| Institution: | 1. Department of Pediatrics, Columbia University, New York, New York;2. Department of Translational Medicine, Federico II University, Naples, Italy;3. Pediatric Department, ASST Lariana, Sant'Anna Hospital, Como, Italy;4. Department of Genetics and Reference Center for Developmental Disorders, Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France;5. Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands;6. Department of Medical Genetics, University of British Columbia, Canada;7. Department of Pediatrics, Baylor College of Medicine, San Antonio, Texas;8. McGill University Health Center, Montreal Children's Hospital, Canada;9. Medical Genetics Unit, IRCCS Ospedale Policlinico San Martino and DINOGMI‐Università degli Studi di Genova, Genoa, Italy;10. Département de Génétique et de Cytogénétique;11. Centre de Référence Déficiences Intellectuelles de Causes Rares;12. GRC UPMC, Déficience Intellectuelle et Autisme, AP‐HP, H?pital Pitié‐Salpêtrière, Paris, France;13. INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, Paris, France;14. Institut für Humangenetik, Universit?tsklinikum Essen, Universit?t Duisburg‐Essen, Essen, Germany;15. Department of Pediatrics‐Clinical Genetics and Metabolism, University of Colorado, Colorado, USA;16. Department of Genetics, Ochsner Health System, Louisiana;17. Department of Pediatrics, University of Illinois, Chicago, Illinois, 60612 USA;18. Division of Clinical Genetics, Children's Mercy Hospital, Kansas City, Missouri;19. Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, Missouri;20. Department of Pediatrics, Southern Illinois University School of Medicine, Springfield, Illinois, 62702 USA;21. Division of Genetics, Department of Pediatrics, A.I. duPont Hospital for Children, Wilmington, Delaware, 19803 USA;22. Department of Medicine, Columbia University, New York, New York;23. Wendy K. Chung, 1150 St. Nicholas Avenue, Room 620, New York, NY 10032. |
| Abstract: | CDC42BPB encodes MRCKβ (myotonic dystrophy‐related Cdc42‐binding kinase beta), a serine/threonine protein kinase, and a downstream effector of CDC42, which has recently been associated with Takenouchi‐Kosaki syndrome, an autosomal dominant neurodevelopmental disorder. We identified 12 heterozygous predicted deleterious variants in CDC42BPB (9 missense, 2 frameshift, and 1 nonsense) in 14 unrelated individuals (confirmed de novo in 11/14) with neurodevelopmental disorders including developmental delay/intellectual disability, autism, hypotonia, and structural brain abnormalities including cerebellar vermis hypoplasia and agenesis/hypoplasia of the corpus callosum. The frameshift and nonsense variants in CDC42BPB are expected to be gene‐disrupting and lead to haploinsufficiency via nonsense‐mediated decay. All missense variants are located in highly conserved and functionally important protein domains/regions: 3 are found in the protein kinase domain, 2 are in the citron homology domain, and 4 in a 20‐amino acid sequence between 2 coiled‐coil regions, 2 of which are recurrent. Future studies will help to delineate the natural history and to elucidate the underlying biological mechanisms of the missense variants leading to the neurodevelopmental and behavioral phenotypes. |
