| Title: | Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy |
| Journal: | Nature Genetics |
| Published: | 30 Mar 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41912933/ |
| DOI: | https://doi.org/10.1038/s41588-026-02551-9 |
| URL: | https://www.nature.com/articles/s41588-026-02551-9.pdf |
Publication 18153
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Abstract
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.</p>
11 Keywords
- Alleles
- Brain Diseases
- Child
- Child, Preschool
- Epilepsy
- Female
- Genes, Recessive
- Humans
- Male
- Mutation
- Neurodevelopmental Disorders
62 Authors
- 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
1 Application
| Application ID | Title |
|---|---|
| 90952 | Leveraging large genome sequencing datasets to enhance the interpretation of rare genomic variants in developmental disorders. |
Enabling scientific discoveries that improve human health