This report not only helps to expand the mutant spectrum of the CTNNB1 gene but also prompts a new insight into genetic diagnosis in patients with both serious intellectual disability and visual defects.
Several of the identified genes that link to ID in humans are predicted to cause malfunction of β-catenin pathways, including mutations in CTNNB1 (β-catenin) itself.
Previous studies have reported heterozygous de novo CTNNB1 mutations as a cause of syndromic intellectual disability (ID) and autism spectrum disorder, and somatic mutations are linked to many cancers.
Recently, de novo, heterozygous, loss-of-function mutations of the CTNNB1 gene were found that partially explain intellectual disability in some patients.
Loss of function mutations in CTNNB1 have been reported in individuals with intellectual disability [MIM #615075] associated with peripheral spasticity, microcephaly and central hypotonia, suggesting a recognisable phenotype associated with haploinsufficiency for this gene.
We describe an 11 year old male Polish patient with a de novo nonsense mutation in CTNNB1 who in addition to the major features of CTNNB1-related syndrome including intellectual disability and microcephaly, exhibited hyperekplexia and apraxia of upward gaze.
Our study provides in vivo evidence that dominant mutations in β-catenin underlie losses in its adhesion-related functions, which leads to severe consequences, including intellectual disability, childhood hypotonia, progressive spasticity of lower limbs, and abnormal craniofacial features in adults.