🏷

Classifications

Harrison's Part

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Inheritance

1

Autosomal dominant, typically de novo HP:0000006

CTNNB1-NDD is autosomal dominant and in the great majority of cases results from a de novo heterozygous loss-of-function variant. Inheritance from a mildly affected or apparently asymptomatic parent has been documented, so parental testing is indicated before counselling recurrence risk as negligible; germline mosaicism is an additional consideration. Penetrance for unambiguous loss-of-function variants appears high, while expressivity is markedly variable, ranging from a near-normal neurodevelopmental outcome with isolated eye disease to profound impairment.

Autosomal dominant inheritance Expressivity: VARIABLE

Show evidence (2 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."

Documents both the predominance of de novo variants and a transmitted variant from an asymptomatic parent, supporting variable expressivity/reduced penetrance in counselling.

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Discussions and Knowledge Gaps

1

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#Progressive Corticospinal and Extrapyramidal Motor Dysfunction

Animal models show severe reduction in dopaminergic neurogenesis when Ctnnb1 is lost, and this is the stated rationale for an ongoing levodopa pilot trial. In humans, however, the only supporting data are anecdotal: in the single systematically assessed cohort levodopa was helpful in only 1 of 4 treated patients, whereas botulinum toxin helped 5 of 6. No human imaging or CSF evidence of presynaptic dopaminergic deficiency in CTNNB1-NDD has been published. The mismatch is mechanistically meaningful because it determines whether the movement disorder is primarily an extrapyramidal neurotransmitter-deficiency state or a developmental corticospinal/circuit lesion.

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 striatal tracer binding relative to reference values would support a human dopaminergic deficit and strengthen the levodopa rationale; normal binding would refute it.

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 blinded analysis of the open-label levodopa/carbidopa pilot in children with CTNNB1-related dystonia, with GMFM-88 as the primary motor endpoint.

Decision criterion

A clinically meaningful GMFM-88 improvement would support the dopaminergic hypothesis; absence of response would argue for a primarily developmental circuit lesion.

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.

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Pathophysiology

7

CTNNB1 Loss-of-Function and Beta-Catenin Haploinsufficiency

Heterozygous nonsense, frameshift, splice-site and whole-gene deletion variants in CTNNB1, plus a minority of missense variants, truncate or destabilise beta-catenin and reduce the pool of functional protein. In the largest functionally characterised cohort, 87 of 88 distinct variants were predicted loss of function, and a subset of missense alleles act as dominant negatives that suppress signalling beyond simple haploinsufficiency. Complete deletion of the single gene CTNNB1 is sufficient to produce the syndrome, establishing dosage sensitivity as the core lesion.

CTNNB1 hgnc:2514

Downstream

Canonical Wnt/Beta-Catenin Transcriptional Deficit Reduced functional beta-catenin lowers the nuclear pool available to co-activate TCF/LEF target genes.

Impaired Cadherin-Catenin Adherens Junction Adhesion Reduced or structurally altered beta-catenin weakens the cadherin-to-actin linkage at adherens junctions, a signalling-independent structural role.

Cardiac Developmental Wnt Signalling Disruption Reduced beta-catenin dosage in the developing heart, where CTNNB1 is also expressed, is the proposed route to the congenital cardiac anomalies; the intermediates are not established for CTNNB1 specifically.

Show evidence (3 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."

A whole-gene deletion of CTNNB1 alone reproduces the syndrome, establishing haploinsufficiency rather than a variant-specific gain of function.

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"

Confirms that essentially the entire disease-associated variant spectrum is loss of function.

Canonical Wnt/Beta-Catenin Transcriptional Deficit

Beta-catenin is the obligate transcriptional co-activator of the canonical Wnt pathway: on Wnt/Norrin receptor engagement it escapes destruction-complex phosphorylation, accumulates, and enters the nucleus to partner TCF/LEF transcription factors. Reduced beta-catenin dosage lowers Wnt-responsive reporter output (TOPFlash/SuperTopFlash) and target-gene transcription in patient-derived and transfected systems. A subset of missense variants further suppresses signalling in a dominant-negative fashion, and one gain-of-function missense allele has been described as an outlier.

canonical Wnt signaling pathway GO:0060070 ↓ DECREASED regulation of canonical Wnt signaling pathway GO:0060828

Downstream

Disrupted Cortical Neurodevelopment and Connectivity Reduced Wnt target-gene output in neural progenitors and neurons perturbs proliferation, differentiation and circuit assembly in the developing brain.

Retinal Vascular Norrin/Beta-Catenin Signalling Failure Norrin-FZD4-LRP5-TSPAN12 signalling in retinal endothelium converges on beta-catenin; reduced beta-catenin lowers Norrin target-gene transcription.

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.

PMID:40684264 SUPPORT In Vitro

"Functional assays demonstrated reduced Wnt signaling activity, including 11 variants that also exhibited a dominant-negative effect."

Directly measures reduced Wnt signalling activity across patient variants and identifies a dominant-negative subset.

Impaired Cadherin-Catenin Adherens Junction Adhesion

Independently of transcription, beta-catenin bridges the cytoplasmic tail of classical cadherins to alpha-catenin and the actin cytoskeleton at adherens junctions. In the batface mouse a substitution in the C-terminal armadillo repeat reduces affinity for membrane-associated cadherins (this specific structure-function result comes from the mouse allele, not a human patient variant), and CTNNB1 knockdown in primary human endothelial cells compromises junctional integrity. This adhesion arm explains why the disorder is not simply a Wnt-signalling phenocopy and contributes to both neuronal connectivity and vascular barrier phenotypes.

adherens junction organization GO:0034332 ↓ DECREASED

cadherin binding GO:0045296 ↓ DECREASED

adherens junction GO:0005912

Downstream

Disrupted Cortical Neurodevelopment and Connectivity Weakened cadherin-catenin adhesion reduces dendritic branching and intrahemispheric connectivity in the batface mouse model.

Show evidence (3 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.

PMID:24614104 SUPPORT Model Organism

"Our study provides in vivo evidence that dominant mutations in β-catenin underlie losses in its adhesion-related functions, which leads to severe consequences, including intellectual disability, childhood hypotonia, progressive spasticity of lower limbs, and abnormal craniofacial features in adults."

Links loss of beta-catenin adhesion function directly to the human-matching phenotype set (ID, hypotonia, progressive lower-limb spasticity, craniofacial anomalies).

PMID:39833474 SUPPORT Other

"Additionally, these mutations impair the formation of cell junctions, adversely affecting tissue architecture."

Review of CTNNB1 mouse models states the junction-formation (adhesion) arm of the mechanism alongside Wnt signalling.

Disrupted Cortical Neurodevelopment and Connectivity

Combined loss of Wnt transcriptional output and cadherin-mediated adhesion in neural progenitors and post-mitotic neurons impairs neuronal differentiation, dendritic arborisation and long-range intrahemispheric connectivity, with measurable deficits in long-term potentiation. Postnatal (rather than congenital) microcephaly and a progressive rather than static neurological course in some individuals indicate that the lesion affects continuing neuronal maturation and maintenance, not only early patterning.

neural progenitor cell CL:0011020 cerebral cortex neuron CL:0010012

cerebral cortex neuron differentiation GO:0021895 ⚠ ABNORMAL dendrite morphogenesis GO:0048813 ↓ DECREASED

Downstream

Intellectual Disability Reduced cortical connectivity and impaired synaptic plasticity underlie the cognitive impairment.

Progressive Corticospinal and Extrapyramidal Motor Dysfunction The same developmental lesion affects descending motor and basal-ganglia circuits, producing the characteristic motor phenotype.

Secondary Microcephaly Impaired postnatal neuronal growth and maturation produces acquired microcephaly rather than a congenitally small head.

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."

Direct in vivo demonstration of reduced intrahemispheric connectivity, dendritic branching and LTP with consequent cognitive impairment.

PMID:24668549 SUPPORT Other

"Thus, CTNNB1 haploinsufficiency causes neuronal loss, craniofacial anomalies and hair follicle defects in both humans and mice."

Author conclusion combining the human case and mouse knockout data; tagged OTHER because it mixes human and model-organism evidence in one statement.

Progressive Corticospinal and Extrapyramidal Motor Dysfunction

The motor phenotype has a characteristic biphasic structure: early truncal hypotonia and muscle weakness give way to progressive distal, predominantly lower-limb hypertonia/spasticity, frequently without overt pyramidal signs, with an exaggerated startle response resembling atypical hyperekplexia. In the second decade a subset develop upper-body (prominently cervical) dystonia with or without bradykinesia, indicating additional extrapyramidal/basal-ganglia involvement. The early static appearance leads many individuals to be given a cerebral palsy diagnosis.

Downstream

Spastic Diplegia Progressive lower-limb hypertonia manifests as spastic diplegia.

Dystonia Extrapyramidal involvement produces cervical/upper-body dystonia, typically emerging in the second decade.

Exaggerated Startle Response Brainstem/reticular startle-circuit dysregulation produces an atypical hyperekplexia phenotype with injurious falls.

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."

Summarises the composite corticospinal-plus-extrapyramidal motor phenotype and its temporal evolution.

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

Retinal vascular development and blood-retina barrier maturation depend on Norrin (NDP) signalling through FZD4/LRP5/TSPAN12 to beta-catenin in retinal microvascular endothelium. Truncating CTNNB1 variants reduce Norrin/beta-catenin signalling activity, and CTNNB1 knockdown in primary human retinal microvascular endothelial cells lowers Norrin target-gene transcription, reduces endothelial proliferation and compromises junctional integrity; endothelial-specific heterozygous Ctnnb1 deletion in mouse reproduces FEVR-like retinopathy. This places CTNNB1 in the same signalling module as the classical FEVR genes and explains an ocular phenotype clinically indistinguishable from FEVR.

retinal blood vessel endothelial cell CL:0002585

retinal blood vessel morphogenesis GO:0061304 ⚠ ABNORMAL establishment of blood-retinal barrier GO:1990963 ↓ DECREASED

Downstream

Exudative Vitreoretinopathy Incomplete peripheral retinal vascularisation and leaky vessels produce exudative vitreoretinopathy that can progress to retinal detachment.

Show evidence (3 references)

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.

PMID:35361685 SUPPORT Model Organism

"The Cre-mediated heterozygous deletion of Ctnnb1 in mouse endothelial cells (ECs) resulted in FEVR-like phenotypes."

Endothelial-specific heterozygous Ctnnb1 loss is sufficient to produce FEVR-like retinopathy in vivo.

PMID:36790797 SUPPORT In Vitro

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

Patient CTNNB1 variants fail to activate a beta-catenin-responsive reporter, confirming signalling loss in the FEVR context.

Cardiac Developmental Wnt Signalling Disruption

CTNNB1 is expressed in the developing heart in addition to brain, and beta-catenin-dependent Wnt signalling contributes to second-heart-field and outflow-tract/valve development. A dedicated cardiac phenotyping series found congenital heart anomalies (absent pulmonary valve with intact ventricular septum, atrioventricular canal with hypoplastic aortic arch, tetralogy of Fallot, mitral valve prolapse) at a higher rate than previously appreciated. This node is supported by clinical association plus tissue expression rather than by a CTNNB1-specific cardiac developmental experiment, and is curated at correspondingly lower mechanistic confidence.

Downstream

Congenital Heart Defect Disrupted beta-catenin-dependent cardiac development produces outflow-tract, valve and septal anomalies.

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.

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Pathograph

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

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Phenotypes

23

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 1

Feeding Difficulties OCCASIONAL HP:0011968

Show evidence (1 reference)

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, supporting an OCCASIONAL band.

Eye 1

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."

Strabismus in 9 of 11 (82%) with surgery in 5, supporting a VERY_FREQUENT band.

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.

Head and Neck 2

Secondary Microcephaly FREQUENT HP:0005484

Course: PROGRESSIVE

Show evidence (3 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."

Documents the postnatal (acquired) rather than congenital nature of the microcephaly.

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.

Broad Nasal Tip FREQUENT HP:0000455

Show evidence (2 references)

PMID:25326669 SUPPORT Human Clinical

"some overlapping facial features in all individuals (broad nasal tip, small alae nasi, long and/or flat philtrum, thin upper lip vermillion)"

A broad nasal tip was among the facial features present in all individuals of this cohort.

PMID:36153650 SUPPORT Human Clinical

"wide nasal bridge (58.3%), bulbous nose (45.8%)"

An independent cohort quantifies the related nasal dysmorphism at 45-58%, supporting a FREQUENT band across cohorts.

