ArticleNature genetics2025
Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption.
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Article in Nature genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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39citing papers in PubMed
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Who cites it
39 citing papers in PubMed.
- Genome sequencing for the diagnosis of intellectual disability as a paradigm for rare diseases in the French healthcare setting: the prospective DEFIDIAG study.Genome medicine · 2025Trial
- De novo variants in the poly(rC)-binding protein gene PCBP1 cause a neurodevelopmental disorder.Molecular psychiatry · 2026Article
- Article
- Whole-genome discovery of pathogenic snRNA variants and efficient extended-exome screening.iScience · 2026Article
- Multiple quality control checkpoints safeguard small nuclear RNA biogenesis and prevent assembly of aberrant spliceosomes.Genes & development · 2026Article
- Guidance for clinical variant classification in genes for spliceosomal small nuclear RNAs.medRxiv : the preprint server for health sciences · 2026Article
- Beyond the gene: isoform diversity as a key contributor to human brain disorders.Current opinion in genetics & development · 2026Review
- Past studies suggest potential therapies for newly discovered retinitis pigmentosa mutations in U6 and U4 snRNAs.RNA (New York, N.Y.) · 2026Article
- The SINTER study: a recall-by-genotype design with multidimensional musculoskeletal phenotyping across internal-medicine outpatient clinics.European journal of epidemiology · 2026Article
- Monoallelic and biallelic RNU4-2 variants in neurodevelopmental disorders.Journal of human genetics · 2026Article
- Translating transcriptomics analysis into diagnostic workflows: clinical variant identification and interpretation in hypothesis-driven and hypothesis-free approaches.EBioMedicine · 2026Article
- Article
- LSM7 coordinates scaRNA-mediated snRNA modification to ensure spliceosome fidelity and spermatogonial stem cell differentiation.Cell death and differentiation · 2026Article
- Genome sequencing boosts diagnostic yield for the developmental and epileptic encephalopathies.medRxiv : the preprint server for health sciences · 2026Article
- Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy.Nature genetics · 2026Article
- Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder.Nature genetics · 2026Article
- Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies.Nature genetics · 2026Article
- Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes.Nature genetics · 2026Article
- Extracellular Vesicle-Mediated U1 snRNA Delivery Restores Aberrant Pre-mRNA Splicing in Human Cells.Biomolecules · 2026Article
- De novo variants in the splicing factor gene SF3B1 are associated with neurodevelopmental disorders.Nature communications · 2026Article
Corrections and comments
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Authors and funding
264 authors.
Caroline Nava *Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, APHP, Hôpital Pitié-Salpêtrière, Paris, France. caroline.nava@aphp.fr.ORCID http://orcid.org/0000-0003-1272-0518
Benjamin Cogne *Laboratoire SeqOIA, Paris, France.ORCID http://orcid.org/0000-0002-5503-6292
Amandine Santini *Univ. Rouen Normandie, Normandie Univ., Inserm U1245, Rouen, France.ORCID http://orcid.org/0009-0001-0738-0531
Elsa LeitãoInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.ORCID http://orcid.org/0000-0001-5051-9714
François LecoquierreLaboratoire SeqOIA, Paris, France.ORCID http://orcid.org/0000-0002-9110-1856
Yuyang ChenBig Data Institute, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0001-5593-6920
Sarah L StentonBroad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-4071-449X
Thomas BesnardNantes Université, CHU de Nantes Service de Génétique Médicale, Nantes, France.
Solveig HeideAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Génétique Médicale, Hôpital Pitié-Salpêtrière, Paris, France.
Sarah BaerService de Neuropédiatrie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Abhilasha JakharCNRS, Inserm, Université de Strasbourg, IGBMC UMR 7104-UMR-S 1258, Illkirch, France.ORCID http://orcid.org/0009-0000-1044-6012
Sonja NeuserInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.ORCID http://orcid.org/0000-0002-2875-8791
Boris KerenAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Génétique Médicale, Hôpital Pitié-Salpêtrière, Paris, France.
Anne FaudetAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Génétique Médicale, Hôpital Pitié-Salpêtrière, Paris, France.
Sylvie ForlaniSorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, APHP, Hôpital Pitié-Salpêtrière, Paris, France.
Marie FaoucherLaboratoire SeqOIA, Paris, France.
Kevin UguenLaboratoire SeqOIA, Paris, France.
