Submission Details

Heterozygous, usually de novo, germline variants in CTNNB1 have been associated with Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV) (MIM #615075), a condition previously described as “Autosomal dominant mental retardation type 19” in resources such as OMIM. The first report of de novo truncating variants in CTNNB1, identified by exome sequencing in three unrelated patients with a common phenotype of severe intellectual disability with absent or very limited speech, microcephaly and spasticity, was published by de Ligt et al. in 2012 (PMID: 23033978). Since then, more than 40 patients have been reported in the literature with de novo variants in CTNNB1 associated with NEDSDV (PMIDs: 24668549, 25326669, 27915094, 28514307, 33116939). The majority of the variants identified are nonsense and frameshift variants, and the disease mechanism is haploinsufficiency. Given the multiple literature reports and consistent findings of de novo loss-of-function variants in CTNNB1 associated with NEDSDV, this gene reaches the maximum score for genetic evidence. Additionally, experimental evidence in vitro and in vivo in a mouse model heterozygous for a p.Tyr653Lys substitution (PMID: 24614104)support the role of CTNNB1 in neurodevelopment. In summary, CTNNB1 is definitely associated with NEDSDV. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 02/03/2021 (SOP Version 8).