De novo heterozygous missense and loss-of-function variants in CDC42BPB are associated with a neurodevelopmental phenotype

Ilana Chilton¹, Volkan Okur¹, Giuseppina Vitiello², Angelo Selicorni³, Milena Mariani³, Alice Goldenberg⁴, Thomas Husson⁴, Dominique Campion⁴, Klaske D Lichtenbelt⁵, Koen van Gassen⁵, Michelle Steinraths⁶, Jennifer Rice⁶, Elizabeth R Roeder⁷, Rebecca O Littlejohn⁷, Myriam Srour⁸, Guillaume Sebire⁸, Andrea Accogli⁹, Delphine Héron¹⁰, Solveig Heide¹⁰, Caroline Nava^{10

11}, Christel Depienne^{11

12}, Austin Larson¹³, Dmitriy Niyazov¹⁴, Meron Azage¹⁴, George Hoganson¹⁵, Jennifer Burton¹⁵, Eric T Rush¹⁶, Janda L Jenkins¹⁶, Carol J Saunders¹⁷, Isabelle Thiffault¹⁷, Joseph T Alaimo¹⁷, Julie Fleischer¹⁸, Daniel Groepper¹⁸, Karen W Gripp¹⁹, Wendy K Chung^{1

20}

Affiliations

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; Centre de Référence Déficiences Intellectuelles de Causes Rares; GRC UPMC, Déficience Intellectuelle et Autisme, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
¹¹ 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.
¹² Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
¹³ Department of Pediatrics-Clinical Genetics and Metabolism, University of Colorado, Colorado, USA.
¹⁴ Department of Genetics, Ochsner Health System, Louisiana.
¹⁵ Department of Pediatrics, University of Illinois, Chicago, Illinois, 60612, USA.
¹⁶ Division of Clinical Genetics, Children's Mercy Hospital, Kansas City, Missouri.
¹⁷ Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, Missouri.
¹⁸ Department of Pediatrics, Southern Illinois University School of Medicine, Springfield, Illinois, 62702, USA.
¹⁹ Division of Genetics, Department of Pediatrics, A.I. duPont Hospital for Children, Wilmington, Delaware, 19803, USA.
²⁰ Department of Medicine, Columbia University, New York, New York.

PMID: 32031333
DOI: 10.1002/ajmg.a.61505

De novo heterozygous missense and loss-of-function variants in CDC42BPB are associated with a neurodevelopmental phenotype

Ilana Chilton et al. Am J Med Genet A. 2020 May.

. 2020 May;182(5):962-973.

doi: 10.1002/ajmg.a.61505. Epub 2020 Feb 7.

Authors

Affiliations

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; Centre de Référence Déficiences Intellectuelles de Causes Rares; GRC UPMC, Déficience Intellectuelle et Autisme, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
¹¹ 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.
¹² Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
¹³ Department of Pediatrics-Clinical Genetics and Metabolism, University of Colorado, Colorado, USA.
¹⁴ Department of Genetics, Ochsner Health System, Louisiana.
¹⁵ Department of Pediatrics, University of Illinois, Chicago, Illinois, 60612, USA.
¹⁶ Division of Clinical Genetics, Children's Mercy Hospital, Kansas City, Missouri.
¹⁷ Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, Missouri.
¹⁸ Department of Pediatrics, Southern Illinois University School of Medicine, Springfield, Illinois, 62702, USA.
¹⁹ Division of Genetics, Department of Pediatrics, A.I. duPont Hospital for Children, Wilmington, Delaware, 19803, USA.
²⁰ Department of Medicine, Columbia University, New York, New York.

PMID: 32031333
DOI: 10.1002/ajmg.a.61505

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.

Keywords: CDC42BPB; MRCKβ; brain abnormalities; exome sequencing; neurodevelopmental disorder.

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References

REFERENCES

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De novo heterozygous missense and loss-of-function variants in CDC42BPB are associated with a neurodevelopmental phenotype

Affiliations

De novo heterozygous missense and loss-of-function variants in CDC42BPB are associated with a neurodevelopmental phenotype

Authors

Affiliations

Abstract

References

REFERENCES

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LinkOut - more resources

Full Text Sources

Medical

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