.

Show evidence (1 reference)

PMID:39067319 SUPPORT Human Clinical

"Treatment efficacy was variable: botulinum toxin was (at least partially) effective in 5/6, levodopa in 1 of 4 treated patients."

Uncontrolled patient observations indicate variable response; the ongoing pilot supplies no posted efficacy results.

Benzodiazepines for Disabling Exaggerated Startle

Action: Pharmacotherapy NCIT:C15986

Agent: clonazepam CHEBI:3756 diazepam CHEBI:49575

Platform: Other

In one electrophysiologically assessed adult, sequential clonazepam then diazepam treatment reduced startle responses and abolished sudden falls. The report is a single treated case, not evidence of established benefit for the whole syndrome.

Show evidence (1 reference)

PMID:36419413 SUPPORT Human Clinical

"Treatment by clonazepam and then with diazepam drastically reduced the startle responses and suppressed sudden falls."

The full text locates this treatment response in one 19-year-old patient, not all twelve people described in the study.

Feeding and Nutritional Support

Action: Supportive Care NCIT:C15747

Platform: Other

Feeding-team assessment addresses swallowing safety, aspiration and nutritional adequacy. GeneReviews describes adapted feeds and enteral support when dysfunction is severe; individual swallowing assessment guides the intervention.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf SUPPORT Human Clinical

"When feeding dysfunction is severe, an NG-tube or G-tube may be necessary."

GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), full text. The full-text care section includes enteral feeding support.

Low Vision and Family Support

Action: Supportive Care NCIT:C15747

Platform: Other

Low-vision services, developmental education, behavioral assessment and social-work support address adaptive function and family needs alongside ophthalmologic and motor care.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf SUPPORT Human Clinical

"Low vision Low vision services Community services through early intervention &/or school district"

GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), full text. The treatment table recommends low-vision services.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf SUPPORT Human Clinical

"Ensure appropriate social work involvement to connect families w/local resources, respite, & support."

GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), full text. GeneReviews includes family resources and respite support.

Dual GSK3 Inhibition (Preclinical)

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

BRD0320 improved beta-catenin abundance, several molecular and electrophysiological measures, learning and motor performance after five daily injections in symptomatic 6-10-week-old germline heterozygous mice. Resting membrane potential was not corrected. Separate alpha- or beta-selective inhibitors were less effective. Human efficacy, chronic safety and optimal treatment age remain unknown, and effects through other GSK3 substrates were not excluded.

Mechanism Target:

ACTIVATES CTNNB1 Loss-of-Function and Beta-Catenin Haploinsufficiency — In the germline heterozygous mouse, dual inhibition raises beta-catenin abundance toward control levels. Human benefit remains untested and beta-catenin-independent effects may contribute.

Show evidence (2 references)

DOI:10.1038/s44321-024-00110-5 SUPPORT Model Organism

"GSK3α,β dual-paralog inhibition (BRD0320) signi ﬁcantly improves learning and memory in the β-cat het mice"

The primary study reports a short mouse experiment, not a human therapeutic result.

DOI:10.1038/s44321-024-00110-5 SUPPORT Model Organism

"However, we cannot rule out a contribution of other β-cat independent GSK3 α,β substrates."

The authors explicitly acknowledge that beta-catenin-independent effects may contribute.

🔬

Diagnosis

Molecular Genetic Testing for CTNNB1 (Positive in affected individuals)

Diagnosis requires a heterozygous pathogenic or likely pathogenic CTNNB1 variant in an individual with compatible findings. Exome/genome or panel sequencing and deletion/duplication analysis address sequence variants and copy-number changes; a variant of uncertain significance does not establish the diagnosis. A clinical cerebral palsy or autism diagnosis can coexist and can be an entry point for molecular testing.

molecular genetic testing NCIT:C19770

Show evidence (2 references)

PMID:35593792 SUPPORT Human Clinical

"The diagnosis of CTNNB1-NDD is established in a proband with suggestive findings and a heterozygous pathogenic variant in CTNNB1 identified by molecular genetic testing"

GeneReviews states the molecular diagnostic criterion.

PMID:36083290 SUPPORT Human Clinical

"NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing."

Supports testing individuals whose entry diagnosis was cerebral palsy, since the molecular entity is the same.

Ultra-Widefield Fluorescein Angiography (Abnormal in a substantial minority with normal office examination)

Retinal vascular disease in CTNNB1 syndrome is frequently occult on routine office ophthalmoscopy. Ultra-widefield fluorescein angiography, if necessary under anaesthesia, detects treatment-requiring FEVR in children with previously normal examinations and should be considered at diagnosis.

fluorescein angiography NCIT:C190541

Show evidence (2 references)

PMID:39145965 SUPPORT Human Clinical

"These findings support consideration of ultra-widefield fluorescein angiography among individuals with CTNNB1 syndrome when feasible, including the use of sedation if such an assessment is not possible in the office setting."

Directly recommends ultra-widefield fluorescein angiography, including under sedation, in CTNNB1 syndrome.

PMID:39145965 SUPPORT Human Clinical

"However, ophthalmoscopy may not be sufficient to detect vision-threatening vitreoretinopathy in all patients."

States the diagnostic limitation of ophthalmoscopy that motivates angiography.

📊

Prevalence

Worldwide (children)

Birth Prevalence 2.6–3.2 per 100,000 1–9 per 100,000 (births)

A mouse-model review cites an estimated birth prevalence of 2.6-3.2 per 100,000 births. This secondary estimate is not a population-based measurement in that review. A cerebral palsy diagnosis can coexist with the molecular diagnosis.

Show evidence (1 reference)

PMID:39833474 SUPPORT Other

"CTNNB1 syndrome is a rare neurodevelopmental disorder, affecting children worldwide with a prevalence of 2.6-3.2 per 100,000 births and often misdiagnosed as cerebral palsy."

States the reported worldwide birth prevalence of CTNNB1 syndrome. This is a background statement in a mouse-model review rather than a primary epidemiological study, so it is tagged OTHER and the figure carries corresponding uncertainty.

Published and clinically ascertained individuals worldwide

Cases In Literature Ultra Rare

The 2022 compilation assembled genetic information from 404 individuals and 392 variant records. These are not 392 distinct alleles. The detailed clinical subset included individuals with isolated vitreoretinopathy, so the collection is not a pure CTNNB1-NDD prevalence denominator.

Show evidence (2 references)

PMID:36083290 SUPPORT Human Clinical

"Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study."

The study reports 404 individuals and 392 variant records across clinical and database sources; the number does not represent 392 unique alleles or population prevalence.

PMID:40145647 SUPPORT Human Clinical

"The CTNNB1 syndrome is a neurodevelopmental disorder considered an ultra-rare disease, first discovered in 2012."

Characterises CTNNB1 syndrome as an ultra-rare disorder, supporting the qualitative prevalence class.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from CTNNB1 Neurodevelopmental Disorder:

Cerebral Palsy

Overlapping Features CTNNB1-NDD can meet clinical criteria for cerebral palsy. Molecular testing identifies an underlying genetic cause rather than necessarily invalidating the clinical motor diagnosis. Progressive or additional findings warrant individualized reassessment.

Familial Exudative Vitreoretinopathy (NDP, FZD4, LRP5, TSPAN12)

Overlapping Features The ocular phenotype of CTNNB1-NDD is indistinguishable from classic FEVR caused by the Norrin receptor-complex genes; the accompanying neurodevelopmental and motor features distinguish CTNNB1-NDD.

Autism Spectrum Disorder

Overlapping Features Autism can coexist with CTNNB1-NDD. Relative visuospatial and adaptive weaknesses were described in small comparison cohorts but are not a validated diagnostic discriminator; molecular testing establishes the genetic diagnosis.

Hereditary Spastic Paraplegia

Overlapping Features Progressive lower-limb spasticity overlaps, but CTNNB1-NDD adds intellectual disability, microcephaly, facial gestalt and retinal vascular disease.

Hyperekplexia (GLRA1, GLRB, SLC6A5)

Overlapping Features The exaggerated startle of CTNNB1-NDD corresponds to atypical hyperekplexia and can prompt consideration of the classic glycinergic hyperekplexia genes.

🔬

Clinical Trials

NCT07270549 PHASE_I RECRUITING

GAIN-CTNNB1: open-label phase I/II, single-arm Urbagen gene addition study; 12 participants aged 2-12 years planned, part A aged 6-12. One bilateral intracerebroventricular dose with prophylactic immunosuppression and five-year safety follow-up. The registry excludes predicted gain-of-function Gly575Arg and dominant-negative Tyr333*, Gln193*, Ala317Valfs8* and Ser352fs* alleles or other incompatible mechanisms. No results posted.

Target Phenotypes: Spastic diplegia HP:0001264 Intellectual disability HP:0001249

Show evidence (3 references)

clinicaltrials:NCT07270549 SUPPORT Human Clinical

"the safety, tolerability, and preliminary efficacy of AAV9 mediated gene replacement therapy (Urbagen) in paediatric patients with CTNNB1 neurodevelopmental disorder."

Establishes that AAV9-mediated CTNNB1 gene replacement has entered first-in-human testing for this disorder.

url:https://clinicaltrials.gov/api/v2/studies/NCT07270549 SUPPORT Human Clinical

"the safety, tolerability, and preliminary efficacy of AAV9 mediated gene replacement therapy (Urbagen) in paediatric patients with CTNNB1 neurodevelopmental disorder."

The detailed registry describes the study purpose. Its hasResults field is false at retrieval, so this record supplies no posted efficacy results.

url:https://clinicaltrials.gov/api/v2/studies/NCT07270549 SUPPORT Human Clinical

The GAIN registry specifies allele-related exclusions; this criterion does not resolve discordant experimental results for Gly575Arg.

NCT07614126 NOT_APPLICABLE RECRUITING

Open-label levodopa/carbidopa pilot in seven planned children aged 1-15 years with CTNNB1-NDD and dystonia. Treatment and follow-up extend to one year; the primary endpoint is GMFM-88 change at six months, with secondary motor, developmental, quality-of-life and tolerability outcomes. The dopaminergic rationale is model-derived and unproven in humans. No results posted.

Target Phenotypes: Dystonia HP:0001332

Show evidence (2 references)

clinicaltrials:NCT07614126 SUPPORT Human Clinical

"These findings suggest that CTNNB1 anomalies lead to secondary dopaminergic deficits, contributing to clinical signs. The hypothesis is that this deficit could be partially corrected by dopamine supplementation."

States the model-derived dopaminergic-deficit rationale for the levodopa pilot; the hypothesis is explicitly unproven in humans.

url:https://clinicaltrials.gov/api/v2/studies/NCT07614126 SUPPORT Human Clinical

"These observations support the hypothesis that L-dopa may improve certain motor and non-motor symptoms in these patients."

The detailed registry describes the study purpose. Its hasResults field is false at retrieval, so this record supplies no posted efficacy results.

NCT07167732 NOT_APPLICABLE RECRUITING

Dragonfly: international prospective observational natural-history study, with 250 participants planned and five-year follow-up. Clinical scales and planned molecular measurements support natural-history and biomarker research; the blood measurements are candidate research endpoints, not validated diagnostic or treatment-response biomarkers. No results posted.

Show evidence (2 references)

clinicaltrials:NCT07167732 SUPPORT Human Clinical

"The aim of the Dragonfly study is to characterise and monitor the neurodevelopment of children and adults diagnosed with CTNNB1 syndrome through an international collaborative effort."

Documents the prospective natural-history study that will supply longitudinal outcome data currently missing for this disorder.

url:https://clinicaltrials.gov/api/v2/studies/NCT07167732 SUPPORT Human Clinical

"The aim of the Dragonfly study is to characterise and monitor the neurodevelopment of children and adults diagnosed with CTNNB1 syndrome through an international collaborative effort."

The detailed registry describes the study purpose. Its hasResults field is false at retrieval, so this record supplies no posted efficacy results.

NCT04812119 NOT_APPLICABLE COMPLETED

GenPhe: Completed remote genotype-phenotype study. The registry reports 100 actual participants; the linked 2025 paper reports 127 enrolled individuals, a distinct reporting count that should not be silently harmonized. Its caregiver assessments inform natural history rather than treatment efficacy. No results posted in the registry.

Show evidence (2 references)

url:https://clinicaltrials.gov/api/v2/studies/NCT04812119 SUPPORT Human Clinical

""statusModule": {"statusVerifiedDate": "2022-11", "overallStatus": "COMPLETED", "expandedAccessInfo": {"hasExpandedAccess": false}, "startDateStruct": {"date": "2021-03-01", "type": "ACTUAL"}, "primaryCompletionDateStruct": {"date": "2022-09-01", "type": "ACTUAL"}, "completionDateStruct":..."

The registry status module records COMPLETED alongside actual start and completion dates.

url:https://clinicaltrials.gov/api/v2/studies/NCT04812119 SUPPORT Human Clinical

"The aim of this study is to explore and define the correlations between genotype and phenotype in patients with CTNNB1 mutations as well as monitor and survey the natural history of the CTNNB1 syndrome."

The detailed registry describes the study purpose. Its hasResults field is false at retrieval, so this record supplies no posted efficacy results.

NCT05168969 NOT_APPLICABLE COMPLETED

Exaggerated Startle: Completed observational study of exaggerated startle in CTNNB1 syndrome, with 10 actual participants recorded. Eligibility requires an exaggerated startle response, so this selected sample cannot estimate prevalence in unselected CTNNB1-NDD. The registry count is not equated with the twelve-person publication. No results posted in the registry.

Show evidence (2 references)

url:https://clinicaltrials.gov/api/v2/studies/NCT05168969 SUPPORT Human Clinical

""statusModule": {"statusVerifiedDate": "2023-04", "overallStatus": "COMPLETED", "expandedAccessInfo": {"hasExpandedAccess": false}, "startDateStruct": {"date": "2022-07-02", "type": "ACTUAL"}, "primaryCompletionDateStruct": {"date": "2022-12-10", "type": "ACTUAL"}, "completionDateStruct":..."

The registry status module records COMPLETED alongside actual start and completion dates.

url:https://clinicaltrials.gov/api/v2/studies/NCT05168969 SUPPORT Human Clinical

"The investigators also have a 3rd patient carrying a CTNNB1 syndrome associated with hyperekplexia."

The detailed registry describes the study purpose. Its hasResults field is false at retrieval, so this record supplies no posted efficacy results.

🐁

Animal Models

Ctnnb1 batface (Bfc), Thr653Lys ENU-induced substitution Mouse

Batface is an ENU-induced Thr653Lys allele with normal protein abundance, reduced cadherin affinity and enhanced Wnt activity. Heterozygotes show altered dendritic development, connectivity, plasticity and cognitive behavior, with increased brain volume; it does not model simple dosage loss or human microcephaly. Acoustic startle magnitude was normal despite impaired prepulse inhibition. Homozygotes are nonviable.

Species

Mouse

Genotype

Ctnnb1 batface (Bfc), Thr653Lys ENU-induced substitution

Genes

CTNNB1 hgnc:2514

Show evidence (1 reference)

PMID:24614104 SUPPORT Model Organism

"In parallel, characterization of a chemically mutagenized mouse line that displays features similar to those of human patients with β-catenin mutations enabled us to investigate the consequences of β-catenin dysfunction through development and into adulthood."

The original paper establishes phenotypic overlap, with distinct molecular and anatomical limitations documented in its full text.

Endothelial-cell-specific (Cre-mediated) heterozygous Ctnnb1 knockout Mouse

Cre-mediated heterozygous deletion of Ctnnb1 restricted to endothelial cells produces FEVR-like retinal phenotypes, isolating the retinal vascular arm of the disorder. Lithium chloride, a GSK-3beta inhibitor that stabilises beta-catenin, partially rescued the defect in this model and in CTNNB1-knockdown human retinal endothelial cells.

Species

Mouse

Genotype

Endothelial-cell-specific (Cre-mediated) heterozygous Ctnnb1 knockout

Genes

CTNNB1 hgnc:2514

Show evidence (1 reference)

PMID:35361685 SUPPORT Model Organism

"Moreover, LiCl treatment partially rescued the defects in CTNNB1-KD HRECs and EC-specific Ctnnb1 heterozygous knockout mice."

Demonstrates partial pharmacological rescue of the retinal vascular phenotype by beta-catenin stabilisation in the endothelial-specific knockout model.

Germline heterozygous Ctnnb1 exon 2-6 deletion generated using E2a-Cre, with Cre bred out Mouse

This model has approximately half-normal beta-catenin abundance, impaired associative learning, grip strength and rotarod performance, altered N-cadherin association, lower DKK1/EN2 and ATPase alpha2/alpha3 protein, and altered dentate-granule-cell excitability. General locomotion was unchanged. Short BRD0320 treatment improved several outcomes after symptom onset; chronic safety and human translation were not tested.

Species

Mouse

Genotype

Germline heterozygous Ctnnb1 exon 2-6 deletion generated using E2a-Cre, with Cre bred out

Show evidence (1 reference)

DOI:10.1038/s44321-024-00110-5 SUPPORT Model Organism

"β-cat global het mice display approximately 50% reductions in β-cat protein levels"

The primary study directly measures protein reduction in a germline heterozygote, contrasting with the batface functional allele.

Lmx1aCre-targeted biallelic Ctnnb1 exon 2-6 deletion or heterozygous exon 3 stabilization Mouse

Both conditional manipulations disrupt callosal midline guidance populations and crossing. The loss model deletes both copies; a midline heterozygous deletion had no callosal phenotype. Only male embryos were analyzed because the Cre transgene is X-linked. These are mechanistic models with a substantial genotype and severity gap from human disease.

Species

Mouse

Genotype

Lmx1aCre-targeted biallelic Ctnnb1 exon 2-6 deletion or heterozygous exon 3 stabilization

Show evidence (1 reference)

PMID:40894864 SUPPORT Model Organism

"our Ctnnb1 LOF model results in gene disruption of both copies and loss of all CTNNB function."

The paper states the critical difference between its loss model and the human heterozygous condition.

