Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, PROTEIN, WAVE, PLASTICITY, DISORDERS, EXCHANGE, COMPLEX, GENES, 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, Exome Sequencing, Wiskott-Aldrich Syndrome Protein Family, Young Adult, NIHR BioResource, Care4Rare Canada Consortium, 06 Biological Sciences, 11 Medical and Health Sciences, 31 Biological sciences, 32 Biomedical and clinical sciences, 42 Health sciences

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.