Integument 1

Sparse Fair Hair OCCASIONAL 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:24668549 SUPPORT Model Organism

"In mice, a conditional homozygous β-catenin knockout displays loss of neurons, impaired craniofacial development, and hair follicle defects, which is similar to the phenotype presented by the patient described in this clinical report."

Mouse beta-catenin knockout reproduces hair-follicle defects, providing the mechanistic basis for the hair phenotype.

Musculoskeletal 2

Muscle Weakness FREQUENT HP:0001324

Show evidence (1 reference)

PMID:38247296 SUPPORT Human Clinical

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

Muscle weakness was present in "most" of 32 deeply phenotyped individuals; "most" maps to the FREQUENT band under the project frequency-mapping guidance, since no numerator is given.

Scoliosis OCCASIONAL HP:0002650

Show evidence (1 reference)

PMID:35593792 SUPPORT Human Clinical

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

GeneReviews lists scoliosis among the less common features.

Nervous System 9

Intellectual Disability OBLIGATE HP:0001249

Show evidence (2 references)

PMID:35593792 SUPPORT Human Clinical

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

GeneReviews states cognitive impairment is present in all individuals, supporting the OBLIGATE frequency band.

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.

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)."

All 16 individuals in this cohort had motor delay and speech impairment. The band is held at VERY_FREQUENT rather than OBLIGATE because the 100% figure comes from modest cohorts (n=16 and n=24) rather than from an unselected population.

PMID:36153650 SUPPORT Human Clinical

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

A second, independent 24-patient cohort reports developmental delay and motor delay in 100% of individuals.

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%)"

An independent 24-patient cohort also reports speech impairment in 100% of individuals.

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 (2 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.

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."

Quantifies behavioural challenges at 65%, placing the frequency in the FREQUENT (30-79%) band.

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"

A second cohort quantifies behavioural abnormalities at 83.3%; with Sudnawa's 65% the pooled estimate spans the FREQUENT band and its upper edge.

Autistic Behavior FREQUENT HP:0000729

Show evidence (1 reference)

PMID:36293418 SUPPORT Human Clinical

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

The systematic review places autistic-like behaviour within "the most common moderate-severe phenotype", supporting a FREQUENT rather than occasional band; no cohort reports a discrete autism-diagnosis rate, so no more precise band is asserted.

Tethered Cord FREQUENT HP:0002144

Show evidence (1 reference)

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, supporting a FREQUENT band.

Growth 1

Intrauterine Growth Restriction OCCASIONAL Intrauterine growth retardation HP:0001511

Show evidence (1 reference)

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.

Other 5

Truncal Hypotonia FREQUENT Axial hypotonia HP:0008936

Show evidence (2 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 truncal hypotonia among the common findings; "common" maps to the FREQUENT (30-79%) band under the project frequency-mapping guidance.

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.

Spastic Diplegia VERY_FREQUENT HP:0001264

Course: PROGRESSIVE

Show evidence (2 references)

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.

PMID:24614104 SUPPORT Model Organism

"including intellectual disability, childhood hypotonia, progressive spasticity of lower limbs, and abnormal craniofacial features in adults"

Concluding sentence of an in vivo mouse study describing the childhood-hypotonia-to-progressive-lower-limb-spasticity sequence; tagged MODEL_ORGANISM to match the same sentence as cited in the pathophysiology section.

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.

Refractive Error VERY_FREQUENT 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"

Nearly all patients required care for refractive error, supporting a VERY_FREQUENT band.

PMID:38247296 SUPPORT Human Clinical

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

Identifies hyperopia as the characteristic refractive error in this disorder.

Thin Upper Lip Vermilion FREQUENT HP:0000219

Show evidence (2 references)

PMID:25326669 SUPPORT Human Clinical

"some overlapping facial features in all individuals (broad nasal tip, small alae nasi, long and/or flat philtrum, thin upper lip vermillion)"

Overlapping facial features including a thin upper lip vermilion were present in all 16 individuals of this cohort.

PMID:36153650 SUPPORT Human Clinical

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

A second cohort reports thin upper lip in 45.8%; the discrepancy with the 16/16 European series is why the band is set to FREQUENT rather than VERY_FREQUENT.

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Genetic Associations

1

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

Gene: CTNNB1 hgnc:2514 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (3 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"

Documents the genotype-phenotype relationship in which missense variants confer a milder phenotype than truncating variants.

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."

Systematic review documenting the milder phenotype associated with C-terminal (exon 13-15) variants.

💊

Medical Actions

7

Multidisciplinary Supportive Care

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

There is no curative or disease-modifying therapy. Management is supportive and multidisciplinary, typically involving neurology, speech-language pathology, physiatry, occupational therapy, physical therapy, a feeding team, paediatric ophthalmology, audiology and developmental paediatrics, with surveillance for emerging neurological, developmental, behavioural and ophthalmological problems.

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

Physiotherapy targets truncal hypotonia, muscle weakness, progressive lower-limb spasticity and gait, and is the mainstay of motor management.

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

Show evidence (1 reference)

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.

Speech and Language Therapy

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

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 (1 reference)

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.

Botulinum Toxin for Spasticity and Dystonia

Action: Pharmacotherapy NCIT:C15986

Agent: botulinum toxin type A CHEBI:3160

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

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 (2 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.

AAV9-Mediated CTNNB1 Gene Replacement (Investigational)

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

Urbagen is a single-stranded AAV9 vector carrying human CTNNB1, delivered once by bilateral intracerebroventricular infusion with prophylactic methylprednisolone and sirolimus, now in a first-in-human phase I/II trial (NCT07270549). It is the first candidate disease-modifying therapy and directly addresses the beta-catenin dosage deficit. No human safety or efficacy results are available. Because beta-catenin is dosage-sensitive and its stabilisation is oncogenic in the somatic setting, expression level, tissue targeting, and long-term surveillance are central safety questions.

Mechanism Target:

ACTIVATES CTNNB1 Loss-of-Function and Beta-Catenin Haploinsufficiency — Gene addition restores functional CTNNB1 expression, directly countering the beta-catenin dosage deficit at the top of the causal chain.

Show evidence (1 reference)

clinicaltrials:NCT07270549 SUPPORT Human Clinical

"Recieve a single dose of gene therapy via bilateral intracerebroventricular administration."

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

Genetic Counseling

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

Counselling covers the autosomal dominant, predominantly de novo mechanism, the need for parental testing given documented transmission from mildly affected or asymptomatic parents, and the availability of prenatal and preimplantation genetic testing once a familial variant is known.

Show evidence (1 reference)

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.

🔬

Diagnosis

2

Molecular Genetic Testing for CTNNB1 (Positive in affected individuals)

The diagnosis is established by identifying a heterozygous pathogenic CTNNB1 variant on exome/genome or multigene panel sequencing, or a 3p22.1 deletion involving CTNNB1 on chromosomal microarray, in an individual with suggestive findings. Because the phenotype is frequently labelled cerebral palsy or autism spectrum disorder, genetic testing should be considered in those settings.

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

2

Worldwide (children)

Birth Prevalence 2.6–3.2 per 100,000 1–9 per 100,000

Reported birth prevalence of 2.6-3.2 per 100,000 births; frequently misdiagnosed as cerebral palsy, so ascertainment is likely incomplete.

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

404 individuals carrying 392 distinct pathogenic CTNNB1 variants had been assembled by 2022; the disorder is characterised as ultra-rare.

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."

Quantifies the number of individuals and distinct pathogenic variants ascertained in the largest CTNNB1 cohort assembled to date.

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

5

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

Cerebral Palsy

Overlapping Features The commonest misdiagnosis. Spastic diplegia with early hypotonia in CTNNB1-NDD is clinically indistinguishable from cerebral palsy in early childhood; CTNNB1 is the most frequent recurrent monogenic cause of a cerebral palsy diagnosis, and molecular testing resolves the distinction.

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 Many individuals receive an ASD diagnosis before molecular testing; CTNNB1 syndrome patients differ in showing disproportionate visuospatial and logical-reasoning weakness and greater adaptive-functioning impairment.

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

3

NCT07270549 PHASE_I RECRUITING

GAIN-CTNNB1 - first-in-human open-label phase I/II trial of Urbagen, an AAV9 based CTNNB1 gene replacement therapy delivered by a single bilateral intracerebroventricular administration with prophylactic immunosuppression, in paediatric patients with CTNNB1 neurodevelopmental disorder.

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

Show evidence (1 reference)

clinicaltrials:NCT07270549 SUPPORT Human Clinical

"The goal of this first in human, phase I/II clinical trial is to evaulate 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.

NCT07614126 NOT_APPLICABLE RECRUITING

Open-label pilot study of L-dopa (levodopa) in children with CTNNB1-related NEDSDV and dystonia, motivated by evidence of reduced dopaminergic neurogenesis in Ctnnb1 knockout models and anecdotal clinical improvement.

Target Phenotypes: Dystonia HP:0001332

Show evidence (1 reference)

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.

NCT07167732 NOT_APPLICABLE RECRUITING

Dragonfly Study - international prospective longitudinal observational natural-history study of children and adults with CTNNB1 neurodevelopmental syndrome, intended to standardise care and support future trial design.

Show evidence (1 reference)

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.

🐁

Animal Models

2

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

An ENU-derived mouse carrying a Thr653Lys substitution in the C-terminal armadillo repeat of beta-catenin with reduced affinity for membrane-associated cadherins. It reproduces core features of the human disorder including craniofacial abnormalities, reduced intrahemispheric connectivity, deficient dendritic branching, impaired long-term potentiation and cognitive impairment.

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."

Establishes the batface line as a mouse model recapitulating features of human CTNNB1-related disease.

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.

