Publication
Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants
Publisher:
Elsevier BV
Date:
11-2022
DOI:
10.1016/J.GIM.2022.08.006
Abstract: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP. Genetic information from 404 in iduals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished in iduals were collected and combined with 68 previously published in iduals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay. The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants. NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.