Research Activities

Since 2021, the CTNNB1 Foundation has funded numerous research projects totaling over 1,500,000€. Collaborating closely with our medical and scientific advisors, we aim to build on successful studies and support new research to improve the lives of affected patients.

We keep our researchers, neurologists, virologists, and other professionals up to date with annual international CTNNB1 Syndrome conferences. To this date we’ve organized three successful conferences – you can read more about them here: LINK

This will allow us to share research findings and work together to determine the path forward for CTNNB1 research. Through these efforts, the CTNNB1 Foundation hopes to help unravel the molecular mechanisms of CTNNB1 syndrome and develop strategies for effective medicines.

To actively advance research toward our goals, CTNNB1 and its advisory boards are following a roadmap to explore and determine which studies should be funded and explored.

Our roadmap includes basic studies and studies focused on finding best treatment solutions. Basic studies include genotype-phenotype correlation study and biochemical characterization of mutations. It includes cell and animal model development and phenotyping. What we have observed from published data and our own data is that there is a lot of diversity in symptom severity.

Our goal is to find solutions for all children. Therefore, we are exploring all currently available technologies based on the gene therapy approach. The most advanced approach is gene replacement therapy, which is currently in the manufacturing process and tested for safety.

In addition, several RNA and DNA-based technologies are being tested for a proof-of-concept. The CTNNB1 Foundation considers these goals equally important and carefully addresses each goal when allocating research funds. Together, we strive for better treatments and a cure.

Research Institutes Involved

University of Sydney & Children's Medical Research Institutes

Assoc. Prof. Dr. Leszek Lisowski and Dr. Wendy Gold, working on gene therapy.

National Institute of Chemistry Slovenia

Duško Lainšček, working on gene therapy.

University Medical Centre Ljubljana, Children's Hospital

Assoc. prof. Dr. Damjan Osredkar is leading the Natural History Study.

Published Research

Explore a collection of research articles on CTNNB1 syndrome, published by scientists from the CTNNB1 Foundation and our partner institutions. These include contributions from Asociación CTNNB1 España, University Medical Centre Ljubljana, Faculty of Medicine Ljubljana, the Children’s Medical Research Institute, and other collaborating organizations.

