Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome
Summary: CTNNB1 neurodevelopmental syndrome is a rare disorder caused by de novo heterozygous variants in the CTNNB1 gene encoding β-catenin. This study aimed to characterize genetic variants in individuals with CTNNB1 neurodevelopmental syndrome, systematically assess the spectrum of clinical pheno...
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Elsevier
2025-10-01
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| Series: | HGG Advances |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666247725000867 |
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| author | Nina Žakelj David Gosar Špela Miroševič Stephan J. Sanders Alicia Ljungdahl Sayeh Kohani Shouhe Huang Lok I Leong Ying An Miou-Jing Teo Fiona Moultrie Roman Jerala Duško Lainšček Vida Forstnerič Petra Sušjan Leszek Lisowski Andrea Perez-Iturralde Jasna Oražem Mrak Ho Yin Edwin Chan Damjan Osredkar |
| author_facet | Nina Žakelj David Gosar Špela Miroševič Stephan J. Sanders Alicia Ljungdahl Sayeh Kohani Shouhe Huang Lok I Leong Ying An Miou-Jing Teo Fiona Moultrie Roman Jerala Duško Lainšček Vida Forstnerič Petra Sušjan Leszek Lisowski Andrea Perez-Iturralde Jasna Oražem Mrak Ho Yin Edwin Chan Damjan Osredkar |
| author_sort | Nina Žakelj |
| collection | DOAJ |
| description | Summary: CTNNB1 neurodevelopmental syndrome is a rare disorder caused by de novo heterozygous variants in the CTNNB1 gene encoding β-catenin. This study aimed to characterize genetic variants in individuals with CTNNB1 neurodevelopmental syndrome, systematically assess the spectrum of clinical phenotypes using standardized measures, and explore potential genotype-phenotype correlations. In this cross-sectional cohort study, individuals diagnosed with CTNNB1 neurodevelopmental syndrome underwent structured interviews using standardized scales to evaluate motor skills, speech, communication, feeding abilities, visual function, neurodevelopment, and psychopathology. Genetic variants were analyzed, and, in a subset of cases, the impact of β-catenin variants on the Wnt/β-catenin signaling pathway was assessed. Across the 127 included participants (mean age, 70 months; range, 7–242 months) from 20 countries, we identified 88 different variants of the CTNNB1 gene, 87 of which were predicted to lead to loss of CTNNB1 function. Functional assays demonstrated reduced Wnt signaling activity, including 11 variants that also exhibited a dominant-negative effect. One missense variant demonstrated a gain-of-function effect. Dominant-negative variants were not clearly associated with a distinct phenotype; however, those with missense variants presented a milder phenotype, including earlier achievement of independent walking, fewer motor impairments, better conceptual and social skills, improved communication, and fewer feeding difficulties. This study describes the genetic, functional, and phenotypic characteristics in individuals with CTNNB1 neurodevelopmental syndrome. Further investigation into the genotypic and phenotypic characteristics of this syndrome and their interrelationships is essential to deepen our understanding of the disorder and inform the development of targeted therapies. |
| format | Article |
| id | doaj-art-42ee76cf12c44e0290f653aa75ecfc73 |
| institution | DOAJ |
| issn | 2666-2477 |
| language | English |
| publishDate | 2025-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | HGG Advances |
| spelling | doaj-art-42ee76cf12c44e0290f653aa75ecfc732025-08-20T03:16:04ZengElsevierHGG Advances2666-24772025-10-016410048310.1016/j.xhgg.2025.100483Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndromeNina Žakelj0David Gosar1Špela Miroševič2Stephan J. Sanders3Alicia Ljungdahl4Sayeh Kohani5Shouhe Huang6Lok I Leong7Ying An8Miou-Jing Teo9Fiona Moultrie10Roman Jerala11Duško Lainšček12Vida Forstnerič13Petra Sušjan14Leszek Lisowski15Andrea Perez-Iturralde16Jasna Oražem Mrak17Ho Yin Edwin Chan18Damjan Osredkar19Department of Pediatric Neurology, University Children’s Hospital, University Medical Centre Ljubljana, Bohoričeva 20, 1525 Ljubljana, SloveniaDepartment of Pediatric Neurology, University Children’s Hospital, University Medical Centre Ljubljana, Bohoričeva 20, 1525 Ljubljana, SloveniaDepartment of Family Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana, SloveniaInstitute of Developmental and Regenerative Medicine, Department of Paediatrics, University of Oxford, OX3 7TY Oxford, UK; Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; New York Genome Center, New York, NY 10013, USAInstitute of Developmental and Regenerative Medicine, Department of Paediatrics, University of Oxford, OX3 7TY Oxford, UK; Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USAInstitute of Developmental and Regenerative Medicine, Department of Paediatrics, University of Oxford, OX3 7TY Oxford, UKSchool of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong SAR, ChinaSchool of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong SAR, ChinaSchool