Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder
Year: 2026
Type: article
Study design: Observational Study
Abstract: We recently showed that mutations in the snRNA genes RNU4-2 and RNU2-2 are prevalent causes of dominant neurodevelopmental disorders (NDDs). Here, by genetic association, we demonstrate the existence of a recessive form of RNU2-2 syndrome. We inferred a log Bayes factor for a recessive model of association of 18.2. Conditional on that model, 17 rare variants had a posterior probability of pathogenicity >0.8. This conservative threshold identified 18 probands and 5 affected siblings, each carrying two alleles in trans at these variants. A relaxed threshold of >0.6 identified a further 13 candidate probands. We identified nine further cases in replication collections. Affected individuals have intellectual disability, global developmental delay and seizures. Recessive RNU2-2 syndrome accounts for ~10% of families with a recessive NDD presently diagnosable by sequencing and affects ~60% as many families as the dominant RNU4-2-related NDD ReNU syndrome. The variants are predicted to destabilize stem loops and binding domains of U2-2 snRNA. Whole-blood RNA sequencing data showed a >90% reduction in the expression of pathogenic U2-2 alleles in biallelic cases and monoallelic carriers, albeit with wild-type compensation in carriers, pointing to a loss-of-expression mechanism. An analysis of rare disease cohorts from the UK, the USA, Italy and the Netherlands identifies a neurodevelopmental disorder caused by biallelic variants in RNU2-2. Individuals with this disorder have substantially reduced levels of U2-2 small nuclear RNA in blood.
Source: Nature Genetics
Authors: Daniel Greene, Rodrigo Mendez, Jon Lees, Mafalda Barbosa, Alessandro Bruselles, Luigi Chiriatti, Federico Ferraro, Cecilia Mancini, Rachel Schot, Frank Sleutels, Enrico Bertini, Devon E. Bonner, Arjan Bouman, Alice S. Brooks, Thomas A. Cassini, Kimberly M. Ezell, Natalia Gomez-Ospina, Tjitske Kleefstra, Michael O’Donoghue, Lynette Rives, Vandana Shashi, Rebecca C. Spillmann, Mohamed Wafik, Undiagnosed Diseases Network, Kathleen Freson, Tahsin Stefan Barakat, Marco Tartaglia, Jonathan A. Bernstein, Andrew D. Mumford, Matthew T. Wheeler, Ernest Turro
Institutions: University of Cambridge, Icahn School of Medicine at Mount Sinai, Stanford Medicine, Stanford University, University of Bristol, Istituto Superiore di Sanità, Bambino Gesù Children's Hospital, Erasmus MC, Vanderbilt University Medical Center, Nottingham University Hospitals NHS Trust, Duke University, Guy's and St Thomas' NHS Foundation Trust, KU Leuven
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: Wellcome Trust, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, ZonMw, Ministero della Salute, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Vlaamse regering, National Institutes of Health, Medical Research Council, Bijzonder Onderzoeksfonds UGent, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke
Awards: G3119194200, G434444879, An integrated and diverse genomic medicine program for undiagnosed diseases, G8498985136, G8899000410, Integrative analysis of whole genomes and transcriptomes from multiple cell types in rare disease patients, Center for Undiagnosed Diseases at Stanford, An integrated and diverse genomic medicine program for undiagnosed diseases, G928405983
OpenAlex ID: W7143540030