The U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together with U5 and ~30 proteins, is part of the U4/U6.U5 tri-snRNP complex, located at the core of the major spliceosome. Recently, recurrent de novo variants in the U4 RNA, transcribed from the RNU4-2 gene, and in at least two other RNU genes were discovered to cause neurodevelopmental disorder. We detected inherited and de novo heterozygous variants in RNU4-2 (n.18_19insA and n.56T>C) and in four out of the five RNU6 paralogues (n.55_56insG and n.56_57insG) in 135 individuals from 62 families with non-syndromic retinitis pigmentosa (RP), a rare form of hereditary blindness. We show that these variants are recurrent among RP families and invariably cluster in close proximity within the three-way junction (between stem-I, the 5' stem-loop and stem-II) of the U4/U6 duplex, affecting its natural conformation. Interestingly, this region binds to numerous splicing factors of the tri-snRNP complex including PRPF3, PRPF8 and PRPF31, previously associated with RP as well. The U4 and U6 variants identified seem to affect snRNP biogenesis, namely the U4/U6 di-snRNP, which is an assembly intermediate of the tri-snRNP. Based on the number of positive cases observed, deleterious variants in RNU4-2 and in RNU6 paralogues could be a significant cause of isolated or dominant RP, accounting for up to 1.2% of all undiagnosed RP cases. This study highlights the role of non-coding genes in rare Mendelian disorders and uncovers pleiotropy in RNU4-2, where different variants underlie neurodevelopmental disorder and RP.

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 Department of Biomolecular Medicine Ghent Belgium

Center for Medical Genetics Ghent University Hospital Department of Biomolecular Medicine 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

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

Centre for Ophthalmology University Eye Hospital University Hospital Tübingen Tübingen Germany

Child Neuropsychiatry IRCCS Mondino Foundation Pavia Italy

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

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 Genome Biology University of Leicester Leicester UK

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

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 Hospital 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 ULS St Maria Lisboa Portugal

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 University Rotterdam Rotterdam The Netherlands

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

Department of Ophthalmology Ghent University Hospital Ghent Belgium

Department of Ophthalmology Instituto de Investigación Sanitaria Fundación Jiménez Díaz University Hospital Universidad Autónoma de Madrid Madrid Spain

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 NYU Grossman School of Medicine New York NY USA

Department of Ophthalmology Oslo University Hospital Oslo Norway

Department of Ophthalmology Pediatric ophthalmology and Ophthalmogenetics 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 Metro Manila 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 Tokyo Japan

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

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 Vaud Switzerland

Department of Optometry and Vision Sciences Department of Surgery 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 Pathology UCT MRC Precision and Genomic Medicine Research Unit Division of Human Genetics Institute of Infectious Disease and Molecular Medicine Faculty of Health Sciences University of Cape Town Cape Town South Africa

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

Department of Precision Medicine Medical Genetics University of Campania Luigi Vanvitelli Naples Italy

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

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

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

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 Tartu University Hospital Tartu Estonia

Eye Disease Clinic Children's University Hospital Riga Riga Latvia

FutureNeuro Research Ireland Centre RCSI University of Medicine and Health Sciences Dublin 2 Leinster Ireland

Genetics and Personalized Medicine Clinic Tartu University Hospital Tartu Estonia

Genomic Medicine Telethon Institute of Genetics and Medicine Pozzuoli NA Italy

Genomics England Ltd London UK

Genomics for Health in Africa

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

INSERM U1298 Montpellier University Institute for Neurosciences of Montpellier Montpellier France

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

Institute for Neurosciences of Montpellier Montpellier University Inserm Montpellier France

Institute of Genetics School of Genetics and Microbiology Trinity College Dublin The University of Dublin Dublin 2 Ireland

Instituto de Investigación Sanitaria La Fe and CIBERER Valencia Spain

JC Self Research Institute Greenwood Genetic Center Greenwood SC USA

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

Medical Genetics and Prenatal Diagnostics Clinic Children's Clinical University Hospital Riga Latvia

Molecular Biology Research Unit St John Eye Hospital Group Jerusalem Palestine

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

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

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

Ophthalmic Genetics Group Institute of Molecular and Clinical Ophthalmology Basel Basel Switzerland

