Language

English

Publication Date

1-8-2026

Journal

Brain

DOI

10.1093/brain/awaf273

PMID

40717498

PMCID

PMC12782166

PubMedCentral® Posted Date

7-28-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Catatonia, Psychotic Disorders, Animals, Zebrafish, Male, Female, Neurodevelopmental Disorders, Child, Adolescent, Adult, Child, Preschool, Developmental Disabilities, Young Adult

Published Open-Access

yes

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