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