De novo variants in PAK1 lead to intellectual disability with macrocephaly and seizures

Author:

Horn Susanne1ORCID,Au Margaret2,Basel-Salmon Lina3456,Bayrak-Toydemir Pinar7,Chapin Alexander8,Cohen Lior3456,Elting Mariet W9,Graham John M2,Gonzaga-Jauregui Claudia10,Konen Osnat511,Holzer Max12,Lemke Johannes1ORCID,Miller Christine E8,Rey Linda K13,Wolf Nicole I14ORCID,Weiss Marjan M9,Waisfisz Quinten9,Mirzaa Ghayda M1516,Wieczorek Dagmar13,Sticht Heinrich17,Abou Jamra Rami1

Affiliation:

1. Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany

2. Department of Pediatrics, Cedars Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California, USA

3. Raphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel

4. Pediatric Genetics Clinic, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel

5. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

6. Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva, Israel

7. Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA; ARUP Laboratories, Salt Lake City, UT, USA

8. ARUP Laboratories, Salt Lake City, UT, USA

9. Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Clinical Genetics, De Boelelaan 1117, Amsterdam, The Netherlands

10. Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA

11. Department of Pediatric Radiology, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel

12. Department for Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany

13. Institute of Human Genetics, University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany

14. Department of Child Neurology, Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, and Amsterdam Neuroscience, Amsterdam, The Netherlands

15. Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA

16. Department of Pediatrics, University of Washington, Seattle, Washington, USA

17. Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

Abstract

Using trio exome sequencing, Horn et al. identify de novo gain-of-function mutations in PAK1 in four unrelated individuals with intellectual disability, macrocephaly and seizures. PAK1 encodes a p21-activated kinase, which has been implicated in brain development and control of brain size.

Funder

National Institute of Neurological Disorders and Stroke

Jordan’s Guardian Angels

National Institutes of Health

Publisher

Oxford University Press (OUP)

Subject

Clinical Neurology

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