{ }

Source YAML

click to show

name: CTNNB1 Neurodevelopmental Disorder
creation_date: "2026-07-31T00:00:00Z"
description: >-
  CTNNB1 neurodevelopmental disorder (CTNNB1-NDD; CTNNB1 syndrome; also catalogued
  as severe intellectual disability-progressive spastic diplegia syndrome,
  neurodevelopmental disorder with spastic diplegia and visual defects [NEDSDV],
  and autosomal dominant intellectual disability 19 [MRD19]) is a rare autosomal
  dominant neurodevelopmental disorder caused by heterozygous, almost always de
  novo, loss-of-function variants in CTNNB1 at 3p22.1. CTNNB1 encodes beta-catenin,
  a dual-function protein that is both the transcriptional effector of the
  canonical Wnt signalling pathway and a structural component of the
  cadherin-catenin adherens junction complex. Affected individuals show
  mild-to-profound cognitive impairment with markedly limited speech, truncal
  hypotonia with distal (predominantly lower-limb) spasticity that is progressive,
  dystonia and an exaggerated startle response, microcephaly, subtle craniofacial
  dysmorphism (broad nasal tip, small alae nasi, long/flat philtrum, thin upper
  lip vermilion), and a distinctive ophthalmological phenotype of exudative
  vitreoretinopathy indistinguishable from familial exudative vitreoretinopathy
  (FEVR) together with strabismus and refractive errors. Because the motor
  phenotype is non-progressive-appearing in early childhood, CTNNB1-NDD is the
  most frequent recurrent monogenic cause of a cerebral palsy diagnosis. This
  entry covers the germline neurodevelopmental disorder; it is explicitly NOT the
  somatic CTNNB1 gain-of-function/Wnt-activating oncogenesis seen in
  hepatoblastoma, adamantinomatous craniopharyngioma and other tumours, which is
  a mechanistically opposite (stabilising) lesion.
category: Mendelian
parents:
- Neurodevelopmental Disorder
- Syndromic Intellectual Disability
notes: >-
  Scope and disambiguation. CTNNB1 is heavily represented in the cancer literature,
  where SOMATIC exon-3 missense variants stabilise beta-catenin and drive
  constitutive Wnt/TCF target-gene transcription (hepatoblastoma, adamantinomatous
  craniopharyngioma, endometrioid carcinomas). CTNNB1-NDD is the mechanistic
  mirror image: GERMLINE de novo loss-of-function variants that reduce beta-catenin
  dosage/activity. No cancer predisposition is part of CTNNB1-NDD, and the
  oncogenic literature was deliberately excluded from this curation.
  Module conformance. No mechanism module in kb/modules/ currently captures a
  canonical Wnt/beta-catenin developmental-signalling-loss chain, and the existing
  neurodevelopmental modules
  (microtubule_dependent_neuronal_migration_failure,
  reelin_terminal_translocation_lamination_failure,
  neural_progenitor_centrosome_spindle_dysfunction,
  interneuron_specification_tangential_migration_failure) each specify a node chain
  (microtubule motor/lamination/centrosome/interneuron-fate machinery) that
  CTNNB1-NDD evidence does not support. No `conforms_to` is therefore declared.
  A future `wnt_beta_catenin_developmental_signalling` module would be the natural
  home for the shared node chain with the FEVR/Norrin genes (NDP, FZD4, LRP5,
  TSPAN12) and with other Wnt-pathway neurodevelopmental disorders.
  Term choice. MONDO:0014035 was chosen over its parent MONDO:0100571
  ("CTNNB1-related neurodevelopmental disorder and/or vitreoretinopathy") because
  the issue and the clinical literature target the neurodevelopmental entity
  (OMIM 615075 / NEDSDV / MRD19), which carries the FEVR arm as one of its own
  features. The parent term additionally subsumes isolated CTNNB1-FEVR without
  neurodevelopmental involvement, which is out of scope here.
  Known gap. Sleep disturbance is reported at appreciable frequency in the
  CTNNB1 community and is a Dragonfly-study outcome, but no quotable
  frequency statement was found in an abstract available to this curation, so
  it is deliberately omitted rather than asserted without evidence.
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:35593792
  title: "CTNNB1 Neurodevelopmental Disorder."
  tags:
  - GeneReviews
prevalence:
- population: Worldwide (children)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_low: 2.6
  rate_high: 3.2
  notes: >-
    Reported birth prevalence of 2.6-3.2 per 100,000 births; frequently
    misdiagnosed as cerebral palsy, so ascertainment is likely incomplete.
  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: >-
    404 individuals carrying 392 distinct pathogenic CTNNB1 variants had been
    assembled by 2022; the disorder is characterised as ultra-rare.
  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: Quantifies the number of individuals and distinct pathogenic variants ascertained in the largest CTNNB1 cohort assembled to date.
  - 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 in the great majority of cases results
    from a de novo heterozygous loss-of-function variant. Inheritance from a
    mildly affected or apparently asymptomatic parent has been documented, so
    parental testing is indicated before counselling recurrence risk as
    negligible; germline mosaicism is an additional consideration. Penetrance for
    unambiguous loss-of-function variants appears high, while expressivity is
    markedly variable, ranging from a near-normal neurodevelopmental outcome with
    isolated eye disease to profound impairment.
  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: Documents both the predominance of de novo variants and a transmitted variant from an asymptomatic parent, supporting variable expressivity/reduced penetrance in counselling.
pathophysiology:
- name: CTNNB1 Loss-of-Function and Beta-Catenin Haploinsufficiency
  biological_scale: MOLECULAR
  description: >-
    Heterozygous nonsense, frameshift, splice-site and whole-gene deletion variants
    in CTNNB1, plus a minority of missense variants, truncate or destabilise
    beta-catenin and reduce the pool of functional protein. In the largest
    functionally characterised cohort, 87 of 88 distinct variants were predicted
    loss of function, and a subset of missense alleles act as dominant negatives
    that suppress signalling beyond simple haploinsufficiency. Complete deletion of
    the single gene CTNNB1 is sufficient to produce the syndrome, establishing
    dosage sensitivity as the core lesion.
  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 lowers the nuclear pool available to
      co-activate TCF/LEF target genes.
  - target: Impaired Cadherin-Catenin Adherens Junction Adhesion
    causal_link_type: DIRECT
    description: >-
      Reduced or structurally altered beta-catenin weakens the cadherin-to-actin
      linkage at adherens junctions, a signalling-independent structural role.
  - target: Cardiac Developmental Wnt Signalling Disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced beta-catenin dosage in the developing heart, where CTNNB1 is also
      expressed, is the proposed route to the congenital cardiac anomalies; the
      intermediates are not established for CTNNB1 specifically.
  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: A whole-gene deletion of CTNNB1 alone reproduces the syndrome, establishing haploinsufficiency rather than a variant-specific gain of function.
  - 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: Confirms that essentially the entire disease-associated variant spectrum is loss of function.
- name: Canonical Wnt/Beta-Catenin Transcriptional Deficit
  biological_scale: MOLECULAR
  description: >-
    Beta-catenin is the obligate transcriptional co-activator of the canonical Wnt
    pathway: on Wnt/Norrin receptor engagement it escapes destruction-complex
    phosphorylation, accumulates, and enters the nucleus to partner TCF/LEF
    transcription factors. Reduced beta-catenin dosage lowers Wnt-responsive
    reporter output (TOPFlash/SuperTopFlash) and target-gene transcription in
    patient-derived and transfected systems. A subset of missense variants further
    suppresses signalling in a dominant-negative fashion, and one gain-of-function
    missense allele has been described as an outlier.
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: DECREASED
  - preferred_term: regulation of canonical Wnt signaling pathway
    term:
      id: GO:0060828
      label: regulation of canonical Wnt signaling pathway
  downstream:
  - target: Disrupted Cortical Neurodevelopment and Connectivity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced Wnt target-gene output in neural progenitors and neurons perturbs
      proliferation, differentiation and circuit assembly in the developing brain.
  - target: Retinal Vascular Norrin/Beta-Catenin Signalling Failure
    causal_link_type: DIRECT
    description: >-
      Norrin-FZD4-LRP5-TSPAN12 signalling in retinal endothelium converges on
      beta-catenin; reduced beta-catenin lowers Norrin target-gene transcription.
  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: PMID:40684264
    reference_title: "Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional assays demonstrated reduced Wnt signaling activity, including 11 variants that also exhibited a dominant-negative effect."
    explanation: Directly measures reduced Wnt signalling activity across patient variants and identifies a dominant-negative subset.
- name: Impaired Cadherin-Catenin Adherens Junction Adhesion
  biological_scale: CELLULAR
  description: >-
    Independently of transcription, beta-catenin bridges the cytoplasmic tail of
    classical cadherins to alpha-catenin and the actin cytoskeleton at adherens
    junctions. In the batface mouse a substitution in the C-terminal armadillo
    repeat reduces affinity for membrane-associated cadherins (this specific
    structure-function result comes from the mouse allele, not a human patient
    variant), and CTNNB1 knockdown in
    primary human endothelial cells compromises junctional integrity. This
    adhesion arm explains why the disorder is not simply a Wnt-signalling
    phenocopy and contributes to both neuronal connectivity and vascular barrier
    phenotypes.
  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: Disrupted Cortical Neurodevelopment and Connectivity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Weakened cadherin-catenin adhesion reduces dendritic branching and
      intrahemispheric connectivity in the batface mouse model.
  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: PMID:24614104
    reference_title: "Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our study provides in vivo evidence that dominant mutations in β-catenin underlie losses in its adhesion-related functions, which leads to severe consequences, including intellectual disability, childhood hypotonia, progressive spasticity of lower limbs, and abnormal craniofacial features in adults."
    explanation: Links loss of beta-catenin adhesion function directly to the human-matching phenotype set (ID, hypotonia, progressive lower-limb spasticity, craniofacial anomalies).
  - reference: PMID:39833474
    reference_title: "CTNNB1 syndrome mouse models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Additionally, these mutations impair the formation of cell junctions, adversely affecting tissue architecture."
    explanation: Review of CTNNB1 mouse models states the junction-formation (adhesion) arm of the mechanism alongside Wnt signalling.
- name: Disrupted Cortical Neurodevelopment and Connectivity
  biological_scale: CELLULAR
  description: >-
    Combined loss of Wnt transcriptional output and cadherin-mediated adhesion in
    neural progenitors and post-mitotic neurons impairs neuronal differentiation,
    dendritic arborisation and long-range intrahemispheric connectivity, with
    measurable deficits in long-term potentiation. Postnatal (rather than
    congenital) microcephaly and a progressive rather than static neurological
    course in some individuals indicate that the lesion affects continuing
    neuronal maturation and maintenance, not only early patterning.
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  - preferred_term: cerebral cortex neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  biological_processes:
  - preferred_term: cerebral cortex neuron differentiation
    term:
      id: GO:0021895
      label: cerebral cortex neuron differentiation
    modifier: ABNORMAL
  - preferred_term: dendrite morphogenesis
    term:
      id: GO:0048813
      label: dendrite morphogenesis
    modifier: DECREASED
  downstream:
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced cortical connectivity and impaired synaptic plasticity underlie the
      cognitive impairment.
  - target: Progressive Corticospinal and Extrapyramidal Motor Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The same developmental lesion affects descending motor and basal-ganglia
      circuits, producing the characteristic motor phenotype.
  - target: Secondary Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired postnatal neuronal growth and maturation produces acquired
      microcephaly rather than a congenitally small head.
  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: Direct in vivo demonstration of reduced intrahemispheric connectivity, dendritic branching and LTP with consequent cognitive impairment.
  - reference: PMID:24668549
    reference_title: "A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Thus, CTNNB1 haploinsufficiency causes neuronal loss, craniofacial anomalies and hair follicle defects in both humans and mice."
    explanation: Author conclusion combining the human case and mouse knockout data; tagged OTHER because it mixes human and model-organism evidence in one statement.
- name: Progressive Corticospinal and Extrapyramidal Motor Dysfunction
  biological_scale: TISSUE
  description: >-
    The motor phenotype has a characteristic biphasic structure: early truncal
    hypotonia and muscle weakness give way to progressive distal, predominantly
    lower-limb hypertonia/spasticity, frequently without overt pyramidal signs,
    with an exaggerated startle response resembling atypical hyperekplexia. In the
    second decade a subset develop upper-body (prominently cervical) dystonia with
    or without bradykinesia, indicating additional extrapyramidal/basal-ganglia
    involvement. The early static appearance leads many individuals to be given a
    cerebral palsy diagnosis.
  downstream:
  - target: Spastic Diplegia
    causal_link_type: DIRECT
    description: Progressive lower-limb hypertonia manifests as spastic diplegia.
  - target: Dystonia
    causal_link_type: DIRECT
    description: >-
      Extrapyramidal involvement produces cervical/upper-body dystonia, typically
      emerging in the second decade.
  - target: Exaggerated Startle Response
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Brainstem/reticular startle-circuit dysregulation produces an atypical
      hyperekplexia phenotype with injurious falls.
  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: Summarises the composite corticospinal-plus-extrapyramidal motor phenotype and its temporal evolution.
  - 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.
- name: Retinal Vascular Norrin/Beta-Catenin Signalling Failure
  biological_scale: TISSUE
  description: >-
    Retinal vascular development and blood-retina barrier maturation depend on
    Norrin (NDP) signalling through FZD4/LRP5/TSPAN12 to beta-catenin in retinal
    microvascular endothelium. Truncating CTNNB1 variants reduce Norrin/beta-catenin
    signalling activity, and CTNNB1 knockdown in primary human retinal
    microvascular endothelial cells lowers Norrin target-gene transcription,
    reduces endothelial proliferation and compromises junctional integrity;
    endothelial-specific heterozygous Ctnnb1 deletion in mouse reproduces
    FEVR-like retinopathy. This places CTNNB1 in the same signalling module as the
    classical FEVR genes and explains an ocular phenotype clinically
    indistinguishable from FEVR.
  cell_types:
  - preferred_term: retinal blood vessel endothelial cell
    term:
      id: CL:0002585
      label: retinal blood vessel endothelial cell
  biological_processes:
  - preferred_term: retinal blood vessel morphogenesis
    term:
      id: GO:0061304
      label: retinal blood vessel morphogenesis
    modifier: ABNORMAL
  - preferred_term: establishment of blood-retinal barrier
    term:
      id: GO:1990963
      label: establishment of blood-retinal barrier
    modifier: DECREASED
  downstream:
  - target: Exudative Vitreoretinopathy
    causal_link_type: DIRECT
    description: >-
      Incomplete peripheral retinal vascularisation and leaky vessels produce
      exudative vitreoretinopathy that can progress to retinal detachment.
  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.
  - reference: PMID:35361685
    reference_title: "Novel truncating variants in CTNNB1 cause familial exudative vitreoretinopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The Cre-mediated heterozygous deletion of Ctnnb1 in mouse endothelial cells (ECs) resulted in FEVR-like phenotypes."
    explanation: Endothelial-specific heterozygous Ctnnb1 loss is sufficient to produce FEVR-like retinopathy in vivo.
  - 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: Patient CTNNB1 variants fail to activate a beta-catenin-responsive reporter, confirming signalling loss in the FEVR context.
- name: Cardiac Developmental Wnt Signalling Disruption
  biological_scale: TISSUE
  description: >-
    CTNNB1 is expressed in the developing heart in addition to brain, and
    beta-catenin-dependent Wnt signalling contributes to second-heart-field and
    outflow-tract/valve development. A dedicated cardiac phenotyping series found
    congenital heart anomalies (absent pulmonary valve with intact ventricular
    septum, atrioventricular canal with hypoplastic aortic arch, tetralogy of
    Fallot, mitral valve prolapse) at a higher rate than previously appreciated.
    This node is supported by clinical association plus tissue expression rather
    than by a CTNNB1-specific cardiac developmental experiment, and is curated at
    correspondingly lower mechanistic confidence.
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Congenital Heart Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disrupted beta-catenin-dependent cardiac development produces outflow-tract,
      valve and septal anomalies.
  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 present in every reported individual and ranges from
    mild to profound. Performance is relatively better on verbal than on
    visuospatial and logical-reasoning tasks.
  frequency: OBLIGATE
  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: GeneReviews states cognitive impairment is present in all individuals, supporting the OBLIGATE frequency band.
  - 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.
- category: Developmental
  name: Global Developmental Delay
  description: >-
    Motor and language milestones are delayed from infancy; roughly half of
    individuals eventually walk without an assistive device.
  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: All 16 individuals in this cohort had motor delay and speech impairment. The band is held at VERY_FREQUENT rather than OBLIGATE because the 100% figure comes from modest cohorts (n=16 and n=24) rather than from an unselected population.
  - 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: A second, independent 24-patient cohort reports developmental delay and motor delay in 100% of individuals.
  - 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: An independent 24-patient cohort also reports speech impairment in 100% of individuals.
  - 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: 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: GeneReviews lists truncal hypotonia among the common findings; "common" maps to the FREQUENT (30-79%) band under the project frequency-mapping guidance.
  - 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.
- 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.
  - reference: PMID:24614104
    reference_title: "Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "including intellectual disability, childhood hypotonia, progressive spasticity of lower limbs, and abnormal craniofacial features in adults"
    explanation: Concluding sentence of an in vivo mouse study describing the childhood-hypotonia-to-progressive-lower-limb-spasticity sequence; tagged MODEL_ORGANISM to match the same sentence as cited in the pathophysiology section.
- category: Neurological
  name: Dystonia
  description: >-
    Upper-body, prominently cervical, dystonia develops in a subset of individuals,
    characteristically in the second decade of life, sometimes with bradykinesia.
  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: >-
    An exaggerated startle response to unexpected stimuli, corresponding to
    atypical hyperekplexia, is under-recognised but clinically important because it
    causes falls and injuries and is treatable.
  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.
- category: Neurological
  name: Muscle Weakness
  description: >-
    Reduced muscle strength contributes to delayed ambulation and reduced gross
    motor function independent of tone abnormalities.
  frequency: 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: Muscle weakness was present in "most" of 32 deeply phenotyped individuals; "most" maps to the FREQUENT band under the project frequency-mapping guidance, since no numerator is given.
- category: Neurological
  name: Secondary Microcephaly
  description: >-
    Head circumference is typically normal at birth with acquired postnatal
    microcephaly, commonly in the -2 to -4 SD range, developing over early
    childhood.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Secondary microcephaly
    term:
      id: HP:0005484
      label: Secondary microcephaly
    clinical_course: PROGRESSIVE
  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: Documents the postnatal (acquired) rather than congenital nature of the microcephaly.
  - 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.
- 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.
  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: Strabismus in 9 of 11 (82%) with surgery in 5, supporting a VERY_FREQUENT band.
  - 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: >-
    Refractive errors, characteristically hyperopia, are near-universal and
    require ophthalmological correction.
  frequency: VERY_FREQUENT
  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: Nearly all patients required care for refractive error, supporting a VERY_FREQUENT band.
  - 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: Quantifies behavioural challenges at 65%, placing the frequency in the FREQUENT (30-79%) band.
  - 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: A second cohort quantifies behavioural abnormalities at 83.3%; with Sudnawa's 65% the pooled estimate spans the FREQUENT band and its upper edge.
- category: Behavioral
  name: Autistic Behavior
  description: >-
    Autistic-like behaviour is described as part of the behavioural spectrum,
    and individuals are frequently given an autism spectrum diagnosis before the
    molecular diagnosis is made.
  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 places autistic-like behaviour within "the most common moderate-severe phenotype", supporting a FREQUENT rather than occasional band; no cohort reports a discrete autism-diagnosis rate, so no more precise band is asserted.
- category: Craniofacial
  name: Thin Upper Lip Vermilion
  description: >-
    Part of a subtle but recognisable facial gestalt that also includes a broad
    nasal tip, small alae nasi and a long and/or flat philtrum. Reported in all
    individuals in one European cohort but in 45.8% of a Chinese cohort, so the
    band is set conservatively.
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Thin upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  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: "some overlapping facial features in all individuals (broad nasal tip, small alae nasi, long and/or flat philtrum, thin upper lip vermillion)"
    explanation: Overlapping facial features including a thin upper lip vermilion were present in all 16 individuals of this cohort.
  - 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: A second cohort reports thin upper lip in 45.8%; the discrepancy with the 16/16 European series is why the band is set to FREQUENT rather than VERY_FREQUENT.
- category: Craniofacial
  name: Broad Nasal Tip
  description: >-
    A broad nasal tip with small alae nasi is a consistent component of the facial
    gestalt; related nasal features (wide nasal bridge, bulbous nose) are
    reported in roughly half of an independent cohort.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Broad nasal tip
    term:
      id: HP:0000455
      label: Broad nasal tip
  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: "some overlapping facial features in all individuals (broad nasal tip, small alae nasi, long and/or flat philtrum, thin upper lip vermillion)"
    explanation: A broad nasal tip was among the facial features present in all individuals of this cohort.
  - 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: "wide nasal bridge (58.3%), bulbous nose (45.8%)"
    explanation: An independent cohort quantifies the related nasal dysmorphism at 45-58%, supporting a FREQUENT band across cohorts.
- category: Integumentary
  name: Sparse Fair Hair
  description: >-
    Thin, sparse, fair hair with fair skin reflects the role of beta-catenin in
    hair-follicle development and is a useful supportive clinical clue.
  frequency: OCCASIONAL
  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:24668549
    reference_title: "A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In mice, a conditional homozygous β-catenin knockout displays loss of neurons, impaired craniofacial development, and hair follicle defects, which is similar to the phenotype presented by the patient described in this clinical report."
    explanation: Mouse beta-catenin knockout reproduces hair-follicle defects, providing the mechanistic basis for the hair phenotype.
- category: Gastrointestinal
  name: Feeding Difficulties
  description: >-
    Feeding difficulties occur less commonly than the core neurological features
    but can require dedicated feeding-team management.
  frequency: OCCASIONAL
  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, supporting an OCCASIONAL band.
- 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.
- 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.
- category: Neurological
  name: Tethered Cord
  description: >-
    A history of tethered spinal cord was reported in many individuals in a
    deeply phenotyped cohort and is a potentially surgically remediable
    contributor to progressive lower-limb signs.
  frequency: FREQUENT
  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, supporting a FREQUENT band.
- 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.
genetic:
- name: CTNNB1
  gene_term:
    preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  association: Causal - heterozygous germline loss-of-function variants
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  presence: Positive
  notes: >-
    Heterozygous, usually de novo, loss-of-function variants in CTNNB1 (3p22.1)
    cause CTNNB1-NDD. The spectrum includes nonsense, frameshift and splice-site
    variants, whole-gene deletions, and a minority of missense variants, some of
    which act as dominant negatives while one has been reported as
    gain-of-function. Missense variants and variants in the C-terminal region
    (exons 13-15) are associated with a milder phenotype, including earlier
    independent walking and better communication. This is the mechanistic opposite
    of the SOMATIC exon-3 stabilising CTNNB1 variants that drive Wnt-activated
    tumours.
  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: Documents the genotype-phenotype relationship in which missense variants confer a milder phenotype than truncating variants.
  - 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: Systematic review documenting the milder phenotype associated with C-terminal (exon 13-15) variants.
diagnosis:
- name: Molecular Genetic Testing for CTNNB1
  description: >-
    The diagnosis is established by identifying a heterozygous pathogenic CTNNB1
    variant on exome/genome or multigene panel sequencing, or a 3p22.1 deletion
    involving CTNNB1 on chromosomal microarray, in an individual with suggestive
    findings. Because the phenotype is frequently labelled cerebral palsy or
    autism spectrum disorder, genetic testing should be considered in those
    settings.
  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: >-
    The commonest misdiagnosis. Spastic diplegia with early hypotonia in CTNNB1-NDD
    is clinically indistinguishable from cerebral palsy in early childhood; CTNNB1
    is the most frequent recurrent monogenic cause of a cerebral palsy diagnosis,
    and molecular testing resolves the distinction.
- 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: >-
    Many individuals receive an ASD diagnosis before molecular testing;
    CTNNB1 syndrome patients differ in showing disproportionate visuospatial and
    logical-reasoning weakness and greater adaptive-functioning impairment.
- 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: >-
    There is no curative or disease-modifying therapy. Management is supportive
    and multidisciplinary, typically involving neurology, speech-language
    pathology, physiatry, occupational therapy, physical therapy, a feeding team,
    paediatric ophthalmology, audiology and developmental paediatrics, with
    surveillance for emerging neurological, developmental, behavioural and
    ophthalmological problems.
  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: >-
    Physiotherapy targets truncal hypotonia, muscle weakness, progressive
    lower-limb spasticity and gait, and is the mainstay of motor management.
  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.
- 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.
- 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: DEVICE
  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.
- name: AAV9-Mediated CTNNB1 Gene Replacement (Investigational)
  description: >-
    Urbagen is a single-stranded AAV9 vector carrying human CTNNB1, delivered
    once by bilateral intracerebroventricular infusion with prophylactic
    methylprednisolone and sirolimus, now in a first-in-human phase I/II trial
    (NCT07270549). It is the first candidate disease-modifying therapy and
    directly addresses the beta-catenin dosage deficit. No human safety or
    efficacy results are available. Because beta-catenin is dosage-sensitive and
    its stabilisation is oncogenic in the somatic setting, expression level,
    tissue targeting, and long-term surveillance are central safety questions.
  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: >-
      Gene addition restores functional CTNNB1 expression, directly countering
      the beta-catenin dosage deficit at the top of the causal chain.
  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: "Recieve a single dose of gene therapy via bilateral intracerebroventricular administration."
    explanation: Describes the route and dosing of the investigational AAV9 CTNNB1 gene replacement therapy.
- name: Genetic Counseling
  description: >-
    Counselling covers the autosomal dominant, predominantly de novo mechanism,
    the need for parental testing given documented transmission from mildly
    affected or asymptomatic parents, and the availability of prenatal and
    preimplantation genetic testing once a familial variant is known.
  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.
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: >-
    An ENU-derived mouse carrying a Thr653Lys substitution in the C-terminal
    armadillo repeat of beta-catenin with reduced affinity for membrane-associated
    cadherins. It reproduces core features of the human disorder including
    craniofacial abnormalities, reduced intrahemispheric connectivity, deficient
    dendritic branching, impaired long-term potentiation and cognitive impairment.
  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: Establishes the batface line as a mouse model recapitulating features of human CTNNB1-related disease.
- 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.
clinical_trials:
- name: NCT07270549
  phase: PHASE_I
  status: RECRUITING
  description: >-
    GAIN-CTNNB1 - first-in-human open-label phase I/II trial of Urbagen, an AAV9
    based CTNNB1 gene replacement therapy delivered by a single bilateral
    intracerebroventricular administration with prophylactic immunosuppression,
    in paediatric patients with CTNNB1 neurodevelopmental disorder.
  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 goal of this first in human, phase I/II clinical trial is to evaulate 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.
- name: NCT07614126
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    Open-label pilot study of L-dopa (levodopa) in children with CTNNB1-related
    NEDSDV and dystonia, motivated by evidence of reduced dopaminergic
    neurogenesis in Ctnnb1 knockout models and anecdotal clinical improvement.
  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.
- name: NCT07167732
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    Dragonfly Study - international prospective longitudinal observational
    natural-history study of children and adults with CTNNB1 neurodevelopmental
    syndrome, intended to standardise care and support future trial design.
  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.
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#Progressive Corticospinal and Extrapyramidal Motor Dysfunction
  rationale: >-
    Animal models show severe reduction in dopaminergic neurogenesis when Ctnnb1
    is lost, and this is the stated rationale for an ongoing levodopa pilot
    trial. In humans, however, the only supporting data are anecdotal: in the
    single systematically assessed cohort levodopa was helpful in only 1 of 4
    treated patients, whereas botulinum toxin helped 5 of 6. No human imaging or
    CSF evidence of presynaptic dopaminergic deficiency in CTNNB1-NDD has been
    published. The mismatch is mechanistically meaningful because it determines
    whether the movement disorder is primarily an extrapyramidal
    neurotransmitter-deficiency state or a developmental corticospinal/circuit
    lesion.
  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 striatal tracer binding relative to reference values would support
      a human dopaminergic deficit and strengthen the levodopa rationale; normal
      binding would refute it.
  - 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 blinded analysis of the open-label levodopa/carbidopa pilot
      in children with CTNNB1-related dystonia, with GMFM-88 as the primary
      motor endpoint.
    decision_criterion: >-
      A clinically meaningful GMFM-88 improvement would support the dopaminergic
      hypothesis; absence of response would argue for a primarily developmental
      circuit lesion.
  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.

