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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. © 2020 Wiley Periodicals, Inc.


Ilana Chilton, Volkan Okur, Giuseppina Vitiello, Angelo Selicorni, Milena Mariani, Alice Goldenberg, Thomas Husson, Dominique Campion, Klaske D Lichtenbelt, Koen van Gassen, Michelle Steinraths, Jennifer Rice, Elizabeth R Roeder, Rebecca O Littlejohn, Myriam Srour, Guillaume Sebire, Andrea Accogli, Delphine Héron, Solveig Heide, Caroline Nava, Christel Depienne, Austin Larson, Dmitriy Niyazov, Meron Azage, George Hoganson, Jennifer Burton, Eric T Rush, Janda L Jenkins, Carol J Saunders, Isabelle Thiffault, Joseph T Alaimo, Julie Fleischer, Daniel Groepper, Karen W Gripp, Wendy K Chung. De novo heterozygous missense and loss-of-function variants in CDC42BPB are associated with a neurodevelopmental phenotype. American journal of medical genetics. Part A. 2020 May;182(5):962-973

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PMID: 32031333

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