DDX3Xrelated

DDX3X-related disorder (often referred to as DDX3X syndrome) is a neurodevelopmental condition caused by pathogenic variants in the DDX3X gene, which encodes a DEAD-box RNA helicase involved in RNA metabolism, translation initiation, and neural development. The gene is located on the X chromosome, and DDX3X-related disease is predominantly reported in females, consistent with an X-linked pattern. Males with DDX3X variants are far less common and, when affected, often harbor mosaic or milder variants. Most pathogenic variants arise de novo, though inherited cases have been described.

Clinical features are highly variable. Intellectual disability or global developmental delay is common, with speech and language delays frequently prominent. Hypotonia, motor delay, and autistic features or other behavioral challenges are commonly described. Epilepsy occurs in a subset of individuals. Facial features are variable and non-specific, and brain imaging can show abnormalities such as corpus callosum anomalies in some cases, though many individuals have normal MRI findings. The phenotype spectrum ranges from mild to more severe impairment, reflecting the diversity of mutations (including missense, nonsense, frameshift, and splice-site variants) and potential mosaicism.

Diagnosis relies on genetic testing, typically exome sequencing or targeted gene panels that include DDX3X. A de novo status supports the diagnosis, while parental testing helps determine inheritance. Management is multidisciplinary and individualized, focusing on developmental therapies (speech, physical, occupational), educational support, and treatment of associated findings such as seizures if present.

Research continues to define genotype-phenotype correlations and the underlying biology of DDX3X in brain development, with models to explore potential targeted therapies in the future.