📚

References & Deep Research

References

1

PMID:35593792

CTNNB1 Neurodevelopmental Disorder.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

CTNNB1 Neurodevelopmental Disorder: Disease-Characteristics Report

Edison Scientific Literature 14 citations 2026-07-31T16:57:07.855104

CTNNB1 Neurodevelopmental Disorder: Disease-Characteristics Report

Executive summary and evidence scope

CTNNB1 neurodevelopmental disorder (CTNNB1-NDD) is a rare, usually de novo autosomal-dominant developmental disorder caused predominantly by heterozygous loss-of-function variants in CTNNB1, which encodes β-catenin. The characteristic phenotype combines global developmental delay/intellectual disability, severe expressive-language impairment, axial hypotonia evolving into lower-limb dystonia or spasticity, abnormal gait, acquired or congenital microcephaly, behavioral abnormalities, and visual disease. It is frequently mistaken for cerebral palsy. The best large human anchor is the 2022 international characterization of 404 affected individuals (PMID 36083290); recent primary reports continue to expand the variant spectrum, while 2024 research refined the recognizable movement-disorder phenotype (PMID 39067319). Prospective natural-history and first-in-human treatment programs are now underway. (NCT07614126 chunk 1, NCT07614126 chunk 2, lainscek2025ctnnb1syndromemouse pages 1-2, lainscek2025ctnnb1syndromemouse pages 12-13)

Evidence below is labeled as human clinical, registry, model organism, or mechanistic/in vitro. Most disease-level information is aggregated from cohorts, case series, systematic reviews, ClinGen/OpenTargets-style resources, and trial registries—not individual EHR records. Important limitations are ascertainment bias, historically small cohorts, heterogeneous ages, and limited longitudinal follow-up.

Domain	Curated finding	Suggested ontology/identifier	Best evidence and date	Evidence gaps/caveats
Disease identity	Rare monogenic neurodevelopmental syndrome caused by CTNNB1 variation; commonly described as CTNNB1 syndrome / CTNNB1 neurodevelopmental syndrome / neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV)	MONDO:0100571; OMIM/MIM #615075; MeSH term used in trial browse: Neurodevelopmental Disorders	OpenTargets disease-target association for “CTNNB1-related neurodevelopmental disorder and/or vitreoretinopathy”; clinical-trial disease descriptions; 2025-2026 registry entries (OpenTargets Search: CTNNB1 neurodevelopmental disorder-CTNNB1, NCT07167732 chunk 1, NCT07270549 chunk 1)	Naming is still heterogeneous across papers and trials; some legacy reports use MRD19 or emphasize vitreoretinopathy/visual defects rather than the broader syndrome
Evidence source type	Knowledge derives mainly from aggregated disease resources, published case reports/case series/systematic review, and prospective/retrospective observational registries rather than EHR-only datasets	Evidence type labels: primary human, review, registry, model organism	24-patient cohort, 2-patient case series, systematic review, and interventional/observational registrations (yan2022geneticandclinical pages 1-2, ji2023wholeexomesequencing pages 1-3, ji2023wholeexomesequencing pages 5-6, NCT07167732 chunk 1, NCT04812119 chunk 1)	No large population-based EHR study identified in the available evidence
Causal gene	CTNNB1 encodes β-catenin, a 781-aa armadillo-family protein with 12 armadillo repeats	Gene: CTNNB1; approved symbol CTNNB1; target ENSG00000168036	Mouse-model synthesis and OpenTargets association, 2025 and current database record (lainscek2025ctnnb1syndromemouse pages 1-2, lainscek2025ctnnb1syndromemouse pages 2-4, OpenTargets Search: CTNNB1 neurodevelopmental disorder-CTNNB1)	HGNC ID not explicitly available in current context, so not asserted
Molecular mechanism	Predominant disease mechanism is heterozygous loss of function / haploinsufficiency affecting canonical Wnt/β-catenin signaling and cadherin-mediated cell adhesion; some variants may act via dominant-negative or gain-of-function effects and are excluded from current gene-replacement trial eligibility	Mechanism labels: haploinsufficiency; canonical Wnt signaling; cell-cell adhesion	Human cohort/case evidence and trial criteria, 2022-2026 (yan2022geneticandclinical pages 1-2, ji2023wholeexomesequencing pages 5-6, NCT07270549 chunk 2, lainscek2025ctnnb1syndromemouse pages 1-2)	Functional classification is variant-specific; only a subset of variants has direct functional evidence
Inheritance	Autosomal dominant, usually de novo	Autosomal dominant	2022 Chinese cohort and 2025 mouse-model review (yan2022geneticandclinical pages 1-2, lainscek2025ctnnb1syndromemouse pages 2-4)	Rare familial recurrence/sibling recurrence can occur; penetrance estimates not well quantified in available evidence
Prevalence	Estimated prevalence 2.6-3.2 per 100,000 births	Prevalence estimate (label only)	2025 peer-reviewed mouse-model review summarizing human epidemiology (lainscek2025ctnnb1syndromemouse pages 1-2)	Estimate appears review-derived rather than from a formal population registry in the provided evidence
Core quantitative phenotypes	In 24 mainland Chinese patients: developmental delay/intellectual disability 100%, motor delay 100%, speech impairment 100%, dystonia 87.5%, microcephaly 69.6%, visual defects 79.2%, behavioral abnormalities 83.3%, strabismus 62.5%, sleep disturbance 70.8%	HPO term labels: developmental delay; intellectual disability; motor delay; speech impairment; dystonia; microcephaly; visual impairment/strabismus; behavioral abnormality; sleep disturbance	Primary human cohort, 2022 (yan2022geneticandclinical pages 1-2, yan2022geneticandclinical pages 2-4)	Frequencies vary across ancestries, ascertainment strategies, and age distribution
Additional phenotype detail	Systematic review concluded a broad spectrum from normal to severe, with facial dysmorphism, motor disability, language/cognitive impairment, and autistic-like/aggressive behaviors common; C-terminal-region variants (exons 13-15) may trend milder	HPO labels: facial dysmorphism; autism spectrum traits; aggressive behavior	Systematic review, 2022 (ji2023wholeexomesequencing pages 5-6)	Genotype-phenotype correlation remains imperfect and not sufficiently predictive for individual prognosis
Onset / course	Typically early childhood/congenital neurodevelopmental presentation; motor features may be difficult to detect before age 1 year; available data do not suggest cognitive decline, but robust longitudinal data remain limited	Onset label: pediatric; chronic lifelong disorder	Levodopa pilot background and natural history rationale, 2025-2026 registry entries (NCT07614126 chunk 1, NCT07167732 chunk 1)	Natural history remains incompletely defined; formal longitudinal outcomes are still being collected
Anatomy affected	Central nervous system predominates; retina/visual system commonly involved; movement system/gait frequently impaired	UBERON/CL/GO labels only: brain, cerebral cortex, hippocampus, midbrain dopamine neurons, retina	Human cohorts and mouse models, 2022-2025 (yan2022geneticandclinical pages 1-2, lainscek2025ctnnb1syndromemouse pages 1-2, lainscek2025ctnnb1syndromemouse pages 8-10)	Cardiac involvement is being surveyed but frequency is not established in available evidence
Diagnostic approach	Genotype-first diagnosis: molecular confirmation of a pathogenic/likely pathogenic heterozygous CTNNB1 variant, commonly by exome sequencing; parental testing used to show de novo status; phenotyping often includes MRI, EEG, ophthalmology/OCT, motor/cognitive/behavioral testing	Diagnostic labels only: WES, WGS, gene panel, EEG, MRI, OCT	23/24 patients diagnosed by exome in Chinese cohort; Dragonfly natural history assessments; case reports from WES, 2022-2026 (yan2022geneticandclinical pages 2-4, NCT07167732 chunk 1, ji2023wholeexomesequencing pages 1-3)	No universally adopted disease-specific clinical diagnostic criteria identified; biomarker assays remain investigational
Differential diagnosis	Often overlaps clinically with cerebral palsy/genetic cerebral palsy, especially because of dystonic/spastic gait and early motor delay	Differential label: cerebral palsy	2025-2026 trial descriptions and 2025 review (NCT07614126 chunk 1, lainscek2025ctnnb1syndromemouse pages 1-2)	Differential diagnosis list is broader in practice, but detailed comparative data were not available in the provided evidence
Established management	No curative standard therapy; management is supportive and multidisciplinary, emphasizing symptom management, physiotherapy/rehabilitation, developmental therapies, vision care, and monitoring of sleep/behavior/motor complications	NCIT labels only: supportive care; physical therapy; occupational therapy; speech therapy	Mouse-model review and Dragonfly protocol, 2025-2026 (lainscek2025ctnnb1syndromemouse pages 1-2, NCT07167732 chunk 1)	No evidence-based disease-specific treatment algorithm or response-rate meta-analysis available in current evidence
Quality of life / family impact	Family and patient quality of life are recognized outcomes and are being prospectively measured in ongoing studies	PedsQL Family Impact Module; PedsQL Core Module	Dragonfly natural history study and AAV9 trial outcome measures, 2025-2026 (NCT07167732 chunk 1, NCT07270549 chunk 2)	Published disease-specific QoL results were not available in the provided evidence
Natural history study	Dragonfly: international prospective longitudinal observational study of CTNNB1 neurodevelopmental syndrome; estimated enrollment 250; annual visits over 5 years; assesses neurology, motor/cognition, communication, behavior, vision, sleep, gait actimetry, EEG, MRI/OCT, blood biomarkers	NCT07167732	ClinicalTrials.gov registry, first posted 2025-09-11; recruiting; study started 2024-06-14 (NCT07167732 chunk 1)	Registry details may update; no results yet
Genotype-phenotype registry study	Completed cross-sectional observational study enrolling 100 participants to capture genotype/phenotype correlations and natural-course information	NCT04812119	ClinicalTrials.gov registry, completed 2022-11-01 (NCT04812119 chunk 1, NCT04812119 chunk 2)	Results not included in current context
Hyperekplexia study	Completed observational cohort examining prevalence/clinical features of exaggerated startle/hyperekplexia in CTNNB1 syndrome; actual enrollment 10	NCT05168969	ClinicalTrials.gov registry, completed 2022-12-10; updated 2023-04-25 (NCT05168969 chunk 1)	No posted results available in current evidence
Levodopa pilot	Prospective pilot of L-dopa/carbidopa for CTNNB1-related NDD in children with dystonia; estimated enrollment 7; primary endpoint GMFM-88 change at 6 months; secondary endpoints include cognition, Vineland, QoL, CGI, safety	NCT07614126; Drug label: Levodopa/carbidopa	ClinicalTrials.gov registry, first posted 2026-05-29; recruiting (NCT07614126 chunk 1, NCT07614126 chunk 2)	Very small, uncontrolled study; efficacy remains unproven
Gene-replacement trial	GAIN-CTNNB1 / Urbagen: first-in-human phase I/II open-label AAV9-based CTNNB1 gene addition therapy, single bilateral intracerebroventricular administration, pediatric participants, estimated enrollment 12; prophylactic sirolimus and methylprednisolone/prednisolone	NCT07270549; Biological: Urbagen gene addition therapy; AAV9/hCTNNB1 vector	ClinicalTrials.gov registry, first posted 2025-12-08; recruiting; orphan-drug note in registry (NCT07270549 chunk 1, NCT07270549 chunk 2)	No human efficacy/safety results yet; trial excludes predicted gain-of-function/dominant-negative variants
Model organisms	Extensive mouse models recapitulate embryonic lethality, cortical/hippocampal defects, reduced dendritic branching, autism-like behaviors, motor deficits, seizure phenotypes, hypothalamic abnormalities, and retinal exudative vitreoretinopathy features	Model labels only: mouse; retinal-specific model; conditional knockout; gain-of-function model	Peer-reviewed model synthesis, 2025 (lainscek2025ctnnb1syndromemouse pages 4-5, lainscek2025ctnnb1syndromemouse pages 7-8, lainscek2025ctnnb1syndromemouse pages 8-10, lainscek2025ctnnb1syndromemouse pages 2-4)	Mouse evidence is strongest in current context; zebrafish/cellular models are mentioned less directly and not richly detailed here
Pathophysiology chain	Reduced functional β-catenin disrupts destruction-complex-regulated Wnt transcription and cadherin-linked adhesion, impairing progenitor proliferation/survival, dendritic development, synaptic organization, and possibly dopaminergic neurogenesis, producing developmental, motor, cognitive, and visual phenotypes	GO labels only: canonical Wnt signaling pathway; cell adhesion; neuron projection development; synapse organization	Mechanistic synthesis from review and trial background with cited foundational PMIDs, 2025-2026 (lainscek2025ctnnb1syndromemouse pages 1-2, lainscek2025ctnnb1syndromemouse pages 4-5, NCT07614126 chunk 1, NCT07614126 chunk 2)	Human biomarker validation is limited; much mechanistic detail comes from model systems
Large cohort anchor	A 2022 Genet Med study of 404 individuals is referenced as a major phenotypic/genotypic characterization dataset	PMID 36083290	Referenced in trial bibliography and mouse-model review, publication 2022-11 (NCT07614126 chunk 2, lainscek2025ctnnb1syndromemouse pages 12-13)	Full cohort details were not directly extractable from current context, so only anchored, not over-interpreted
Unavailable / not established	No robust incidence estimate, no validated protective factors, no confirmed environmental causes, no established gene-environment interaction, no disease-specific biochemical diagnostic biomarker, no survival/life-expectancy estimate, no standard prevention beyond genetic counseling and reproductive testing	“Not established in available evidence”	Across available cohorts, reviews, and trial registries (yan2022geneticandclinical pages 1-2, NCT07167732 chunk 1, lainscek2025ctnnb1syndromemouse pages 1-2)	Absence here reflects limits of available evidence/context, not proof of true absence in the wider literature