{ }

Source YAML

click to show

name: CTNNB1 Neurodevelopmental Disorder
creation_date: '2026-07-31T00:00:00Z'
description: CTNNB1 neurodevelopmental disorder (CTNNB1-NDD; CTNNB1 syndrome; NEDSDV; MRD19) is an autosomal dominant disorder usually caused by a de novo heterozygous loss-of-function variant in CTNNB1, encoding beta-catenin. Beta-catenin mediates canonical Wnt transcription and cadherin-dependent cell adhesion. Developmental and speech delay, variable cognitive impairment, axial hypotonia, limb hypertonia, dystonia, microcephaly, behavioral difficulties and visual abnormalities characterize the disorder. Motor impairment can meet clinical criteria for cerebral palsy; its course varies between individuals. Retinal vascular disease may remain undetected on routine ophthalmoscopy. Most pathogenic alleles reduce beta-catenin function, but selected variants have dominant-negative or assay-dependent activating effects. This entry covers the germline neurodevelopmental disorder, including its ocular manifestations.
category: Mendelian
parents:
- Neurodevelopmental Disorder
- Syndromic Intellectual Disability
notes: CTNNB1-related disease spans syndromic neurodevelopmental presentations and isolated vitreoretinopathy. MONDO:0014035 identifies the neurodevelopmental entity corresponding to OMIM 615075; its broader parent also includes isolated eye disease. A young child presenting with retinal disease may develop recognizable neurodevelopmental findings later. Somatic CTNNB1 variants driving tumors represent a distinct clinical setting. GeneReviews reports no evidence of increased cancer risk with germline loss-of-function variants; this is not a lifetime risk estimate for every variant class. Published cohorts differ in recruitment, age and assessments and may overlap, so their counts and phenotype percentages are not pooled. The Bookshelf PDF cited by URL is the full text of GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), not a separate study. Detailed ClinicalTrials.gov API references document eligibility, enrollment and result availability alongside the brief trial records.
disease_term:
  preferred_term: CTNNB1 syndrome
  term:
    id: MONDO:0014035
    label: severe intellectual disability-progressive spastic diplegia syndrome
synonyms:
- CTNNB1 syndrome
- CTNNB1-NDD
- CTNNB1-related neurodevelopmental disorder
- neurodevelopmental disorder with spastic diplegia and visual defects
- NEDSDV
- MRD19
- autosomal dominant intellectual disability 19
- CTNNB1 haploinsufficiency syndrome
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  - classification_value: NEUROLOGIC
references:
- reference: PMID:39833474
  title: CTNNB1 syndrome mouse models.
- reference: PMID:36083290
  title: Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.
- reference: PMID:40145647
  title: 'Cognitive and Adaptive Functioning of CTNNB1 Syndrome Patients: A Comparison With Autism Spectrum Disorder and Cerebral Palsy.'
- reference: PMID:35593792
  title: CTNNB1 Neurodevelopmental Disorder.
  tags:
  - GeneReviews
- reference: PMID:36790797
  title: Familial Exudative Vitreoretinopathy and Systemic Abnormalities in Patients With CTNNB1 Mutations.
- reference: PMID:25326669
  title: 'De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum.'
- reference: PMID:24668549
  title: A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency.
- reference: PMID:40684264
  title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
- reference: PMID:24614104
  title: Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features.
- reference: DOI:10.1038/s44321-024-00110-5
  title: Inhibition of GSK3α,β rescues cognitive phenotypes in a preclinical mouse model of CTNNB1 syndrome
- reference: PMID:40894864
  title: An evolutionarily conserved role for CTNNB1/β-CATENIN in regulating the development of the corpus callosum.
- reference: PMID:39067319
  title: 'Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology.'
- reference: PMID:35361685
  title: Novel truncating variants in CTNNB1 cause familial exudative vitreoretinopathy.
- reference: PMID:37455656
  title: 'Congenital heart defects in CTNNB1 syndrome: Raising clinical awareness.'
- reference: PMID:38247296
  title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
- reference: PMID:36153650
  title: Genetic and clinical characteristics of 24 mainland Chinese patients with CTNNB1 loss-of-function variants.
- reference: PMID:36293418
  title: 'Correlation between Phenotype and Genotype in CTNNB1 Syndrome: A Systematic Review of the Literature.'
- reference: PMID:36419413
  title: 'Startle Disease: An Overlooked Symptom of CTNNB1-Related Neurodevelopmental Disorder With Spastic Diplegia and Visual Defects.'
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
  title: https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
  tags:
  - GeneReviews
- reference: PMID:39145965
  title: Vitreoretinopathy in Asymptomatic Children With CTNNB1 Syndrome.
- reference: clinicaltrials:NCT07270549
  title: 'GAIN-CTNNB1: A Phase I/II Open-Label Trial To Evaluate the Safety, Tolerability, and Preliminary Efficacy of Intracerebroventricular Administration of an AAV9 Based Gene Replacement Therapy in Paediatric Patients With CTNNB1 Neurodevelopmental Syndrome'
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07270549
  title: https://clinicaltrials.gov/api/v2/studies/NCT07270549
- reference: clinicaltrials:NCT07614126
  title: Prospective Pilot Study of L-dopa Treatment in Patients With a Neurodevelopmental Disorder Related to a Pathogenic Variant of the CTNNB1 Gene
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07614126
  title: https://clinicaltrials.gov/api/v2/studies/NCT07614126
- reference: clinicaltrials:NCT07167732
  title: 'Dragonfly Study: An International, Prospective, Longitudinal, Observational Natural History Study of Children and Adults Living With CTNNB1 Neurodevelopmental Syndrome'
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07167732
  title: https://clinicaltrials.gov/api/v2/studies/NCT07167732
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT04812119
  title: https://clinicaltrials.gov/api/v2/studies/NCT04812119
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT05168969
  title: https://clinicaltrials.gov/api/v2/studies/NCT05168969
prevalence:
- population: Worldwide (children)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_low: 2.6
  rate_high: 3.2
  notes: A mouse-model review cites an estimated birth prevalence of 2.6-3.2 per 100,000 births. This secondary estimate is not a population-based measurement in that review. A cerebral palsy diagnosis can coexist with the molecular diagnosis.
  evidence:
  - reference: PMID:39833474
    reference_title: CTNNB1 syndrome mouse models.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CTNNB1 syndrome is a rare neurodevelopmental disorder, affecting children worldwide with a prevalence of 2.6-3.2 per 100,000 births and often misdiagnosed as cerebral palsy.
    explanation: States the reported worldwide birth prevalence of CTNNB1 syndrome. This is a background statement in a mouse-model review rather than a primary epidemiological study, so it is tagged OTHER and the figure carries corresponding uncertainty.
- population: Published and clinically ascertained individuals worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: The 2022 compilation assembled genetic information from 404 individuals and 392 variant records. These are not 392 distinct alleles. The detailed clinical subset included individuals with isolated vitreoretinopathy, so the collection is not a pure CTNNB1-NDD prevalence denominator.
  evidence:
  - reference: PMID:36083290
    reference_title: Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study.
    explanation: The study reports 404 individuals and 392 variant records across clinical and database sources; the number does not represent 392 unique alleles or population prevalence.
  - reference: PMID:40145647
    reference_title: 'Cognitive and Adaptive Functioning of CTNNB1 Syndrome Patients: A Comparison With Autism Spectrum Disorder and Cerebral Palsy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The CTNNB1 syndrome is a neurodevelopmental disorder considered an ultra-rare disease, first discovered in 2012.
    explanation: Characterises CTNNB1 syndrome as an ultra-rare disorder, supporting the qualitative prevalence class.
inheritance:
- name: Autosomal dominant, typically de novo
  expressivity: VARIABLE
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: CTNNB1-NDD is autosomal dominant and usually results from a de novo heterozygous pathogenic variant. Familial transmission and presumed parental germline mosaicism are documented. Apparently unaffected relatives can have subtle retinal vascular findings, so absence of reported symptoms does not establish absence of disease. Parental testing informs recurrence counseling; disease severity cannot be predicted reliably from that of another family member.
  evidence:
  - reference: PMID:35593792
    reference_title: CTNNB1 Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CTNNB1-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with CTNNB1-NDD inherited a CTNNB1 pathogenic variant from a parent.
    explanation: GeneReviews states the autosomal dominant, predominantly de novo inheritance and the rare inherited exception.
  - reference: PMID:36790797
    reference_title: Familial Exudative Vitreoretinopathy and Systemic Abnormalities in Patients With CTNNB1 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Among the eight families with CTNNB1 mutations, seven were de novo mutations, and one proband inherited the mutation from his asymptomatic mother.
    explanation: Seven of eight probands had de novo variants. The transmitting mother and sister in the remaining family had no visual complaints but showed mild retinal vascular abnormalities on detailed examination, demonstrating variable expressivity.
  - reference: PMID:36790797
    reference_title: Familial Exudative Vitreoretinopathy and Systemic Abnormalities in Patients With CTNNB1 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His mother and elder sister were asymptomatic with bilateral best corrected visual acuity of 20/20; however, supernumerary branches were detected in scanning laser ophthalmoscope (SLO) and fundus fluorescein angiography (FFA).
    explanation: Detailed examination detected retinal findings despite normal visual acuity and no reported symptoms.
pathophysiology:
- name: CTNNB1 Loss-of-Function and Beta-Catenin Haploinsufficiency
  biological_scale: MOLECULAR
  description: Heterozygous truncating, splice-disrupting and deletion alleles commonly reduce functional beta-catenin dosage. Nonsense-mediated RNA decay was demonstrated in lymphocyte-derived cells from two patients; it must not be assumed for every truncation. Missense variants and some expressed truncations can instead alter specific functions or inhibit wild-type protein. The 2025 cohort contained 88 distinct variants, 87 predicted to reduce function, but prediction, protein abundance and reporter activity are different measurements.
  genes:
  - preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  downstream:
  - target: Canonical Wnt/Beta-Catenin Transcriptional Deficit
    causal_link_type: DIRECT
    description: Reduced functional beta-catenin can lower Wnt-responsive transcription; the effect depends on allele and tissue.
  - target: Impaired Cadherin-Catenin Adherens Junction Adhesion
    causal_link_type: DIRECT
    description: Lower beta-catenin abundance reduces N-cadherin association in a germline heterozygous mouse.
  - target: Reduced Neural Progenitor Expansion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Conditional knockout models support a developmental consequence of beta-catenin loss; the magnitude in human heterozygotes remains uncertain.
  - target: Reduced Brain Sodium-Potassium ATPase Abundance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Germline heterozygous mice have lower ATPase alpha2 and alpha3 protein levels; the intervening regulatory mechanism remains unresolved.
  - target: Disorganization of Callosal Midline Guidance Cells
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Midline-restricted biallelic loss disrupts guidance populations in mice; translation to human heterozygosity is provisional.
  - target: Cardiac Developmental Wnt Signalling Disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: A developmental cardiac contribution is proposed from the clinical association, not established by a disease-specific experiment.
  - target: Retinal Vascular Norrin/Beta-Catenin Signalling Failure
    causal_link_type: DIRECT
    description: Endothelial beta-catenin deficiency reduces Norrin-responsive transcription.
  - target: Compromised Retinal Endothelial Junction Integrity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: CTNNB1 knockdown produces junctional defects in human retinal endothelial cells.
  genetic_context:
    gene:
      preferred_term: CTNNB1
      term:
        id: hgnc:2514
        label: CTNNB1
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: Heterozygous loss-of-function alleles are usually de novo; transmitted alleles and presumed parental mosaicism also occur. Nonsense-mediated decay is experimentally established for selected alleles.
  evidence:
  - reference: PMID:25326669
    reference_title: 'De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report on 16 additional individuals from 15 families in whom we newly identified de novo loss-of-function CTNNB1 mutations (six nonsense, five frameshift, one missense, two splice mutation, and one whole gene deletion).
    explanation: Documents the loss-of-function variant spectrum (nonsense, frameshift, splice, missense and whole-gene deletion) underlying the haploinsufficiency mechanism.
  - reference: PMID:24668549
    reference_title: A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Array CGH karyotyping showed a 333 kb de novo microdeletion on 3p22 covering the entire genomic sequence of a single gene, CTNNB1, which codes for β-catenin.
    explanation: The deletion encompasses the entire CTNNB1 gene and supports dosage sensitivity. The abstract describes a single complete gene; this does not exclude partial neighboring-gene involvement.
  - reference: PMID:40684264
    reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we identified 88 different variants of the CTNNB1 gene, 87 of which were predicted to lead to loss of CTNNB1 function
    explanation: The 2025 cohort reports 88 distinct variants and predicts loss of function for 87. This prediction does not establish an identical molecular mechanism for every allele.
  - reference: PMID:24614104
    reference_title: Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: This was observed in 2 of the 4 individuals using allele-specific cDNA amplification of EBV-treated patient lympho- cytes in the presence or absence of cycloheximide
    explanation: Nonsense-mediated decay was tested in patient-derived lymphocytes, not in the batface mouse. The finding supports haploinsufficiency for the tested human alleles.
- name: Variant-Specific Dominant-Negative Wnt Inhibition
  biological_scale: MOLECULAR
  description: 'Selected variants inhibit Wnt reporter activity when coexpressed with wild-type CTNNB1. HEK293T experiments identified Leu388Pro and Leu424Arg missense alleles; SK-N-MC experiments identified four truncating protein variants in eleven participants: Tyr333*, Gln193*, Ala317Valfs8* and Ser352fs*. The 2025 abstract refers to eleven variants, whereas the body distinguishes four protein variants. Overexpressed cDNA does not demonstrate escape from endogenous nonsense-mediated decay. These assays do not define a clinically validated subtype.'
  downstream:
  - target: Canonical Wnt/Beta-Catenin Transcriptional Deficit
    causal_link_type: DIRECT
    description: Wild-type cotransfection assays demonstrate reduced reporter output for this subset.
  evidence:
  - reference: PMID:36083290
    reference_title: Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants.
    explanation: TOPFlash reporter assays demonstrate reduced/dominant-negative WNT signalling output for disease-associated CTNNB1 missense variants.
  - reference: PMID:40684264
    reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: However, four variants (p.Y333∗, p.Q193∗, p.A317Vfs8∗, and p.S352fs∗) showed reduced levels of TOPFlash-luciferase activity suggesting a dominant negative mechanism
    explanation: The full-text cotransfection experiment identifies four truncating variants, rather than eleven distinct dominant-negative protein variants.
- name: Canonical Wnt/Beta-Catenin Transcriptional Deficit
  biological_scale: MOLECULAR
  description: 'Reduced beta-catenin-mediated transcription is demonstrated by Wnt-responsive reporter assays for many patient variants and by lower DKK1 and EN2 protein levels in a germline heterozygous mouse. It is not universal across every variant or assay: Gly575Arg had normal, reduced or increased reporter activity in three experimental contexts. Reporter activity alone cannot classify an allele or predict clinical severity.'
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: DECREASED
  downstream:
  - target: Reduced Neural Progenitor Expansion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Wnt-dependent progenitor regulation is implicated by conditional mouse experiments; human developmental intermediates remain incompletely established.
  evidence:
  - reference: PMID:25326669
    reference_title: 'De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Beta-catenin is a key downstream component of the canonical Wnt signaling pathway.
    explanation: Background statement establishing beta-catenin as the downstream effector of canonical Wnt signalling; the substantive functional claims for this node rest on the two IN_VITRO items below.
  - reference: PMID:36083290
    reference_title: Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants.
    explanation: TOPFlash reporter assays demonstrate reduced/dominant-negative WNT signalling output for disease-associated CTNNB1 missense variants.
  - reference: DOI:10.1038/s44321-024-00110-5
    reference_title: Inhibition of GSK3α,β rescues cognitive phenotypes in a preclinical mouse model of CTNNB1 syndrome
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Protein expression levels of two canonical Wnt target genes, DKK1 and EN2, are reduced in the β-cat het hippocampus
    explanation: The germline heterozygous mouse supplies in vivo evidence of reduced Wnt target proteins. LEF1 abundance was unchanged.
- name: Impaired Cadherin-Catenin Adherens Junction Adhesion
  biological_scale: MOLECULAR
  description: Beta-catenin participates in cadherin-associated adhesion complexes. The batface Thr653Lys allele reduces cadherin binding despite normal beta-catenin abundance and enhanced Wnt activity; it is not a simple dosage-loss model. A separate germline heterozygous deletion model also shows reduced beta-catenin association with N-cadherin. These results support an adhesion contribution while leaving its relative importance in individual human alleles unresolved.
  biological_processes:
  - preferred_term: adherens junction organization
    term:
      id: GO:0034332
      label: adherens junction organization
    modifier: DECREASED
  molecular_functions:
  - preferred_term: cadherin binding
    term:
      id: GO:0045296
      label: cadherin binding
    modifier: DECREASED
  cellular_components:
  - preferred_term: adherens junction
    term:
      id: GO:0005912
      label: adherens junction
  downstream:
  - target: Impaired Dendritic Arborization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced adhesion and abnormal dendritic maturation coexist in batface neurons; a contribution is supported, but exclusive mediation is not established.
  evidence:
  - reference: PMID:24614104
    reference_title: Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The mouse mutant, designated batface (Bfc), carries a Thr653Lys substitution in the C-terminal armadillo repeat of β-catenin and displayed a reduced affinity for membrane-associated cadherins.
    explanation: Demonstrates in vivo that a disease-modelling beta-catenin substitution reduces binding to membrane cadherins, the adhesion arm of the mechanism.
  - reference: DOI:10.1038/s44321-024-00110-5
    reference_title: Inhibition of GSK3α,β rescues cognitive phenotypes in a preclinical mouse model of CTNNB1 syndrome
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: β-cat association with N-cadherin is reduced in β-cat het mice, relative to littermate controls
    explanation: Co-immunoprecipitation demonstrates reduced association in the germline haploinsufficient mouse independently of the batface allele.
- name: Reduced Neural Progenitor Expansion
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: Conditional neural beta-catenin knockout models show reduced progenitor proliferation and increased apoptosis. These severe tissue-specific perturbations suggest a developmental route to reduced brain growth but do not demonstrate neuronal loss in living patients. Human microcephaly can be congenital or acquired, and no single timing or mechanism explains every case.
