Format

Send to

Choose Destination
Brain. 2019 Sep 1;142(9):2617-2630. doi: 10.1093/brain/awz198.

Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size.

Author information

1
Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany.
2
Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA.
3
MIND Institute, University of California Davis, Sacramento, CA, USA.
4
HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, USA.
5
Department of Pathology and Laboratory Medicine, University of California at Davis, Sacramento, CA, USA.
6
Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA, USA.
7
Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, Heidelberg, Germany.
8
Bloorview Research Institute, University of Toronto, Toronto, Canada.
9
Department of Pediatrics, Ochsner Health System and University of Queensland, New Orleans, LA, USA.
10
Greenwood Genetic Center, Greenwood, SC, USA.
11
GeneDx, Clinical Genomics, 207 Perry Parkway Gaithersburg, MD, USA.
12
Department of Pediatrics, University of Melbourne, VIC, Australia.
13
Victorian Clinical Genetics Services, Parkville, VIC, Australia.
14
Murdoch Children's Research Institute, Parkville, VIC, Australia.
15
Service de Génétique Moléculaire et Génomique, CHU, Rennes, F-35033, France.
16
Univ Rennes, CNRS, IGDR, UMR 6290, Rennes, F-35000, France.
17
Epilepsy Research Centre, Austin Health, Heidelberg, VIC, Australia.
18
Joe DiMaggio Children's Hospital, Hollywood, FL, USA.
19
The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Canada.
20
Riley Hospital for Children, Indianapolis, IN, USA.
21
Service de Génétique Clinique, CHU, Rennes, F-35203, France.
22
UCSF Benioff Children's Hospital, San Francisco, CA, USA.
23
Austin Health Clinical Genetics Service, Heidelberg, VIC, Australia.
24
Department of Medicine, University of Melbourne, Parkville, VIC, Australia.
25
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
26
Institute of Biochemistry, Emil-Fischer-Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
27
Department of Psychiatry and Behavioral Sciences, University of California Davis, Davis, CA, USA.
28
McLaughlin Centre, University of Toronto, Toronto, ON, Canada.

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.

KEYWORDS:

WDFY3 ; brain size; intellectual disability; neurodevelopmental delay

PMID:
31327001
PMCID:
PMC6736092
[Available on 2020-09-01]
DOI:
10.1093/brain/awz198

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center