Publication: Monoallelic de novo variants in DDX17 cause a novel neurodevelopmental disorder

Published in:

Authors: Eleanor Seaby, Annie Godwin, Valentine Clerc, Géraldine Meyer-Dilhet, Xavier Grand, Tia Fletcher, Laloe Monteiro, Valerio Carelli, Flavia Palombo, Marco Seri, Giulia Olivucci, Mina Grippa, Claudia Ciaccio, Stefano D’arrigo, Maria Iascone, Marion Bermudez, Jan Fischer, Nataliya Di Donato, Sophie Goesswein, Marco Leung, Daniel Koboldt, Cortlandt Myers, Dennis Bartholomew, Gudny Anna Arnadottir, Kari Stefansson, Patrick Sulem, Ethan Goldberg, Ange-Line Bruel, Frederic Tran Mau Them, Marjolaine Willems, Hans Tomas Bjornsson, Hakon Bjorn Hognason, Eirny Tholl Thorolfsdottir, Emanuele Agolini, Antonio Novelli, Giuseppe Zampino, Roberta Onesimo, Katherine Lachlan, Diana Baralle, Heidi Rehm, Anne O’donnell-Luria, Julien Courchet, Matt Guille, Cyril Bourgeois, Sarah Ennis

Summary

Abstract Introduction DDX17 is an RNA helicase shown to be involved in critical processes during the early phases of neuronal differentiation. Globally, we identified 11 patients with neurodevelopmental phenotypes with de novo monoallelic variants in DDX17 . All 11 patients had a neurodevelopmental phenotype, whereby intellectual disability, delayed speech and language, and motor delay predominated. Materials and methods We performed in utero cortical electroporation in the brain of developing mice, assessing axon complexity and outgrowth of electroporated neurons, comparing wild-type and Ddx17 knockdown. We then undertook ex vivo cortical electroporation on neuronal progenitors to quantitively assess axonal development at a single cell resolution. Homozygous and heterozygous ddx17 crispant knockouts in Xenopus tropicalis were generated for assessment of morphology, performed behavioural assays, and neuronal outgrowth measurements. We further undertook transcriptomic analysis of neuroblastoma SH-SY5Y cells, to identify differentially expressed genes in DDX17-KD cells compared to controls. Results Knockdown of Ddx17 in electroporated mouse neurons in vivo showed delayed neuronal migration as well as decreased cortical axon complexity. Mouse primary cortical neurons revealed reduced axon outgrowth upon knockdown of Ddx17 in vitro . The axon outgrowth phenotype was replicated in crispant ddx17 tadpoles, including in a heterozygous model. Crispant tadpoles had clear functional neural defects and showed an impaired neurobehavioral phenotype. Transcriptomic analysis identified a statistically significant number of differentially expressed genes involved in neurodevelopmental processes in DDX17-KD cells compared to control cells. Discussion We have identified a new gene, DDX17 , representing a rare cause of neurodevelopmental delay. We provide evidence for the role of the gene and mechanistic basis of dysfunctional neurodevelopment in both mammalian and non-mammalian species.

Link to HAL – hal-04737565

Link to DOI – 10.1101/2023.10.11.23295963