20.500.12556/DiRROS-24375 Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome CTNNB1 neurodevelopmental syndrome is a rare disorder caused by de novo heterozygous variants in the CTNNB1 gene encoding β-catenin. This study aims 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 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. CTNNB1 neurodevelopmental syndrome β-catenin genotype phenotype genotype-phenotype correlations true false true Angleški jezik Ni določen Neznano 2025-11-26 13:36:15 2025-11-26 13:36:15 2025-11-27 03:58:56 0000-00-00 00:00:00 2025 0 0 Nasl. z nasl. zaslona; Opis vira z dne 30. 7. 2025; str. 1-16 no. 4, [article no.] 100483 Vol. 6 2025 0000-00-00 Zaloznikova Objavljeno apc 0000-00-00 0000-00-00 0000-00-00 616.8:575 2666-2477 10.1016/j.xhgg.2025.100483 244247299 RAZ_Zakelj_Nina_2025.pdf RAZ_Zakelj_Nina_2025.pdf 1 8BE22763EFA7141E29728EA2CF87F436 beca5db591d3898dfbcae3648a8834b2e1f167609300c1eab71bc17847f1931b b1c635d3-cac4-11f0-94a7-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=36288 https://www.cell.com/hgg-advances/fulltext/S2666-2477(25)00086-7 0 ca37b0d0-cac4-11f0-94a7-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=36290 Univerzitetni klinični center Ljubljana 0 0 0