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De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures.

Am J Hum Genet. 2018 Jun 21;:

Authors: 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, NIHR BioResource, Care4Rare Canada Consortium, Boycott KM, Kernohan KD, Dyack S, Raymond FL

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.

PMID: 29961568 [PubMed – as supplied by publisher]

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