Small nuclear RNAs (snRNAs) combine with specific proteins to generate small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. U4 snRNA forms a duplex with U6 and, together with U5, contributes to the tri-snRNP spliceosomal complex. Variants in RNU4-2, which encodes U4, have recently been implicated in neurodevelopmental disorders. Here we show that heterozygous inherited and de novo variants in RNU4-2 and in four RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8 and RNU6-9), which encode U6, recur in individuals with nonsyndromic retinitis pigmentosa (RP), a genetic disorder causing progressive blindness. These variants cluster within the three-way junction of the U4/U6 duplex, a site that interacts with tri-snRNP splicing factors also known to cause RP (PRPF3, PRPF8, PRPF31), and seem to affect snRNP biogenesis. Based on our cohort, deleterious variants in RNU4-2 and RNU6 paralogs may explain up to ~1.4% of otherwise undiagnosed RP cases. This study highlights the contribution of noncoding RNA genes to Mendelian disease and reveals pleiotropy in RNU4-2, where distinct variants underlie neurodevelopmental disorder and retinal degeneration.

Australian Inherited Retinal Disease Registry and DNA Bank Department of Medical Technology and Physics Sir Charles Gairdner Hospital Perth Western Australia Australia

Bonei Olam Center for Rare Jewish Genetic Diseases Brooklyn NY USA

Center for Biomedical Network Research on Rare Diseases Instituto de Salud Carlos 3 Madrid Spain

Center for Medical Genetics Ghent University Hospital Ghent Belgium

Center for Rare Disease University of Tübingen Tübingen Germany

Center for Rare Retinal Diseases AugenZentrum Siegburg MVZ Augenärztliches Diagnostik und Therapiecentrum Siegburg GmbH Siegburg Germany

Centre for Gene Therapy and Regenerative Medicine King's College London London UK

Clinical Translation Group Institute of Molecular and Clinical Ophthalmology Basel Basel Switzerland

College of Medical and Dental Sciences University of Birmingham Birmingham UK

Department of Biochemistry Faculty of Medicine UNAM Mexico City Mexico

Department of Biomolecular Medicine Ghent University Ghent Belgium

Department of Cell Therapy and Regenerative Medicine Andalusian Molecular Biology and Regenerative Medicine Centre CABIMER Seville Spain

Department of Child Neurology and Psychiatry IRCCS Mondino Foundation Pavia Italy

Department of Clinical Genetics Erasmus MC University Medical Center Rotterdam the Netherlands

Department of Clinical Genetics Institute of Clinical Medicine University of Tartu Tartu Estonia

Department of Clinical Pharmacology Medical University of Vienna Vienna Austria

Department of Epidemiology and Human Genetics Center School of Public Health University of Texas Health Science Center at Houston Houston TX USA

Department of Genetic Physical Anthropology and Animal Physiology University of the Basque Country Leioa Spain

Department of Genetics and Genomics Instituto de Investigación Sanitaria Fundación Jiménez Díaz University Hospital Universidad Autónoma de Madrid Madrid Spain

Department of Genetics Genomics and Cancer Sciences University of Leicester Leicester UK

Department of Genetics Institute of Ophthalmology Conde de Valenciana Mexico City Mexico

Department of Genetics Microbiology and Statistics Faculty of Biology University of Barcelona Barcelona Spain

Department of Head and Skin Ghent University Ghent Belgium

Department of Histology and Embryology Medical University of Warsaw Warsaw Poland

Department of Human Genetics Radboud University Medical Center Nijmegen the Netherlands

Department of Inherited Retinal Dystrophies Ophthalmic Genetics Group OMMA Ophthalmological Institute of Athens Athens Greece

Department of Internal Medicine Radboud University Medical Center Nijmegen the Netherlands

Department of Medical Genetics Saint Etienne University Hospital Saint Etienne France

Department of Medical Genetics ULS Santa Maria Lisboa Portugal

Department of Medical Retina Singapore National Eye Centre Singapore Singapore

Department of Medicine and Surgery Medical Genetics University of Parma Parma Italy

