Early onset or syndromic epilepsy

Gene: WASF1

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

Reported in Ito et al 2018 - 3 de novo truncating variants were identified in 5 unrelated indivdiuals with moderate to profound intellectual disability with autistic features and seizures. (4/5).

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
intellectual disability

Publications

• 29961568

Green List (high evidence)

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, 9:04 a.m.

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 variants 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 variant showed a truncated WASF1 and a defect in actin remodeling. The study provides evidence that de novo heterozygous variats in WASF1 cause a rare form of intellectual disability."

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, 8:58 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