Epileptic encephalopathy

Gene: WASF1

Comment on mode of pathogenicity: Although the authors have suggested that the underlying disease mechanism is a gain-of-function or dominant-negative, the mode of pathogenicity has not been listed as such for this gene within PanelApp as the variants are all truncating and so will be identified using the loss of function criteria.

Created: 16 Jul 2018, 9:06 a.m.

Green List (high evidence)

From Ito Y, et al (2018) PMID: 29961568 Identified de novo heterozygous truncating variants in WASF1 that caused a Neurodevelopmental disorder in individuals with Intellectual Disability associated with autistic features, seizures, and developmental delay. The three de novo variants, identified in five unrelated affected individuals from non-consanguineous families and are unrelated, are all predicted to affect the actin-binding C-terminal WCA region of WASF1. The clustering of truncating pathogenic variants reported here and the presence of a truncated protein in cells from affected individuals imply either a gain-of-function or dominant-negative mechanism of disease. The three mutations were c.1516C>T (p.Arg506Ter), which occurred in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. The study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability.

Created: 5 Jul 2018, 8:53 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
ID associated with autistic features, seizures, and developmental delay; intellectual disability

Publications

• 29961568