Article Dans Une Revue Brain - A Journal of Neurology Année : 2025

Monoallelic de novo variants in DDX17 cause a neurodevelopmental disorder

1 University of Southampton
2 BROAD INSTITUTE - Broad Institute of MIT and Harvard
3 University of Portsmouth
4 PGNM - Physiopathologie et génétique du neurone et du muscle / Pathophysiology and Genetics of Neuron and Muscle
5 LBMC UMR 5239 - Laboratoire de biologie et modélisation de la cellule
6 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
7 IRCCS-ISNB - Istituto delle Scienze Neurologiche
8 UNIBO - Alma Mater Studiorum Università di Bologna = University of Bologna [Bologne]
9 AOUB - IRCCS Azienda Ospedaliero-Universitaria di Bologna
10 Fondazione IRCCS Istituto Neurologico "Carlo Besta"
11 Azienda Ospedaliera Ospedale Papa Giovanni XXIII [Bergamo, Italy]
12 Universitätsklinikum Carl Gustav Carus = University Hospital Carl Gustav Carus [Dresde]
13 OSU - The Ohio State University [Columbus]
14 Nationwide Children's Hospital
15 deCODE Genetics/Amgen [Reykjavik, Iceland]
16 CHOP - Children’s Hospital of Philadelphia
17 University of Pennsylvania [Philadelphia]
18 Perelman School of Medicine
19 FHU TRANSLAD (CHU de Dijon)
20 GAD - Génétique des anomalies du développement : GAD (CTM UMR 1231)
21 INM - Institut des Neurosciences de Montpellier
22 CHU Montpellier = Montpellier University Hospital
23 Landspitali National University Hospital of Iceland
24 IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital
25 Fondazione Policlinico Universitario Agostino Gemelli IRCCS
26 Unicatt - Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma]
27 University Hospital Southampton NHS Foundation Trust
28 Massachusetts General Hospital [Boston]
29 Boston Children's Hospital
Diana Baralle

Résumé

DDX17 is an RNA helicase shown to be involved in critical processes during the early phases of neuronal differentiation. Globally, we compiled a case series of 11 patients with neurodevelopmental phenotypes harbouring de novo monoallelic variants in DDX17. All 11 patients in our case series had a neurodevelopmental phenotype, whereby intellectual disability, delayed speech and language, and motor delay predominated. 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 quantitatively assess axonal development at a single cell resolution. Mosaic ddx17 crispants and heterozygous knockouts in Xenopus tropicalis were generated for assessment of morphology, 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. 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 and in heterozygotes. Heterozygous tadpoles had clear neurodevelopmental 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. We have identified potential neurodevelopment disease-causing variants in a gene not previously associated with genetic disease, DDX17. We provide evidence for the role of the gene in neurodevelopment in both mammalian and non-mammalian species and in controlling the expression of key neurodevelopment genes.

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Dates et versions

hal-04943083 , version 1 (13-03-2025)

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Eleanor Seaby, Annie Godwin, Géraldine Meyer-Dilhet, Valentine Clerc, Xavier Grand, et al.. Monoallelic de novo variants in DDX17 cause a neurodevelopmental disorder. Brain - A Journal of Neurology , 2025, 148 (4), pp.1155-1168. ⟨10.1093/brain/awae320⟩. ⟨hal-04943083⟩
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