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  downstream:
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced developmental brain growth is a plausible contributor; congenital and postnatal microcephaly both occur.
  evidence:
  - reference: PMID:39833474
    reference_title: CTNNB1 syndrome mouse models.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Lower proliferation and increased apoptosis
    explanation: The mouse-model review describes neural conditional knockout experiments. The evidence is a secondary summary of models, not direct human histology.
- name: Impaired Dendritic Arborization
  biological_scale: CELLULAR
  description: Batface cortical cultures develop reduced dendritic branching at later culture stages, despite initially increased neurite outgrowth. Separately, siRNA reduction of Ctnnb1 in wild-type mouse cortical cultures reduces neurite extension. These model observations support impaired neuronal maturation; they do not establish an identical defect in every human neuron.
  biological_processes:
  - preferred_term: dendrite morphogenesis
    term:
      id: GO:0048813
      label: dendrite morphogenesis
    modifier: DECREASED
  downstream:
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Altered dendritic development offers a model-supported contribution to cognitive impairment; the intervening human circuit effects are unresolved.
  evidence:
  - reference: PMID:24614104
    reference_title: Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In association with this decreased cadherin interaction, we found that the mutation results in decreased intrahemispheric connections, with deficits in dendritic branching, long-term potentiation, and cognitive function.
    explanation: The batface model links reduced cadherin interaction with dendritic, connectivity and plasticity deficits; it does not establish those defects in human neurons.
  - reference: PMID:24614104
    reference_title: Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Transfection of this siRNA decreased β-catenin expression by 54% in WT cultures
    explanation: A separate knockdown experiment in wild-type mouse cultures approximates a dosage reduction. The measurement was gene expression; it should not be described as a protein assay.
- name: Impaired Hippocampal Synaptic Potentiation
  biological_scale: CELLULAR
  description: Hippocampal slices from batface heterozygous mice show reduced long-term potentiation after tetanic or theta-burst stimulation. Basal transmission and paired-pulse measures were not significantly changed. This supports a selective plasticity defect in an adhesion-impaired, Wnt-activating mouse allele, rather than a direct measurement of human cognition.
  downstream:
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The mouse plasticity deficit provides a possible contribution to learning impairment, without proving its prevalence or magnitude in humans.
  evidence:
  - reference: PMID:24614104
    reference_title: Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: long-term potentiation (LTP) induced by either tetanic (Figure 8F) or θ-burst (Figure 8G) stimulation was significantly reduced in slices from Bfc/+ animals
    explanation: Direct ex vivo electrophysiology in batface mice demonstrates impaired potentiation.
- name: Reduced Brain Sodium-Potassium ATPase Abundance
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: In germline Ctnnb1 heterozygous mice, hippocampal and frontal cortical ATPase alpha2 and alpha3 protein levels are reduced, whereas alpha1 is unchanged. Their role in the excitability phenotype is plausible but not isolated by a pump-specific rescue, and this molecular finding has not been established in patients.
  downstream:
  - target: Altered Hippocampal Neuronal Excitability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced activity-dependent ion-gradient regulation is proposed to contribute to the electrophysiological changes; parallel rescue by GSK3 inhibition is not proof of exclusive mediation.
  evidence:
  - reference: DOI:10.1038/s44321-024-00110-5
    reference_title: Inhibition of GSK3α,β rescues cognitive phenotypes in a preclinical mouse model of CTNNB1 syndrome
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Na/K ATPases α2 and α3 catalytic subunit levels are reduced, whereas Na/K ATPase α1 catalytic subunit levels are not altered in the β-cat het hippocampus and frontal cortex, compared to wild-type littermates
    explanation: The primary mouse study directly reports reduced alpha2 and alpha3 abundance; alpha1 is unchanged in the full figure legend.
- name: Altered Hippocampal Neuronal Excitability
  biological_scale: CELLULAR
  description: Dentate gyrus granule cells in germline heterozygous mice have a depolarized resting potential and lower firing threshold, but lower maximal firing rates under strong current injection. This mixed phenotype should not be summarized as uniformly increased or decreased excitability. Dual GSK3 inhibition improves several measures without normalizing the resting potential. Equivalent electrophysiological changes have not been established in patients.
  downstream:
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The mouse functional changes offer a potential route to altered learning and memory; the human intermediates remain unresolved.
  evidence:
  - reference: DOI:10.1038/s44321-024-00110-5
    reference_title: Inhibition of GSK3α,β rescues cognitive phenotypes in a preclinical mouse model of CTNNB1 syndrome
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Taken together, the functional changes suggest reduced threshold for excitability and potential depolarization block.
    explanation: The authors interpret patch-clamp recordings as a reduced threshold with possible depolarization block, not a simple global hyperexcitability state.
- name: Disorganization of Callosal Midline Guidance Cells
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: In Lmx1a-lineage mouse models, biallelic beta-catenin loss or constitutive stabilization disrupts the glial wedge, indusium griseum glia and midline guidance-neuron organization. The similar gain- and loss-of-function phenotypes leave the relative roles of transcription and adhesion unresolved. Midline heterozygous deletion did not produce a callosal defect, limiting direct extrapolation to human haploinsufficiency.
  downstream:
  - target: Failure of Callosal Axon Midline Crossing
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Disorganized midline guidance populations contribute to failed crossing and Probst bundles in the conditional mouse models.
  evidence:
  - reference: PMID:40894864
    reference_title: An evolutionarily conserved role for CTNNB1/β-CATENIN in regulating the development of the corpus callosum.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: These results suggest that misoriented and dysmorphic midline glial cells impair axonal guidance across the midline in Ctnnb1 LOF and GOF brains.
    explanation: Cell-type-specific mouse experiments identify the midline guidance population as a mechanistic contributor.
  - reference: PMID:40894864
    reference_title: An evolutionarily conserved role for CTNNB1/β-CATENIN in regulating the development of the corpus callosum.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We do not find a CC phenotype in Lmx1aCre; Ctnnb1 loxP/+ mice, indicating that the threshold requirement for CTNNB1 for CC crossing is met in heterozygote mice.
    explanation: The negative heterozygote result limits the match between this model and human CTNNB1-NDD.
- name: Failure of Callosal Axon Midline Crossing
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: Conditional Lmx1a-lineage gain- and biallelic loss-of-function models show near-complete failure of callosal crossing and Probst bundles while the anterior commissure remains intact. Five patients from the GenPhe cohort had abnormal callosal MRI morphology, but equivalent cellular defects were not demonstrated in them.
  downstream:
  - target: Hypoplasia of the Corpus Callosum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The mouse crossing defect supplies a candidate developmental explanation for human callosal abnormalities, with an explicit genotype and severity gap.
  evidence:
  - reference: PMID:40894864
    reference_title: An evolutionarily conserved role for CTNNB1/β-CATENIN in regulating the development of the corpus callosum.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Immunostaining for L1CAM, an adhesion molecule enriched in axonal tracts, reveals a near-complete failure of CC crossing at the midline in both Ctnnb1 LOF and GOF brains
    explanation: Axonal staining directly demonstrates failed crossing in the conditional mouse models.
- name: Developmental Motor Circuit Dysfunction
  biological_scale: TISSUE
  description: A developmental motor-circuit contribution is inferred from the combined spasticity, dystonia and weakness phenotype, but the responsible human pathways and lesion sites have not been established. Clinical progression varies; a selected movement-disorder series reported later cervical dystonia in three patients, whereas a broader cohort already showed dystonia across ages. The clinical diagnosis of cerebral palsy can coexist with CTNNB1-NDD. Specific corticospinal, basal-ganglia or brainstem pathology must not be inferred from these signs alone.
  downstream:
  - target: Spastic Diplegia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Developmental motor-network dysfunction is a proposed basis for the lower-limb tone abnormality.
  - target: Dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: An altered motor-network contribution is plausible; the precise human circuit mechanism is unresolved.
  evidence:
  - reference: PMID:39067319
    reference_title: 'Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 13 patients presented progressive lower limbs hypertonia without overt pyramidal signs. Five patients reported exaggerated startle, three developed upper body (prominently cervical) dystonia in the second decade, with or without bradykinesia (2/13).
    explanation: Systematic movement-disorder phenotyping of 14 patients establishing the progressive lower-limb hypertonia, startle and later dystonia/bradykinesia components.
  - reference: PMID:39067319
    reference_title: 'Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CTNNB1-syndrome is associated with a peculiar, but recognizable movement disorder phenotype, encompassing complex gait disorders with progressive lower limb hypertonia, exaggerated startle, and possible occurrence in the second decade of life of upper body dystonia with or without bradykinesia.
    explanation: The clinical series establishes a movement-disorder pattern; it does not demonstrate an anatomical lesion or dopaminergic deficiency.
  - reference: PMID:36083290
    reference_title: Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP).
    explanation: Establishes that the CTNNB1 motor phenotype is the commonest recurrent monogenic cause of a cerebral palsy diagnosis.
  mechanism_confidence: PROVISIONAL
- name: Retinal Vascular Norrin/Beta-Catenin Signalling Failure
  biological_scale: MOLECULAR
  description: In retinal endothelial experimental systems, CTNNB1 knockdown reduces Norrin-responsive target transcripts. Truncating variants reduce reporter activity. This is one mechanistic arm of retinal disease and does not establish that every CTNNB1 allele has identical activity across assays.
  cell_types:
  - preferred_term: retinal blood vessel endothelial cell
    term:
      id: CL:0002585
      label: retinal blood vessel endothelial cell
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: DECREASED
  downstream:
  - target: Reduced Retinal Endothelial Proliferation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced beta-catenin transcriptional output is accompanied by impaired proliferation in knockdown cells; the full target-gene chain is unresolved.
  evidence:
  - reference: PMID:35361685
    reference_title: Novel truncating variants in CTNNB1 cause familial exudative vitreoretinopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: These variants caused truncation and degradation of β-catenin that reduced Norrin/β-catenin signalling activity. Additionally, knockdown (KD) of CTNNB1 in HRECs led to diminished mRNA levels of Norrin/β-catenin targeted genes, reduced cell proliferation and compromised junctional integrity.
    explanation: Mechanistically links CTNNB1 truncating variants to reduced Norrin/beta-catenin signalling, endothelial proliferation and junctional integrity in human retinal microvascular endothelial cells.
- name: Reduced Retinal Endothelial Proliferation
  biological_scale: CELLULAR
  description: CTNNB1 knockdown in primary human retinal microvascular endothelial cells reduces proliferation. Endothelial heterozygous deletion in mice produces FEVR-like disease, supporting a retinal vascular role while not isolating proliferation from other endothelial effects.
  cell_types:
  - preferred_term: retinal blood vessel endothelial cell
    term:
      id: CL:0002585
      label: retinal blood vessel endothelial cell
  downstream:
  - target: Exudative Vitreoretinopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced endothelial expansion contributes to incomplete retinal vascular development; additional junctional effects may contribute.
  evidence:
  - reference: PMID:35361685
    reference_title: Novel truncating variants in CTNNB1 cause familial exudative vitreoretinopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: These variants caused truncation and degradation of β-catenin that reduced Norrin/β-catenin signalling activity. Additionally, knockdown (KD) of CTNNB1 in HRECs led to diminished mRNA levels of Norrin/β-catenin targeted genes, reduced cell proliferation and compromised junctional integrity.
    explanation: Mechanistically links CTNNB1 truncating variants to reduced Norrin/beta-catenin signalling, endothelial proliferation and junctional integrity in human retinal microvascular endothelial cells.
- name: Compromised Retinal Endothelial Junction Integrity
  biological_scale: CELLULAR
  description: CTNNB1 knockdown compromises junctional integrity in primary human retinal microvascular endothelial cells. This cellular phenotype provides an adhesion-related contribution to retinal vascular dysfunction distinct from proliferation; the relative contributions to human FEVR remain unresolved.
  cell_types:
  - preferred_term: retinal blood vessel endothelial cell
    term:
      id: CL:0002585
      label: retinal blood vessel endothelial cell
  downstream:
  - target: Exudative Vitreoretinopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Defective endothelial junctions offer an additional route to retinal vascular dysfunction.
  evidence:
  - reference: PMID:35361685
    reference_title: Novel truncating variants in CTNNB1 cause familial exudative vitreoretinopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: These variants caused truncation and degradation of β-catenin that reduced Norrin/β-catenin signalling activity. Additionally, knockdown (KD) of CTNNB1 in HRECs led to diminished mRNA levels of Norrin/β-catenin targeted genes, reduced cell proliferation and compromised junctional integrity.
    explanation: Mechanistically links CTNNB1 truncating variants to reduced Norrin/beta-catenin signalling, endothelial proliferation and junctional integrity in human retinal microvascular endothelial cells.
- name: Cardiac Developmental Wnt Signalling Disruption
  biological_scale: TISSUE
  description: Congenital cardiac anomalies are reported in CTNNB1-NDD, and beta-catenin is expressed in the heart. A developmental Wnt contribution is plausible, but the cited clinical series does not establish a specific second-heart-field, valve or outflow-tract mechanism.
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Congenital Heart Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: A beta-catenin-dependent cardiac developmental contribution is proposed from the clinical association; its molecular intermediates remain unestablished.
  evidence:
  - reference: PMID:37455656
    reference_title: 'Congenital heart defects in CTNNB1 syndrome: Raising clinical awareness.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CTNNB1 is highly expressed in brain as well as in other tissues, including heart.
    explanation: Background statement of cardiac CTNNB1 expression; it makes a heart-development contribution plausible but does not demonstrate it, consistent with the PROVISIONAL mechanism confidence of this node.
  - reference: PMID:37455656
    reference_title: 'Congenital heart defects in CTNNB1 syndrome: Raising clinical awareness.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Notably, five patients showed congenital heart anomalies including absent pulmonary valve with intact ventricular septum, atrioventricular canal with hypoplastic aortic arch, tetralogy of Fallot, and mitral valve prolapse.
    explanation: Documents the spectrum of congenital heart defects observed in a dedicated CTNNB1 cardiac series.
phenotypes:
- category: Cognitive
  name: Intellectual Disability
  description: Cognitive impairment is a central feature and ranges from mild to profound. Verbal abilities can be stronger than visuospatial and logical reasoning. Visual and fine motor impairments may lower test performance, and selected cognitive domains can fall within the average range; individual standardized assessment is needed.
  diagnostic: true
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:35593792
    reference_title: CTNNB1 Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CTNNB1 neurodevelopmental disorder (CTNNB1-NDD) is characterized in all individuals by mild-to-profound cognitive impairment
    explanation: The earlier GeneReviews synthesis describes cognitive impairment in all reported individuals; newer direct assessments show wider variation, so this is not used to assert an obligatory formal ID diagnosis.
  - reference: PMID:40145647
    reference_title: 'Cognitive and Adaptive Functioning of CTNNB1 Syndrome Patients: A Comparison With Autism Spectrum Disorder and Cerebral Palsy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: No cognitive differences were found among verbal tasks between groups, even though CTNNB1 syndrome patients obtained significantly lower scores in visuospatial and logical tasks.
    explanation: Characterises the cognitive profile, with disproportionate visuospatial and logical-reasoning weakness.
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These data suggest that cognitive functioning within this population is more variable than previously appreciated, and it is important to understand individual strengths and weaknesses to maximize cognitive and learning interventions.
    explanation: The in-person study qualifies older descriptions of universal intellectual disability; no single frequency band is assigned to formally measured intellectual disability.
- category: Developmental
  name: Global Developmental Delay
  description: Motor and language milestones are delayed from infancy. Half of the 32 participants in one cross-sectional cohort walked without an assistive device at assessment; this is not an estimate of eventual lifetime ambulation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:25326669
    reference_title: 'De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients have ID, motor delay and speech impairment (both mostly severe) and abnormal muscle tone (truncal hypotonia and distal hypertonia/spasticity).
    explanation: The 16-person cohort reports motor delay and speech impairment in all individuals; small ascertained cohorts do not establish universality.
  - reference: PMID:36153650
    reference_title: Genetic and clinical characteristics of 24 mainland Chinese patients with CTNNB1 loss-of-function variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: developmental delay/intellectual disability (100%), motor delay (100%), speech impairment (100%)
    explanation: 'The full-text denominators vary by assessment: developmental delay/ID was recorded in 18 assessed individuals, and speech was assessed in five age-eligible children. These percentages must not be applied to all 24 participants.'
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Half of individuals walked without an assistive device.
    explanation: Quantifies gross-motor outcome in a deeply phenotyped cohort of 32 individuals.
- category: Neurological
  name: Severe Speech Impairment
  description: Expressive speech is severely limited or absent in most individuals; receptive language is typically better preserved than expressive, and augmentative and alternative communication is often required.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:25326669
    reference_title: 'De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients have ID, motor delay and speech impairment (both mostly severe)
    explanation: Speech impairment, mostly severe, was present in all 16 individuals of this cohort. The band is held at VERY_FREQUENT rather than OBLIGATE given the modest cohort sizes underlying the 100% figures.
  - reference: PMID:36153650
