Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/21388
Title: Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size.
Austin Authors: Le Duc, Diana;Giulivi, Cecilia;Hiatt, Susan M;Napoli, Eleonora;Panoutsopoulos, Alexios;Harlan De Crescenzo, Angelo;Kotzaeridou, Urania;Syrbe, Steffen;Anagnostou, Evdokia;Azage, Meron;Bend, Renee;Begtrup, Amber;Brown, Natasha J;Büttner, Benjamin;Cho, Megan T;Cooper, Gregory M;Doering, Jan H;Dubourg, Christèle;Everman, David B;Hildebrand, Michael S ;Santos, Francis Jeshira Reynoso;Kellam, Barbara;Keller-Ramey, Jennifer;Lemke, Johannes R;Liu, Shuxi;Niyazov, Dmitriy;Payne, Katelyn;Person, Richard;Quélin, Chloé;Schnur, Rhonda E;Smith, Brooke T;Strober, Jonathan;Walker, Susan;Wallis, Mathew J ;Walsh, Laurence;Yang, Sandra;Yuen, Ryan K C;Ziegler, Andreas;Sticht, Heinrich;Pride, Michael C;Orosco, Lori;Martínez-Cerdeño, Verónica;Silverman, Jill L;Crawley, Jacqueline N;Scherer, Stephen W;Zarbalis, Konstantinos S;Jamra, Rami
Affiliation: Joe DiMaggio Children's Hospital, Hollywood, FL 33021, USA
GeneDx, Clinical Genomics, 207 Perry Parkway Gaithersburg, MD 20877, USA
Greenwood Genetic Center, Greenwood, SC 29646, USA
Department of Pediatrics, Ochsner Health System and University of Queensland, New Orleans, LA 70121, USA
Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, USA
Department of Pathology and Laboratory Medicine, University of California at Davis, Sacramento, CA 95817, USA
HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA
MIND Institute, University of California Davis, Sacramento, CA 95817, USA
Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, M5G 0A4, Canada
Univ Rennes, CNRS, IGDR, UMR 6290, Rennes, F-35000, France
Service de Génétique Moléculaire et Génomique, CHU, Rennes, F-35033, France
Service de Génétique Clinique, CHU, Rennes, F-35203, France
Murdoch Children's Research Institute, Parkville, VIC 3052, Australia
Austin Health Clinical Genetics Service, Austin Health, Heidelberg, Victoria, Australia
Bloorview Research Institute, University of Toronto, Toronto, M4G 1R8, Canada
Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, Heidelberg, 69120, Germany
Institute of Human Genetics, University Medical Center Leipzig, Leipzig, 04103, Germany
Institute of Biochemistry, Emil-Fischer-Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, 91054, Germany
Department of Psychiatry and Behavioral Sciences, University of California Davis, Davis, CA 95616, USA
UCSF Benioff Children's Hospital, San Francisco, CA 94158, USA
Riley Hospital for Children, Indianapolis, IN 46202, USA
Department of Medicine, University of Melbourne, Parkville, VIC 3010, Australia
McLaughlin Centre, University of Toronto, Toronto, ON M5G 0A4, Canada
Victorian Clinical Genetics Services, Parkville, VIC 3052, Australia
Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Department of Pediatrics, University of Melbourne, VIC 3010, Australia
Issue Date: 20-Jul-2019
metadata.dc.date: 2019-09-01
Publication information: Brain : a journal of neurology 2019; 142(9): 2617-2630
Abstract: The 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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/21388
DOI: 10.1093/brain/awz198
ORCID: 0000-0003-2739-0515
PubMed URL: 31327001
Type: Journal Article
Subjects: WDFY3
brain size
intellectual disability
neurodevelopmental delay
Appears in Collections:Journal articles

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