De Novo and Inherited Variants in DDX39B Cause a Novel Neurodevelopmental Syndrome

Authors

• Kevin T A Booth
• Sharayu V Jangam
• Martin M C Chui
• Kayla Treat
• Lorenzo Graziani
• Alessia Soldano
• Yao Ruan
• Jeffrey Wan-Hei Hui
• Kerry White
• Celanie K Christensen
• Ty Lynnes
• Shinya Yamamoto
• Oguz Kanca
• Mandy H Y Tsang
• Sally A Lynch
• Sureni V Mullegama
• Julia Baptista
• Daniela Iancu
• Shelagh K Joss
• Sandra Y Y Wong
• Christopher C Y Mak
• Anna K Y Kwong
• Hugo J Bellen
• Erin Conboy
• Remo Sanges
• Anskar Yu-Hung Leung
• Michael F Wangler
• Brian H Y Chung
• Francesco Vetrini

Language

English

Publication Date

8-1-2025

Journal

Brain

DOI

10.1093/brain/awaf035

PMID

39918047

PMCID

PMC12316012

PubMedCentral® Posted Date

2-7-2025

PubMedCentral® Full Text Version

Post-print

Abstract

DDX39B is a conserved member of the DEAD-box family of ATP-dependent RNA helicases, critical in mRNA metabolism across eukaryotes. DDX39B is also a core component of the TRanscription-EXport (TREX) super protein complex, and recent studies have highlighted the important role of its subunits in neurodevelopmental disorders. Here, we describe six individuals from five families, four harbouring de novo missense variants in DDX39B and one with an inherited splicing variant, presenting with variable developmental delay, congenital hypotonia, epilepsy, short stature, skeletal abnormalities, dysmorphic features and microcephaly in three patients.

3D molecular modelling predicts these variants would alter protein structure. In vitro studies using overexpression of HA-tagged human DDX39B protein in 293FT cells revealed variants p.(Gly92Asp) and c.433-1G>T impaired interaction with DDX39B and other TREX complex members, while variants p.(Gly37Cys), p.(Ser44Arg) and p.(Arg123Gln) did not affect TREX complex assembly. Blood transcriptomics studies demonstrated significantly elevated aberrant splicing events in individuals carrying the p.(Gly37Cys), p.(Arg123Gln) or c.433-1G>T variant, compared to controls, suggesting a mRNA signature of disrupted mRNA splicing and export. To understand variant effects in vivo, we generated Drosophila transgenic DDX39B-reference and variant flies. Human reference DDX39B, when overexpressed ubiquitously, led to lethality, but the patient variants did not, suggesting that the mutants are loss-of-function alleles. Zebrafish anti-sense morpholino knockdown of DDX39B led to reduced head size and body length consistent with the patient phenotypes, and these effects were mitigated by synthesized mRNA, indicating a loss-of-function effect of DDX39B.

Collectively, our human genetic data, coupled with in silico, in vitro and in vivo data, support DDX39B as a novel candidate gene in a potential group of disorders called TREX-complex-related neurodevelopmental syndrome.

Keywords

Humans, DEAD-box RNA Helicases, Male, Female, Animals, Neurodevelopmental Disorders, Child, Child, Preschool, Pedigree, Mutation, Missense, Zebrafish, Developmental Disabilities, HEK293 Cells, Infant, Adolescent, neurodevelopmental disorder, DDX39B, TRanscription-EXport (TREX) super protein complex, zebrafish and Drosophila functional studies, transcriptomics

Published Open-Access

yes

Recommended Citation

Booth, Kevin T A; Jangam, Sharayu V; Chui, Martin M C; et al., "De Novo and Inherited Variants in DDX39B Cause a Novel Neurodevelopmental Syndrome" (2025). Duncan NRI Faculty and Staff Publications. 206.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/206