Biallelic germline variants in the hematologic malignancy predisposition gene DDX41 cause retinal dystrophy through dysregulation of retinal homeostasis

DDX41 encodes a DEAD-box ATPase RNA helicase essential for RNA splicing, innate immune signaling, and hematopoiesis. Monoallelic germline DDX41 pathogenic variants represent the most common inherited predisposition to adult-onset myeloid malignancies, but their role in retinal disorders has remained unexplored. Using next-generation sequencing, we identified nine distinct germline DDX41 variants in biallelic combinations across ten families with inherited retinal disease, including one family previously reported by Diness et al. (2018), in whom retinal involvement had not been recognized. Patient fibroblasts homozygous for the missense variant c.1187T > C (p.I396T) and Ddx41 I396T/I396T mouse retinas exhibited markedly reduced DDX41 protein levels. Electroretinography demonstrated early and severe visual dysfunction, establishing a direct requirement for DDX41 in retinal physiology. DDX41 is localized to nuclei of all major retinal cell types and to photoreceptor synapses. Biochemical assays showed that disease-associated variants disrupted RNA binding through misfolding and aggregation, causing loss of function. Transcriptomic and proteomic profiling of mutant retinas revealed dysregulation of pathways involved in photoreceptor maintenance, RNA processing, immune signaling, and adherens junctions. Immunofluorescence analysis demonstrated altered Müller glial organization, and reactive gliosis. Retinal interactome analysis further characterized DDX41-associated protein networks enriched in synaptic function, RNA processing, and membrane trafficking pathways. These findings identify DDX41 deficiency as a previously unrecognized cause of early-onset severe retinal dystrophy (EOSRD). Clinically, they extend the spectrum of DDX41‑related disease beyond hematologic malignancies, indicating that individuals with biallelic variants may present with early‑onset visual impairment. More broadly, this work underscores the essential role of RNA helicases in neural tissue integrity and shows that disruption of DDX41 impairs retinal homeostasis and visual function.