    reference_title: Genetic and clinical characteristics of 24 mainland Chinese patients with CTNNB1 loss-of-function variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: speech impairment (100%)
    explanation: The full text reports speech impairment in all five children assessed at age three years or older, not all 24 participants.
  - reference: PMID:36293418
    reference_title: 'Correlation between Phenotype and Genotype in CTNNB1 Syndrome: A Systematic Review of the Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The CTNNB1 Syndrome is a rare neurodevelopmental disorder associated with developmental delay, intellectual disability, and delayed or absent speech.
    explanation: A systematic review of the published literature lists delayed or absent speech as a defining feature.
- category: Neurological
  name: Truncal Hypotonia
  description: Central/axial hypotonia is evident in infancy and early childhood and characteristically coexists with distal hypertonia, producing the hypotonic-trunk/spastic-limb pattern typical of the disorder.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Truncal hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: PMID:35593792
    reference_title: CTNNB1 Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Other common findings include truncal hypotonia, peripheral spasticity, dystonia, behavior problems, microcephaly, and refractive errors and strabismus.
    explanation: The abstract describes a common feature; the direct 96.9% cohort measurement below supplies the assigned frequency band.
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Most individuals had truncal hypotonia, muscle weakness, hypertonia, dystonia, microcephaly, and many had a history of tethered cord.
    explanation: Deep phenotyping of 32 individuals confirms truncal hypotonia in most.
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| - Truncal hypotonic | 96.9 |'
    explanation: Table 1 reports axial hypotonia on examination in 96.9% of the 32 conference participants, supporting VERY_FREQUENT in this selected cohort.
- category: Neurological
  name: Spastic Diplegia
  description: Progressive hypertonia and spasticity predominantly of the lower limbs develops after an initial hypotonic phase, often without overt pyramidal signs, and is the feature that most commonly leads to a cerebral palsy diagnosis.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Spastic diplegia
    term:
      id: HP:0001264
      label: Spastic diplegia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:39067319
    reference_title: 'Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 13 patients presented progressive lower limbs hypertonia without overt pyramidal signs.
    explanation: 13 of 14 systematically assessed patients had progressive lower-limb hypertonia, supporting a very frequent, progressive spastic diplegia.
- category: Neurological
  name: Dystonia
  description: Dystonia can affect the limbs or upper body. A selected movement-disorder series described cervical-predominant dystonia emerging in the second decade in three individuals; broader cohorts identify dystonia more frequently, so that presentation does not define its full spectrum.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:35593792
    reference_title: CTNNB1 Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Other common findings include truncal hypotonia, peripheral spasticity, dystonia, behavior problems, microcephaly, and refractive errors and strabismus.
    explanation: GeneReviews lists dystonia among the common findings, supporting a FREQUENT band.
  - reference: PMID:39067319
    reference_title: 'Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: three developed upper body (prominently cervical) dystonia in the second decade, with or without bradykinesia (2/13)
    explanation: Characterises the anatomical distribution and second-decade onset of dystonia. The low cross-sectional fraction here (3/14) reflects the age-dependence of the upper-body form specifically; overall dystonia frequency across cohorts is higher (see the 87.5% figure below), so the band is set from the pooled picture.
  - reference: PMID:36153650
    reference_title: Genetic and clinical characteristics of 24 mainland Chinese patients with CTNNB1 loss-of-function variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: dystonia (87.5%) and microcephaly (69.6%)
    explanation: In a 24-patient Chinese cohort dystonia was present in 87.5%; together with the 3/14 upper-body figure from Garone and the GeneReviews "common findings" wording, a FREQUENT band is the conservative pooled estimate.
- category: Neurological
  name: Bradykinesia
  description: Bradykinesia accompanies dystonia in a minority of individuals in the second decade, indicating extrapyramidal involvement.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Bradykinesia
    term:
      id: HP:0002067
      label: Bradykinesia
  evidence:
  - reference: PMID:39067319
    reference_title: 'Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: three developed upper body (prominently cervical) dystonia in the second decade, with or without bradykinesia (2/13)
    explanation: Bradykinesia was documented in 2 of 13 patients with motor disorders, consistent with an OCCASIONAL (5-29%) band.
- category: Neurological
  name: Exaggerated Startle Response
  description: Unexpected stimuli may provoke exaggerated startle with stiff falls, injury and fear of walking. Electrophysiology in one patient supported a nonepileptic startle response, and symptomatic benefit from benzodiazepines was reported in that individual. The selected 12-case series does not estimate population prevalence.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Exaggerated startle response
    term:
      id: HP:0002267
      label: Exaggerated startle response
  evidence:
  - reference: PMID:36419413
    reference_title: 'Startle Disease: An Overlooked Symptom of CTNNB1-Related Neurodevelopmental Disorder With Spastic Diplegia and Visual Defects.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All 12 patients presented exaggerated startle responses to an unexpected stimulus. They provoked falls in 8 patients, causing injuries in 3, and 3 patients were afraid to walk. This startle disorder corresponds to atypic hyperekplexia.
    explanation: Case series characterising the startle phenotype as atypical hyperekplexia with injurious falls.
  - reference: PMID:39067319
    reference_title: 'Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Five patients reported exaggerated startle
    explanation: Exaggerated startle in 5 of 14 systematically assessed patients (approximately 36%), supporting a FREQUENT band.
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| - Startle | 59.4 |'
    explanation: Startle was elicited on examination in 59.4% of the 32-person cohort, supporting FREQUENT without deriving a prevalence estimate from the startle-selected case series.
- category: Neurological
  name: Muscle Weakness
  description: Reduced muscle strength contributes to delayed ambulation and reduced gross motor function independent of tone abnormalities.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Most individuals had truncal hypotonia, muscle weakness, hypertonia, dystonia, microcephaly, and many had a history of tethered cord.
    explanation: This qualitative summary describes weakness in most of the 32 conference participants; the 90.6% table measurement supplies the VERY_FREQUENT band.
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| - Muscle weakness | 90.6 |'
    explanation: Table 1 reports weakness in 90.6% of 32 examined participants, supporting VERY_FREQUENT in this selected cohort.
- category: Neurological
  name: Microcephaly
  description: Microcephaly can be congenital or develop postnatally. Its frequency varies with cohort and age; head size was below the study threshold in 60% of participants measured in the 2024 in-person cohort. Postnatal progression occurs in some individuals but is not obligatory. A 2025 caregiver cohort reported microcephaly in 70.1%; earlier reports varied with ascertainment.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:25326669
    reference_title: 'De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The craniofacial phenotype comprised microcephaly (typically -2 to -4 SD) in 12 of 16
    explanation: Quantifies microcephaly in 12 of 16 individuals (75%) with the typical severity range, supporting a FREQUENT band.
  - reference: PMID:24668549
    reference_title: A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Postnatal microcephaly and progressive ataxia and spasticity appeared later.
    explanation: This individual developed postnatal microcephaly. Other patients have congenital microcephaly, so this case does not define universal onset.
  - reference: PMID:36153650
    reference_title: Genetic and clinical characteristics of 24 mainland Chinese patients with CTNNB1 loss-of-function variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: dystonia (87.5%) and microcephaly (69.6%)
    explanation: Independently quantifies microcephaly at 69.6% in a 24-patient cohort, within the FREQUENT (30-79%) band.
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We reported microcephaly in 60% at the time of assessment, by direct in-person head circumference measurement.
    explanation: The in-person cohort supports FREQUENT; congenital and postnatal onset are both described in the broader literature.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: is often acquired but may be present at birth.
    explanation: GeneReviews explicitly recognizes congenital as well as acquired microcephaly.
- category: Ophthalmological
  name: Exudative Vitreoretinopathy
  description: A retinal vascular phenotype indistinguishable from familial exudative vitreoretinopathy (FEVR), with incomplete peripheral retinal vascularisation, exudation, and in severe cases traction and retinal detachment. It is frequently occult on office ophthalmoscopy and may only be revealed by ultra-widefield fluorescein angiography, sometimes under anaesthesia. Estimates range from 7.1% in a remote caregiver cohort to 5/11 in a small angiography series; examination method and selection materially affect detection.
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Exudative vitreoretinopathy
    term:
      id: HP:0030490
      label: Exudative vitreoretinopathy
  evidence:
  - reference: PMID:35593792
    reference_title: CTNNB1 Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: in up to 39% of reported individuals by exudative vitreoretinopathy, an ophthalmologic finding consistent with familial exudative vitreoretinopathy (FEVR)
    explanation: GeneReviews reports exudative vitreoretinopathy in up to 39% of individuals, placing the frequency in the FREQUENT (30-79%) band.
  - reference: PMID:39145965
    reference_title: Vitreoretinopathy in Asymptomatic Children With CTNNB1 Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: FEVR was present in 5 of 11 patients and in 9 eyes. The presence of disease requiring treatment was identified in 6 eyes, including 1 retinal detachment.
    explanation: In children with previously normal office retinal examinations, angiography detected FEVR in 5 of 11, including treatment-requiring disease and a retinal detachment.
- category: Ophthalmological
  name: Strabismus
  description: Strabismus is very common and frequently requires surgical correction.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:39145965
    reference_title: Vitreoretinopathy in Asymptomatic Children With CTNNB1 Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A total of 9 patients had a diagnosis of strabismus, and 5 patients had undergone strabismus surgery.
    explanation: The abstract reports strabismus in 9/11. The full-text body gives a different surgery count; no uniform surgical-treatment rate is inferred.
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Visual problems included strabismus, hyperopia, and familial exudative vitreoretinopathy.
    explanation: Confirms strabismus among the visual problems in a deeply phenotyped cohort.
- category: Ophthalmological
  name: Refractive Error
  description: Hyperopia, myopia and astigmatism occur. Frequencies vary across series. The combined statement that nearly all patients require care for refractive error and strabismus does not establish near-universal refractive error by itself.
  phenotype_term:
    preferred_term: Abnormality of refraction
    term:
      id: HP:0000539
      label: Abnormality of refraction
  evidence:
  - reference: PMID:39145965
    reference_title: Vitreoretinopathy in Asymptomatic Children With CTNNB1 Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: nearly all patients with CTNNB1 syndrome required ophthalmic care for refractive error and strabismus
    explanation: This combined care statement supports ophthalmic involvement, but does not supply a separate frequency for refractive error.
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Visual problems included strabismus, hyperopia, and familial exudative vitreoretinopathy.
    explanation: Identifies hyperopia as the characteristic refractive error in this disorder.
- category: Behavioral
  name: Behavioral Problems
  description: Behavioural difficulties are common and include autistic-like behaviour, aggression, and prominent externalising problems relative to comparison neurodevelopmental groups.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Based upon the Child Behavior Checklist total problems score, the majority (65%) of individuals had behavioral challenges.
    explanation: The 65% estimate concerns the 17 participants with a completed Child Behavior Checklist, not all 32 enrolled individuals.
  - reference: PMID:40145647
    reference_title: 'Cognitive and Adaptive Functioning of CTNNB1 Syndrome Patients: A Comparison With Autism Spectrum Disorder and Cerebral Palsy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Externalizing problems were more prevalent in the CTNNB1 syndrome group compared with the control groups.
    explanation: Characterises the behavioural profile as disproportionately externalising relative to ASD and cerebral palsy comparison groups.
  - reference: PMID:36153650
    reference_title: Genetic and clinical characteristics of 24 mainland Chinese patients with CTNNB1 loss-of-function variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we discovered that 20 patients (83.3%) exhibited various behavioral abnormalities
    explanation: The Chinese cohort reports behavioral abnormalities in 20/24; its broad assessment differs from the Child Behavior Checklist and the estimates are not pooled.
- category: Behavioral
  name: Autistic Behavior
  description: Autistic traits and formal autism diagnoses are reported, but screening traits and diagnoses are distinct. A prior ASD diagnosis was reported in 11/32 (34.4%) in the conference cohort; other studies use different assessment methods.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:36293418
    reference_title: 'Correlation between Phenotype and Genotype in CTNNB1 Syndrome: A Systematic Review of the Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: behavioral abnormalities (e.g., autistic-like or aggressive behavior)
    explanation: The systematic review establishes autistic-like behavior in the clinical spectrum; a direct cohort supplies a formal diagnosis frequency separately.
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '- Autism spectrum disorder | 34.4'
    explanation: The conference cohort table reports a prior ASD diagnosis in 34.4%; this is not interchangeable with screening traits.
- category: Craniofacial
  name: Thin Upper Lip Vermilion
  description: A thin upper lip is part of the variable facial gestalt. It was reported in 78.0% of the 2025 caregiver cohort and 45.8% of the 24-person Chinese cohort; both estimates support FREQUENT.
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Thin upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  evidence:
  - reference: PMID:40684264
    reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a thin upper lip (78.0%; 95% CI, 70.0%–84.3%)
    explanation: The remote study of 127 participants reports thin upper lip in 78.0%, within FREQUENT; caregiver ascertainment limits generalizability.
  - reference: PMID:36153650
    reference_title: Genetic and clinical characteristics of 24 mainland Chinese patients with CTNNB1 loss-of-function variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: long philtrum (45.8%) and thin upper lip (45.8%)
    explanation: Thin upper lip occurred in 11/24 individuals (45.8%) in the Chinese cohort, also within FREQUENT; the two cohorts are not pooled.
- category: Craniofacial
  name: Broad Nasal Tip
  description: A broad nasal tip was reported in 96.1% of the 2025 caregiver cohort. Wide nasal bridge and bulbous nose reported in other studies are related but distinct assessments.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Broad nasal tip
    term:
      id: HP:0000455
      label: Broad nasal tip
  evidence:
  - reference: PMID:40684264
    reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a broad nasal tip (96.1%; 95% CI, 91.1%–98.3%)
    explanation: The 2025 caregiver cohort reports this specifically defined facial feature; frequencies from differently defined nasal findings are not pooled.
- category: Integumentary
  name: Sparse Fair Hair
  description: Thin or sparse hair occurs with variable pigmentation. The 2025 remote cohort reported thin hair in 66.9%, whereas sparse hair was reported in 3/24 of a Chinese cohort; these are related but nonidentical assessments.
  phenotype_term:
    preferred_term: Sparse hair
    term:
      id: HP:0008070
      label: Sparse hair
  evidence:
  - reference: PMID:24668549
    reference_title: A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Initial clinical evaluation revealed an overall developmental delay, mildly dysmorphic features, thin, sparse fair hair, and fair skin.
    explanation: Documents the thin, sparse, fair hair phenotype in the index CTNNB1 whole-gene-deletion patient.
  - reference: PMID:40684264
    reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: thin hair (66.9%; 95% CI, 58.4%–74.5%)
    explanation: Thin hair was common in the remote cohort; this does not establish the frequency of fair pigmentation or identically defined sparse hair.
- category: Gastrointestinal
  name: Feeding Difficulties
  description: Feeding difficulties can include swallowing problems and oromotor dyspraxia and may contribute to aspiration or inadequate weight gain. GeneReviews tabulates feeding difficulties in 14 of 35 assessed individuals.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:35593792
    reference_title: CTNNB1 Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Less common features include intrauterine growth restriction, feeding difficulties, and scoliosis.
    explanation: GeneReviews classifies feeding difficulties among the less common features.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Short stature 8/39 (20.5%) Feeding difficulties 14/35 (40%) Scoliosis 6/30 (20%)
    explanation: The GeneReviews table reports 14/35 (40%), supporting FREQUENT. Its abstract wording less common is relative to the core manifestations.
- category: Growth
  name: Intrauterine Growth Restriction
  description: Prenatal growth restriction is a less common feature of the disorder.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:35593792
    reference_title: CTNNB1 Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Less common features include intrauterine growth restriction, feeding difficulties, and scoliosis.
    explanation: GeneReviews lists intrauterine growth restriction among the less common features.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: IUGR 10/44 (22.7%) Short stature 8/39 (20.5%)
    explanation: The GeneReviews full-text table supplies the denominator for prenatal growth restriction.
- category: Skeletal
  name: Scoliosis
  description: Scoliosis is a less common feature and warrants surveillance given the underlying tone abnormalities and reduced ambulation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:35593792
    reference_title: CTNNB1 Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Less common features include intrauterine growth restriction, feeding difficulties, and scoliosis.
    explanation: GeneReviews lists scoliosis among the less common features.
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '- Scoliosis | 15.6'
    explanation: The conference cohort table reports scoliosis in 15.6%.
- category: Neurological
  name: Tethered Cord
  description: A history of tethered cord was reported in 25% of a 32-person conference cohort. Selection may inflate this estimate. Progressive weakness, sensory changes, scoliosis or foot deformity can prompt assessment for an additional spinal contributor to motor impairment.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Tethered cord
    term:
      id: HP:0002144
      label: Tethered cord
  evidence:
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Most individuals had truncal hypotonia, muscle weakness, hypertonia, dystonia, microcephaly, and many had a history of tethered cord.
    explanation: Documents a history of tethered cord in many of 32 individuals.