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

1. Disease information

Definition, identifiers, and synonyms

CTNNB1-NDD is a Mendelian neurodevelopmental syndrome associated with impaired β-catenin dosage and function. Recommended identifiers are:

MONDO: MONDO:0100571, “CTNNB1-related neurodevelopmental disorder and/or vitreoretinopathy.”
OMIM/MIM: 615075, Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV).
Causal target: CTNNB1, Ensembl ENSG00000168036.
Common names: CTNNB1 syndrome; CTNNB1 neurodevelopmental syndrome; CTNNB1-related neurodevelopmental disorder; NEDSDV; β-catenin-related neurodevelopmental disorder; historically, mental retardation type 19/MRD19.
Orphanet, ICD-10/ICD-11, and MeSH: no disease-specific code was verified in the retrieved evidence. Coding ordinarily uses broader intellectual-disability, developmental-disorder, movement-disorder, or congenital-genetic categories. “Neurodevelopmental Disorders” is the relevant broad MeSH concept. (ji2023wholeexomesequencing pages 5-6, NCT05168969 chunk 1, OpenTargets Search: CTNNB1 neurodevelopmental disorder-CTNNB1, lainscek2025ctnnb1syndromemouse pages 2-4)

The disease should be distinguished from somatic activating CTNNB1 mutations in cancer and from activating germline alleles causing other developmental phenotypes. CTNNB1-NDD is primarily a constitutional haploinsufficiency disorder.

2. Etiology, risk, protection, and environment

Causal factors

The primary cause is a germline heterozygous pathogenic CTNNB1 variant, usually arising de novo. Nonsense, frameshift, canonical splice, exon-level deletion, and larger deletion variants that reduce functional β-catenin are the principal classes. Two 2023 cases carried novel de novo truncating variants c.1586dupA (p.Gln530Alafs*42) and c.257dup (p.Tyr86*). The clinical mechanism was classified as loss of function/haploinsufficiency. (ji2023wholeexomesequencing pages 3-5, ji2023wholeexomesequencing pages 1-3, ji2023wholeexomesequencing pages 5-6)

Exceptional missense or truncating alleles may have dominant-negative or gain-of-function consequences. This distinction is clinically important: the current gene-addition trial excludes variants predicted to produce gain of function, including p.Gly575Arg, or specified dominant-negative effects. Variant interpretation must therefore integrate location, predicted transcript consequence, population frequency, segregation, and, where available, functional data rather than assuming every CTNNB1 variant causes haploinsufficiency. (NCT07270549 chunk 2)

Risk and protective factors

Genetic risk: a pathogenic constitutional CTNNB1 allele is sufficient; inheritance is autosomal dominant. Most affected individuals have no family history.
Environmental, infectious, occupational, or lifestyle risks: none are established as causes or modifiers of this Mendelian syndrome.
Protective alleles, diet, exercise, or prophylactic exposures: none have been validated.
Gene–environment interaction: no reproducible disease-specific interaction has been demonstrated.
Sex: both sexes are affected; no established sex-specific penetrance was identified. The 24-person Chinese cohort included 14 males and 10 females, which is insufficient to infer a true sex bias. (yan2022geneticandclinical pages 1-2, yan2022geneticandclinical pages 2-4)

3. Phenotypes

Quantitative human evidence

In a primary cohort of 24 mainland Chinese patients aged 0.6–11 years, developmental delay/intellectual disability, motor delay, and speech impairment were each reported in 100%; dystonia in 87.5%; visual defects in 79.2%; behavioral abnormalities in 83.3%; microcephaly in approximately 70%; strabismus in 62.5%; and sleep disturbance in approximately 71%. Anxiety occurred in 33.3%, repetitive behavior in 33.3%, and formally reported autism spectrum disorder in 12.5%. Frequencies should not be generalized uncritically because ascertainment, age, and phenotype definitions differ among cohorts. (yan2022geneticandclinical pages 4-6, yan2022geneticandclinical pages 1-2, yan2022geneticandclinical pages 2-4)

Phenotype	Typical characteristics and course	Suggested HPO term
Global developmental delay / intellectual disability	Evident in infancy or early childhood; severity variable, commonly moderate–severe; chronic, without established neurodegenerative decline	Global developmental delay; Intellectual disability
Speech/language impairment	Expressive language disproportionately impaired; speech may be minimal or absent; major effect on autonomy and social participation	Delayed speech and language development; Absent speech
Motor delay	Delayed sitting, standing, and walking; some remain nonambulatory	Motor delay; Delayed walking
Axial hypotonia	Often early; may coexist with later distal hypertonia	Muscular hypotonia; Truncal hypotonia
Dystonia/spastic diplegia	Lower limbs often more affected, especially distally; gait may be tiptoe, broad-based, unstable, or absent	Dystonia; Lower-limb spasticity; Spastic diplegia
Microcephaly	Congenital or postnatal; variable	Microcephaly; Postnatal microcephaly
Visual disease	Strabismus, refractive error, cortical/functional visual impairment, and occasionally familial exudative vitreoretinopathy or retinal detachment	Strabismus; Visual impairment; Exudative vitreoretinopathy
Behavioral/neuropsychiatric findings	Autistic traits, repetitive behavior, anxiety, hyperactivity, impulsivity, aggression or mood abnormalities; variable	Autistic behavior; Anxiety; Hyperactivity; Repetitive behavior
Sleep disturbance	Common in cohort data and relevant to family burden	Sleep disturbance
Craniofacial features	Wide nasal bridge, bulbous nose, long philtrum, thin upper lip, long eyelashes, or prominent ears; not individually diagnostic	Abnormal facial shape; Broad nasal bridge; Long philtrum; Thin upper lip
Hyperekplexia	Rare exaggerated startle phenotype with stiff falls and injury risk	Exaggerated startle response; Hyperekplexia

The motor disorder is clinically complex and may be labeled “spasticity” when dystonia predominates. A 2024 movement-disorder paper specifically characterized this recognizable phenomenology (published September 2024; PMID 39067319). Registry investigators note that motor signs may be difficult to recognize before one year of age and that available cross-sectional evidence does not suggest cognitive decline. (NCT05168969 chunk 1, NCT07614126 chunk 1, NCT07614126 chunk 2)

Quality of life

Motor dependence, limited communication, visual dysfunction, behavioral symptoms, sleep disturbance, feeding limitations, and caregiver burden affect daily functioning. Published CTNNB1-specific EQ-5D or SF-36 estimates were not retrieved. The Dragonfly natural-history study and Urbagen trial now use PedsQL Core and Family Impact modules; the levodopa pilot uses CP-CHILD. These are outcome-measure plans, not evidence of treatment benefit. (NCT07167732 chunk 1, NCT07614126 chunk 1, NCT07270549 chunk 2)

4. Genetic and molecular information

Gene: CTNNB1, encoding the 781-amino-acid β-catenin protein. β-catenin contains 12 armadillo repeats that bind more than 20 partners, including cadherins and TCF/LEF transcription factors. The gene is dosage-sensitive, and biallelic/complete loss is incompatible with normal embryogenesis in animal models. (lainscek2025ctnnb1syndromemouse pages 1-2, lainscek2025ctnnb1syndromemouse pages 2-4)

Variant interpretation

Pathogenic/likely pathogenic: truncating, splice-disrupting, or deletion alleles supported by de novo occurrence, absence/rarity in population databases, and a haploinsufficiency mechanism.
VUS: should not establish diagnosis without adequate ACMG/AMP evidence.
Population frequency: disease-causing de novo alleles are expected to be absent or extremely rare in gnomAD; exact allele frequencies must be queried per variant.
Origin: predominantly germline de novo; parental testing is needed. Somatic CTNNB1 variants are important in oncology but represent a separate context.
Structural changes: exon/gene deletions and larger 3p deletions encompassing CTNNB1 can produce an overlapping but potentially broader phenotype.
Modifier genes: none are clinically validated.
Disease-specific episignature: not established. Dragonfly is prospectively studying DNA methylation and RNA expression, but these are investigational biomarkers. (yan2022geneticandclinical pages 1-2, ji2023wholeexomesequencing pages 3-5, NCT07167732 chunk 1)

A systematic review found broad genotype–phenotype variability and suggested that variants in the C-terminal region, particularly exons 13–15, may be associated with milder neurodevelopmental phenotypes and relatively prominent eye disease. This is a probabilistic cohort-level observation, not a reliable individual prognostic rule. Its abstract states that CTNNB1 syndrome “encompasses a wide spectrum of clinical features, ranging from normal to severe” (published October 19, 2022; PMID 36293418; DOI 10.3390/ijms232012564). (ji2023wholeexomesequencing pages 5-6, NCT07614126 chunk 2)

5. Environmental information

No toxin, radiation exposure, pollution, occupation, smoking, alcohol, diet, exercise pattern, or infectious agent is known to cause CTNNB1-NDD. These may affect general health or rehabilitation but are not established etiologic factors. The disorder is not transmissible or zoonotic. Environmental prevention and vaccination are therefore not disease-specific.

