DDX23 gain-of-function linked to autism spectrum disorder with intellectual disability, motor delay, and seizure

DDX23, a member of the DEAD-box RNA helicase superfamily, is crucial for RNA processing and translation initiation during gametogenesis and cell division. This study aims to determine the disease-causing potential and clinical relevance of rare de novo DDX23 missense variants identified in individuals with neurodevelopmental and cardiopulmonary anomalies.

Clinical and genetic analyses were performed on 3 individuals presenting with developmental delay or intellectual disability, facial dysmorphisms, brain structural abnormalities, and cardiopulmonary defects. Exome sequencing identified rare de novo monoallelic missense variants at p.Arg528-p.(Arg528Cys), p.(Arg528His), or p.(Arg528Gln)-in DDX23. In silico prediction tools were used to assess the potential functional impact of these variants. To test their disease-causing role in vivo, wild-type and two mutant DDX23 alleles, p.(Arg528Cys) and p.(Arg528His), were expressed ubiquitously or in a tissue-specific manner in a humanized Drosophila model.

All 3 individuals carried a de novo missense variants at p.Arg528-p.(Arg528Cys), p.(Arg528His), or p.(Arg528Gln)-all predicted in silico to be deleterious, with dominant effects. Expression of the p.(Arg528Cys) and p.(Arg528His) alleles in Drosophila resulted in severely compromised development and survival, with either ubiquitous or tissue-specific expression leading to a complete loss of progeny. These findings demonstrate a robust functional impact of the variants consistent with a gain-of-function mechanism.

Our study identifies recurrent de novo missense variants in DDX23 as the genetic cause of a neurodevelopmental syndrome. Functional assays in Drosophila confirm the disease-causing potential of these variants and support a gain-of-function mechanism for the p.(Arg528Cys) and p.(Arg528His) alleles.