of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong SAR, ChinaSchool of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong SAR, ChinaMDUK Oxford Neuromuscular Centre, Department of Paediatrics, University of Oxford and NIHR Oxford Biomedical Research Center, OX3 9DU Oxford, UKDepartment of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia; Centre for Technologies of Gene and Cell Therapy, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, SloveniaDepartment of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia; Centre for Technologies of Gene and Cell Therapy, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, SloveniaDepartment of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, SloveniaDepartment of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, SloveniaTranslational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia; Australian Genome Therapeutics Centre, Children’s Medical Research Institute and Sydney Children’s Hospitals Network, Westmead, NSW 2145, Australia; Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Warsaw, PolandTranslational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, AustraliaDepartment of Pediatric Neurology, University Children’s Hospital, University Medical Centre Ljubljana, Bohoričeva 20, 1525 Ljubljana, SloveniaSchool of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong SAR, China; Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong, Hong Kong SAR, ChinaDepartment of Pediatric Neurology, University Children’s Hospital, University Medical Centre Ljubljana, Bohoričeva 20, 1525 Ljubljana, Slovenia; Center for Developmental Neuroscience, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; Corresponding authorSummary: CTNNB1 neurodevelopmental syndrome is a rare disorder caused by de novo heterozygous variants in the CTNNB1 gene encoding β-catenin. This study aimed to characterize genetic variants in individuals with CTNNB1 neurodevelopmental syndrome, systematically assess the spectrum of clinical phenotypes using standardized measures, and explore potential genotype-phenotype correlations. In this cross-sectional cohort study, individuals diagnosed with CTNNB1 neurodevelopmental syndrome underwent structured interviews using standardized scales to evaluate motor skills, speech, communication, feeding abilities, visual function, neurodevelopment, and psychopathology. Genetic variants were analyzed, and, in a subset of cases, the impact of β-catenin variants on the Wnt/β-catenin signaling pathway was assessed. Across the 127 included participants (mean age, 70 months; range, 7–242 months) from 20 countries, we identified 88 different variants of the CTNNB1 gene, 87 of which were predicted to lead to loss of CTNNB1 function. Functional assays demonstrated reduced Wnt signaling activity, including 11 variants that also exhibited a dominant-negative effect. One missense variant demonstrated a gain-of-function effect. Dominant-negative variants were not clearly associated with a distinct phenotype; however, those with missense variants presented a milder phenotype, including earlier achievement of independent walking, fewer motor impairments, better conceptual and social skills, improved communication, and fewer feeding difficulties. This study describes the genetic, functional, and phenotypic characteristics in individuals with CTNNB1 neurodevelopmental syndrome. Further investigation into the genotypic and phenotypic characteristics of this syndrome and their interrelationships is essential to deepen our understanding of the disorder and inform the development of targeted therapies.http://www.sciencedirect.com/science/article/pii/S2666247725000867CTNNB1 neurodevelopmental syndromeβ-cateningenotypephenotypegenotype-phenotype correlationsdevelopmental delay |
| spellingShingle | Nina Žakelj David Gosar Špela Miroševič Stephan J. Sanders Alicia Ljungdahl Sayeh Kohani Shouhe Huang Lok I Leong Ying An Miou-Jing Teo Fiona Moultrie Roman Jerala Duško Lainšček Vida Forstnerič Petra Sušjan Leszek Lisowski Andrea Perez-Iturralde Jasna Oražem Mrak Ho Yin Edwin Chan Damjan Osredkar Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome HGG Advances CTNNB1 neurodevelopmental syndrome β-catenin genotype phenotype genotype-phenotype correlations developmental delay |
| title | Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome |
| title_full | Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome |
| title_fullStr | Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome |
| title_full_unstemmed | Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome |
| title_short | Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome |
| title_sort | genotypic functional and phenotypic characterization in ctnnb1 neurodevelopmental syndrome |
| topic | CTNNB1 neurodevelopmental syndrome β-catenin genotype phenotype genotype-phenotype correlations developmental delay |
| url | http://www.sciencedirect.com/science/article/pii/S2666247725000867 |
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