RNU2-2 biallelic variants reveal a prevalent recessive neurodevelopmental syndrome

A UK-led genetic analysis of 100KGP and Genomics England data identifies biallelic variants in RNU2-2 as the cause of a recessive neurodevelopmental disorder (ReNU2 syndrome), with strong BeviMed support and replication across multiple cohorts. Affected individuals typically present with intellectual disability, global developmental delay and seizures, and the disorder arises from loss of U2-2 snRNA expression due to destabilizing variants in stem-loop and binding regions of the RNA. Monoallelic carriers show partial compensation by increased U2-1, while biallelic cases exhibit markedly reduced U2-2 in blood. The recessive form is relatively prevalent—about 60% as common as the dominant RNU4-2 ReNU syndrome in the UK—highlighting diagnostic and counseling implications, especially in populations with consanguinity.