CTNNB1 syndrome is a monogenetic neurodevelopmental disorder caused by de novo heterozygous loss-of-function pathogenic variants in the CTNNB1 gene, which encodes β-catenin, and it is characterized by insufficient β-catenin and cognitive and motor disabilities, with co-morbid intellectual disability (ID) and autism spectrum disorder (ASD) in a subset of individuals. This evidence concerns the gene CTNNB1 and severe intellectual disability-progressive spastic diplegia syndrome.