Konrad PlatzerInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.ORCID http://orcid.org/0000-0001-6127-6308
Alexandra AfenjarAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Centre de Référence Malformations et Maladies Congénitales du Cervelet et Déficiences Intellectuelles de Causes Rares, UF de Génétique Clinique, Hôpital Trousseau, Paris, France.
Jean-Luc AlessandriService de Génétique, CHU de La Réunion, Saint-Pierre, France.
Stephanie AndresMedicover München Ost MVZ Humangenetik, Munich, Germany.
Chloé AngeliniService de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France.ORCID http://orcid.org/0000-0002-5825-5319
Bernard AralGCS AURAGEN, Lyon, France.
Benoit ArveilerService de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France.ORCID http://orcid.org/0000-0002-2987-2932
Tania Attie-BitachLaboratoire SeqOIA, Paris, France.
Marion Aubert MuccaService de Génétique Médicale, CHU Purpan, Toulouse, France.
Guillaume BanneauGCS AURAGEN, Lyon, France.
Tahsin Stefan BarakatDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.ORCID http://orcid.org/0000-0003-1231-1562
Giulia BarciaLaboratoire SeqOIA, Paris, France.
Stéphanie BaulacSorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, APHP, Hôpital Pitié-Salpêtrière, Paris, France.ORCID http://orcid.org/0000-0001-6430-4693
Claire BeneteauGCS AURAGEN, Lyon, France.ORCID http://orcid.org/0000-0002-1682-523X
Fouzia BenkerdouAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Génétique Médicale, Hôpital Pitié-Salpêtrière, Paris, France.
Virginie BernardGCS AURAGEN, Lyon, France.
Stéphane BézieauNantes Université, CHU de Nantes Service de Génétique Médicale, Nantes, France.ORCID http://orcid.org/0000-0003-0095-1319
Dominique BonneauDepartment of Genetics, Angers University Hospital, Angers, France.
Marie-Noelle Bonnet-DupeyronConsultations de Génétique, Centre Hospitalier de Valence, Valence, France.
Simon BoussionUniv. Lille, CHU Lille, ULR7364 - RADEME, Lille, France.
Odile BouteUniv. Lille, CHU Lille, ULR7364 - RADEME, Lille, France.
Elise Brischoux-BoucherCentre de Génétique Humaine-CHU Besançon, Université de Bourgogne-Franche-Comté, Besançon, France.
Samantha J BryenCentre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0002-4140-8622
Julien BurattiAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Génétique Médicale, Hôpital Pitié-Salpêtrière, Paris, France.ORCID http://orcid.org/0000-0002-0901-0905
Tiffany BusaMedical Genetics Department, Timone Children's Hospital, APHM, Marseille, France.
Almuth CaliebeInstitute of Human Genetics, University Hospitals Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Kiel, Germany.ORCID http://orcid.org/0000-0003-2157-425X
Yline CapriAssistance Publique-Hôpitaux de Paris (APHP), Département de Génétique, Hôpital Robert-Debré, Paris, France.
Kévin CassinariLaboratoire SeqOIA, Paris, France.
Roseline CaumesUniv. Lille, CHU Lille, ULR7364 - RADEME, Lille, France.
Camille CenniService de Génétique Moléculaire, Chromosomique et Clinique, CHU de Nîmes, Nîmes, France.
Pascal ChambonLaboratoire SeqOIA, Paris, France.
Perrine CharlesAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Génétique Médicale, Hôpital Pitié-Salpêtrière, Paris, France.
John ChristodoulouDepartment of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.ORCID http://orcid.org/0000-0002-8431-0641
Cindy ColsonUniv. Lille, CHU Lille, ULR7364 - RADEME, Lille, France.
Solène ConradNantes Université, CHU de Nantes Service de Génétique Médicale, Nantes, France.
Auriane CospainLaboratoire de Génétique Moléculaire et Génomique, FHU GenOMedS, CHU Rennes, Rennes, France.ORCID http://orcid.org/0000-0002-0007-4195
Juliette CoursimaultUniv. Rouen Normandie, Normandie Univ., Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Abnormalities, Rouen, France.
Thomas CourtinAssistance Publique-Hôpitaux de Paris (APHP), Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants malades, Paris, France.
Madeline CouseCentre for Computational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
Charles CouttonGCS AURAGEN, Lyon, France.
