Pathogenic Variants in <i>RNU2‐2</i> , a Non‐coding Spliceosomal <scp>RNA</scp> , Cause a Distinctive Developmental and Epileptic Encephalopathy
Annie Ting Gee Chiu, Mark F. Bennett, Harshini Thiyagarajah, Amy Schneider, Sian M.W. Macdonald, Tom Witkowski, Edith P. Almanza Fuerte, Talia J. Allan, Nico Lieffering, Blake Robinson, Christy W. LaFlamme, Soham Sengupta, The Australian Undiagnosed Diseases Network (UDN‐Aus), Clara W. T. Chung, Michael Cardamone, Cassandra Gray, Piero Perucca, Samuel F. Berkovic, Heather C. Mefford, Michael S. Hildebrand, Ingrid E. Scheffer
Abstract
RNU2-2 is a non-coding small nuclear RNA (snRNA) that forms part of the spliceosome. We identified recurrent pathogenic RNU2-2 variants in 4 of 672 (0.6%) patients with developmental and epileptic encephalopathies (DEEs) of unknown cause. An additional patient was subsequently included. Patients with RNU2-2 DEE had median seizure onset age of 24 months, focal and generalized seizures, status epilepticus (n = 5), severe to profound impairment, hyperventilation (n = 3), and obstructive sleep apnea (n = 3). Electroencephalography showed sleep-activated multifocal epileptiform discharges (n = 4) and hippocampal sclerosis on magnetic resonance imaging (n = 3). Pathogenic variants in RNU2-2 cause a distinctive severe DEE.SnRNAs are emerging as an important cause of genetic DEEs. ANN NEUROL 2026;99:51-58.