Monoallelic de novo variants in DDX17 cause a novel neurodevelopmental disorder

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. ### Competing Interest Statement Valerio Carelli acts as consultant and investigator in clinical trials for Chiesi Pharmaceuticals (Leber hereditary optic neuropathy), GenSIght Biologics (Leber hereditary optic neuropathy), and Stealth BioTherapeutics (mitochondrial myopathies). Heidi Rehm received funding for rare disease research from Illumina and Microsoft. ### Funding Statement The study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Genomics England (Ethics approval by the Health Research Authority [NRES Committee East of England] REC: 14/EE/1112; IRAS: 166046) approved the project RR357 (Translational genomics: Optimising novel gene discovery for 100,000 rare disease patients), facilitating the identification and dissemination of a novel gene and phenotype in the index case. For all other cases included, written consent (as approved by each institute's institutional review board/ethics committee) was provided to publish any phenotype and genotype data. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Transcriptomic data were deposited in the Gene Expression Omnibus (GEO) database under the record GSE223072. The following secure token has been created to allow review of record while it remains in private status: wrwfgmgibzedhwx. The embargo will be released upon acceptance of the manuscript. The published article includes all remaining data generated or analyzed during this study.