Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy.

Jackson, A.; Blakes, AJM.; Alhaddad, B.; Henry, OJ.; Delgado-Vega, AM.; Wall, E.; Abdelhadi, O.; Agrawal, S.; Bakur, K.; Blair, E.; Brady, AF.; Brittain, H.; Chandler, KE.; Clarke, N.; Danelli, M.; Drinkall, N.; Duba, I.; Elmslie, F.; Ellingford, J.; Ewans, LJ.; Fennell, AP.; Gazdagh, G.; Heller, SP.; Hammarsjo, A.; Karrman, K.; Kini, U.; Lesko, N.; Lindstrand, A.; Macintosh, R.; Mansour, S.; Menzies, L.; Metcalfe, K.; Milhench, A.; Nashef, L.; O'Keefe, RT.; Pacheco, NP.; Palmer, EE.; Parida, A.; Prescott, K.; Redman, M.; Renieri, A.; Fallerini, C.; Rizzo, CL.; Sachdev, R.; Simons, C.; Sisodiya, SM.; Stewart, H.; Stodberg, T.; Banos-Pinero, B.; Taylan, F.; Thomas, HB.; Tinella, F.; Wiafe, S.; Wedell, A.; Whiffin, N.; Walker, S.; Rius, R.; Chae, JH.; Nordgren, A.; Alkuraya, F.; Lord, J.; Banka, S.

Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy.

All Authors

Jackson, A.

Blakes, AJM.

Alhaddad, B.

Henry, OJ.

Delgado-Vega, AM.

Wall, E.

Abdelhadi, O.

Agrawal, S.

Bakur, K.

Blair, E.

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LTHT Author

Prescott, Katrina
Redman, Melody

LTHT Department

Pathology
Clinical Genetics
Yorkshire Regional Genetics Service

Publication Date

2026

Item Type

Journal Article

Subject

NEURODEVELOPMENTAL DISORDERS , GENETIC DISEASES , INBORN

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.