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De novo heterozygous missense and loss‐of‐function variants in CDC42BPB are associated with a neurodevelopmental phenotype
Author(s) -
Chilton Ilana,
Okur Volkan,
Vitiello Giuseppina,
Selicorni Angelo,
Mariani Milena,
Goldenberg Alice,
Husson Thomas,
Campion Dominique,
Lichtenbelt Klaske D.,
Gassen Koen,
Steinraths Michelle,
Rice Jennifer,
Roeder Elizabeth R.,
Littlejohn Rebecca O.,
Srour Myriam,
Sebire Guillaume,
Accogli Andrea,
Héron Delphine,
Heide Solveig,
Nava Caroline,
Depienne Christel,
Larson Austin,
Niyazov Dmitriy,
Azage Meron,
Hoganson George,
Burton Jennifer,
Rush Eric T.,
Jenkins Janda L.,
Saunders Carol J.,
Thiffault Isabelle,
Alaimo Joseph T.,
Fleischer Julie,
Groepper Daniel,
Gripp Karen W.,
Chung Wendy K.
Publication year - 2020
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.61505
Subject(s) - missense mutation , frameshift mutation , genetics , biology , haploinsufficiency , nonsense , nonsense mutation , phenotype , hypotonia , gene
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.