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

Ito, Y; Carss, KJ; Duarte, ST; Hartley, T; Keren, B; Kurian, MA; Marey, I; Charles, P; Mendonça, C; Nava, C; et al. 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 (2018) De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures. Am J Hum Genet, 103 (1). pp. 144-153. ISSN 1537-6605 https://doi.org/10.1016/j.ajhg.2018.06.001
SGUL Authors: Southgate, Laura

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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.

Item Type: Article
Additional Information: 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/)
Keywords: 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, NIHR BioResource, Care4Rare Canada Consortium, Humans, Seizures, Heterozygote, Mutation, Adult, Female, Male, Wiskott-Aldrich Syndrome Protein Family, Young Adult, Intellectual Disability, Whole Exome Sequencing, 06 Biological Sciences, 11 Medical And Health Sciences, Genetics & Heredity
Journal or Publication Title: Am J Hum Genet
ISSN: 1537-6605
Language: eng
Dates:
DateEvent
5 July 2018Published
28 June 2018Published Online
4 June 2018Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Projects:
Project IDFunderFunder ID
FS/10/013/28073British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
G0800671Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
RG65966National Institute for Health Researchhttp://dx.doi.org/10.13039/501100000272
PubMed ID: 29961568
Web of Science ID: WOS:000438168800013
Go to PubMed abstract
URI: http://sgultest.da.ulcc.ac.uk/id/eprint/111379
Publisher's version: https://doi.org/10.1016/j.ajhg.2018.06.001

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