Longitudinal Behavior Phenotype Hallmarks in RNU4-2 Syndrome: Implications for Clinical Management

Abstract

Pathogenic variants in the non-coding spliceosomal gene RNU4-2 underlie ReNU syndrome, one of the most prevalent monogenic causes of neurodevelopmental disorders, accounting for ~0.4% of cases. Despite increasing recognition, little is known about the longitudinal behavioral and neuropsychiatric phenotype of affected individuals. We report two patients with RNU4-2 variants, providing a comprehensive description of their developmental trajectories from infancy to adolescence. Both exhibited global developmental delay, impaired adaptive functioning, and significant language deficits. Distinctive features included persistent attention deficits and Autistic Spectrum Disorder, which emerged as hallmarks of the Syndrome. Case-specific differences were notable: one patient developed self-injurious behavior and social anxiety during adolescence, while the other presented with epilepsy and structural brain anomalies. Neuroimaging revealed convergent features, including white matter reduction, corpus callosum thinning, and ventricular dysmorphisms. Our findings highlight the importance of early, individualized interventions, with particular emphasis on augmentative and alternative communication strategies and cognitive-behavioral approaches to mitigate communicative frustration, behavioral dysregulation, and social anxiety. This study provides the first longitudinal neuropsychiatric characterization of RNU4-2-related disorder, delineating clinical hallmarks, and therapeutic windows. A better understanding of developmental trajectories in this condition is essential to optimize patient management and improve long-term outcomes.

Keywords: RNU4‐2 syndrome; autism spectrum disorder; behavior phenotype; clinical management; developement disability; intellectual disability; longitudinal assessment.