Ophthalmology department HUB Erasme Hospital Brussels Belgium

Oxford Eye Hospital Oxford University Hospitals NHS Foundation Trust Oxford UK

Pallas Kliniken AG Pallas Klinik Zürich Zürich Switzerland

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 2 Leinster Ireland

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

Section of Pediatric Ophthalmology Strabismus and Ocular Genetics Makati Medical Center Makati City Philippines

Serviço de Oftalmologia Instituto de Oftalmologia Dr Gama Pinto Lisboa Portugal

SPKSO Ophthalmic University Hospital in Warsaw Warsaw Poland

The Rotterdam Eye Hospital Rotterdam Ophthalmic Institute Rotterdam The Netherlands

UCL Institute of Ophthalmology University College London London UK

Université de Lille INSERM U1172 LilNCog Lille Neuroscience and Cognition Lille France

University of Leeds Leeds UK

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

Zobrazit více v PubMed

Verbakel S. K. et al. Non-syndromic retinitis pigmentosa. Prog Retin Eye Res 66, 157–186 (2018). 10.1016/j.preteyeres.2018.03.005 PubMed DOI

Peter V. G. et al. The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis. PNAS Nexus 2, pgad043 (2023). 10.1093/pnasnexus/pgad043 PubMed DOI PMC

Perea-Romero I. et al. Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications. Sci Rep 11, 1526 (2021). 10.1038/s41598-021-81093-y PubMed DOI PMC

Conti G. M. et al. Genetics of Retinitis Pigmentosa and Other Hereditary Retinal Disorders in Western Switzerland. Ophthalmic Res 67, 172–182 (2024). 10.1159/000536036 PubMed DOI

Hanany M., Rivolta C. & Sharon D. Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases. Proc Natl Acad Sci U S A 117, 2710–2716 (2020). 10.1073/pnas.1913179117 PubMed DOI PMC

Karczewski K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020). 10.1038/s41586-020-2308-7 PubMed DOI PMC

Fu X. D. Non-coding RNA: a new frontier in regulatory biology. Natl Sci Rev 1, 190–204 (2014). 10.1093/nsr/nwu008 PubMed DOI PMC

Chen Y. et al. De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome. Nature 632, 832–840 (2024). 10.1038/s41586-024-07773-7 PubMed DOI PMC

Greene D. et al. Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders. Nat Med 30, 2165–2169 (2024). 10.1038/s41591-024-03085-5 PubMed DOI PMC

Jackson A., Thaker N., Blakes A. & Banka S. Analysis of R-loop forming regions identifies RNU2-2P and RNU5B-1 as neurodevelopmental disorder genes. medRxiv, 2024.2010.2004.24314692 (2024). 10.1101/2024.10.04.24314692 DOI

Nava C. et al. Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption. medRxiv, 2024.2010.2007.24314689 (2024). 10.1101/2024.10.07.24314689 DOI

Greene D. et al. Mutations in the U2 snRNA gene RNU2-2P cause a severe neurodevelopmental disorder with prominent epilepsy. medRxiv, 2024.2009.2003.24312863 (2024). 10.1101/2024.09.03.24312863 DOI

Weisschuh N. et al. Genetic architecture of inherited retinal degeneration in Germany: A large cohort study from a single diagnostic center over a 9-year period. Hum Mutat 41, 1514–1527 (2020). 10.1002/humu.24064 PubMed DOI

Mozaffari-Jovin S. et al. The Prp8 RNase H-like domain inhibits Brr2-mediated U4/U6 snRNA unwinding by blocking Brr2 loading onto the U4 snRNA. Genes Dev 26, 2422–2434 (2012). 10.1101/gad.200949.112 PubMed DOI PMC

Liu S. et al. Binding of the human Prp31 Nop domain to a composite RNA-protein platform in U4 snRNP. Science 316, 115–120 (2007). 10.1126/science.1137924 PubMed DOI

Chen S. et al. A genomic mutational constraint map using variation in 76,156 human genomes. Nature 625, 92–100 (2024). 10.1038/s41586-023-06045-0 PubMed DOI PMC

Sudlow C. et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med 12, e1001779 (2015). 10.1371/journal.pmed.1001779 PubMed DOI PMC

