This study identifies a novel gene, RNU4-2, which encodes the U4 small nuclear RNA (snRNA), as a cause of neurodevelopmental disorders (NDD). The RNU4-2 gene is highly expressed in the developing human brain and contains a critical 18-base pair region that is depleted of variants in the general population but enriched with variants in individuals with NDD. Specifically, a highly recurrent single-base insertion (n.64_65insT) was identified in 77.4% of individuals with NDD, all of whom had the same variant on the maternal allele. RNA sequencing data from five individuals with RNU4-2 variants showed systematic disruption of 5' splice-site use, consistent with the known role of this region in spliceosome activation. The authors estimate that variants in this region explain 0.4% of all NDD cases. This discovery highlights the importance of non-coding genes in rare disorders and provides a diagnosis for thousands of individuals with undiagnosed NDD worldwide.This study identifies a novel gene, RNU4-2, which encodes the U4 small nuclear RNA (snRNA), as a cause of neurodevelopmental disorders (NDD). The RNU4-2 gene is highly expressed in the developing human brain and contains a critical 18-base pair region that is depleted of variants in the general population but enriched with variants in individuals with NDD. Specifically, a highly recurrent single-base insertion (n.64_65insT) was identified in 77.4% of individuals with NDD, all of whom had the same variant on the maternal allele. RNA sequencing data from five individuals with RNU4-2 variants showed systematic disruption of 5' splice-site use, consistent with the known role of this region in spliceosome activation. The authors estimate that variants in this region explain 0.4% of all NDD cases. This discovery highlights the importance of non-coding genes in rare disorders and provides a diagnosis for thousands of individuals with undiagnosed NDD worldwide.