Variants in <i>DENND2B</i> are associated with vulnerability for neurodevelopmental impairment, psychosis and catatonia

DENND2B is a DENN (differentially expressed in normal and neoplastic cells) domain-containing protein that has important roles in regulating the cell cycle, cell division and ciliogenesis, but to date has not been associated with any human disease. Here, we report on 11 individuals with monoallelic variants in DENND2B with a shared constellation of features and perform in silico and in vivo zebrafish modelling of the DENND2B variants identified in these patients. Features shared among these patients include developmental delay, intellectual disability and psychiatric/behavioural concerns, and episodes of psychosis and/or catatonia. Additional features common to our cohort include epilepsy, muscle weakness/hypotonia and a wide range of congenital anomalies across different organ systems. Identified patient variants affect well-conserved amino acids and are predicted to be deleterious to DENND2B function by in silico prediction algorithms and structural modelling. Nine of the 10 observed patient variants were modelled in zebrafish and confirmed to result in loss of DENND2B function. Altogether, these findings suggest that monoallelic loss-of-function variants in DENND2B cause a novel autosomal dominant neurodevelopmental disorder with variable vulnerability to psychosis and/or catatonia.

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Publication Details

Journal
Brain
Published
2025-07-26
DOI
https://doi.org/10.1093/brain/awaf273
Citations
1
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
1.82
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article

Variants in DENND2B are associated with vulnerability for neurodevelopmental impairment, psychosis and catatonia

Sumaya Alkanderi, Jamie C Stark, Boris Keren, Jennifer Howe et al.
1 citations
Brain
Genomics and Rare Diseases
1.82
article

Variants in DENND2B are associated with vulnerability for neurodevelopmental impairment, psychosis and catatonia

Sumaya Alkanderi, Jamie C Stark, Boris Keren, Jennifer Howe, Theresa Brunet, Michelle R. Christie, Roberto Mendoza‐Londono, Lailá Bastaki, Ingrid M. Wentzensen, Katie Angione, Danielle A. Baribeau, Lindsay C. Burrage, James J. Dowling, Ashish R. Deshwar, Jacob A. S. Vorstman, Stephen W. Scherer, Gregory Costain, Jill Anne Rosenfeld, Reem M. Elshafie, Kenneth Alexis Myers, Deborah Baldwin, Thanuja Selvanayagam, Scott Demarest, Emanuela Pannia, Chiara Ceolin, Simon J. Harris, Ny Hoang, Jane Summers, Moira Lewis, Harsha Murthy, Megan Abbott, Philippe M. Campeau, Benjamin Cogné, Alexandra Afenjar, S Rieger, Sunny Cui, William J. Craigen, Bertrand Isidor, Sydney Scholten, Chung Ting Tsoi, Lauren Verhaeghe
article en
1 citations

Abstract

DENND2B is a DENN (differentially expressed in normal and neoplastic cells) domain-containing protein that has important roles in regulating the cell cycle, cell division and ciliogenesis, but to date has not been associated with any human disease. Here, we report on 11 individuals with monoallelic variants in DENND2B with a shared constellation of features and perform in silico and in vivo zebrafish modelling of the DENND2B variants identified in these patients. Features shared among these patients include developmental delay, intellectual disability and psychiatric/behavioural concerns, and episodes of psychosis and/or catatonia. Additional features common to our cohort include epilepsy, muscle weakness/hypotonia and a wide range of congenital anomalies across different organ systems. Identified patient variants affect well-conserved amino acids and are predicted to be deleterious to DENND2B function by in silico prediction algorithms and structural modelling. Nine of the 10 observed patient variants were modelled in zebrafish and confirmed to result in loss of DENND2B function. Altogether, these findings suggest that monoallelic loss-of-function variants in DENND2B cause a novel autosomal dominant neurodevelopmental disorder with variable vulnerability to psychosis and/or catatonia.

BrainVol. 149(1)
GenVec (US), Centre National de la Recherche Scientifique (FR), Inserm (FR), Baylor College of Medicine (US), University of Toronto (CA), Heidelberg University (DE), Hospital for Sick Children (CA), Holland Bloorview Kids Rehabilitation Hospital (CA), McGill University Health Centre (CA), University Hospital Heidelberg (DE), Centre Hospitalier Universitaire Sainte-Justine (CA), Texas Scottish Rite Hospital for Children (US), LMU Klinikum (DE), Sorbonne Université (FR), Hôpital Armand-Trousseau (FR), Children's Hospital Colorado (US), Xinqiao Hospital (CN), Institut thématique Génétique, génomique et bioinformatique (FR), ID Genomics (United States) (US), Institute of Human Genetics (PL), Pitié-Salpêtrière Hospital (FR), Ministry of Health (KW), Institut du Thorax (FR), BC Children's Hospital (CA), Génétique Médicale & Génomique Fonctionelle (FR), Baylor Genetics (US), Ludwig-Maximilians-Universität München (DE), University of Colorado Denver (US), Nantes Université (FR)
Openalex Percentile: Top 14%
Genomics and Rare Diseases
1.82
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