Isabelle CreveauxGCS AURAGEN, Lyon, France.
Alissa M D'GamaEpilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
Benjamin DauriatGCS AURAGEN, Lyon, France.
Jean-Madeleine de Sainte AgatheAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Génétique Médicale, Hôpital Pitié-Salpêtrière, Paris, France.ORCID http://orcid.org/0000-0002-7753-8226
Giulia Del GobboChildren's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Andrée Delahaye-DuriezLaboratoire SeqOIA, Paris, France.ORCID http://orcid.org/0000-0003-4324-7372
Julian DelanneCentre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Centre de Référence Déficiences Intellectuelles de Causes Rares, FHU TRANSLAD, Institut GIMI, Dijon, France.
Anne-Sophie Denommé-PichonGCS AURAGEN, Lyon, France.ORCID http://orcid.org/0000-0002-8986-8222
Anne Dieux-CoeslierUniv. Lille, CHU Lille, ULR7364 - RADEME, Lille, France.
Laura Do Souto FerreiraNantes Université, CHU de Nantes Service de Génétique Médicale, Nantes, France.
Martine Doco-FenzyNantes Université, CHU de Nantes Service de Génétique Médicale, Nantes, France.
Stephan DrukewitzInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Véronique DubocUniversité Côte d'Azur, Centre Hospitalier Universitaire de Nice, Inserm U1081, CNRS UMR7284, IRCAN, Nice, France.
Christèle DubourgLaboratoire SeqOIA, Paris, France.ORCID http://orcid.org/0000-0003-1345-4522
Yannis DuffourdInserm UMR1231 GAD, Université Bourgogne, Dijon, France.
David DymentChildren's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Salima El ChehadehService de Génétique Médicale, Institut de Génétique Médicale d'Alsace (IGMA), CHU Strasbourg, Strasbourg, France.ORCID http://orcid.org/0000-0003-1613-6570
Monique ElmalehAssistance Publique-Hôpitaux de Paris (AP-HP), DMU DREAM, Hôpital Robert Debré, Service de Radiologie Pédiatrique, Paris, France.
Laurence FaivreCentre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Centre de Référence Déficiences Intellectuelles de Causes Rares, FHU TRANSLAD, Institut GIMI, Dijon, France.ORCID http://orcid.org/0000-0001-9770-444X
Samuel FennellyService de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France.
Hanna FischerSozialpädiatrisches Zentrum Konstanz, Konstanz, Germany.
Mélanie FradinService de Génétique Clinique, Centre de Référence 'Anomalies du Développement et Syndromes Malformatifs' de l'Inter-région Ouest, FHU GenOMedS, CHU Rennes Hôpital Sud, Rennes, France.ORCID http://orcid.org/0000-0002-2535-2198
Camille Galludec VaillantAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Génétique Médicale, Hôpital Pitié-Salpêtrière, Paris, France.
Benjamin GanneGCS AURAGEN, Lyon, France.
Jamal GhoumidUniv. Lille, CHU Lille, ULR7364 - RADEME, Lille, France.
Himanshu GoelGeneral Genetics Service, Hunter Genetics, Waratah, New South Wales, Australia.
Zeynep Gokce-SamarDepartment of Epilepsy, Sleep and Pediatric Neurophysiology, Hospices Civils de Lyon, Lyon, France.
Alice GoldenbergUniv. Rouen Normandie, Normandie Univ., Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Abnormalities, Rouen, France.
Romain Gonfreville RobertNantes Université, CHU de Nantes Service de Génétique Médicale, Nantes, France.
Svetlana GorokhovaGCS AURAGEN, Lyon, France.ORCID http://orcid.org/0000-0001-6870-4061
Louise GoujonAssistance Publique-Hôpitaux de Paris (APHP), Département de Génétique, Hôpital Robert-Debré, Paris, France.
Victoria GranierService de Génétique Médicale, CHU Purpan, Toulouse, France.
Mathilde GrasAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Génétique Médicale, Hôpital Pitié-Salpêtrière, Paris, France.ORCID http://orcid.org/0000-0002-2376-8026
John M GreallyDepartment of Pediatrics, Division of Pediatric Genetic, Medicine, Children's Hospital at Montefiore/Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.ORCID http://orcid.org/0000-0001-6069-7960
Bianca GreitenInstitute of Human Genetics, University Hospitals Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Kiel, Germany.