Denny J. C. et al. The “All of Us” Research Program. N Engl J Med 381, 668–676 (2019). 10.1056/NEJMsr1809937 PubMed DOI PMC

Caulfield M. National Genomic Research Library (2017). 10.6084/m9.figshare.4530893.v7 DOI

Daiger S. P., Bowne S. J. & Sullivan L. S. Genes and Mutations Causing Autosomal Dominant Retinitis Pigmentosa. Cold Spring Harb Perspect Med 5 (2014). 10.1101/cshperspect.a017129 PubMed DOI PMC

Sullivan L. S. et al. Prevalence of disease-causing mutations in families with autosomal dominant retinitis pigmentosa: a screen of known genes in 200 families. Invest Ophthalmol Vis Sci 47, 3052–3064 (2006). 10.1167/iovs.05-1443 PubMed DOI PMC

Hardin J. W., Warnasooriya C., Kondo Y., Nagai K. & Rueda D. Assembly and dynamics of the U4/U6 di-snRNP by single-molecule FRET. Nucleic Acids Res 43, 10963–10974 (2015). 10.1093/nar/gkv1011 PubMed DOI PMC

Landrum M. J. et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res 42, D980–985 (2014). 10.1093/nar/gkt1113 PubMed DOI PMC

Zhong Z. et al. Two novel mutations in PRPF3 causing autosomal dominant retinitis pigmentosa. Sci Rep 6, 37840 (2016). 10.1038/srep37840 PubMed DOI PMC

Denison R. A., Van Arsdell S. W., Bernstein L. B. & Weiner A. M. Abundant pseudogenes for small nuclear RNAs are dispersed in the human genome. Proc Natl Acad Sci U S A 78, 810–814 (1981). 10.1073/pnas.78.2.810 PubMed DOI PMC

Tanackovic G. et al. PRPF mutations are associated with generalized defects in spliceosome formation and pre-mRNA splicing in patients with retinitis pigmentosa. Hum Mol Genet 20, 2116–2130 (2011). 10.1093/hmg/ddr094 PubMed DOI PMC

D’Haene E. et al. Comparative 3D genome analysis between neural retina and retinal pigment epithelium reveals differential cis-regulatory interactions at retinal disease loci. Genome Biol 25, 123 (2024). 10.1186/s13059-024-03250-6 PubMed DOI PMC

Prasetyo N. K. & Gardner P. P. Assessing the robustness of human ncRNA notation at HGNC. bioRxiv, 2024.2012.2008.627405 (2024). 10.1101/2024.12.08.627405 DOI

Hamel C. Retinitis pigmentosa. Orphanet J Rare Dis 1, 40 (2006). 10.1186/1750-1172-1-40 PubMed DOI PMC

Grover S. et al. Visual acuity impairment in patients with retinitis pigmentosa at age 45 years or older. Ophthalmology 106, 1780–1785 (1999). 10.1016/s0161-6420(99)90342-1 PubMed DOI

Bodenbender J. P. et al. Clinical and Genetic Findings in a Cohort of Patients with PRPF31-Associated Retinal Dystrophy. Am J Ophthalmol 267, 213–229 (2024). 10.1016/j.ajo.2024.06.020 PubMed DOI

Waseem N. H. et al. Mutations in the gene coding for the pre-mRNA splicing factor, PRPF31, in patients with autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci 48, 1330–1334 (2007). 10.1167/iovs.06-0963 PubMed DOI

Maubaret C. G. et al. Autosomal dominant retinitis pigmentosa with intrafamilial variability and incomplete penetrance in two families carrying mutations in PRPF8. Invest Ophthalmol Vis Sci 52, 9304–9309 (2011). 10.1167/iovs.11-8372 PubMed DOI

Yusuf I. H. et al. Clinical Characterization of Retinitis Pigmentosa Associated With Variants in SNRNP200. JAMA Ophthalmol 137, 1295–1300 (2019). 10.1001/jamaophthalmol.2019.3298 PubMed DOI PMC

Buskin A. et al. Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa. Nat Commun 9, 4234 (2018). 10.1038/s41467-018-06448-y PubMed DOI PMC

