Author(s):
Ito, Y ; Carss, KJ ; Duarte, ST ; Hartley, T ; Keren, B ; Kurian, MA ; Marey, I ; Charles, P ; Mendonça, C ; Nava, C ; Pfundt, R ; Sanchis-Juan, A ; van Bokhoven, H ; van Essen, A ; van Ravenswaaij-Arts, C ; Boycott, KM ; Kernohan, KD ; Dyack, S ; Raymond, FL
Date: 2018
Persistent ID: http://hdl.handle.net/10400.17/3441
Origin: Repositório do Centro Hospitalar de Lisboa Central, EPE
Subject(s): Adult; Female; Heterozygote; Humans; Intellectual Disability; Male; Mutation; Seizures; Whole Exome Sequencing; Wiskott-Aldrich Syndrome Protein Family; Young Adult; HDE NEU PED
Description
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.
