Monoallelic de novo variants in DDX17 cause a novel neurodevelopmental disorder (2023)

Seaby, E.G., Godwin, A., Clerc, V., Meyer-Dilhet, G., Grand, X., Fletcher, T., Monteiro, L., Carelli, V., Palombo, F., Seri, M., Olivucci, G., Grippa, M., Ciaccio, C., D’Arrigo, S., Iascone, M., Bermudez, M., Fischer, J., Di Donato, N., Goesswein, S., Leung, M. L., Koboldt, D. C., Myers, C., Bartholomew, D., Arnadottir, G. A., Stefansson, K., Sulem, P., Goldberg, E.M., Bruel, A-L., Tran Mau Them, F., Willems, M., Bjornsson, H.T., Hognason, H., B., Thorolfsdottir, E.T., Agolini, E., Novelli, A., Zampino, G., Onesimo, R., Lachlan, K., Baralle, D., Rehm, H.L., O’Donnell-Luria, A., Courchet, J., Guille, M., Bourgeois, C.F. & Ennis, S. (2023). Monoallelic de novo variants in DDX17 cause a novel neurodevelopmental disorder. medRxiv, 2023.10.11.23295963



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 SH121 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, 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.
: 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