De Novo truncating mutations in WASF1 cause intellectual disability with seizures
File(s)
Author(s)
Type
Journal Article
Abstract
Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs 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. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability.
Date Issued
2018-07-05
Date Acceptance
2018-06-04
Citation
American Journal of Human Genetics, 2018, 103 (1), pp.144-153
ISSN
0002-9297
Publisher
Elsevier (Cell Press)
Start Page
144
End Page
153
Journal / Book Title
American Journal of Human Genetics
Volume
103
Issue
1
Copyright Statement
Crown Copyright © 2018 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Sponsor
Medical Research Council (MRC)
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/29961568
PII: S0002-9297(18)30194-0
Grant Number
MR/J011711/1
Subjects
WASF1
WAVE1 complex
actin cytoskeleton
autism
developmental delay
lamellipodia
neurodevelopmental disorder
recurrent de novo truncating mutations
seizures
Adult
Female
Heterozygote
Humans
Intellectual Disability
Male
Mutation
Seizures
Whole Exome Sequencing
Wiskott-Aldrich Syndrome Protein Family
Young Adult
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2018-06-28