Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/21388
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dc.contributor.authorLe Duc, Diana-
dc.contributor.authorGiulivi, Cecilia-
dc.contributor.authorHiatt, Susan M-
dc.contributor.authorNapoli, Eleonora-
dc.contributor.authorPanoutsopoulos, Alexios-
dc.contributor.authorHarlan De Crescenzo, Angelo-
dc.contributor.authorKotzaeridou, Urania-
dc.contributor.authorSyrbe, Steffen-
dc.contributor.authorAnagnostou, Evdokia-
dc.contributor.authorAzage, Meron-
dc.contributor.authorBend, Renee-
dc.contributor.authorBegtrup, Amber-
dc.contributor.authorBrown, Natasha J-
dc.contributor.authorBüttner, Benjamin-
dc.contributor.authorCho, Megan T-
dc.contributor.authorCooper, Gregory M-
dc.contributor.authorDoering, Jan H-
dc.contributor.authorDubourg, Christèle-
dc.contributor.authorEverman, David B-
dc.contributor.authorHildebrand, Michael S-
dc.contributor.authorSantos, Francis Jeshira Reynoso-
dc.contributor.authorKellam, Barbara-
dc.contributor.authorKeller-Ramey, Jennifer-
dc.contributor.authorLemke, Johannes R-
dc.contributor.authorLiu, Shuxi-
dc.contributor.authorNiyazov, Dmitriy-
dc.contributor.authorPayne, Katelyn-
dc.contributor.authorPerson, Richard-
dc.contributor.authorQuélin, Chloé-
dc.contributor.authorSchnur, Rhonda E-
dc.contributor.authorSmith, Brooke T-
dc.contributor.authorStrober, Jonathan-
dc.contributor.authorWalker, Susan-
dc.contributor.authorWallis, Mathew J-
dc.contributor.authorWalsh, Laurence-
dc.contributor.authorYang, Sandra-
dc.contributor.authorYuen, Ryan K C-
dc.contributor.authorZiegler, Andreas-
dc.contributor.authorSticht, Heinrich-
dc.contributor.authorPride, Michael C-
dc.contributor.authorOrosco, Lori-
dc.contributor.authorMartínez-Cerdeño, Verónica-
dc.contributor.authorSilverman, Jill L-
dc.contributor.authorCrawley, Jacqueline N-
dc.contributor.authorScherer, Stephen W-
dc.contributor.authorZarbalis, Konstantinos S-
dc.contributor.authorJamra, Rami-
dc.date2019-09-01-
dc.date.accessioned2019-08-12T05:00:05Z-
dc.date.available2019-08-12T05:00:05Z-
dc.date.issued2019-07-20-
dc.identifier.citationBrain : a journal of neurology 2019; 142(9): 2617-2630-
dc.identifier.urihttps://ahro.austin.org.au/austinjspui/handle/1/21388-
dc.description.abstractThe underpinnings of mild to moderate neurodevelopmental delay remain elusive, often leading to late diagnosis and interventions. Here, we present data on exome and genome sequencing as well as array analysis of 13 individuals that point to pathogenic, heterozygous, mostly de novo variants in WDFY3 (significant de novo enrichment P = 0.003) as a monogenic cause of mild and non-specific neurodevelopmental delay. Nine variants were protein-truncating and four missense. Overlapping symptoms included neurodevelopmental delay, intellectual disability, macrocephaly, and psychiatric disorders (autism spectrum disorders/attention deficit hyperactivity disorder). One proband presented with an opposing phenotype of microcephaly and the only missense-variant located in the PH-domain of WDFY3. Findings of this case are supported by previously published data, demonstrating that pathogenic PH-domain variants can lead to microcephaly via canonical Wnt-pathway upregulation. In a separate study, we reported that the autophagy scaffolding protein WDFY3 is required for cerebral cortical size regulation in mice, by controlling proper division of neural progenitors. Here, we show that proliferating cortical neural progenitors of human embryonic brains highly express WDFY3, further supporting a role for this molecule in the regulation of prenatal neurogenesis. We present data on Wnt-pathway dysregulation in Wdfy3-haploinsufficient mice, which display macrocephaly and deficits in motor coordination and associative learning, recapitulating the human phenotype. Consequently, we propose that in humans WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway. In summary, we present WDFY3 as a novel gene linked to mild to moderate neurodevelopmental delay and intellectual disability and conclude that variants putatively causing haploinsufficiency lead to macrocephaly, while an opposing pathomechanism due to variants in the PH-domain of WDFY3 leads to microcephaly.-
