A study identifies RNU4-2, a non-coding RNA gene, as a cause of a severe neurodevelopmental disorder (NDD). The gene encodes U4 small nuclear RNA (snRNA), a key component of the major spliceosome. Variants in RNU4-2, particularly a highly recurrent single base insertion (n.64_65insT), are found in 115 individuals with NDD, explaining approximately 0.4% of cases. These variants are concentrated in a 18 base pair region of RNU4-2 that is highly conserved and depleted of variation in the general population. The variants are predominantly maternally inherited and are associated with severe neurodevelopmental phenotypes, including global developmental delay, intellectual disability, and autism spectrum disorder. The study shows that these variants disrupt 5' splice-site use, consistent with the role of this region in spliceosome activation. RNU4-2 is highly expressed in the developing human brain, unlike other U4 homologues. The findings highlight the importance of non-coding genes in rare disorders and suggest that RNU4-2 variants could provide a diagnosis for thousands of individuals with NDD worldwide. The study also underscores the value of large-scale genome sequencing in identifying new genetic causes of NDD.A study identifies RNU4-2, a non-coding RNA gene, as a cause of a severe neurodevelopmental disorder (NDD). The gene encodes U4 small nuclear RNA (snRNA), a key component of the major spliceosome. Variants in RNU4-2, particularly a highly recurrent single base insertion (n.64_65insT), are found in 115 individuals with NDD, explaining approximately 0.4% of cases. These variants are concentrated in a 18 base pair region of RNU4-2 that is highly conserved and depleted of variation in the general population. The variants are predominantly maternally inherited and are associated with severe neurodevelopmental phenotypes, including global developmental delay, intellectual disability, and autism spectrum disorder. The study shows that these variants disrupt 5' splice-site use, consistent with the role of this region in spliceosome activation. RNU4-2 is highly expressed in the developing human brain, unlike other U4 homologues. The findings highlight the importance of non-coding genes in rare disorders and suggest that RNU4-2 variants could provide a diagnosis for thousands of individuals with NDD worldwide. The study also underscores the value of large-scale genome sequencing in identifying new genetic causes of NDD.