ReNU Syndrome and the RNU4-2 Mutation: A Missed Cause of Childhood Neurodevelopmental Delay

ReNU syndrome is a rare but increasingly recognized syndromic neurodevelopmental disorder caused by heterozygous de novo variants in the non-coding gene RNU4-2, which encodes the U4 small nuclear RNA (snRNA), a critical component of the major spliceosome. Recurrent pathogenic variants cluster within an 18-base-pair critical region of RNU4-2 and disrupt normal spliceosome function by altering 5′ splice-site usage. In large cohorts, most affected individuals harbor a recurrent single-base insertion (n.64_65insT), accounting for the majority of pathogenic variants, and RNU4-2 variants may explain ~0.4% of undiagnosed neurodevelopmental disorders. Clinically, ReNU syndrome is characterized by global developmental delay, intellectual disability, hypotonia, delayed motor milestones, limited speech, feeding difficulties, distinctive facial features, and structural brain anomalies. Given the emerging understanding of its prevalence and severe phenotype, we highlight the urgent need to incorporate RNU4-2 analysis into diagnostic genomic testing for pediatric neurodevelopmental disorders. Increasing awareness and equitable access to comprehensive genetic testing will improve diagnosis and counseling for affected families worldwide.