Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.

Area of Science:

• Genetics and Developmental Biology
• Neuroscience
• Molecular Biology

Background:

• CTNNB1 neurodevelopmental syndrome arises from de novo variants in the CTNNB1 gene, which encodes β-catenin.
• Understanding the genetic and phenotypic spectrum is crucial for diagnosis and management.

Purpose of the Study:

• Characterize genetic variants in CTNNB1 neurodevelopmental syndrome.
• Assess clinical phenotypes using standardized measures.
• Explore genotype-phenotype correlations.

Main Methods:

• Cross-sectional cohort study of 127 individuals with CTNNB1 neurodevelopmental syndrome.
• Structured interviews and standardized scales for motor, speech, feeding, and cognitive assessments.
• Genetic variant analysis and functional assays of Wnt/β-catenin signaling pathway.

Main Results:

• Identified 88 CTNNB1 variants, mostly loss-of-function (87).
• Demonstrated reduced Wnt signaling; 11 variants showed dominant-negative effects, one missense variant showed gain-of-function.
• Missense variants correlated with milder phenotypes: earlier walking, fewer motor issues, better cognitive and social skills, improved communication, and fewer feeding difficulties.

Conclusions:

• This study provides a comprehensive genetic, functional, and phenotypic profile of CTNNB1 neurodevelopmental syndrome.
• Further research into genotype-phenotype interrelationships is vital for developing targeted therapies.