Paul GueguenLaboratoire SeqOIA, Paris, France.
Anne-Marie GuerrotUniv. Rouen Normandie, Normandie Univ., Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Abnormalities, Rouen, France.
Saurav GuhaMolecular Diagnostics, New York Genome Center, New York City, NY, USA.ORCID http://orcid.org/0000-0002-0620-5408
Anne GuimierAssistance Publique-Hôpitaux de Paris (APHP), Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants malades, Paris, France.
Tobias B HaackInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0001-6033-4836
Hamza Hadj AbdallahLaboratoire SeqOIA, Paris, France.
Yosra HallebService de Génétique Médicale, Centre Hospitalier du Mans, Le Mans, France.
Radu HarbuzGCS AURAGEN, Lyon, France.
Madeleine HarrisMurdoch Children's Research Institute, Parkville, Victoria, Australia.ORCID http://orcid.org/0000-0003-3961-1725
Julia HentschelInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Bénédicte HéronAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Neurologie Pédiatrique, Hôpital Armand Trousseau-La Roche Guyon, Fédération Hospitalo-Universitaire I2-D2, Paris, France.
Marc-Phillip HitzInstitute of Human Genetics, University Hospitals Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Kiel, Germany.ORCID http://orcid.org/0000-0001-9894-6897
A Micheil InnesDepartment of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.ORCID http://orcid.org/0000-0001-9881-5467
Vincent JadasService de Pédiatrie, CHMS Chambéry, CAMSP Chambéry, Chambéry, France.
Louis JanuelGCS AURAGEN, Lyon, France.
Nolwenn Jean-MarçaisService de Génétique Clinique, Centre de Référence 'Anomalies du Développement et Syndromes Malformatifs' de l'Inter-région Ouest, FHU GenOMedS, CHU Rennes Hôpital Sud, Rennes, France.
Vaidehi JobanputraMolecular Diagnostics, New York Genome Center, New York City, NY, USA.
Florence JobicClinical Genetics Unit, University Hospital of Amiens, Amiens, France.
Ludmila JorneaSorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, APHP, Hôpital Pitié-Salpêtrière, Paris, France.
Céline JostCentre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Centre de Référence Déficiences Intellectuelles de Causes Rares, FHU TRANSLAD, Institut GIMI, Dijon, France.ORCID http://orcid.org/0009-0005-2130-6900
Sophie JuliaService de Génétique Médicale, CHU Purpan, Toulouse, France.
Frank J KaiserInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Daniel KaschtaInstitute of Human Genetics, University Hospitals Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Kiel, Germany.
Sabine KayaInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Petra KettelerInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.ORCID http://orcid.org/0000-0002-8138-0441
Bochra KhadijaInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Fabian KilpertInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.ORCID http://orcid.org/0000-0001-6401-2180
Cordula KnoppInstitute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany.
Florian KraftInstitute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany.ORCID http://orcid.org/0000-0002-5324-9155
Ilona KreyInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Marilyn LackmyUnité de Génétique Clinique, Centre de Compétences Maladies Rares Anomalies du Développement, CHRU de Pointe à Pitre, Guadeloupe, France.
Fanny LaffargueService de Génétique Médicale, CHU de Clermont-Ferrand, Clermont-Ferrand, France.
Laetitia LambertService de Génétique Clinique, CHRU Nancy, Vandoeuvre les Nancy, France.
Ryan LamontDepartment of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Vincent LaugelService de Neuropédiatrie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Steven LaurieCentro Nacional de Análisis Genómico (CNAG), Universitat de Barcelona (UB), Barcelona, Spain.ORCID http://orcid.org/0000-0003-3913-5829
Julie L LauzonDepartment of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Louis LebretonGCS AURAGEN, Lyon, France.ORCID http://orcid.org/0000-0002-8583-1326
Marine LebrunGCS AURAGEN, Lyon, France.
Marine LegendreService de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France.
Eric LeguernSorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, APHP, Hôpital Pitié-Salpêtrière, Paris, France.
Daphné LehalleAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Génétique Médicale, Hôpital Pitié-Salpêtrière, Paris, France.
Elodie LejeuneAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Génétique Médicale, Hôpital Pitié-Salpêtrière, Paris, France.