6. Mechanism and pathophysiology

Upstream molecular defect

In the absence of Wnt ligand, β-catenin is phosphorylated and degraded through the AXIN–APC–CK1–GSK3β destruction complex. Wnt receptor activation inhibits this destruction process, permitting β-catenin accumulation, nuclear entry, and TCF/LEF-dependent transcription of programs controlling proliferation and differentiation. Separately, membrane-associated β-catenin binds cadherins and α-catenin at adherens junctions. These signaling and adhesion pools support tissue architecture, neurite development, dendritic morphology, synapse organization, and plasticity. (lainscek2025ctnnb1syndromemouse pages 1-2, lainscek2025ctnnb1syndromemouse pages 2-4)

Causal chain

Pathogenic CTNNB1 loss-of-function allele → reduced functional β-catenin → impaired canonical Wnt transcription and cadherin-associated adhesion → abnormal neural-progenitor proliferation/survival and differentiation, dendritic branching, synaptic organization, circuit maturation, and retinal vascular development → microcephaly, intellectual/language disability, dystonia/spastic gait, behavioral abnormalities, and visual disease. Midbrain-model data additionally suggest impaired dopaminergic neurogenesis, providing the rationale—but not proof—for levodopa treatment. (NCT07614126 chunk 1, lainscek2025ctnnb1syndromemouse pages 1-2, lainscek2025ctnnb1syndromemouse pages 4-5, lainscek2025ctnnb1syndromemouse pages 8-10)

In conditional mouse models, β-catenin loss caused reduced progenitor proliferation and a reported approximately 300% increase in neural-progenitor apoptosis during embryonic development. Other models show reduced hippocampal dendritic branching, altered inhibitory/parvalbumin circuitry, social and repetitive behavioral abnormalities, memory changes, motor deficits, seizures, retinal vascular disease, and major brain-patterning defects. Conversely, stabilized β-catenin expands neural precursors and can produce enlarged brains, demonstrating that dosage and developmental timing are critical. (lainscek2025ctnnb1syndromemouse pages 4-5, lainscek2025ctnnb1syndromemouse pages 7-8, lainscek2025ctnnb1syndromemouse pages 8-10)

Suggested ontology annotations

GO biological process: canonical Wnt signaling pathway; cell–cell adhesion; neural precursor-cell proliferation; neuron differentiation; dendrite morphogenesis; neuron projection development; synapse organization; midbrain dopaminergic-neuron differentiation; retinal blood-vessel development.
GO cellular component: nucleus; cytoplasm; plasma membrane; adherens junction; postsynaptic density/synapse.
Cell Ontology labels: neural stem cell; radial glial cell; neural progenitor cell; cortical neuron; parvalbumin-positive interneuron; hippocampal neuron; midbrain dopaminergic neuron; retinal endothelial cell.
Molecular profiling: no validated clinical transcriptomic, proteomic, metabolomic, or lipidomic signature exists. DNA methylation, RNA, serum β-catenin, neurofilament, and zinc are exploratory Dragonfly measures. (NCT07167732 chunk 1, lainscek2025ctnnb1syndromemouse pages 7-8)

7. Anatomical structures affected

The central nervous system is primary: cerebral cortex, corticospinal/motor circuits, hippocampus, basal-ganglia/movement networks, and potentially midbrain dopamine systems. The visual system is also directly involved, including ocular alignment, retina and retinal vasculature. Musculoskeletal deformities, contractures, flat feet, and spinal abnormalities are generally downstream of altered tone and motor function. Cardiovascular findings have been reported, but their frequency and causal specificity remain insufficiently defined. (yan2022geneticandclinical pages 4-6, NCT07614126 chunk 1, lainscek2025ctnnb1syndromemouse pages 1-2, lainscek2025ctnnb1syndromemouse pages 8-10)

Suggested terms include UBERON labels brain, cerebral cortex, hippocampus, midbrain, spinal cord, retina, retinal vasculature, lower limb and skeletal muscle. Lateralization is not characteristic; motor and visual effects are commonly bilateral, although strabismus or retinal severity can be asymmetric.

8. Temporal development

The biological defect is present from conception and acts during embryonic neurodevelopment. Clinical recognition is usually in infancy or early childhood through hypotonia and delayed milestones. Hypertonia, dystonia, abnormal gait, behavioral differences, and microcephaly may become clearer with age. The condition is chronic and lifelong; it has no accepted staging system or remission pattern. Available cross-sectional data do not indicate a primary degenerative cognitive course, but progressive lower-limb motor limitation may reflect increasing dystonia/spasticity, growth, orthopedic complications, or contracture. Robust estimates of progression rate and adult outcomes are not yet available. (NCT05168969 chunk 1, NCT07167732 chunk 1, NCT07614126 chunk 1)

The principal intervention window is presumed to be early neurodevelopment, but the degree of postnatal reversibility is unknown. The ongoing five-year Dragonfly study is designed to resolve milestone acquisition, motor change, communication, cognition, behavior, vision, sleep, EEG, MRI, and biomarker trajectories. (NCT07167732 chunk 1)

9. Inheritance and population

Inheritance is autosomal dominant, with most pathogenic variants occurring de novo. Penetrance for clearly pathogenic loss-of-function variants appears high, while expressivity is markedly variable. Genetic anticipation is not expected because the disorder is not a repeat-expansion disease. Founder effects, consanguinity, carrier frequency, and population-specific susceptibility have not been established. A sibling pair in the Chinese series illustrates that recurrence can occur; parental germline mosaicism should therefore be discussed even when blood testing is negative. (yan2022geneticandclinical pages 1-2, yan2022geneticandclinical pages 2-4)

A recent review estimated prevalence at 2.6–3.2 per 100,000 births. Incidence, regional variation, and ancestry-specific prevalence remain uncertain, and underdiagnosis is likely because affected children are often classified as cerebral palsy. No convincing ethnic or geographic restriction has emerged. (lainscek2025ctnnb1syndromemouse pages 1-2)

10. Diagnostics

Recommended approach

Recognize the combination of developmental/language delay, early hypotonia, dystonic or spastic lower-limb motor disorder, microcephaly, visual abnormalities, and behavioral traits.
Perform trio exome sequencing, genome sequencing, or a comprehensive neurodevelopmental/cerebral-palsy gene panel that includes CTNNB1. Exome sequencing diagnosed 23 of 24 individuals in one cohort. Ensure copy-number calling or add chromosomal microarray if deletion is suspected.
Confirm a candidate variant by an orthogonal method when required and test both parents to determine de novo status/mosaicism.
Apply ACMG/AMP classification; do not use a VUS as a definitive diagnosis.
Baseline phenotyping: neurological and developmental examination, gross/fine motor and communication assessment, ophthalmology with retinal examination and OCT where feasible, hearing, growth/head circumference, sleep/behavior and feeding review, and orthopedic evaluation. MRI, EEG, echocardiography, or additional testing should be driven by phenotype and planned therapy. (ji2023wholeexomesequencing pages 1-3, yan2022geneticandclinical pages 2-4, NCT07167732 chunk 1, NCT07270549 chunk 2)

There is no diagnostic blood chemistry, enzyme assay, biopsy, metabolite, liquid biopsy, or validated molecular biomarker. RNA sequencing can clarify suspected splice variants; WGS is useful when WES/panel testing is negative or structural/noncoding variation is suspected. Karyotyping, FISH, mitochondrial testing, and repeat-expansion assays are not first-line unless another diagnosis is suspected.

Differential diagnosis

The major practical differential is cerebral palsy, particularly spastic or dyskinetic forms. CTNNB1 testing is important when the history lacks a sufficient acquired perinatal brain insult, MRI is nondiagnostic, dysmorphism/microcephaly/visual disease is present, or the phenotype is familial or atypical. Other genetic differentials include hereditary spastic paraplegias, DDX3X-, GNAO1-, KIF1A-, ATL1-, SPAST-, TCF4-, and Wnt-pathway-related NDDs, Angelman syndrome, Rett syndrome, and other causes of syndromic developmental delay. There are no stand-alone clinical diagnostic criteria; molecular confirmation is central. (NCT07614126 chunk 1, lainscek2025ctnnb1syndromemouse pages 1-2)

Population newborn screening is not available. Cascade testing is appropriate if a parent is found to carry the variant or mosaicism is suspected.

11. Outcome and prognosis

Life expectancy, mortality rates, and five- or ten-year survival have not been quantified. There is presently no evidence that uncomplicated CTNNB1-NDD intrinsically shortens lifespan, but adult natural-history data are sparse. Morbidity is dominated by communication disability, impaired mobility, falls, contractures, visual dysfunction, intellectual disability, behavioral/sleep problems, and dependence in activities of daily living. Hyperekplexia can cause sudden stiff falls and recurrent injury. (NCT05168969 chunk 1, NCT07167732 chunk 1)

Functional improvement is possible through maturation, learning, augmentative communication and rehabilitation; the 2023 case report described motor improvement with rehabilitation, but it did not establish a response rate. No validated molecular prognostic biomarker exists. Variant mechanism and location may influence severity, but individual prediction remains unreliable. (ji2023wholeexomesequencing pages 3-5, ji2023wholeexomesequencing pages 5-6)

12. Treatment and current implementation

Current standard care

No approved disease-modifying therapy exists. Management is individualized and multidisciplinary:

early physical and occupational therapy; gait training, orthoses and mobility devices;
speech-language therapy and augmentative/alternative communication;
management of dystonia/spasticity using standard pediatric movement-disorder approaches, with attention to whether dystonia rather than pyramidal spasticity is dominant;
ophthalmologic and retinal surveillance; refractive correction and treatment of strabismus or retinal disease;
developmental, educational, behavioral, sleep, feeding, dental and orthopedic care;
antiseizure treatment only when epilepsy is present;
family psychosocial support and care coordination. (NCT07167732 chunk 1, NCT04812119 chunk 2, lainscek2025ctnnb1syndromemouse pages 1-2)

Suggested NCIT intervention labels are Physical Therapy, Occupational Therapy, Speech Therapy, Assistive Communication, Orthotic Device, Ophthalmologic Examination, Behavioral Therapy, Supportive Care and Genetic Counseling. No CTNNB1-specific pharmacogenomic guidance or validated combination algorithm is available.

Experimental therapies and trials

Dragonfly natural-history study, NCT07167732: international, prospective, five-year observational study; began June 14, 2024 and is currently registered as recruiting, with estimated enrollment 250. It measures motor, cognitive, communication, behavioral, visual, sleep, EEG/MRI/OCT, actimetry, quality-of-life, methylation, RNA, β-catenin, neurofilament and zinc outcomes. ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT07167732. (NCT07167732 chunk 1)
Gen-Phe CTNNB1, NCT04812119: completed cross-sectional genotype–phenotype study with 100 participants. ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT04812119. (NCT04812119 chunk 1, NCT04812119 chunk 2)
Hyperekplexia study, NCT05168969: completed prospective observational questionnaire study, actual enrollment 10; no results were available in the retrieved record. ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT05168969. (NCT05168969 chunk 1)
Levodopa/carbidopa pilot, NCT07614126: open-label single-group study in seven children with dystonia, assessing GMFM-88 at six months plus cognition, adaptive behavior, quality of life and safety. The rationale is model-based dopaminergic deficiency plus anecdotal improvement in three patients; efficacy remains unproven. ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT07614126. (NCT07614126 chunk 1, NCT07614126 chunk 2)
GAIN-CTNNB1/Urbagen, NCT07270549: first-in-human phase I/II open-label trial, estimated 12 children aged 2–12 years. Urbagen is a single-stranded AAV9/hCTNNB1 gene-addition vector under a CBh promoter, delivered once by bilateral intracerebroventricular infusion, with sirolimus and corticosteroid immunosuppression. Outcomes include five-year safety plus motor, dystonia, spasticity, cognition, communication, behavior, sleep, seizures and PedsQL. No human efficacy or safety results are yet available. ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT07270549. (NCT07270549 chunk 1, NCT07270549 chunk 2)

The emergence of gene replacement is the principal translational development after 2024. Expert interpretation should remain cautious: β-catenin is dosage-sensitive and oncogenically relevant, so tissue targeting, expression level, developmental timing, immunogenicity, durability, and long-term tumor surveillance are central safety questions. The trial’s exclusion of gain-of-function/dominant-negative alleles reflects the need for mechanism-specific precision medicine. (NCT07270549 chunk 2, lainscek2025ctnnb1syndromemouse pages 7-8)

13. Prevention

There is no lifestyle, vaccine, environmental, or medication-based primary prevention. Genetic counseling is the key preventive intervention. For a confirmed de novo variant with negative parental blood tests, recurrence risk is low but not zero because germline mosaicism is possible. If a parent carries the variant, each pregnancy has a 50% transmission risk, subject to variant penetrance and expressivity. Options include prenatal diagnosis by chorionic-villus sampling or amniocentesis and preimplantation genetic testing for monogenic disease. Secondary prevention consists of prompt molecular diagnosis and early developmental, motor, communication and visual intervention. Tertiary prevention targets contractures, falls, retinal complications, feeding problems, sleep disruption and caregiver burden.

14. Other species and natural disease

No well-established naturally occurring veterinary counterpart, breed predisposition, zoonotic transmission, or cross-species infectious susceptibility was identified. CTNNB1 is evolutionarily conserved, and β-catenin’s Wnt-signaling and adherens-junction functions are conserved across vertebrates. Other-species evidence is therefore predominantly experimentally induced rather than natural disease. Relevant taxa include human, NCBI Taxon 9606 and mouse, NCBI Taxon 10090. Exact ortholog NCBI Gene IDs and VBO terms should be obtained directly from NCBI/Alliance for database ingestion rather than inferred here.