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Tethered cord was reported in 25% of participants, which is higher than other studies
    explanation: The 32-person conference cohort reports 25%, within OCCASIONAL; the authors explicitly note possible ascertainment bias.
- category: Cardiovascular
  name: Congenital Heart Defect
  description: Congenital heart anomalies including absent pulmonary valve with intact ventricular septum, atrioventricular canal with hypoplastic aortic arch, tetralogy of Fallot and mitral valve prolapse occur at a higher rate than historically appreciated, supporting dedicated cardiac assessment at diagnosis.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:37455656
    reference_title: 'Congenital heart defects in CTNNB1 syndrome: Raising clinical awareness.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report on a new series of 19 NEDSDV patients (mean age 10.3 years), nine of whom bearing novel CTNNB1 variants. Notably, five patients showed congenital heart anomalies
    explanation: Five of 19 patients (26%) had congenital heart anomalies, consistent with an OCCASIONAL (5-29%) band.
  - reference: PMID:37455656
    reference_title: 'Congenital heart defects in CTNNB1 syndrome: Raising clinical awareness.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: While congenital heart defects had occasionally been reported so far, the present findings configure a higher rate of cardiac anomalies, suggesting dedicated heart examination to NEDSDV clinical management.
    explanation: Supports the recommendation for dedicated cardiac examination and the higher-than-expected rate.
- name: Sleep Disturbance
  category: Neurologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  description: Sleep problems include difficulty initiating sleep, short sleep duration and parasomnias. Parent-reported problems affected 56.3% in the 2025 remote cohort. A sleep-screening questionnaire score alone does not diagnose obstructive sleep apnea.
  evidence:
  - reference: PMID:40684264
    reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Parents also reported that 56.3% of children living with the CTNNB1 syndrome (95% CI, 47.6%–64.7%) had sleeping problems.
    explanation: The 127-participant remote caregiver study supports FREQUENT. Recruitment and parent reporting limit generalizability.
- name: Gait Ataxia
  category: Neurological
  phenotype_term:
    preferred_term: Gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
  description: Ataxic gait was recorded in 43.8% of the 32-person conference cohort; gait abnormalities can be mixed.
  evidence:
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '- Ataxic gait | 43.8'
    explanation: Table 1 of the 32-person conference cohort reports ataxic gait in 43.8%; mixed gait abnormalities were assessed in person.
  frequency: FREQUENT
- name: Pes Planus
  category: Skeletal
  phenotype_term:
    preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
  description: Flat feet were observed in 71.9% of the conference cohort.
  evidence:
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Musculoskeletal abnormalities included pes planus in 71.9%
    explanation: The examination of 32 conference participants identified pes planus in 71.9%, supporting FREQUENT in this selected cohort.
  frequency: FREQUENT
- name: Constipation
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  description: Constipation was reported in 50% of the conference cohort.
  evidence:
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Gastrointestinal problems were common and included constipation in 50% and gastroesophageal reflux disease in 18.8%.
    explanation: The medical history of the 32 conference participants records constipation in 50%, supporting FREQUENT.
  frequency: FREQUENT
- name: Gastroesophageal Reflux
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  description: Gastroesophageal reflux disease was reported in 18.8% of the conference cohort.
  evidence:
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: gastroesophageal reflux disease in 18.8%
    explanation: The 32-person conference cohort reports gastroesophageal reflux disease in 18.8%, supporting OCCASIONAL.
  frequency: OCCASIONAL
- name: Attention Deficit Hyperactivity Disorder
  category: Behavioral
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  description: A prior ADHD diagnosis was reported in 25% of the conference cohort; screening symptoms and a formal diagnosis are not interchangeable.
  evidence:
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '- Attention-deficit/hyperactivity disorder | 25'
    explanation: Table 1 records a prior ADHD diagnosis in 25% of the 32 conference participants; this is a diagnosis history rather than a symptom-screening estimate.
  frequency: OCCASIONAL
- name: Anxiety
  category: Behavioral
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  description: An anxiety diagnosis was reported in 15.6% of the conference cohort; caregiver internalizing-symptom screening yielded a different, higher estimate.
  evidence:
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '- Anxiety | 15.6'
    explanation: Table 1 records an anxiety diagnosis in 15.6% of the 32 conference participants; the broader internalizing-symptom screen is a different measure.
  frequency: OCCASIONAL
- name: Motor Stereotypies
  category: Behavioral
  phenotype_term:
    preferred_term: Motor stereotypy
    term:
      id: HP:0000733
      label: Motor stereotypy
  description: Stereotypic movements were recorded in 40.6% of the conference cohort.
  evidence:
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '- Stereotypies | 40.6'
    explanation: Table 1 reports stereotypies in 40.6% of the 32 conference participants, supporting FREQUENT.
  frequency: FREQUENT
- name: Long Philtrum
  category: Craniofacial
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  description: A long philtrum was reported in 11/24 individuals in the Chinese cohort; the later remote study reported a higher frequency with different ascertainment.
  evidence:
  - reference: PMID:36153650
    reference_title: Genetic and clinical characteristics of 24 mainland Chinese patients with CTNNB1 loss-of-function variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Characteristic facial phenotype included long eyelashes (10/24), wide nasal bridge (14/24), bulbous nasal tip (11/24), long philtrum (11/24), and thin upper lip (11/24).
    explanation: The Chinese cohort documents a long philtrum in 11/24 individuals, supporting FREQUENT without pooling with the differently ascertained remote cohort.
  frequency: FREQUENT
- name: Long Eyelashes
  category: Craniofacial
  phenotype_term:
    preferred_term: Long eyelashes
    term:
      id: HP:0000527
      label: Long eyelashes
  description: Long eyelashes were reported in 10/24 individuals in the Chinese cohort.
  evidence:
  - reference: PMID:36153650
    reference_title: Genetic and clinical characteristics of 24 mainland Chinese patients with CTNNB1 loss-of-function variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Characteristic facial phenotype included long eyelashes (10/24), wide nasal bridge (14/24), bulbous nasal tip (11/24), long philtrum (11/24), and thin upper lip (11/24).
    explanation: Long eyelashes were observed in 10/24 individuals in the Chinese cohort, supporting FREQUENT.
  frequency: FREQUENT
- name: Large Ears
  category: Craniofacial
  phenotype_term:
    preferred_term: Macrotia
    term:
      id: HP:0000400
      label: Macrotia
  description: Large ears were reported in 78.7% of the 2025 caregiver cohort. This is not established as an ancestry-specific feature.
  evidence:
  - reference: PMID:40684264
    reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: large ears (78.7%; 95% CI, 70.8%–85.0%)
    explanation: The remote study of 127 participants reports large ears in 78.7%; caregiver reporting and recruitment limit generalizability.
  frequency: FREQUENT
- name: Developmental Regression
  category: Neurological
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  description: Caregivers reported regression in 35.1% of the 2025 cohort, most often in speech or babbling. This report does not establish progressive neurodegeneration; tone, vision and ascertainment can affect function.
  evidence:
  - reference: PMID:40684264
    reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A substantial proportion (35.1%; 95% CI, 26.9%–44.4%) of respondents reported signs of developmental regression
    explanation: In the remote study of 127 participants, 35.1% of respondents reported regression. This retrospective caregiver report does not demonstrate progressive neurodegeneration.
  frequency: FREQUENT
- name: Hypoplasia of the Corpus Callosum
  category: Neurological
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  description: Four participants in the 2025 cohort had a smaller corpus callosum among five with abnormal callosal morphology. A linked mechanistic study examined five patients from the same registered cohort, so these are not independent case counts.
  evidence:
  - reference: PMID:40684264
    reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Of these 26 participants, 5 also had an abnormal corpus callosum (CC) morphology, accompanied with a smaller CC volume in 4 participants.
    explanation: Among 121 participants with imaging, 26 had abnormal findings, five had abnormal callosal morphology and four had smaller callosal volume. The related mechanistic paper draws from the same cohort.
- name: Seizures
  category: Neurological
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  description: Seizures occur in a minority; the 2025 remote cohort reported 3.9%, whereas earlier selected cohorts reported higher proportions. Epileptiform EEG abnormalities and exaggerated startle do not by themselves establish epilepsy.
  evidence:
  - reference: PMID:40684264
    reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: seizures (3.9%; 95% CI, 1.7%–8.9%)
    explanation: The 127-person remote caregiver cohort reports seizures in 3.9%; ascertainment differs from earlier selected clinical series, so a pooled frequency band is not assigned.
- name: Short Stature
  category: Growth
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  description: Short stature was reported in 8/39 individuals in the GeneReviews synthesis.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: IUGR 10/44 (22.7%) Short stature 8/39 (20.5%)
    explanation: The full-text GeneReviews synthesis reports short stature in 8/39 assessed individuals (20.5%), supporting OCCASIONAL.
  frequency: OCCASIONAL
- name: Toe Walking
  category: Neurological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Tip-toe gait
    term:
      id: HP:0030051
      label: Tip-toe gait
  description: Toe walking was reported in 37.5% of the conference cohort and can coexist with spastic or ataxic gait.
  evidence:
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '- Toe walking | 37.5'
    explanation: Table 1 reports toe walking in 37.5% of the 32 conference participants; this can overlap with other gait findings.
- name: Hyperopia
  category: Ophthalmological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypermetropia
    term:
      id: HP:0000540
      label: Hypermetropia
  description: Farsightedness was reported in 47.2% of the 2025 caregiver cohort.
  evidence:
  - reference: PMID:40684264
    reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 47.2% had farsightedness (95% CI, 38.7%–55.9%)
    explanation: The remote study of 127 participants reports farsightedness in 47.2%, supporting FREQUENT in this caregiver-assessed cohort.
- name: Myopia
  category: Ophthalmological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  description: Nearsightedness was reported in 16.5% of the 2025 caregiver cohort.
  evidence:
  - reference: PMID:40684264
    reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: near-sightedness (16.5%; 95% CI, 11.1%–24.0%)
    explanation: The remote study of 127 participants reports nearsightedness in 16.5%, supporting OCCASIONAL in this caregiver-assessed cohort.
- name: Underdeveloped Nasal Alae
  category: Craniofacial
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Underdeveloped nasal alae
    term:
      id: HP:0000430
      label: Underdeveloped nasal alae
  description: Small alae nasi were reported in 77.2% of the 2025 caregiver cohort.
  evidence:
  - reference: PMID:40684264
    reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: small alae nasi (77.2%; 95% CI, 69.1%–83.6%)
    explanation: The remote study of 127 participants reports small alae nasi in 77.2%; this specifically defined finding is distinct from a broad nasal tip.
- name: Sparse Eyebrows
  category: Craniofacial
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Sparse eyebrow
    term:
      id: HP:0045075
      label: Sparse eyebrow
  description: Sparse eyebrows were described in nine of 24 individuals in the Chinese cohort.
  evidence:
  - reference: PMID:36153650
    reference_title: Genetic and clinical characteristics of 24 mainland Chinese patients with CTNNB1 loss-of-function variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: One affected individual was found to have narrowed forehead and nine with sparse eyebrows.
    explanation: Nine of 24 individuals in the Chinese cohort had sparse eyebrows, supporting FREQUENT.
- name: Cerebral White Matter Abnormalities
  category: Neurological
  phenotype_term:
    preferred_term: Abnormal cerebral white matter morphology
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  description: Reported MRI abnormalities included white matter volume loss, signal abnormalities and delayed myelination. Twenty-six of 121 imaged participants in the 2025 cohort had white matter findings; 76.5% in the paper uses only the 34 abnormal scans as denominator. This does not establish a degenerative leukodystrophy.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40684264
    reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: White matter abnormalities were reported in 26 of these 34 participants (76.5%). Among these, 15 participants were reported to have white matter volume loss, 11 participants had abnormal signal intensity, and 8 had delayed myelinization.
    explanation: The imaging categories overlap and are kept as a variable spectrum; the frequency among all 121 imaged participants is about 21.5%.
- name: Cryptorchidism
  category: Genitourinary
  description: Cryptorchidism was reported in 3/18 males (17%) in the conference cohort; two had undergone orchiopexy. The frequency refers to males.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cryptorchidism was noted in 3 males (17%) and two males required orchiopexy (11%).
    explanation: The conference cohort included 18 males; cryptorchidism in three gives a male-specific frequency of 17%, with orchiopexy in two.
  frequency: OCCASIONAL
- name: Astigmatism
  category: Ophthalmological
  description: Astigmatism was reported in 3/24 individuals in the Chinese cohort.
  phenotype_term:
    preferred_term: Astigmatism
    term:
      id: HP:0000483
      label: Astigmatism
  evidence:
  - reference: PMID:36153650
    reference_title: Genetic and clinical characteristics of 24 mainland Chinese patients with CTNNB1 loss-of-function variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Astigmatism | 3 | 24 | 12.5
    explanation: The Chinese cohort table reports astigmatism in 3/24 individuals (12.5%), supporting OCCASIONAL.
  frequency: OCCASIONAL
- name: Appendicular Hypotonia
  category: Neurological
  description: Peripheral hypotonia can occur in addition to the more typical limb hypertonia. It was recorded in 12.5% of the conference cohort.
  phenotype_term:
    preferred_term: Appendicular hypotonia
    term:
      id: HP:0012389
      label: Appendicular hypotonia
  evidence:
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '- Peripheral hypotonia | 12.5'
    explanation: Table 1 reports peripheral hypotonia in 12.5% of the 32 conference participants; it is distinct from the much more common axial hypotonia.
  frequency: OCCASIONAL
- name: Self-Injurious Behavior
  category: Behavioral
  description: Self-injury was reported in 2/24 individuals in the Chinese cohort; other summaries combine it with aggression, so their larger combined estimate is not used as an individual-feature frequency.
  phenotype_term:
    preferred_term: Self-injurious behavior
    term:
      id: HP:0100716
      label: Self-injurious behavior
  evidence:
  - reference: PMID:36153650
    reference_title: Genetic and clinical characteristics of 24 mainland Chinese patients with CTNNB1 loss-of-function variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Self‐injury | 2 | 24 | 8.3
    explanation: The Chinese cohort table records self-injury in 2/24 individuals (8.3%); combined aggression/self-mutilation estimates are not used for this specific feature.
  frequency: OCCASIONAL
- name: Aggressive Behavior
  category: Behavioral
  description: Aggression is described among behavioral difficulties. Some reports combine aggression and self-mutilation, limiting a separate frequency estimate.
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  evidence:
  - reference: PMID:38247296
    reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we documented frequent externalizing behaviors (delinquent and aggressive behaviors)
    explanation: The conference study describes aggressive externalizing behavior. Child Behavior Checklist data were available for 17 of 32 participants, and the quoted summary does not supply a separate aggression frequency.
genetic:
- name: CTNNB1
  gene_term:
    preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  association: Causal - heterozygous germline variants, predominantly loss of function
  relationship_type: CAUSATIVE
  presence: Positive
  notes: The common mechanism is heterozygous loss of function, usually de novo, with transmitted alleles and presumed parental germline mosaicism also documented. Deletions and an inversion disrupting CTNNB1 occur as well as sequence variants. Missense variants are not uniformly mild or functionally equivalent. The 2025 clinical missense subgroup contained only four individuals; the earlier C-terminal severity association was exploratory and included isolated FEVR. Gly575Arg showed normal activity in a 2022 HEK293T reporter, reduced activity in 2023 SuperTopFlash cells, and increased activity and thermal stability in 2025 SK-N-MC experiments. Reporter context and protein tags matter; no general genotype-based prognosis or validated molecular subtype follows from these results.
  evidence:
  - reference: PMID:36083290
    reference_title: Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075)
    explanation: Establishes germline CTNNB1 loss of function as the cause of the disorder and confirms the OMIM identity (615075) matching the MONDO xref.
  - reference: PMID:40684264
    reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: those with missense variants presented a milder phenotype, including earlier achievement of independent walking, fewer motor impairments, better conceptual and social skills, improved communication, and fewer feeding difficulties
    explanation: This exploratory association concerns only four individuals with missense variants and is not a general prediction for future patients.
  - reference: PMID:36293418
    reference_title: 'Correlation between Phenotype and Genotype in CTNNB1 Syndrome: A Systematic Review of the Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: While mutations cannot be more generally categorized by location, it is generally observed that the C-terminal protein region (exons 13, 14, 15) correlates with a milder phenotype.
    explanation: The systematic review used a small, heterogeneous subset including isolated FEVR; the positional association is exploratory and not sufficient to assign a clinical subtype.
  - reference: PMID:40684264
    reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: However, four variants (p.Y333∗, p.Q193∗, p.A317Vfs8∗, and p.S352fs∗) showed reduced levels of TOPFlash-luciferase activity suggesting a dominant negative mechanism
    explanation: The full-text cotransfection experiment identifies four truncating variants, rather than eleven distinct dominant-negative protein variants.
  - reference: PMID:40684264
    reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: As a subgroup, we did not find evidence that variants with a dominant negative effect led to clear genotype-phenotype correlations
    explanation: The experimentally defined dominant-negative subset did not establish a distinct clinical subtype.
  variants:
  - name: p.Leu388Pro
    description: A missense allele with a dominant-negative Wnt reporter effect in HEK293T cotransfection experiments.
    evidence:
    - reference: PMID:36083290
      reference_title: Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We were able to resolve p.Leu388Pro and p.Leu424Arg as likely dominant negative variants affecting the WNT signalling pathway
      explanation: The experiment supports an allele-specific reporter effect, not a universal missense mechanism.
  - name: p.Leu424Arg
    description: A missense allele with a dominant-negative Wnt reporter effect in HEK293T cotransfection experiments.
    evidence:
    - reference: PMID:36083290
      reference_title: Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We were able to resolve p.Leu388Pro and p.Leu424Arg as likely dominant negative variants affecting the WNT signalling pathway
      explanation: The experiment supports an allele-specific reporter effect, not a universal missense mechanism.
  - name: p.Tyr333Ter
    description: One of four truncating protein variants showing dominant-negative reporter effects with wild-type cotransfection in the 2025 study. Protein shorthand follows the publication; cDNA expression does not prove endogenous transcript stability.
    evidence:
    - reference: PMID:40684264
      reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: However, four variants (p.Y333∗, p.Q193∗, p.A317Vfs8∗, and p.S352fs∗) showed reduced levels of TOPFlash-luciferase activity suggesting a dominant negative mechanism
      explanation: The body identifies four truncating protein variants found in eleven participants.
  - name: p.Gln193Ter
    description: One of four truncating protein variants showing dominant-negative reporter effects with wild-type cotransfection in the 2025 study. Protein shorthand follows the publication; cDNA expression does not prove endogenous transcript stability.
    evidence:
    - reference: PMID:40684264
      reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: However, four variants (p.Y333∗, p.Q193∗, p.A317Vfs8∗, and p.S352fs∗) showed reduced levels of TOPFlash-luciferase activity suggesting a dominant negative mechanism
      explanation: The body identifies four truncating protein variants found in eleven participants.
  - name: p.Ala317ValfsTer8
    description: One of four truncating protein variants showing dominant-negative reporter effects with wild-type cotransfection in the 2025 study. Protein shorthand follows the publication; cDNA expression does not prove endogenous transcript stability.
    evidence:
    - reference: PMID:40684264
      reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: However, four variants (p.Y333∗, p.Q193∗, p.A317Vfs8∗, and p.S352fs∗) showed reduced levels of TOPFlash-luciferase activity suggesting a dominant negative mechanism
      explanation: The body identifies four truncating protein variants found in eleven participants.
  - name: p.Ser352fsTer
    description: One of four truncating protein variants showing dominant-negative reporter effects with wild-type cotransfection in the 2025 study. Protein shorthand follows the publication; cDNA expression does not prove endogenous transcript stability.
    evidence:
    - reference: PMID:40684264
      reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: However, four variants (p.Y333∗, p.Q193∗, p.A317Vfs8∗, and p.S352fs∗) showed reduced levels of TOPFlash-luciferase activity suggesting a dominant negative mechanism
      explanation: The body identifies four truncating protein variants found in eleven participants.
  - name: p.Gly575Arg
    description: 'An assay-dependent allele: normal reporter output in the 2022 HEK293T study, reduced output in 2023 SuperTopFlash cells, and increased activity and thermal stability in 2025 SK-N-MC cells. The gene-addition trial excludes it under its predicted gain-of-function criterion.'
    evidence:
    - reference: PMID:40684264
      reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: For p.G575R, the Tm was shifted to 55.32 ± 0.51°C, indicating that the p.G575R mutant protein is more stable than the WT protein
      explanation: Thermal shift experiments support greater stability in this system. Degradation-complex resistance was proposed, not directly measured.
    - reference: PMID:36083290
      reference_title: Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The functional impact of p.Gly575Arg was not evident using this assay; however, given that this variant is recurrent, there is already sufficient evidence to determine that it is pathogenic.
      explanation: The 2022 functional assay did not resolve an abnormal effect; this conflicts with the later reporter results.
    - reference: PMID:36790797
      reference_title: Familial Exudative Vitreoretinopathy and Systemic Abnormalities in Patients With CTNNB1 Mutations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Compared to wild-type CTNNB1, the CTNNB1 mutants failed to induce luciferase reporter activity in SuperTopFlash (STF) cells.
      explanation: The tested set included Gly575Arg; the full text reports reduced reporter activity in this experimental context.
  - name: p.Leu577Arg
    description: A nearby missense allele with reduced reporter activity and lower thermal stability in SK-N-MC cells.
    evidence:
    - reference: PMID:40684264
      reference_title: Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: the Tm of p.L577R was 46.02 ± 0.84°C, suggesting that the p.L577R mutant protein was less stable
      explanation: Contrasting effects of nearby Gly575Arg and Leu577Arg caution against predicting mechanism from position alone.
  - name: c.2137+5G>T
    description: A transmitted intronic variant in a FEVR family; the mother and sister had subtle retinal vascular abnormalities despite normal acuity. Splice disruption was predicted, without a reported patient RNA assay.
    evidence:
    - reference: PMID:36790797
      reference_title: Familial Exudative Vitreoretinopathy and Systemic Abnormalities in Patients With CTNNB1 Mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Five of the 7 CTNNB1 mutations were found to be novel, namely, c.888_889dup (p.Thr297Ilefs*9), c.1707del (p.Ile569Metfs*12), c.2138-4_2140del, c.1543C>T (p.Arg515*), and c.2137+5G>T.
      explanation: The full-text variant list and pedigree identify the allele; its functional splice consequence remains a prediction.
  - name: CTNNB1 exons 2-6 deletion
    description: An intragenic deletion reported in the conference cohort.
    evidence:
    - reference: PMID:38247296
      reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: included exons 2-6 of CTNNB1.
      explanation: Direct clinical copy-number evidence supports the deletion class.
  - name: Inv(3)(p24.3p22.1)
    description: A chromosomal inversion involving CTNNB1 exons 1-9 in the conference cohort.
    evidence:
    - reference: PMID:38247296
      reference_title: Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: involved exon 1-9 of the CTNNB1 gene
      explanation: The rearrangement expands the diagnostic variant spectrum beyond coding substitutions.
diagnosis:
- name: Molecular Genetic Testing for CTNNB1
  description: Diagnosis requires a heterozygous pathogenic or likely pathogenic CTNNB1 variant in an individual with compatible findings. Exome/genome or panel sequencing and deletion/duplication analysis address sequence variants and copy-number changes; a variant of uncertain significance does not establish the diagnosis. A clinical cerebral palsy or autism diagnosis can coexist and can be an entry point for molecular testing.
  presence: Positive in affected individuals
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:35593792
    reference_title: CTNNB1 Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The diagnosis of CTNNB1-NDD is established in a proband with suggestive findings and a heterozygous pathogenic variant in CTNNB1 identified by molecular genetic testing
    explanation: GeneReviews states the molecular diagnostic criterion.
  - reference: PMID:36083290
    reference_title: Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.
    explanation: Supports testing individuals whose entry diagnosis was cerebral palsy, since the molecular entity is the same.
- name: Ultra-Widefield Fluorescein Angiography
  description: Retinal vascular disease in CTNNB1 syndrome is frequently occult on routine office ophthalmoscopy. Ultra-widefield fluorescein angiography, if necessary under anaesthesia, detects treatment-requiring FEVR in children with previously normal examinations and should be considered at diagnosis.
  presence: Abnormal in a substantial minority with normal office examination
  diagnosis_term:
    preferred_term: fluorescein angiography
    term:
      id: NCIT:C190541
      label: Fluorescein Angiography
  evidence:
  - reference: PMID:39145965
    reference_title: Vitreoretinopathy in Asymptomatic Children With CTNNB1 Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These findings support consideration of ultra-widefield fluorescein angiography among individuals with CTNNB1 syndrome when feasible, including the use of sedation if such an assessment is not possible in the office setting.
    explanation: Directly recommends ultra-widefield fluorescein angiography, including under sedation, in CTNNB1 syndrome.
  - reference: PMID:39145965
    reference_title: Vitreoretinopathy in Asymptomatic Children With CTNNB1 Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, ophthalmoscopy may not be sufficient to detect vision-threatening vitreoretinopathy in all patients.
    explanation: States the diagnostic limitation of ophthalmoscopy that motivates angiography.
differential_diagnoses:
- name: Cerebral Palsy
  description: CTNNB1-NDD can meet clinical criteria for cerebral palsy. Molecular testing identifies an underlying genetic cause rather than necessarily invalidating the clinical motor diagnosis. Progressive or additional findings warrant individualized reassessment.
- name: Familial Exudative Vitreoretinopathy (NDP, FZD4, LRP5, TSPAN12)
  description: The ocular phenotype of CTNNB1-NDD is indistinguishable from classic FEVR caused by the Norrin receptor-complex genes; the accompanying neurodevelopmental and motor features distinguish CTNNB1-NDD.
- name: Autism Spectrum Disorder
  description: Autism can coexist with CTNNB1-NDD. Relative visuospatial and adaptive weaknesses were described in small comparison cohorts but are not a validated diagnostic discriminator; molecular testing establishes the genetic diagnosis.
- name: Hereditary Spastic Paraplegia
  description: Progressive lower-limb spasticity overlaps, but CTNNB1-NDD adds intellectual disability, microcephaly, facial gestalt and retinal vascular disease.
- name: Hyperekplexia (GLRA1, GLRB, SLC6A5)
  description: The exaggerated startle of CTNNB1-NDD corresponds to atypical hyperekplexia and can prompt consideration of the classic glycinergic hyperekplexia genes.
treatments:
- name: Multidisciplinary Supportive Care
  description: No established curative or disease-modifying treatment is supported by the cited clinical literature. Multidisciplinary care addresses motor, communication, feeding, visual, behavioral and family needs. Gene addition is in early clinical testing; GSK3 inhibition has preclinical mouse evidence. Neither constitutes proven human disease modification.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:35593792
    reference_title: CTNNB1 Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There is no curative treatment. Supportive care by a multidisciplinary team often includes a neurologist, speech-language pathologist, physiatrist, occupational therapist, physical therapist, feeding team, pediatric ophthalmologist, audiologist, and developmental pediatrician.
    explanation: GeneReviews defines the standard of care as multidisciplinary supportive management in the absence of curative treatment.
  - reference: PMID:39833474
    reference_title: CTNNB1 syndrome mouse models.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: There is currently no effective treatment option available for patients with CTNNB1 syndrome, with support largely focused on the management of symptoms and physiotherapy
    explanation: Confirms the absence of disease-modifying therapy and the symptom-management/physiotherapy focus of current care.
- name: Physical Therapy and Motor Rehabilitation
  description: Physical therapy, stretching, positioning and individualized mobility aids address hypotonia, weakness, spasticity and gait limitations. Occupational therapy addresses fine motor and adaptive tasks. These are expert supportive-care recommendations rather than CTNNB1-specific controlled efficacy results.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Spastic diplegia
    term:
      id: HP:0001264
      label: Spastic diplegia
  - preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:39833474
    reference_title: CTNNB1 syndrome mouse models.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: with support largely focused on the management of symptoms and physiotherapy
    explanation: Identifies physiotherapy as a core component of current supportive management.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: wheelchairs, walkers, bath chairs, orthotics, adaptive strollers
    explanation: GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), full text. GeneReviews lists individualized assistive equipment.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
    explanation: GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), full text. GeneReviews provides explicit occupational-therapy guidance.
- name: Speech and Language Therapy
  description: Speech-language therapy including augmentative and alternative communication addresses the severe expressive speech impairment that is near-universal in the disorder.
  treatment_term:
    preferred_term: speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:35593792
    reference_title: CTNNB1 Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Supportive care by a multidisciplinary team often includes a neurologist, speech-language pathologist
    explanation: GeneReviews includes speech-language pathology in the standard multidisciplinary care team.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Consider evaluation for alternative means of communication
    explanation: GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), full text. GeneReviews specifically recommends considering augmentative and alternative communication.
- name: Botulinum Toxin for Spasticity and Dystonia
  description: Botulinum toxin injection was at least partially effective for the movement disorder in most treated patients in a systematically assessed cohort; levodopa was much less consistently helpful.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: botulinum toxin type A
      term:
        id: CHEBI:3160
        label: Botulinum toxin type A
  therapeutic_modality: OTHER
  target_phenotypes:
  - preferred_term: Spastic diplegia
    term:
      id: HP:0001264
      label: Spastic diplegia
  - preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  notes: Symptomatic chemodenervation only - it mitigates the functional consequences of hypertonia and dystonia and does not act on the upstream CTNNB1/Wnt lesion, so no `target_mechanisms` edge is declared.
  evidence:
  - reference: PMID:39067319
    reference_title: 'Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Treatment efficacy was variable: botulinum toxin was (at least partially) effective in 5/6, levodopa in 1 of 4 treated patients.'
    explanation: Reports partial or better response to botulinum toxin in 5 of 6 treated patients and limited levodopa benefit.
- name: Ophthalmological Surveillance and FEVR Treatment
  description: Regular paediatric ophthalmology review with refractive correction and strabismus management, plus ultra-widefield fluorescein angiography to detect occult vitreoretinopathy; treatment-requiring peripheral retinal non-perfusion is managed with laser photocoagulation and, when detachment occurs, vitreoretinal surgery.
  treatment_term:
    preferred_term: laser photocoagulation
    term:
      id: NCIT:C217424
      label: Laser Photocoagulation
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Exudative vitreoretinopathy
    term:
      id: HP:0030490
      label: Exudative vitreoretinopathy
  evidence:
  - reference: PMID:39145965
    reference_title: Vitreoretinopathy in Asymptomatic Children With CTNNB1 Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The presence of disease requiring treatment was identified in 6 eyes, including 1 retinal detachment.
    explanation: Establishes that a meaningful proportion of eyes harbour treatment-requiring retinal disease, justifying active ophthalmological management.
  - reference: PMID:35593792
    reference_title: CTNNB1 Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Surveillance: Monitor neurologic findings for response to supportive interventions and emergence of new findings or concerns regarding developmental/educational progress, behavior issues, ophthalmologic findings and vision, and family support.'
    explanation: GeneReviews specifies ophthalmological findings and vision as a required surveillance domain.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'For significant retinal findings: argon laser photocoagulation, scleral buckling &/or pars plana vitrectomy to attempt to halt progressive changes & ↓ complications'
    explanation: The full-text GeneReviews treatment table explicitly lists laser photocoagulation and vitreoretinal procedures for significant retinal findings.
- name: AAV9-Mediated CTNNB1 Gene Replacement (Investigational)
  description: Urbagen is an investigational single-stranded AAV9 vector carrying human CTNNB1, administered once by bilateral intracerebroventricular infusion in the open-label phase I/II GAIN study (NCT07270549). Twelve participants aged 2-12 years are planned, with part A restricted to 6-12 years. Prophylaxis includes methylprednisolone followed by prednisolone and sirolimus. The registry excludes selected predicted gain-of-function and dominant-negative alleles, including Gly575Arg and four truncating variants. Gene addition aims to increase functional dosage; no human safety or efficacy results are posted. Its benefit and long-term safety remain unestablished.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  therapeutic_modality: GENE_THERAPY
  target_mechanisms:
  - target: CTNNB1 Loss-of-Function and Beta-Catenin Haploinsufficiency
    treatment_effect: ACTIVATES
    description: The vector is intended to increase functional CTNNB1 expression in eligible loss-of-function genotypes. Restoration of dosage or clinical benefit has not yet been demonstrated in trial results.
  evidence:
  - reference: clinicaltrials:NCT07270549
    reference_title: 'GAIN-CTNNB1: A Phase I/II Open-Label Trial To Evaluate the Safety, Tolerability, and Preliminary Efficacy of Intracerebroventricular Administration of an AAV9 Based Gene Replacement Therapy in Paediatric Patients With CTNNB1 Neurodevelopmental Syndrome'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: gene therapy via bilateral intracerebroventricular administration.
    explanation: Describes the route and dosing of the investigational AAV9 CTNNB1 gene replacement therapy.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07270549
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT07270549
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '* Participant has a mutation in the CTNNB1 gene which is predicted to result in a gain-of-function effect (e.g. p.G575R) or dominant negative effect (e.g. p.Y333\\*, p.Q193\\*, p.A317Vfs8\\* and p.S352fs\\*) on the Wnt/β-catenin pathway, or any variant that, in the opinion of the PI, is inconsistent with the mechanism of action of the gene replacement therapy.'
    explanation: The GAIN registry specifies allele-related exclusions; this criterion does not resolve discordant experimental results for Gly575Arg.
- name: Genetic Counseling
  description: Counseling covers autosomal dominant inheritance, parental testing, variable expressivity and possible germline mosaicism. GeneReviews gives a 50% transmission risk when a parent carries the variant and an empirical approximately 1% sibling recurrence estimate when it is absent from both parents’ leukocyte DNA. These estimates require family-specific interpretation; phenotype severity cannot be reliably predicted. Prenatal and preimplantation testing are possible after identifying the familial pathogenic variant.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:35593792
    reference_title: CTNNB1 Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Once the CTNNB1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
    explanation: GeneReviews states the reproductive-testing options that genetic counselling addresses.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism
    explanation: GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), full text. GeneReviews supplies the empirical estimate when parental leukocyte testing is negative.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Each child of an individual with CTNNB1-NDD has a 50% chance of inheriting the CTNNB1 pathogenic variant.
    explanation: The full-text GeneReviews genetic counseling section states the transmission risk for an affected individual; this differs from sibling recurrence when both parents test negative.
- name: Baclofen and Tizanidine for Tone Abnormalities
  description: GeneReviews lists baclofen, including intrathecal delivery in selected cases, and tizanidine as specialist-directed symptomatic options. Controlled CTNNB1-specific efficacy is not established.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of Levodopa, baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.
