TY - JOUR
T1 - De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures
AU - NIHR BioResource
AU - Care4Rare Canada Consortium
AU - Ito, Yoko
AU - Carss, Keren J.
AU - Duarte, Sofia T.
AU - Hartley, Taila
AU - Keren, Boris
AU - Kurian, Manju A.
AU - Marey, Isabelle
AU - Charles, Perinne
AU - Mendonça, Carla
AU - Nava, Caroline
AU - Pfundt, Rolph
AU - Sanchis-Juan, Alba
AU - van Bokhoven, Hans
AU - van Essen, Anthony
AU - van Ravenswaaij-Arts, Conny
AU - Aitman, Timothy
AU - Bennett, David
AU - Caulfield, Mark
AU - Chinnery, Patrick
AU - Gale, Daniel
AU - Koziell, Ania
AU - Kuijpers, Taco W.
AU - Laffan, Michael A.
AU - Maher, Eamonn
AU - Markus, Hugh S.
AU - Morrell, Nicholas W.
AU - Ouwehand, Willem H.
AU - Perry, David J.
AU - Raymond, F. Lucy
AU - Roberts, Irene
AU - Smith, Kenneth G.C.
AU - Thrasher, Adrian
AU - Watkins, Hugh
AU - Williamson, Catherine
AU - Woods, Geoffrey
AU - Ashford, Sofie
AU - Bradley, John R.
AU - Fletcher, Debra
AU - Hammerton, Tracey
AU - James, Roger
AU - Kingston, Nathalie
AU - Penkett, Christopher J.
AU - Stirrups, Kathleen
AU - Veltman, Marijke
AU - Young, Tim
AU - Brown, Matthew
AU - Houweling, Arjan C.
AU - in't Veld, Anna Huis
AU - Noordegraaf, Anton Vonk
AU - Nejentsev, Sergey
AU - Clements-Brod, Naomi
AU - Davis, John
AU - Dewhurst, Eleanor
AU - Sivapalaratnam, Suthesh
PY - 2018/7/5
Y1 - 2018/7/5
N2 - 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.
AB - 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.
KW - WASF1
KW - WAVE1 complex
KW - actin cytoskeleton
KW - autism
KW - developmental delay
KW - lamellipodia
KW - neurodevelopmental disorder
KW - recurrent de novo truncating mutations
KW - seizures
UR - http://www.scopus.com/inward/record.url?scp=85048711435&partnerID=8YFLogxK
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85048711435&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29961568
U2 - https://doi.org/10.1016/j.ajhg.2018.06.001
DO - https://doi.org/10.1016/j.ajhg.2018.06.001
M3 - Article
C2 - 29961568
SN - 0002-9297
VL - 103
SP - 144
EP - 153
JO - American journal of human genetics
JF - American journal of human genetics
IS - 1
ER -