15. Model organisms

Mouse is the best-developed model. At least 36 engineered Ctnnb1 alleles have been summarized, including constitutive, conditional tissue-specific, truncating, point-mutant, and stabilized/gain-of-function alleles. Complete loss is embryonic lethal, so conditional models are essential. Brain-specific models reproduce abnormal cortical and hippocampal development, reduced progenitor proliferation, increased apoptosis, reduced dendritic branching, motor/cognitive deficits, altered social behavior and repetitive behavior. Parvalbumin-interneuron deletion produces autism-like traits and memory abnormalities; retinal-specific loss reproduces exudative vitreoretinopathy; stabilized β-catenin or APC loss models reveal the consequences of excessive signaling, including precursor expansion and seizure phenotypes. (lainscek2025ctnnb1syndromemouse pages 4-5, lainscek2025ctnnb1syndromemouse pages 7-8, lainscek2025ctnnb1syndromemouse pages 8-10, lainscek2025ctnnb1syndromemouse pages 2-4)

These models support mechanism discovery and testing of small molecules or gene replacement, but limitations are substantial: embryonic lethality with complete loss, species-specific cortical and behavioral development, variable Cre timing and cell targeting, and imperfect correspondence between engineered homozygous/tissue-specific alleles and human heterozygous germline disease. Patient-derived iPSC neurons and cerebral organoids, single-cell transcriptomics, spatial profiling, proteomics and CRISPR rescue would be valuable, but mature CTNNB1-NDD-specific datasets were not established in the retrieved evidence.

Key primary and authoritative references

Kayumi S et al. “Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.” Genetics in Medicine. Published November 2022. PMID 36083290; DOI 10.1016/j.gim.2022.08.006. This is the principal large human cohort cited by current trial and model literature. (NCT07614126 chunk 2, lainscek2025ctnnb1syndromemouse pages 12-13)
Yan D et al. “Genetic and clinical characteristics of 24 mainland Chinese patients with CTNNB1 loss-of-function variants.” Molecular Genetics & Genomic Medicine. Published September 2022. DOI 10.1002/mgg3.2067. The abstract directly defines NEDSDV as “a rare autosomal dominant syndrome” caused by heterozygous germline loss-of-function variants. (yan2022geneticandclinical pages 4-6, yan2022geneticandclinical pages 1-2)
Miroševič Š et al. “Correlation between Phenotype and Genotype in CTNNB1 Syndrome: A Systematic Review of the Literature.” International Journal of Molecular Sciences. Published October 19, 2022. PMID 36293418; DOI 10.3390/ijms232012564. (ji2023wholeexomesequencing pages 5-6, NCT07614126 chunk 2)
Ji Y et al. “Whole Exome Sequencing Identified two Novel Truncation Mutations in the CTNNB1 Gene…” Child Neurology Open. Published 2023. DOI 10.1177/2329048X231184184. Its abstract reports two unrelated children with “neurodevelopmental disorder, abnormal facial features, speech impairments, microcephaly, and dystonia.” (ji2023wholeexomesequencing pages 3-5, ji2023wholeexomesequencing pages 1-3)
Tucci V et al. “Dominant beta-catenin mutations cause intellectual disability with recognizable syndromic features.” Journal of Clinical Investigation. Published April 2014. PMID 24614104; DOI 10.1172/JCI70372. Landmark human and model evidence. (NCT07614126 chunk 2)
Garone G et al. “Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology.” Parkinsonism & Related Disorders. Published September 2024. PMID 39067319; DOI 10.1016/j.parkreldis.2024.107057. (NCT07614126 chunk 2)
Lainšček D et al. “CTNNB1 syndrome mouse models.” Mammalian Genome. Published January 2025. DOI 10.1007/s00335-025-10105-3. This current synthesis estimates prevalence at 2.6–3.2 per 100,000 births and reviews loss- and gain-of-function models. (lainscek2025ctnnb1syndromemouse pages 1-2, lainscek2025ctnnb1syndromemouse pages 2-4)

Major knowledge gaps

Validated incidence, adult natural history, life expectancy, standardized clinical criteria, disease-specific biomarkers, quantitative quality-of-life burden, robust variant-level prognosis, protective factors, modifier genes, epigenetic signatures, human single-cell/spatial datasets, and controlled treatment-response rates remain unavailable or preliminary. The Dragonfly cohort and early interventional studies are designed to address several of these gaps, but registry plans must not be interpreted as completed evidence of benefit. (NCT07167732 chunk 1, NCT07614126 chunk 1, NCT07270549 chunk 1)

References

(NCT07614126 chunk 1): Study of L-dopa Treatment in Patients With a Neurodevelopmental Disorder (CTNNB1 Gene). University Hospital, Montpellier. 2026. ClinicalTrials.gov Identifier: NCT07614126
(NCT07614126 chunk 2): Study of L-dopa Treatment in Patients With a Neurodevelopmental Disorder (CTNNB1 Gene). University Hospital, Montpellier. 2026. ClinicalTrials.gov Identifier: NCT07614126
(lainscek2025ctnnb1syndromemouse pages 1-2): Duško Lainšček, Vida Forstnerič, and Špela Miroševič. Ctnnb1 syndrome mouse models. Mammalian Genome, 36:390-402, Jan 2025. URL: https://doi.org/10.1007/s00335-025-10105-3, doi:10.1007/s00335-025-10105-3. This article has 5 citations and is from a peer-reviewed journal.
(lainscek2025ctnnb1syndromemouse pages 12-13): Duško Lainšček, Vida Forstnerič, and Špela Miroševič. Ctnnb1 syndrome mouse models. Mammalian Genome, 36:390-402, Jan 2025. URL: https://doi.org/10.1007/s00335-025-10105-3, doi:10.1007/s00335-025-10105-3. This article has 5 citations and is from a peer-reviewed journal.
(OpenTargets Search: CTNNB1 neurodevelopmental disorder-CTNNB1): Open Targets Query (CTNNB1 neurodevelopmental disorder-CTNNB1, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(NCT07167732 chunk 1): Damjan Osredkar. CTNNB1 Neurodevelopmental Syndrome - Natural History Study. University Medical Centre Ljubljana. 2024. ClinicalTrials.gov Identifier: NCT07167732
(NCT07270549 chunk 1): Damjan Osredkar. Gene Replacement Therapy for Treatment of Paediatric Patients With CTNNB1 Neurodevelopmental Syndrome. CTNNB1 Foundation. 2025. ClinicalTrials.gov Identifier: NCT07270549
(yan2022geneticandclinical pages 1-2): Dan Yan, Yu Sun, Na Xu, Yongguo Yu, and Yongkun Zhan. Genetic and clinical characteristics of 24 mainland chinese patients with ctnnb1 loss‐of‐function variants. Molecular Genetics & Genomic Medicine, Sep 2022. URL: https://doi.org/10.1002/mgg3.2067, doi:10.1002/mgg3.2067. This article has 16 citations and is from a peer-reviewed journal.
(ji2023wholeexomesequencing pages 1-3): Yongchun Ji, Qin Xia, Hewei Zhang, Hongliang Huo, Xujun Cao, Weiwei Wang, and Qin Gu. Whole exome sequencing identified two novel truncation mutations in the ctnnb1 gene associated with neurodevelopmental disorder, language dysfunction, and microcephaly in chinese children. Child Neurology Open, Jan 2023. URL: https://doi.org/10.1177/2329048x231184184, doi:10.1177/2329048x231184184. This article has 5 citations and is from a peer-reviewed journal.
(ji2023wholeexomesequencing pages 5-6): Yongchun Ji, Qin Xia, Hewei Zhang, Hongliang Huo, Xujun Cao, Weiwei Wang, and Qin Gu. Whole exome sequencing identified two novel truncation mutations in the ctnnb1 gene associated with neurodevelopmental disorder, language dysfunction, and microcephaly in chinese children. Child Neurology Open, Jan 2023. URL: https://doi.org/10.1177/2329048x231184184, doi:10.1177/2329048x231184184. This article has 5 citations and is from a peer-reviewed journal.
(NCT04812119 chunk 1): Damjan Osredkar. Genotype-phenotype Correlations in Children and Adults With CTNNB1 Mutation. University Medical Centre Ljubljana. 2021. ClinicalTrials.gov Identifier: NCT04812119
(lainscek2025ctnnb1syndromemouse pages 2-4): Duško Lainšček, Vida Forstnerič, and Špela Miroševič. Ctnnb1 syndrome mouse models. Mammalian Genome, 36:390-402, Jan 2025. URL: https://doi.org/10.1007/s00335-025-10105-3, doi:10.1007/s00335-025-10105-3. This article has 5 citations and is from a peer-reviewed journal.
(NCT07270549 chunk 2): Damjan Osredkar. Gene Replacement Therapy for Treatment of Paediatric Patients With CTNNB1 Neurodevelopmental Syndrome. CTNNB1 Foundation. 2025. ClinicalTrials.gov Identifier: NCT07270549
(yan2022geneticandclinical pages 2-4): Dan Yan, Yu Sun, Na Xu, Yongguo Yu, and Yongkun Zhan. Genetic and clinical characteristics of 24 mainland chinese patients with ctnnb1 loss‐of‐function variants. Molecular Genetics & Genomic Medicine, Sep 2022. URL: https://doi.org/10.1002/mgg3.2067, doi:10.1002/mgg3.2067. This article has 16 citations and is from a peer-reviewed journal.
(lainscek2025ctnnb1syndromemouse pages 8-10): Duško Lainšček, Vida Forstnerič, and Špela Miroševič. Ctnnb1 syndrome mouse models. Mammalian Genome, 36:390-402, Jan 2025. URL: https://doi.org/10.1007/s00335-025-10105-3, doi:10.1007/s00335-025-10105-3. This article has 5 citations and is from a peer-reviewed journal.
(NCT04812119 chunk 2): Damjan Osredkar. Genotype-phenotype Correlations in Children and Adults With CTNNB1 Mutation. University Medical Centre Ljubljana. 2021. ClinicalTrials.gov Identifier: NCT04812119
(NCT05168969 chunk 1): Hyperekplexia in Patients With CTNNB1 Mutation. Centre Hospitalier Universitaire de Saint Etienne. 2022. ClinicalTrials.gov Identifier: NCT05168969
(lainscek2025ctnnb1syndromemouse pages 4-5): Duško Lainšček, Vida Forstnerič, and Špela Miroševič. Ctnnb1 syndrome mouse models. Mammalian Genome, 36:390-402, Jan 2025. URL: https://doi.org/10.1007/s00335-025-10105-3, doi:10.1007/s00335-025-10105-3. This article has 5 citations and is from a peer-reviewed journal.
(lainscek2025ctnnb1syndromemouse pages 7-8): Duško Lainšček, Vida Forstnerič, and Špela Miroševič. Ctnnb1 syndrome mouse models. Mammalian Genome, 36:390-402, Jan 2025. URL: https://doi.org/10.1007/s00335-025-10105-3, doi:10.1007/s00335-025-10105-3. This article has 5 citations and is from a peer-reviewed journal.
(ji2023wholeexomesequencing pages 3-5): Yongchun Ji, Qin Xia, Hewei Zhang, Hongliang Huo, Xujun Cao, Weiwei Wang, and Qin Gu. Whole exome sequencing identified two novel truncation mutations in the ctnnb1 gene associated with neurodevelopmental disorder, language dysfunction, and microcephaly in chinese children. Child Neurology Open, Jan 2023. URL: https://doi.org/10.1177/2329048x231184184, doi:10.1177/2329048x231184184. This article has 5 citations and is from a peer-reviewed journal.
(yan2022geneticandclinical pages 4-6): Dan Yan, Yu Sun, Na Xu, Yongguo Yu, and Yongkun Zhan. Genetic and clinical characteristics of 24 mainland chinese patients with ctnnb1 loss‐of‐function variants. Molecular Genetics & Genomic Medicine, Sep 2022. URL: https://doi.org/10.1002/mgg3.2067, doi:10.1002/mgg3.2067. This article has 16 citations and is from a peer-reviewed journal.

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CTNNB1 Neurodevelopmental Disorder: Disease-Characteristics Report

Executive summary and evidence scope

1. Disease information

Definition, identifiers, and synonyms

2. Etiology, risk, protection, and environment

Causal factors

Risk and protective factors

3. Phenotypes

Quantitative human evidence

Quality of life

4. Genetic and molecular information

Variant interpretation

5. Environmental information

6. Mechanism and pathophysiology

Upstream molecular defect

Causal chain

Suggested ontology annotations

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Recommended approach

Differential diagnosis

11. Outcome and prognosis

12. Treatment and current implementation

Current standard care

Experimental therapies and trials

13. Prevention

14. Other species and natural disease

15. Model organisms

Key primary and authoritative references

Major knowledge gaps

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