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2019

ANUÁRIO DO HOSPITAL
DONA ESTEFÂNIA

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DE NOVO TRUNCATING MUTATIONS IN WASF1 CAUSE INTELLECTUAL DISABILITY WITH SEIZURES

Yoko Ito1, Keren J. Carss2,3, Sofia T. Duarte4, Taila Hartley1, Boris Keren5, Manju A. Kurian6, Isabelle Marey5, Perinne Charles5, Carla Mendonça7, Caroline Nava5,8, Rolph Pfundt9, Alba Sanchis-Juan2,3, Hans van Bokhoven9, Anthony van Essen10, Conny van Ravenswaaij-Arts10, NIHR BioResource Care4 - Rare Canada Consortium, Kym M. Boycott1,11, Kristin D. Kernohan1 Sarah Dyack12 and F. Lucy Raymond 3,13

1 - Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada
2 - Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK
3 - NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK
4 - Unidade de Neuropediatria, Área da Mulher, Criança e Adolescente, Hospital Dona Estefânia, Centro Hospitalar Universitário, de Lisboa Central, Lisboa, Portugal
5 - Département de Génétique et Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital de la Pitié-Salpêtrière, Assistance Publique – Hôpitaux de Paris, Paris, France
6 - Developmental Neurosciences, Great Ormond Street Institute of Child Health, University College London, London, UK
7 - Centro de Neuropediatria e Desenvolvimento, Centro Hospitalar Universitário do Algarve, Faro, Portugal
8 - Sorbonne Universités, Université Pierre et Marie Curie, Paris 75013, France
9 - Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, the Netherlands
10 - University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, the Netherlands
11 - Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada
12 - Department of Pediatrics, Dalhousie University, Halifax, NS B3K 6R8, Canada
13 - Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK

- Publicação em versão integral na revista American Journal of Human Genetics
- Am J Hum Genet. 2018 Jul 5; 103(1): 144–153.

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.

Palavras Chave: Intellectual Disability; Epilepsy; WASF1 mutations