De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures

Ito, Yoko, Carss, Keren J, Duarte, Sofia T, Hartley, Taila, Keren, Boris, Kurian, Manju A, Marey, Isabelle, Charles, Perinne, Mendonca, Carla, Nava, Caroline
et al (show 9 more authors) (2018) De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures. AMERICAN JOURNAL OF HUMAN GENETICS, 103 (1). pp. 144-153.

Access the full-text of this item by clicking on the Open Access link.


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.

Item Type: Article
Uncontrolled Keywords: NIHR BioResource, Care4Rare Canada Consortium, Humans, Seizures, Heterozygote, Mutation, Adult, Female, Male, Wiskott-Aldrich Syndrome Protein Family, Young Adult, Intellectual Disability, Exome Sequencing
Depositing User: Symplectic Admin
Date Deposited: 03 Sep 2019 15:43
Last Modified: 03 Feb 2023 05:03
DOI: 10.1016/j.ajhg.2018.06.001
Open Access URL:
Related URLs: