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

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

Collaborators (356)

Aitman T, Bennett D, Caulfield M, Chinnery P, Gale D, Koziell A, Kuijpers TW, Laffan MA, Maher E, Markus HS, Morrell NW, Ouwehand WH, Perry DJ, Raymond FL, Roberts I, Smith KGC, Thrasher A, Watkins H, Williamson C, Woods G, Ashford S, Bradley JR, Fletcher D, Hammerton T, James R, Kingston N, Penkett CJ, Stirrups K, Veltman M, Young T, Brown M, Clements-Brod N, Davis J, Dewhurst E, Dolling H, Erwood M, Frary A, Linger R, Martin JM, Papadia S, Rehnstrom K, Stark H, Allsup D, Austin S, Bakchoul T, Bariana TK, Bolton-Maggs P, Chalmers E, Collins J, Collins P, Erber WN, Everington T, Favier R, Freson K, Furie B, Gattens M, Gebhart J, Gomez K, Greene D, Greinacher A, Gresele P, Hart D, Heemskerk JWM, Henskens Y, Kazmi R, Keeling D, Kelly AM, Lambert MP, Lentaigne C, Liesner R, Makris M, Mangles S, Mathias M, Millar CM, Mumford A, Nurden P, Payne J, Pasi J, Peerlinck K, Revel-Vilk S, Richards M, Rondina M, Roughley C, Schulman S, Schulze H, Scully M, Sivapalaratnam S, Stubbs M, Tait RC, Talks K, Thachil J, Toh CH, Turro E, Van Geet C, De Vries M, Warner TQ, Watson H, Westbury S, Furnell A, Mapeta R, Rayner-Matthews P, Simeoni I, Staines S, Stephens J, Watt C, Whitehorn D, Attwood A, Daugherty L, Deevi SVV, Halmagyi C, Hu F, Matser V, Meacham S, Megy K, Shamardina O, Titterton C, Tuna S, Yu P, von Ziegenweldt J, Astle W, Bleda M, Carss KJ, Gräf S, Haimel M, Lango-Allen H, Richardson S, Calleja P, Rankin S, Turek W, Anderson J, Bryson C, Carmichael J, McJannet C, Stock S, Allen L, Ambegaonkar G, Armstrong R, Arno G, Bitner-Glindzicz M, Brady A, Canham N, Chitre M, Clement E, Clowes V, Deegan P, Deshpande C, Doffinger R, Firth H, Flinter F, French C, Gardham A, Ghali N, Gissen P, Grozeva D, Henderson R, Hensiek A, Holden S, Holder M, Holder S, Hurst J, Josifova D, Krishnakumar D, Kurian MA, Lees M, MacLaren R, Maw A, Mehta S, Michaelides M, Moore A, Murphy E, Park SM, Parker A, Patch C, Paterson J, Rankin J, Reid E, Rosser E, Sanchis-Juan A, Sandford R, Santra S, Scott R, Sohal A, Stein P, Thomas E, Thompson D, Tischkowitz M, Vogt J, Wakeling E, Wassmer E, Webster A, Ali S, Ali S, Boggard HJ, Church C, Coghlan G, Cookson V, Corris PA, Creaser-Myers A, DaCosta R, Dormand N, Eyries M, Gall H, Ghataorhe PK, Ghio S, Ghofrani A, Gibbs JSR, Girerd B, Greenhalgh A, Hadinnapola C, Houweling AC, Humbert M, In't Veld AH, Kennedy F, Kiely DG, Kovacs G, Lawrie A, Ross RVM, Machado R, Masati L, Meehan S, Moledina S, Montani D, Othman S, Peacock AJ, Pepke-Zaba J, Pollock V, Polwarth G, Ranganathan L, Rhodes CJ, Rue-Albrecht K, Schotte G, Shipley D, Soubrier F, Southgate L, Scelsi L, Suntharalingam J, Tan Y, Toshner M, Treacy CM, Trembath R, Vonk Noordegraaf A, Walker S, Wanjiku I, Wharton J, Wilkins M, Wort SJ, Yates K, Alachkar H, Antrobus R, Arumugakani G, Bacchelli C, Baxendale H, Bethune C, Bibi S, Booth C, Browning M, Burns S, Chandra A, Cooper N, Davies S, Devlin L, Drewe E, Edgar D, Egner W, Ghurye R, Gilmour K, Goddard S, Gordins P, Grigoriadou S, Hackett S, Hague R, Harper L, Hayman G, Herwadkar A, Huissoon A, Jolles S, Kelleher P, Kumararatne D, Lear S, Longhurst H, Lorenzo L, Maimaris J, Manson A, McDermott E, Murng S, Nejentsev S, Noorani S, Oksenhendler E, Ponsford M, Qasim W, Quinti I, Richter A, Samarghitean C, Sargur R, Savic S, Seneviratne S, Sewell C, Staples E, Stauss H, Thaventhiran J, Thomas M, Welch S, Willcocks L, Yeatman N, Yong P, Ancliff P, Babbs C, Layton M, Louka E, McGowan S, Mead A, Roy N, Chambers J, Dixon P, Estiu C, Hague B, Marschall HU, Simpson M, Chong S, Emmerson I, Ginsberg L, Gosal D, Hadden R, Horvath R, Mahdi-Rogers M, Manzur A, Marshall A, Matthews E, McCarthy M, Reilly M, Renton T, Rice A, Themistocleous A, Vale T, Van Zuydam N, Walker S, Ormondroyd L, Hudson G, Wei W, Yu Wai Man P, Whitworth J, Afzal M, Colby E, Saleem M, Alavijeh OS, Cook HT, Johnson S, Levine AP, Wong EKS, Tan R, Boycott KM, MacKenzie A, Majewski J, Brudno M, Bulman D, Dyment D.

Author information

1
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1 Canada.
2
Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK; NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
3
Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, 1169-045 Lisbon, Portugal.
4
Département de Génétique et Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, 75651 Paris, France.
5
Developmental Neurosciences, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
6
Centro de Neuropediatria e Desenvolvimento, Centro Hospitalar Universitário do Algarve, Faro 8000, Portugal.
7
Département de Génétique et Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, 75651 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie, Paris 75013, France.
8
Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, Box 9101, 6500 HB Nijmegen, the Netherlands.
9
University of Groningen, University Medical Centre Groningen, Department of Genetics, P.O. Box 30.001, 9700 RB Groningen, the Netherlands.
10
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1 Canada; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada.
11
Department of Pediatrics, Dalhousie University, Halifax, NS B3K 6R8, Canada.
12
NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK. Electronic address: flr24@cam.ac.uk.

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.

KEYWORDS:

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

PMID:
29961568
PMCID:
PMC6037130
[Available on 2019-01-05]
DOI:
10.1016/j.ajhg.2018.06.001
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