Department of Molecular Medicine University of Pavia Pavia Italy

Department of Neuroscience Biodonostia Health Research Institute Donostia San Sebastián Spain

Department of Ophthalmology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Ophthalmology Amsterdam University Medical Center Amsterdam the Netherlands

Department of Ophthalmology and Human Genetics University of Michigan Ann Arbor MI USA

Department of Ophthalmology and Vision Sciences Ocular Genetics Program The Hospital for Sick Children Toronto Ontario Canada

Department of Ophthalmology Columbia University Irving Medical Center New York NY USA

Department of Ophthalmology Erasmus MC University Medical Center Rotterdam the Netherlands

Department of Ophthalmology Federal University of São Paulo UNIFESP São Paulo Brazil

Department of Ophthalmology Fundación Jiménez Díaz University Hospital Madrid Spain

Department of Ophthalmology Ghent University Hospital Ghent Belgium

Department of Ophthalmology HUB Erasme Hospital Brussels Belgium

Department of Ophthalmology Leeds Teaching Hospitals NHS Trust St James's University Hospital Leeds UK

Department of Ophthalmology Leiden University Medical Center Leiden the Netherlands

Department of Ophthalmology Medical University of Warsaw Warsaw Poland

Department of Ophthalmology Nagoya University Graduate School of Medicine Nagoya Japan

Department of Ophthalmology New Zealand National Eye Centre Faculty of Medical and Health Science University of Auckland Auckland New Zealand

Department of Ophthalmology NYU Grossman School of Medicine New York NY USA

Department of Ophthalmology Oslo University Hospital Oslo Norway

Department of Ophthalmology Pediatric Ophthalmology and Ophthalmogenetics University Hospitals Leuven Leuven Belgium

Department of Ophthalmology Radboud University Medical Center Nijmegen the Netherlands

Department of Ophthalmology Rambam Health Care Campus Haifa Israel

Department of Ophthalmology Rothschild Foundation Hospital Paris France

Department of Ophthalmology School of Medicine University of Crete Heraklion Crete Greece

Department of Ophthalmology School of Medicine University of Ioannina Ioannina Greece

Department of Ophthalmology Section of Pediatric Ophthalmology Strabismus and Ocular Genetics DOH Eye Center East Avenue Medical Center Quezon City Philippines

Department of Ophthalmology Semmelweis University Budapest Hungary

Department of Ophthalmology Shiley Eye Institute University of California San Diego La Jolla CA USA

Department of Ophthalmology The Jikei University School of Medicine Minato ku Japan

Department of Ophthalmology TUM University Hospital School of Medicine and Health Technical University of Munich Munich Germany

Department of Ophthalmology University Hospital Necker Enfants Malades APHP Paris Cité University Paris France

Department of Ophthalmology University Hospital of Lund Lund Sweden

Department of Ophthalmology University of Basel Basel Switzerland

Department of Ophthalmology University of California San Francisco Wayne and Gladys Valley Center for Vision San Francisco CA USA

Department of Ophthalmology University of the Basque Country San Sebastián Spain

Department of Ophthalmology; Oculogenetics Unit Jules Gonin University Hospital; University of Lausanne Lausanne Switzerland

Department of Optometry and Vision Sciences The University of Melbourne Melbourne Victoria Australia

Department of Otorhinolaryngology Hearing and Genes Radboud University Medical Center Nijmegen the Netherlands

Department of Paediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Pediatric Surgery Division of Pediatric Ophthalmology Montreal Children's Hospital McGill University Health Center Montreal Quebec Canada

Department of Pediatrics Amalia Children's Hospital Radboud University Medical Center Nijmegen the Netherlands

Department of Physiology Development and Neuroscience University of Cambridge Cambridge UK

Departments of Ophthalmology Pathology and Cell Biology Columbia Stem Cell Initiative Vagelos College of Physicians and Surgeons Columbia University Irving Medical Center New York NY USA

Division of Molecular and Cellular Biology National Institute of Sensory Organs NHO Tokyo Medical Center Tokyo Japan

Division of Molecular Medicine Leeds Institute of Medical Research School of Medicine University of Leeds Leeds UK

eCODE genetics Amgen Inc Reykjavik Iceland

Edward S Harkness Eye Institute Jonas Children's Vision Care Columbia University Irving Medical Center New York Presbyterian Hospital New York NY USA

European Vision Institute Basel Switzerland

Eye Clinic Multidisciplinary Department of Medical Surgical and Dental Sciences University of Campania Luigi Vanvitelli Naples Italy

Eye Clinic Tartu University Hospital Tartu Estonia

Eye Disease Clinic Children's University Hospital Riga Riga Latvia

Faculty of Biology Medicine and Health School of Biological Sciences Division of Evolution Infection and Genomics University of Manchester Manchester UK

Faculty of Medicine School of Health Sciences University of Iceland Reykjavik Iceland

FutureNeuro Research Ireland Centre RCSI University of Medicine and Health Sciences Dublin Ireland

GCS Auragen Plan France Medecine Genomique Lyon France

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Hadassah Medical Center Division of Ophthalmology The Hebrew University of Jerusalem Jerusalem Israel

iNOVA4Health NOVA Medical School Faculdade de Ciências Médicas NMS FCM Universidade NOVA de Lisboa Lisboa Portugal

Institute for Medical Genetics and Applied Genomics University of Tübingen Institute for Ophthalmic Research University Hospital Tübingen Tübingen Germany

Institute for Neurosciences of Montpellier Montpellier University INSERM Montpellier France

Institute for Ophthalmic Research Centre for Ophthalmology University Hospital Tübingen Tübingen Germany

Institute of Genetics School of Genetics and Microbiology Trinity College Dublin The University of Dublin Dublin Ireland

Instituto de Investigación Sanitaria La Fe and CIBERER Valencia Spain

JC Self Research Institute Greenwood Genetic Center Greenwood SC USA

Laboratoire de Biologie Médicale SeqOIA Site Broussais Paris France

Laboratory of Basic Immunology Faculdade de Medicina Universidade de Lisboa Lisboa Portugal

Laboratory of RNA Biology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Manchester Centre for Genomic Medicine Manchester University NHS Foundation Trust Saint Mary's Hospital Manchester UK

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Molecular Genetics Laboratory Montpellier University CHU Montpellier Montpellier France

National Institute of Health Research Biomedical Research Centre Moorfields Eye Hospital London UK

National Reference Centre for Inherited Sensory Diseases University of Montpellier Montpellier University Hospital Montpellier France

Neurogenetics Research Center IRCCS Mondino Foundation Pavia Italy

Ocular Genomics Institute Massachusetts Eye and Ear Harvard Medical School Boston MA USA

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Ophthalmology and Visual Sciences Academic Clinical Program Duke NUS Graduate Medical School Singapore Singapore

Oxford Eye Hospital Oxford University Hospitals NHS Foundation Trust Oxford UK

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Physicians Dialysis Miami FL USA

Rappaport Faculty of Medicine Technion Israel Institute of Technology Haifa Israel

Retina Foundation of the Southwest Dallas TX USA

School of Biological Sciences Division of Evolution Infection and Genomics The University of Manchester Manchester UK

School of Pharmacy and Biomolecular Sciences RCSI University of Medicine and Health Sciences Dublin Ireland

Section of Ophthalmology King's College London St Thomas' Hospital Campus London UK

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Vista Vision Eye Clinic Brescia Italy

Vitreous Retina Macula Consultants of New York New York NY USA

West Midlands Clinical Genetics Unit Birmingham Women's and Children's NHS Foundation Trust Birmingham UK

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medRxiv. 2025 Jan 06:2025.01.06.24317169. doi: 10.1101/2025.01.06.24317169. PubMed

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