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.

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)

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

1. Recognize the combination of developmental/language delay, early hypotonia, dystonic or spastic lower-limb motor disorder, microcephaly, visual abnormalities, and behavioral traits.
2. 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.
3. Confirm a candidate variant by an orthogonal method when required and test both parents to determine de novo status/mosaicism.
4. Apply ACMG/AMP classification; do not use a VUS as a definitive diagnosis.
5. 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

1. 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)
2. 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)
3. 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)
4. 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)
5. 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)
6. 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)
7. 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

1. (NCT07614126 chunk 1): Study of L-dopa Treatment in Patients With a Neurodevelopmental Disorder (CTNNB1 Gene). University Hospital, Montpellier. 2026. ClinicalTrials.gov Identifier: NCT07614126

2. (NCT07614126 chunk 2): Study of L-dopa Treatment in Patients With a Neurodevelopmental Disorder (CTNNB1 Gene). University Hospital, Montpellier. 2026. ClinicalTrials.gov Identifier: NCT07614126

3. (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.

4. (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.

5. (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.

6. (NCT07167732 chunk 1): Damjan Osredkar. CTNNB1 Neurodevelopmental Syndrome - Natural History Study. University Medical Centre Ljubljana. 2024. ClinicalTrials.gov Identifier: NCT07167732

7. (NCT07270549 chunk 1): Damjan Osredkar. Gene Replacement Therapy for Treatment of Paediatric Patients With CTNNB1 Neurodevelopmental Syndrome. CTNNB1 Foundation. 2025. ClinicalTrials.gov Identifier: NCT07270549

8. (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.

9. (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.

10. (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.

11. (NCT04812119 chunk 1): Damjan Osredkar. Genotype-phenotype Correlations in Children and Adults With CTNNB1 Mutation. University Medical Centre Ljubljana. 2021. ClinicalTrials.gov Identifier: NCT04812119

12. (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.

13. (NCT07270549 chunk 2): Damjan Osredkar. Gene Replacement Therapy for Treatment of Paediatric Patients With CTNNB1 Neurodevelopmental Syndrome. CTNNB1 Foundation. 2025. ClinicalTrials.gov Identifier: NCT07270549

14. (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.

15. (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.

16. (NCT04812119 chunk 2): Damjan Osredkar. Genotype-phenotype Correlations in Children and Adults With CTNNB1 Mutation. University Medical Centre Ljubljana. 2021. ClinicalTrials.gov Identifier: NCT04812119

17. (NCT05168969 chunk 1): Hyperekplexia in Patients With CTNNB1 Mutation. Centre Hospitalier Universitaire de Saint Etienne. 2022. ClinicalTrials.gov Identifier: NCT05168969

18. (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.

19. (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.

20. (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.

21. (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.

Artifacts

• Edison artifact artifact-00