Mutations in the U2 snRNA gene cause a severe neurodevelopmental disorder with prominent epilepsy.

The major spliceosome comprises the five snRNAs U1, U2, U4, U5 and U6. We recently showed that mutations in 2, which encodes U4 snRNA, cause one of the most prevalent monogenic neurodevelopmental disorders. Here, we report that recurrent germline mutations in , a 191bp gene encoding U2 snRNA, are responsible for a related disorder. By genetic association, we implicated recurrent single nucleotide mutations at nucleotide positions 4 and 35 of among nine cases. We replicated this finding in six additional cases, bringing the total to 15. The disorder is characterized by intellectual disability, neurodevelopmental delay, autistic behavior, microcephaly, hypotonia, epilepsy and hyperventilation. All cases display a severe and complex seizure phenotype. Our findings cement the role of major spliceosomal snRNAs in the etiologies of neurodevelopmental disorders.