    explanation: GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), full text. The full-text motor-care section lists these symptomatic options.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Botulinum toxin & intrathecal baclofen injection may be considered.
    explanation: GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), full text. The treatment table includes consideration of intrathecal baclofen.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: baclofen
      term:
        id: CHEBI:2972
        label: baclofen
    - preferred_term: tizanidine
      term:
        id: CHEBI:63629
        label: tizanidine
- name: Levodopa for Dystonia (Limited Evidence)
  description: A selected movement-disorder series reported benefit in only one of four treated patients. The open-label levodopa/carbidopa pilot is testing motor outcomes; a response does not itself prove presynaptic dopamine deficiency.
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:39067319
    reference_title: 'Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Treatment efficacy was variable: botulinum toxin was (at least partially) effective in 5/6, levodopa in 1 of 4 treated patients.'
    explanation: Uncontrolled patient observations indicate variable response; the ongoing pilot supplies no posted efficacy results.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: L-dopa
      term:
        id: CHEBI:15765
        label: L-dopa
    - preferred_term: carbidopa
      term:
        id: CHEBI:3395
        label: carbidopa
- name: Benzodiazepines for Disabling Exaggerated Startle
  description: In one electrophysiologically assessed adult, sequential clonazepam then diazepam treatment reduced startle responses and abolished sudden falls. The report is a single treated case, not evidence of established benefit for the whole syndrome.
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:36419413
    reference_title: 'Startle Disease: An Overlooked Symptom of CTNNB1-Related Neurodevelopmental Disorder With Spastic Diplegia and Visual Defects.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Treatment by clonazepam and then with diazepam drastically reduced the startle responses and suppressed sudden falls.
    explanation: The full text locates this treatment response in one 19-year-old patient, not all twelve people described in the study.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: clonazepam
      term:
        id: CHEBI:3756
        label: clonazepam
    - preferred_term: diazepam
      term:
        id: CHEBI:49575
        label: diazepam
- name: Feeding and Nutritional Support
  description: Feeding-team assessment addresses swallowing safety, aspiration and nutritional adequacy. GeneReviews describes adapted feeds and enteral support when dysfunction is severe; individual swallowing assessment guides the intervention.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.
    explanation: GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), full text. The full-text care section includes enteral feeding support.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Low Vision and Family Support
  description: Low-vision services, developmental education, behavioral assessment and social-work support address adaptive function and family needs alongside ophthalmologic and motor care.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Low vision Low vision services Community services through early intervention &/or school district
    explanation: GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), full text. The treatment table recommends low-vision services.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK580527/pdf/Bookshelf_NBK580527.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
    explanation: GeneReviews, CTNNB1 Neurodevelopmental Disorder (PMID:35593792), full text. GeneReviews includes family resources and respite support.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Dual GSK3 Inhibition (Preclinical)
  description: BRD0320 improved beta-catenin abundance, several molecular and electrophysiological measures, learning and motor performance after five daily injections in symptomatic 6-10-week-old germline heterozygous mice. Resting membrane potential was not corrected. Separate alpha- or beta-selective inhibitors were less effective. Human efficacy, chronic safety and optimal treatment age remain unknown, and effects through other GSK3 substrates were not excluded.
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: DOI:10.1038/s44321-024-00110-5
    reference_title: Inhibition of GSK3α,β rescues cognitive phenotypes in a preclinical mouse model of CTNNB1 syndrome
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: GSK3α,β dual-paralog inhibition (BRD0320) signi ﬁcantly improves learning and memory in the β-cat het mice
    explanation: The primary study reports a short mouse experiment, not a human therapeutic result.
  - reference: DOI:10.1038/s44321-024-00110-5
    reference_title: Inhibition of GSK3α,β rescues cognitive phenotypes in a preclinical mouse model of CTNNB1 syndrome
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: However, we cannot rule out a contribution of other β-cat independent GSK3 α,β substrates.
    explanation: The authors explicitly acknowledge that beta-catenin-independent effects may contribute.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: CTNNB1 Loss-of-Function and Beta-Catenin Haploinsufficiency
    treatment_effect: ACTIVATES
    description: In the germline heterozygous mouse, dual inhibition raises beta-catenin abundance toward control levels. Human benefit remains untested and beta-catenin-independent effects may contribute.
animal_models:
- species: Mouse
  genotype: Ctnnb1 batface (Bfc), Thr653Lys ENU-induced substitution
  genes:
  - preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  associated_phenotypes:
  - Intellectual disability
  - Reduced intrahemispheric connectivity
  - Impaired long-term potentiation
  description: Batface is an ENU-induced Thr653Lys allele with normal protein abundance, reduced cadherin affinity and enhanced Wnt activity. Heterozygotes show altered dendritic development, connectivity, plasticity and cognitive behavior, with increased brain volume; it does not model simple dosage loss or human microcephaly. Acoustic startle magnitude was normal despite impaired prepulse inhibition. Homozygotes are nonviable.
  evidence:
  - reference: PMID:24614104
    reference_title: Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In parallel, characterization of a chemically mutagenized mouse line that displays features similar to those of human patients with β-catenin mutations enabled us to investigate the consequences of β-catenin dysfunction through development and into adulthood.
    explanation: The original paper establishes phenotypic overlap, with distinct molecular and anatomical limitations documented in its full text.
- species: Mouse
  genotype: Endothelial-cell-specific (Cre-mediated) heterozygous Ctnnb1 knockout
  genes:
  - preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  associated_phenotypes:
  - Exudative vitreoretinopathy
  description: Cre-mediated heterozygous deletion of Ctnnb1 restricted to endothelial cells produces FEVR-like retinal phenotypes, isolating the retinal vascular arm of the disorder. Lithium chloride, a GSK-3beta inhibitor that stabilises beta-catenin, partially rescued the defect in this model and in CTNNB1-knockdown human retinal endothelial cells.
  evidence:
  - reference: PMID:35361685
    reference_title: Novel truncating variants in CTNNB1 cause familial exudative vitreoretinopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Moreover, LiCl treatment partially rescued the defects in CTNNB1-KD HRECs and EC-specific Ctnnb1 heterozygous knockout mice.
    explanation: Demonstrates partial pharmacological rescue of the retinal vascular phenotype by beta-catenin stabilisation in the endothelial-specific knockout model.
- species: Mouse
  genotype: Germline heterozygous Ctnnb1 exon 2-6 deletion generated using E2a-Cre, with Cre bred out
  description: This model has approximately half-normal beta-catenin abundance, impaired associative learning, grip strength and rotarod performance, altered N-cadherin association, lower DKK1/EN2 and ATPase alpha2/alpha3 protein, and altered dentate-granule-cell excitability. General locomotion was unchanged. Short BRD0320 treatment improved several outcomes after symptom onset; chronic safety and human translation were not tested.
  evidence:
  - reference: DOI:10.1038/s44321-024-00110-5
    reference_title: Inhibition of GSK3α,β rescues cognitive phenotypes in a preclinical mouse model of CTNNB1 syndrome
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: β-cat global het mice display approximately 50% reductions in β-cat protein levels
    explanation: The primary study directly measures protein reduction in a germline heterozygote, contrasting with the batface functional allele.
- species: Mouse
  genotype: Lmx1aCre-targeted biallelic Ctnnb1 exon 2-6 deletion or heterozygous exon 3 stabilization
  description: Both conditional manipulations disrupt callosal midline guidance populations and crossing. The loss model deletes both copies; a midline heterozygous deletion had no callosal phenotype. Only male embryos were analyzed because the Cre transgene is X-linked. These are mechanistic models with a substantial genotype and severity gap from human disease.
  evidence:
  - reference: PMID:40894864
    reference_title: An evolutionarily conserved role for CTNNB1/β-CATENIN in regulating the development of the corpus callosum.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: our Ctnnb1 LOF model results in gene disruption of both copies and loss of all CTNNB function.
    explanation: The paper states the critical difference between its loss model and the human heterozygous condition.
clinical_trials:
- name: NCT07270549
  phase: PHASE_I
  status: RECRUITING
  description: 'GAIN-CTNNB1: open-label phase I/II, single-arm Urbagen gene addition study; 12 participants aged 2-12 years planned, part A aged 6-12. One bilateral intracerebroventricular dose with prophylactic immunosuppression and five-year safety follow-up. The registry excludes predicted gain-of-function Gly575Arg and dominant-negative Tyr333*, Gln193*, Ala317Valfs8* and Ser352fs* alleles or other incompatible mechanisms. No results posted.'
  target_phenotypes:
  - preferred_term: Spastic diplegia
    term:
      id: HP:0001264
      label: Spastic diplegia
  - preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: clinicaltrials:NCT07270549
    reference_title: 'GAIN-CTNNB1: A Phase I/II Open-Label Trial To Evaluate the Safety, Tolerability, and Preliminary Efficacy of Intracerebroventricular Administration of an AAV9 Based Gene Replacement Therapy in Paediatric Patients With CTNNB1 Neurodevelopmental Syndrome'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the safety, tolerability, and preliminary efficacy of AAV9 mediated gene replacement therapy (Urbagen) in paediatric patients with CTNNB1 neurodevelopmental disorder.
    explanation: Establishes that AAV9-mediated CTNNB1 gene replacement has entered first-in-human testing for this disorder.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07270549
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT07270549
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the safety, tolerability, and preliminary efficacy of AAV9 mediated gene replacement therapy (Urbagen) in paediatric patients with CTNNB1 neurodevelopmental disorder.
    explanation: The detailed registry describes the study purpose. Its hasResults field is false at retrieval, so this record supplies no posted efficacy results.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07270549
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT07270549
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '* Participant has a mutation in the CTNNB1 gene which is predicted to result in a gain-of-function effect (e.g. p.G575R) or dominant negative effect (e.g. p.Y333\\*, p.Q193\\*, p.A317Vfs8\\* and p.S352fs\\*) on the Wnt/β-catenin pathway, or any variant that, in the opinion of the PI, is inconsistent with the mechanism of action of the gene replacement therapy.'
    explanation: The GAIN registry specifies allele-related exclusions; this criterion does not resolve discordant experimental results for Gly575Arg.
- name: NCT07614126
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: Open-label levodopa/carbidopa pilot in seven planned children aged 1-15 years with CTNNB1-NDD and dystonia. Treatment and follow-up extend to one year; the primary endpoint is GMFM-88 change at six months, with secondary motor, developmental, quality-of-life and tolerability outcomes. The dopaminergic rationale is model-derived and unproven in humans. No results posted.
  target_phenotypes:
  - preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: clinicaltrials:NCT07614126
    reference_title: Prospective Pilot Study of L-dopa Treatment in Patients With a Neurodevelopmental Disorder Related to a Pathogenic Variant of the CTNNB1 Gene
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These findings suggest that CTNNB1 anomalies lead to secondary dopaminergic deficits, contributing to clinical signs. The hypothesis is that this deficit could be partially corrected by dopamine supplementation.
    explanation: States the model-derived dopaminergic-deficit rationale for the levodopa pilot; the hypothesis is explicitly unproven in humans.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07614126
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT07614126
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These observations support the hypothesis that L-dopa may improve certain motor and non-motor symptoms in these patients.
    explanation: The detailed registry describes the study purpose. Its hasResults field is false at retrieval, so this record supplies no posted efficacy results.
- name: NCT07167732
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: 'Dragonfly: international prospective observational natural-history study, with 250 participants planned and five-year follow-up. Clinical scales and planned molecular measurements support natural-history and biomarker research; the blood measurements are candidate research endpoints, not validated diagnostic or treatment-response biomarkers. No results posted.'
  evidence:
  - reference: clinicaltrials:NCT07167732
    reference_title: 'Dragonfly Study: An International, Prospective, Longitudinal, Observational Natural History Study of Children and Adults Living With CTNNB1 Neurodevelopmental Syndrome'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The aim of the Dragonfly study is to characterise and monitor the neurodevelopment of children and adults diagnosed with CTNNB1 syndrome through an international collaborative effort.
    explanation: Documents the prospective natural-history study that will supply longitudinal outcome data currently missing for this disorder.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07167732
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT07167732
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The aim of the Dragonfly study is to characterise and monitor the neurodevelopment of children and adults diagnosed with CTNNB1 syndrome through an international collaborative effort.
    explanation: The detailed registry describes the study purpose. Its hasResults field is false at retrieval, so this record supplies no posted efficacy results.
- name: NCT04812119
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: 'GenPhe: Completed remote genotype-phenotype study. The registry reports 100 actual participants; the linked 2025 paper reports 127 enrolled individuals, a distinct reporting count that should not be silently harmonized. Its caregiver assessments inform natural history rather than treatment efficacy. No results posted in the registry.'
  evidence:
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT04812119
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT04812119
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '"statusModule": {"statusVerifiedDate": "2022-11", "overallStatus": "COMPLETED", "expandedAccessInfo": {"hasExpandedAccess": false}, "startDateStruct": {"date": "2021-03-01", "type": "ACTUAL"}, "primaryCompletionDateStruct": {"date": "2022-09-01", "type": "ACTUAL"}, "completionDateStruct": {"date": "2022-11-01", "type": "ACTUAL"}'
    explanation: The registry status module records COMPLETED alongside actual start and completion dates.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT04812119
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT04812119
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The aim of this study is to explore and define the correlations between genotype and phenotype in patients with CTNNB1 mutations as well as monitor and survey the natural history of the CTNNB1 syndrome.
    explanation: The detailed registry describes the study purpose. Its hasResults field is false at retrieval, so this record supplies no posted efficacy results.
- name: NCT05168969
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: 'Exaggerated Startle: Completed observational study of exaggerated startle in CTNNB1 syndrome, with 10 actual participants recorded. Eligibility requires an exaggerated startle response, so this selected sample cannot estimate prevalence in unselected CTNNB1-NDD. The registry count is not equated with the twelve-person publication. No results posted in the registry.'
  evidence:
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT05168969
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT05168969
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '"statusModule": {"statusVerifiedDate": "2023-04", "overallStatus": "COMPLETED", "expandedAccessInfo": {"hasExpandedAccess": false}, "startDateStruct": {"date": "2022-07-02", "type": "ACTUAL"}, "primaryCompletionDateStruct": {"date": "2022-12-10", "type": "ACTUAL"}, "completionDateStruct": {"date": "2022-12-10", "type": "ACTUAL"}'
    explanation: The registry status module records COMPLETED alongside actual start and completion dates.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT05168969
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT05168969
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The investigators also have a 3rd patient carrying a CTNNB1 syndrome associated with hyperekplexia.
    explanation: The detailed registry describes the study purpose. Its hasResults field is false at retrieval, so this record supplies no posted efficacy results.
discussions:
- discussion_id: ctnnb1_dopaminergic_deficit
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: Does the reduced midbrain dopaminergic neurogenesis seen in Ctnnb1 knockout mouse models translate into a dopaminergic deficit in human CTNNB1-NDD that is sufficient to make levodopa a rational therapy?
  attaches_to:
  - pathophysiology#Developmental Motor Circuit Dysfunction
  rationale: Conditional Ctnnb1 mouse models motivate a dopaminergic hypothesis, but a specific presynaptic deficit has not been established by the cited human studies. In a selected movement-disorder series levodopa helped 1/4 treated patients and botulinum toxin 5/6. These uncontrolled responses cannot determine which neuronal pathway causes the motor phenotype.
  proposed_experiments:
  - experiment_id: ctnnb1_dopaminergic_imaging
    name: Presynaptic dopaminergic imaging in CTNNB1-NDD
    description: DaTscan or FDOPA PET in individuals with molecularly confirmed CTNNB1-NDD and dystonia, compared with age-matched reference data, to test whether a presynaptic nigrostriatal dopaminergic deficit is present in humans.
    decision_criterion: Reduced tracer measures would support a presynaptic abnormality. Normal measures would weaken that specific hypothesis without excluding altered dopamine signaling or a symptomatic levodopa benefit.
  - experiment_id: ctnnb1_csf_neurotransmitters
    name: CSF neurotransmitter metabolite profiling in CTNNB1-NDD
    description: Measurement of CSF homovanillic acid and 5-hydroxyindoleacetic acid in a CTNNB1-NDD cohort to detect a biochemical dopaminergic deficiency.
    decision_criterion: Low CSF homovanillic acid would provide biochemical support for the dopaminergic-deficit model.
  - experiment_id: ctnnb1_levodopa_pilot
    name: Completion of the NCT07614126 levodopa pilot
    description: Completion and prespecified analysis of the open-label levodopa/carbidopa pilot, with GMFM-88 as the primary motor endpoint. The registered study is unblinded.
    decision_criterion: Improvement would support symptomatic benefit for further controlled testing; either response or nonresponse is insufficient by itself to establish or refute a specific dopaminergic mechanism.
  evidence:
  - reference: PMID:39067319
    reference_title: 'Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Treatment efficacy was variable: botulinum toxin was (at least partially) effective in 5/6, levodopa in 1 of 4 treated patients.'
    explanation: Human treatment-response data are weak for levodopa relative to botulinum toxin, tempering the model-derived dopaminergic hypothesis.

📚