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De novo heterozygous missense and loss-of-function variants in CDC42BPB are associated with a neurodevelopmental
Ilana Chilton1, Volkan Okur1, Giuseppina Vitiello2
1Department of Pediatrics, Columbia University, New York, New York.
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.
Insights
Genetic variants in CDC42BPB, encoding MRCKβ, are linked to neurodevelopmental disorders. This study identifies 12 deleterious variants in 14 individuals, highlighting a new genetic cause for these conditions.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- CDC42BPB encodes MRCKβ, a kinase involved in cell processes.
- MRCKβ is a downstream effector of CDC42.
- Takenouchi-Kosaki syndrome, a neurodevelopmental disorder, is linked to CDC42.
Purpose of the Study:
- To investigate the role of CDC42BPB variants in neurodevelopmental disorders.
- To identify genetic causes of developmental delay, intellectual disability, autism, and brain abnormalities.
Main Methods:
- Exome sequencing to identify variants in CDC42BPB.
- Analysis of variant pathogenicity and inheritance patterns (de novo mutations).
- Assessment of variant locations in conserved and functional protein domains.
Main Results:
- Identified 12 heterozygous predicted deleterious CDC42BPB variants in 14 individuals.
- Confirmed de novo occurrence in 11 out of 14 cases.
- Observed neurodevelopmental issues including intellectual disability, autism, hypotonia, and brain malformations (cerebellar hypoplasia, corpus callosum agenesis/hypoplasia).
- Frameshift and nonsense variants likely cause gene disruption and haploinsufficiency.
- Missense variants located in critical functional domains (kinase, citron homology, coiled-coil regions).
Conclusions:
- Heterozygous predicted deleterious variants in CDC42BPB are associated with a spectrum of neurodevelopmental disorders.
- Both gene-disrupting and missense variants contribute to the phenotype.
- Further research is needed to understand the mechanisms underlying these variants and their impact on neurodevelopment.
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