Biallelic variants in RNU2-2 cause a remarkably frequent developmental epileptic encephalopathy
Jackson, A.; Blakes, A.; Wall, E.; Clarke, N.; Abdelhadi, O.; Agrawal, S.; Blair, E.; Brady, A. F.; Brittain, H.; Chandler, K. E.; Drinkall, N.; Elmslie, F.; Ewans, L.; Fennell, A.; Gazdagh, G.; Kini, U.; Macintosh, R.; Mansour, S.; Menzies, L.; Metcalfe, K.; Milhench, A.; Palmer, E.; Parida, A.; Prescott, K.; Redman, M.; Renieri, A.; Rius, R.; Rizzo, C. L.; Sachdev, R.; Simons, C.; Sisodiya, S.; Stewart, H.; Thomas, H.; Tinella, F.; Walker, S.; Whiffin, N.; O'Keefe, R. T.; Lord, J.; Banka, S.
Show 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 novel recessive RNU2-2 syndrome, delineate its unique genetic architecture and show that clinically it manifests as a severe developmental epileptic encephalopathy. We find that candidate biallelic variants are significantly correlated with reduced U2-2 abundance, implicating compromised transcript stability as likely pathomechanism. We identify 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.
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