De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures

NIHR BioResource; Care4Rare Canada Consortium

doi:10.1016/j.ajhg.2018.06.001

De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures

NIHR BioResource, Care4Rare Canada Consortium

Medicine

Résultat de recherche: Article › examen par les pairs

28 Citations (Scopus)

Résumé

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.

Langue d'origine	English
Pages (de-à)	144-153
Nombre de pages	10
Journal	American Journal of Human Genetics
Volume	103
Numéro de publication	1
DOI	https://doi.org/10.1016/j.ajhg.2018.06.001
Statut de publication	Published - juill. 5 2018

Note bibliographique

Funding Information:
We thank the four affected individuals involved in this study and their families. This work was supported by the Cambridge Biomedical Research Centre and the National Institute for Health Research (NIHR) for the NIHR BioResource (grant number RG65966). This work was supported by the Care4Rare Canada Consortium (Enhanced Care for Rare Genetic Diseases in Canada), which is funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, the Ontario Research Fund, Genome Quebec, and the Children's Hospital of Eastern Ontario Foundation.

Funding Information:
We thank the four affected individuals involved in this study and their families. This work was supported by the Cambridge Biomedical Research Centre and the National Institute for Health Research (NIHR) for the NIHR BioResource (grant number RG65966 ). This work was supported by the Care4Rare Canada Consortium (Enhanced Care for Rare Genetic Diseases in Canada), which is funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, the Ontario Research Fund, Genome Quebec, and the Children’s Hospital of Eastern Ontario Foundation.

Publisher Copyright:
© 2018

ASJC Scopus Subject Areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2018.06.001

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title = "De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures",

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.",

author = "{NIHR BioResource} and {Care4Rare Canada Consortium} and Yoko Ito and Carss, {Keren J.} and Duarte, {Sofia T.} and Taila Hartley and Boris Keren and Kurian, {Manju A.} and Isabelle Marey and Perinne Charles and Carla Mendon{\c c}a and Caroline Nava and Rolph Pfundt and Alba Sanchis-Juan and {van Bokhoven}, Hans and {van Essen}, Anthony and {van Ravenswaaij-Arts}, Conny and Timothy Aitman and David Bennett and Mark Caulfield and Patrick Chinnery and Daniel Gale and Ania Koziell and Kuijpers, {Taco W.} and Laffan, {Michael A.} and Eamonn Maher and Markus, {Hugh S.} and Morrell, {Nicholas W.} and Ouwehand, {Willem H.} and Perry, {David J.} and Raymond, {F. Lucy} and Irene Roberts and Smith, {Kenneth G.C.} and Adrian Thrasher and Hugh Watkins and Catherine Williamson and Geoffrey Woods and Sofie Ashford and Bradley, {John R.} and Debra Fletcher and Tracey Hammerton and Roger James and Nathalie Kingston and Penkett, {Christopher J.} and Kathleen Stirrups and Marijke Veltman and Tim Young and Matthew Brown and Naomi Clements-Brod and John Davis and Eleanor Dewhurst and Sarah Dyack",

note = "Funding Information: We thank the four affected individuals involved in this study and their families. This work was supported by the Cambridge Biomedical Research Centre and the National Institute for Health Research (NIHR) for the NIHR BioResource (grant number RG65966). This work was supported by the Care4Rare Canada Consortium (Enhanced Care for Rare Genetic Diseases in Canada), which is funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, the Ontario Research Fund, Genome Quebec, and the Children's Hospital of Eastern Ontario Foundation. Funding Information: We thank the four affected individuals involved in this study and their families. This work was supported by the Cambridge Biomedical Research Centre and the National Institute for Health Research (NIHR) for the NIHR BioResource (grant number RG65966 ). This work was supported by the Care4Rare Canada Consortium (Enhanced Care for Rare Genetic Diseases in Canada), which is funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, the Ontario Research Fund, Genome Quebec, and the Children{\textquoteright}s Hospital of Eastern Ontario Foundation. Publisher Copyright: {\textcopyright} 2018",

year = "2018",

month = jul,

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doi = "10.1016/j.ajhg.2018.06.001",

language = "English",

volume = "103",

pages = "144--153",

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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 - Clements-Brod, Naomi

AU - Davis, John

AU - Dewhurst, Eleanor

AU - Dyack, Sarah

N1 - Funding Information: We thank the four affected individuals involved in this study and their families. This work was supported by the Cambridge Biomedical Research Centre and the National Institute for Health Research (NIHR) for the NIHR BioResource (grant number RG65966). This work was supported by the Care4Rare Canada Consortium (Enhanced Care for Rare Genetic Diseases in Canada), which is funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, the Ontario Research Fund, Genome Quebec, and the Children's Hospital of Eastern Ontario Foundation. Funding Information: We thank the four affected individuals involved in this study and their families. This work was supported by the Cambridge Biomedical Research Centre and the National Institute for Health Research (NIHR) for the NIHR BioResource (grant number RG65966 ). This work was supported by the Care4Rare Canada Consortium (Enhanced Care for Rare Genetic Diseases in Canada), which is funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, the Ontario Research Fund, Genome Quebec, and the Children’s Hospital of Eastern Ontario Foundation. Publisher Copyright: © 2018

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.

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JO - American Journal of Human Genetics

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ER -

De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures

Résumé

Note bibliographique

ASJC Scopus Subject Areas

Accès au document

Autres fichiers et liens

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