Monoallelicde novovariants inDDX17cause a novel neurodevelopmental disorder

Abstract

AbstractIntroductionDDX17 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 withde novomonoallelic variants inDDX17. All 11 patients had a neurodevelopmental phenotype, whereby intellectual disability, delayed speech and language, and motor delay predominated.Materials and methodsWe performedin uterocortical electroporation in the brain of developing mice, assessing axon complexity and outgrowth of electroporated neurons, comparing wild-type and Ddx17 knockdown. We then undertookex vivocortical electroporation on neuronal progenitors to quantitively assess axonal development at a single cell resolution. Homozygous and heterozygousddx17crispant knockouts inXenopus tropicaliswere 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.ResultsKnockdown of Ddx17 in electroporated mouse neuronsin vivoshowed delayed neuronal migration as well as decreased cortical axon complexity. Mouse primary cortical neurons revealed reduced axon outgrowth upon knockdown ofDdx17 in vitro. The axon outgrowth phenotype was replicated in crispantddx17tadpoles, 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.DiscussionWe 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.