Publication date:	Article title:	Summary:
26.9.2025	Tethered Cord in CTNNB1 Neurodevelopmental Disorder, a Not-so-Rare Comorbidity: Results of a Parent Survey and a Clinical Example	This study provides important evidence suggesting a potential link between pathogenic CTNNB1 variants and tethered cord formation. Given the implications for patient care, we recommend considering spinal imaging in individuals with CTNNB1 neurodevelopmental disorder, particularly in patients with progressive spasticity or bladder dysfunction.
19.9.2025	An evolutionarily conserved role for CTNNB1/β-CATENIN in regulating the development of the corpus callosum	This study investigated how mutations in the CTNNB1 gene affect the development of the corpus callosum (CC), the bundle of nerve fibers that connects the two brain hemispheres. Researchers observed CC abnormalities in five individuals with CTNNB1 mutations and modeled these effects in mice. By selectively altering CTNNB1/β-catenin function in early embryonic midline brain cells, they showed that key guidance structures were disrupted. These changes led to failed CC fiber crossing and the formation of abnormal nerve bundles. The results show that balanced CTNNB1 activity is essential for proper CC development, and its disruption likely explains the CC defects seen in CTNNB1 syndrome.
18.7.2025	Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome	This study systematically characterized the genetics and clinical features of CTNNB1 syndrome. Researchers assessed 127 individuals from 20 countries using standardized measures of motor, speech, communication, feeding, vision, and behavior. They identified 88 different CTNNB1 variants, with nearly all predicted to reduce gene function. Laboratory tests confirmed impaired Wnt/β-catenin signaling, and some variants showed a dominant-negative effect, while one missense variant increased signaling activity. Although dominant-negative variants were not clearly linked to unique clinical patterns, individuals with missense variants generally had milder symptoms, such as earlier walking, better communication, and fewer feeding issues. These findings provide the most comprehensive overview to date of the genetic and clinical spectrum of CTNNB1 syndrome.
16.4.2025	Novel CTNNB1 Gene Variants in Spanish CTNNB1 Syndrome Patients: Clinical and Psychological Manifestations	This study provides a detailed clinical and psychological characterization of 25 Spanish individuals with CTNNB1 syndrome, a rare neurodevelopmental disorder caused by de novo pathogenic variants. Using standardized assessments and caregiver questionnaires, researchers evaluated motor skills, development, behavior, communication, sleep, and daily living abilities. The most common features included microcephaly, motor impairments, vision problems, sleep disturbances, and sensory difficulties. Developmental milestones – such as walking, speech, and daily living skills – were generally delayed, with verbal participants functioning better than nonverbal peers. Nearly all patients had adaptive skills below age expectations, and around 60% showed autism spectrum disorder (ASD) symptoms. Behavioral issues were frequent, with high scores on both internalizing (e.g., anxiety) and externalizing (e.g., aggression) problems. The findings highlight the importance of early intervention and tailored therapies, particularly addressing sleep, behavioral, and adaptive skill challenges, which strongly affect quality of life for individuals with CTNNB1 syndrome and their families.
27.3.2025	Cognitive and Adaptive Functioning of CTNNB1 Syndrome Patients: A Comparison With Autism Spectrum Disorder and Cerebral Palsy	This study compared the cognitive and adaptive functioning of children with CTNNB1 syndrome to those with autism spectrum disorder (ASD) and cerebral palsy (CP). A total of 55 participants (25 CTNNB1, 17 ASD, 13 CP) were assessed using standardized neuropsychological tests and parent questionnaires. Results showed that while CTNNB1 patients performed similarly to the other groups on verbal tasks, they had lower scores in visuospatial and logical reasoning. In adaptive functioning, ASD patients outperformed CTNNB1 patients across most areas, whereas CP patients only differed in gross motor skills. Notably, externalizing behavioral problems (such as aggression or impulsivity) were more common in the CTNNB1 group. Importantly, cognitive and adaptive skills in CTNNB1 patients improved with age, highlighting developmental progress over time. This is the first study to directly compare CTNNB1 with ASD and CP, helping to better define its unique profile and guide tailored interventions.
20.2.2025	A Systematic Review of Cognitive and Behavioural Symptoms in CTNNB1 Syndrome	This study systematically reviewed existing research on cognitive behavioural aspects of CTNNB1 syndrome. The review included 42 studies describing patients with genetic confirmation of the condition, focusing on cognition, motor development, language, behavior, and autism-related features. Findings showed a highly variable symptom profile, with most individuals achieving key developmental milestones later than expected and with differing levels of impairment. However, standardized tools to assess cognitive and behavioral domains were rarely used, and only two adult cases were reported in detail, leaving major gaps in understanding the syndrome’s progression into adulthood. The authors emphasize the need for larger studies and standardized assessment protocols to better define the cognitive and behavioral features of CTNNB1 syndrome and to guide long-term care strategies.
12.2.2025	Paving the way toward treatment solutions for CTNNB1 syndrome: a patient organization perspective	This study summarizes the global efforts of the CTNNB1 community, including patient organizations and researchers, to advance treatments for CTNNB1 syndrome. Since 2019, international collaborations have supported research into the genetic and molecular basis of the condition, including genotype–phenotype studies, biochemical analyses of CTNNB1 mutations, creation of patient-derived stem cell models, and development of preclinical mouse models. These tools have revealed important insights into how CTNNB1 haploinsufficiency affects brain function. Multiple therapeutic strategies are now under development, ranging from small molecules and RNA-based approaches to AAV9 gene replacement therapy. The article highlights both the progress made and the resources available to the research community, with a long-term vision of offering personalized treatment options tailored to each patient’s needs.
2025	CTNNB1 syndrome mouse models
19.10.2022	Correlation between Phenotype and Genotype in CTNNB1 Syndrome: A Systematic Review of the Literature	This study systematically reviewed published cases of CTNNB1 syndrome. By analyzing data from multiple databases, researchers collected information on patients’ genetic variants alongside clinical features such as motor abilities, head size, muscle tone, brain scans, eye abnormalities, language development, and behavior. The findings revealed broad variability in both genetics and symptoms. Most individuals showed a moderate-to-severe phenotype, including microcephaly, facial differences, motor disabilities, cognitive and language impairments, and behavioral challenges like autistic-like or aggressive traits. Importantly, certain mutations – particularly nonsense and missense variants in exons 13–15 – were associated with milder outcomes, often limited to eye abnormalities. Overall, the review demonstrates that CTNNB1 syndrome presents a wide clinical spectrum, with some genetic variants linked to less severe manifestations. These insights may guide future diagnosis and management strategies.