Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy
Disease areas:
brain
mental health
Last updated:
Author(s):
Adam Jackson, Alexander J. M. Blakes, Bader Alhaddad, Olivia J. Henry, Angelica M. Delgado-Vega, Elizabeth Wall, Ola Abdelhadi, Shakti Agrawal, Khadijah Bakur, Edward Blair, Angela F. Brady, Helen Brittain, Kate E. Chandler, Natasha Clarke, Miriana Danelli, Nicholas Drinkall, Irene Duba, Frances Elmslie, Jamie Ellingford, Lisa J. Ewans, Andrew P. Fennell, Gabriella Gazdagh, Simon P. Heller, Anna Hammarsjö, Kristina Karrman, Usha Kini, Nicole Lesko, Anna Lindstrand, Rebecca Macintosh, Sahar Mansour, Lara Menzies, Kay Metcalfe, Alison Milhench, Lina Nashef, Raymond T. O'Keefe, Nadja Pekkola Pacheco, Elizabeth E. Palmer, Amitav Parida, Katrina Prescott, Melody Redman, Alessandra Renieri, Chiara Fallerini, Caterina Lo Rizzo, Rani Sachdev, Cas Simons, Sanjay M. Sisodiya, Helen Stewart, Tommy Stödberg, Benito Banos-Pinero, Fulya Taylan, Huw B. Thomas, Flavia Tinella, Samuel Wiafe, Anna Wedell, Nicola Whiffin, Susan Walker, Rocio Rius, Jong Hee Chae, Ann Nordgren, Fowzan Alkuraya, Jenny Lord, Siddharth Banka
Neurodevelopmental disorders (NDDs) affect 2-4% of the population, are predominantly genetic and remain unsolved in ~50% of individuals. We show that rare biallelic variants in RNU2-2 are enriched and over-transmitted in individuals with unresolved NDDs. We define a recessive RNU2-2 syndrome, delineate its unique genetic architecture and show that it manifests clinically as a severe developmental and epileptic encephalopathy. We find that candidate biallelic variants are significantly correlated with reduced U2-2 abundance, implicating compromised transcript stability as a probable pathomechanism. We identify a decreased ratio of U2-2 to its paralog U2-1 as a potential diagnostic biomarker for this condition. We show that the recessive RNU2-2 syndrome is genetically, clinically and mechanistically distinct from the dominant RNU2-2 disorder. Within our cohort, the recessive RNU2-2 syndrome emerges as by far the most frequent recessive NDD, greatly disproportionate to the small genomic footprint of this non-protein-coding gene.