dc.language.isoeng-
dc.subjectWDFY3-
dc.subjectbrain size-
dc.subjectintellectual disability-
dc.subjectneurodevelopmental delay-
dc.titlePathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size.-
dc.typeJournal Article-
dc.identifier.journaltitleBrain : a journal of neurology-
dc.identifier.affiliationJoe DiMaggio Children's Hospital, Hollywood, FL 33021, USAen
dc.identifier.affiliationGeneDx, Clinical Genomics, 207 Perry Parkway Gaithersburg, MD 20877, USAen
dc.identifier.affiliationGreenwood Genetic Center, Greenwood, SC 29646, USAen
dc.identifier.affiliationDepartment of Pediatrics, Ochsner Health System and University of Queensland, New Orleans, LA 70121, USAen
dc.identifier.affiliationInstitute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, USAen
dc.identifier.affiliationDepartment of Pathology and Laboratory Medicine, University of California at Davis, Sacramento, CA 95817, USAen
dc.identifier.affiliationHudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USAen
dc.identifier.affiliationMIND Institute, University of California Davis, Sacramento, CA 95817, USAen
dc.identifier.affiliationDepartment of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USAen
dc.identifier.affiliationDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canadaen
dc.identifier.affiliationThe Centre for Applied Genomics, The Hospital for Sick Children, Toronto, M5G 0A4, Canadaen
dc.identifier.affiliationUniv Rennes, CNRS, IGDR, UMR 6290, Rennes, F-35000, Franceen
dc.identifier.affiliationService de Génétique Moléculaire et Génomique, CHU, Rennes, F-35033, Franceen
dc.identifier.affiliationService de Génétique Clinique, CHU, Rennes, F-35203, Franceen
dc.identifier.affiliationMurdoch Children's Research Institute, Parkville, VIC 3052, Australiaen
dc.identifier.affiliationAustin Health Clinical Genetics Service, Austin Health, Heidelberg, Victoria, Australiaen
dc.identifier.affiliationBloorview Research Institute, University of Toronto, Toronto, M4G 1R8, Canadaen
dc.identifier.affiliationDivision of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, Heidelberg, 69120, Germanyen
dc.identifier.affiliationInstitute of Human Genetics, University Medical Center Leipzig, Leipzig, 04103, Germanyen
dc.identifier.affiliationInstitute of Biochemistry, Emil-Fischer-Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, 91054, Germanyen
dc.identifier.affiliationDepartment of Psychiatry and Behavioral Sciences, University of California Davis, Davis, CA 95616, USAen
dc.identifier.affiliationUCSF Benioff Children's Hospital, San Francisco, CA 94158, USAen
dc.identifier.affiliationRiley Hospital for Children, Indianapolis, IN 46202, USAen
dc.identifier.affiliationDepartment of Medicine, University of Melbourne, Parkville, VIC 3010, Australiaen
dc.identifier.affiliationMcLaughlin Centre, University of Toronto, Toronto, ON M5G 0A4, Canadaen
dc.identifier.affiliationVictorian Clinical Genetics Services, Parkville, VIC 3052, Australiaen
dc.identifier.affiliationEpilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australiaen
dc.identifier.affiliationDepartment of Pediatrics, University of Melbourne, VIC 3010, Australiaen
dc.identifier.doi10.1093/brain/awz198-
dc.identifier.orcid0000-0003-2739-0515-
dc.identifier.pubmedid31327001-
dc.type.austinJournal Article-
local.name.researcherHildebrand, Michael S
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.cerifentitytypePublications-
item.fulltextNo Fulltext-
item.grantfulltextnone-
item.languageiso639-1en-
item.openairetypeJournal Article-
crisitem.author.deptEpilepsy Research Centre-
crisitem.author.deptMedicine (University of Melbourne)-
crisitem.author.deptClinical Genetics-
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