PUBLICATION
Variants in DENND2B are associated with vulnerability for neurodevelopmental impairment, psychosis and catatonia
- Authors
- Murthy, H., Hoang, N., Stark, J.C., Cui, S., Pannia, E., Tsoi, C.T., Harris, S., Ceolin, C., Verhaeghe, L., Scholten, S., Baribeau, D., Summers, J., Costain, G., Selvanayagam, T., Howe, J.L., Lewis, M.E.S., Brunet, T., Rieger, S., Rosenfeld, J.A., Craigen, W.J., Burrage, L.C., Christie, M.R., Baldwin, D., Wentzensen, I.M., Keren, B., Cogne, B., Isidor, B., Afenjar, A., Elshafie, R.M., Bastaki, L., Alkanderi, S., Myers, K.A., Demarest, S., Angione, K., Abbott, M., Campeau, P.M., Dowling, J.J., Mendoza-Londono, R., Scherer, S.W., Deshwar, A.R., Vorstman, J.
- ID
- ZDB-PUB-250729-3
- Date
- 2025
- Source
- Brain : a journal of neurology 149: 252-261 (Journal)
- Registered Authors
- Deshwar, Ashish, Dowling, Jim, Murthy, Harsha
- Keywords
- DENND2B, haploinsufficiency, neurodevelopmental disorder, neuropsychiatric, seizure, zebrafish
- MeSH Terms
-
- Adolescent
- Adult
- Animals
- Catatonia*/genetics
- Child
- Child, Preschool
- Developmental Disabilities/genetics
- Female
- Humans
- Male
- Neurodevelopmental Disorders*/genetics
- Psychotic Disorders*/genetics
- Young Adult
- Zebrafish
- PubMed
- 40717498 Full text @ Brain
Citation
Murthy, H., Hoang, N., Stark, J.C., Cui, S., Pannia, E., Tsoi, C.T., Harris, S., Ceolin, C., Verhaeghe, L., Scholten, S., Baribeau, D., Summers, J., Costain, G., Selvanayagam, T., Howe, J.L., Lewis, M.E.S., Brunet, T., Rieger, S., Rosenfeld, J.A., Craigen, W.J., Burrage, L.C., Christie, M.R., Baldwin, D., Wentzensen, I.M., Keren, B., Cogne, B., Isidor, B., Afenjar, A., Elshafie, R.M., Bastaki, L., Alkanderi, S., Myers, K.A., Demarest, S., Angione, K., Abbott, M., Campeau, P.M., Dowling, J.J., Mendoza-Londono, R., Scherer, S.W., Deshwar, A.R., Vorstman, J. (2025) Variants in DENND2B are associated with vulnerability for neurodevelopmental impairment, psychosis and catatonia. Brain : a journal of neurology. 149:252-261.
Abstract
Introduction 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.
Methods 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.
Results Features shared among these patients include developmental delay, intellectual disability and psychiatric/behavioral 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 modeling. Nine of the ten observed patient variants were modelled in zebrafish and confirmed to result in loss of DENND2B function.
Conclusions Altogether, these findings suggest that monoallelic loss of function variants in DENND2B cause a novel autosomal dominant neurodevelopmental disorder with variable vulnerability for psychosis and/or catatonia.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping