Deep Phenotyping in ReNU Syndrome Identifies a Recognizable Age-Dependent Clinical Trajectory.

Pathogenic variants in the noncoding gene RNU4-2 cause ReNU syndrome, a common neurodevelopmental disorder. Although the core phenotype is well described, longitudinal symptom progression and family perspectives remain insufficiently characterized. We identified 11 individuals with RNU4-2 pathogenic variants through reanalysis of clinical whole genome sequencing (WGS) data from a previously undiagnosed cohort. Using deep phenotyping, including retrospective medical record review and parental insights, we delineated a recognizable age-dependent clinical trajectory. Infancy was characterized by feeding difficulties, hypotonia, decelerating head growth, and visual abnormalities; early childhood by gait disturbances, autistic behavior, and seizure onset; and later childhood by persistent severe speech impairment with emerging orthopedic complications. Notably, feeding problems and seizures improved over time in several individuals. Core features included developmental delay, intellectual disability, speech abnormalities, hypotonia, autism, postnatal growth retardation, visual and brain abnormalities, and similar facial features. Parents emphasized strong social connectedness and affection and often described infancy as the most challenging stage due to feeding difficulties and failure to thrive. This study refines the natural history of ReNU syndrome and provides guidance for clinical management and counselling. It also highlights the value of routine WGS reanalysis as novel disease genes are identified.