De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures

被引：30

作者：

Ito, Yoko ^{[1
]}

Carss, Keren J. ^{[2
,3
]}

Duarte, Sofia T. ^{[4
]}

Hartley, Taila ^{[1
]}

Keren, Boris ^{[5
,6
]}

Kurian, Manju A. ^{[7
]}

Marey, Isabelle ^{[5
,6
]}

Charles, Perinne ^{[5
,6
]}

Mendonca, Carla ^{[8
]}

Nava, Caroline ^{[5
,6
,9
]}

Pfundt, Rolph ^{[10
]}

Sanchis-Juan, Alba ^{[2
,3
]}

van Bokhoven, Hans ^{[10
]}

van Essen, Anthony ^{[11
]}

van Ravenswaaij-Arts, Conny ^{[11
]}

Boycott, Kym M. ^{[1
,12
]}

Kernohan, Kristin D. ^{[1
]}

Dyack, Sarah ^{[13
]}

Raymond, F. Lucy ^{[3
,14
]}

机构：

[1] Univ Ottawa, Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON K1H 8L1, Canada

[2] Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England

[3] Cambridge Univ Hosp NHS Fdn Trust, NIHR BioResource, Cambridge Biomed Campus, Cambridge CB2 0QQ, England

[4] Ctr Hosp Lisboa Cent, Hosp Dona Estefania, P-1169045 Lisbon, Portugal

[5] Hop La Pitie Salpetriere, AP HP, Dept Genet, F-75651 Paris, France

[6] Hop La Pitie Salpetriere, AP HP, Ctr Reference Deficiences Intellectuelles Causes, F-75651 Paris, France

[7] UCL, Great Ormond St Inst Child Hlth, Dev Neurosci, London WC1N 1EH, England

[8] Ctr Hosp Univ Algarve, Ctr Neuropediat & Desenvolvimento, P-8000 Faro, Portugal

[9] Univ Paris 06, Sorbonne Univ, F-75013 Paris, France

[10] Radboudumc, Donders Inst Brain Cognit & Behav, Dept Human Genet, Box 9101, NL-6500 HB Nijmegen, Netherlands

[11] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, POB 30-001, NL-9700 RB Groningen, Netherlands

[12] Childrens Hosp Eastern Ontario, Dept Genet, Ottawa, ON K1H 8L1, Canada

[13] Dalhousie Univ, Dept Pediat, Halifax, NS B3K 6R8, Canada

[14] Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Cambridge CB2 0XY, England

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2018年 / 103卷 / 01期

基金：

加拿大健康研究院;

关键词：

PROTEIN; WAVE; PLASTICITY; DISORDERS; EXCHANGE; COMPLEX; GENES;

D O I：

10.1016/j.ajhg.2018.06.001

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：144 / 153

页数：10

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