De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures

Am J Hum Genet. 2018 Jul 5;103(1):144-153. doi: 10.1016/j.ajhg.2018.06.001. Epub 2018 Jun 28.


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.

Keywords: WASF1; WAVE1 complex; actin cytoskeleton; autism; developmental delay; lamellipodia; neurodevelopmental disorder; recurrent de novo truncating mutations; seizures.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Exome Sequencing / methods
  • Female
  • Heterozygote
  • Humans
  • Intellectual Disability / genetics*
  • Male
  • Mutation / genetics*
  • Seizures / genetics*
  • Wiskott-Aldrich Syndrome Protein Family / genetics*
  • Young Adult


  • WASF1 protein, human
  • Wiskott-Aldrich Syndrome Protein Family