Azizzadeh Pormehr L., Ahmadian S., Daftarian N., Mousavi S. A. & Shafiezadeh M. PRPF31 reduction causes mis-splicing of the phototransduction genes in human organotypic retinal culture. Eur J Hum Genet 28, 491–498 (2020). 10.1038/s41431-019-0531-1 PubMed DOI PMC

Veltman J. A. & Brunner H. G. De novo mutations in human genetic disease. Nat Rev Genet 13, 565–575 (2012). 10.1038/nrg3241 PubMed DOI

Petersen-Jones S. M. et al. Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach. J Clin Invest 128, 190–206 (2018). 10.1172/jci95161 PubMed DOI PMC

Lee W. et al. Cis-acting modifiers in the ABCA4 locus contribute to the penetrance of the major disease-causing variant in Stargardt disease. Hum Mol Genet 30, 1293–1304 (2021). 10.1093/hmg/ddab122 PubMed DOI PMC

Robson A. G. et al. ISCEV Standard for full-field clinical electroretinography (2022 update). Doc Ophthalmol 144, 165–177 (2022). 10.1007/s10633-022-09872-0 PubMed DOI PMC

Li H. & Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009). 10.1093/bioinformatics/btp324 PubMed DOI PMC

DePristo M. A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43, 491–498 (2011). 10.1038/ng.806 PubMed DOI PMC

Wang K., Li M. & Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38, e164 (2010). 10.1093/nar/gkq603 PubMed DOI PMC

Yeo G. & Burge C. B. Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 11, 377–394 (2004). 10.1089/1066527041410418 PubMed DOI

Jaganathan K. et al. Predicting Splicing from Primary Sequence with Deep Learning. Cell 176, 535–548.e524 (2019). 10.1016/j.cell.2018.12.015 PubMed DOI

Freeman P. J., Hart R. K., Gretton L. J., Brookes A. J. & Dalgleish R. VariantValidator: Accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat 39, 61–68 (2018). 10.1002/humu.23348 PubMed DOI PMC

Richards S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17, 405–424 (2015). 10.1038/gim.2015.30 PubMed DOI PMC

Ellard S. et al. ACGS best practice guidelines for variant classification 2019. Assoc. Clin. Genet. Sci, 1–32 (2019).

Gruber A. R., Lorenz R., Bernhart S. H., Neuböck R. & Hofacker I. L. The Vienna RNA websuite. Nucleic Acids Res 36, W70–74 (2008). 10.1093/nar/gkn188 PubMed DOI PMC

Johnson P. Z. & Simon A. E. RNAcanvas: interactive drawing and exploration of nucleic acid structures. Nucleic Acids Res 51, W501–w508 (2023). 10.1093/nar/gkad302 PubMed DOI PMC

McHarg S. et al. Mast cell infiltration of the choroid and protease release are early events in age-related macular degeneration associated with genetic risk at both chromosomes 1q32 and 10q26. Proc Natl Acad Sci U S A 119, e2118510119 (2022). 10.1073/pnas.2118510119 PubMed DOI PMC

Langmead B. & Salzberg S. L. Fast gapped-read alignment with Bowtie 2. Nat Methods 9, 357–359 (2012). 10.1038/nmeth.1923 PubMed DOI PMC

Li H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009). 10.1093/bioinformatics/btp352 PubMed DOI PMC

Wang J. et al. ATAC-Seq analysis reveals a widespread decrease of chromatin accessibility in age-related macular degeneration. Nat Commun 9, 1364 (2018). 10.1038/s41467-018-03856-y PubMed DOI PMC

Cherry T. J. et al. Mapping the cis-regulatory architecture of the human retina reveals noncoding genetic variation in disease. Proc Natl Acad Sci U S A 117, 9001–9012 (2020). 10.1073/pnas.1922501117 PubMed DOI PMC

Van de Sompele S. et al. Multi-omics approach dissects cis-regulatory mechanisms underlying North Carolina macular dystrophy, a retinal enhanceropathy. Am J Hum Genet 109, 2029–2048 (2022). 10.1016/j.ajhg.2022.09.013 PubMed DOI PMC

Roithová A. et al. The Sm-core mediates the retention of partially-assembled spliceosomal snRNPs in Cajal bodies until their full maturation. Nucleic Acids Res 46, 3774–3790 (2018). 10.1093/nar/gky070 PubMed DOI PMC