Gaetan LescaGCS AURAGEN, Lyon, France.ORCID http://orcid.org/0000-0001-7691-9492
Marion Lesieur-SebellinLaboratoire SeqOIA, Paris, France.
Jonathan LevyLaboratoire SeqOIA, Paris, France.ORCID http://orcid.org/0000-0002-8822-816X
Agnès LinglartDepartment of Endocrinology and Diabetology for Children, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.ORCID http://orcid.org/0000-0003-3455-002X
Stanislas LyonnetAssistance Publique-Hôpitaux de Paris (APHP), Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants malades, Paris, France.
Kevin LüthyInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.ORCID http://orcid.org/0000-0002-4510-3826
Alan S MaDepartment of Clinical Genetics, Sydney Children's Hospitals Network Westmead, Sydney, New South Wales, Australia.
Corinne MachAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Génétique Médicale, Hôpital Pitié-Salpêtrière, Paris, France.
Jean-Louis MandelInstitute of Genetics and Cellular and Molecular Biology (IGBMC), INSERM-U964, CNRS-UMR7104, University of Strasbourg, Illkirch, France.ORCID http://orcid.org/0000-0002-0535-6589
Lamisse Mansour-HendiliLaboratoire SeqOIA, Paris, France.
Julien MarcadierDepartment of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Victor MarinGCS AURAGEN, Lyon, France.ORCID http://orcid.org/0009-0000-7439-192X
Henri MargotGCS AURAGEN, Lyon, France.ORCID http://orcid.org/0000-0003-1353-0716
Valentine MarquetGCS AURAGEN, Lyon, France.
Angèle MayUniv. Rouen Normandie, Normandie Univ., Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Abnormalities, Rouen, France.
Johannes A MayrUniversity Children's Hospital, Salzburger Landesklinken (SALK) and Paracelsus Medical University, Salzburg, Austria.ORCID http://orcid.org/0000-0001-6970-336X
Catherine MeriddaService de Génétique, CHU Caen, Caen, France.
Vincent MichaudGCS AURAGEN, Lyon, France.ORCID http://orcid.org/0000-0002-5788-392X
Caroline MichotAssistance Publique-Hôpitaux de Paris (APHP), Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants malades, Paris, France.
Gwenael NadeauLaboratoire de Cytogénétique, CH de Chambéry, Chambéry, France.
Sophie NaudionService de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France.
Laetitia NguyenAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Génétique Médicale, Hôpital Pitié-Salpêtrière, Paris, France.
Mathilde NizonNantes Université, CHU de Nantes Service de Génétique Médicale, Nantes, France.
Frédérique NowakHealth Technologies Institute, Inserm, Paris, France.
Sylvie OdentUniversity of Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes)-UMR 6290, ERL U1305, Rennes, France.
Valerie OlinAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Génétique Médicale, Hôpital Pitié-Salpêtrière, Paris, France.
Ikeoluwa A Osei-OwusuBroad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Matthew OsmondChildren's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.ORCID http://orcid.org/0000-0002-5886-873X
Katrin ÕunapDepartment of Genetics and Personalized Medicine, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.ORCID http://orcid.org/0000-0002-4594-6364
Laurent PasquierService de Génétique Clinique, Centre de Référence 'Anomalies du Développement et Syndromes Malformatifs' de l'Inter-région Ouest, FHU GenOMedS, CHU Rennes Hôpital Sud, Rennes, France.ORCID http://orcid.org/0000-0003-3985-1286
Sandrine PassemardNeuroDiderot, Inserm, Université Paris Cité, Paris, France.ORCID http://orcid.org/0000-0002-0242-4566
Melissa PaulyInstitute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.ORCID http://orcid.org/0000-0001-8875-0022
Olivier PatatService de Génétique Médicale, CHU Purpan, Toulouse, France.
Marine PensecService de Génétique Médicale et Biologie de la Reproduction, CHRU de Brest, Brest, France.
Laurence Perrin-SabourinAssistance Publique-Hôpitaux de Paris (APHP), Département de Génétique, Hôpital Robert-Debré, Paris, France.
Florence PetitUniv. Lille, CHU Lille, ULR7364 - RADEME, Lille, France.
Christophe PhilippeGCS AURAGEN, Lyon, France.ORCID http://orcid.org/0000-0001-7098-6520
Marc PlanesService de Génétique Médicale et Biologie de la Reproduction, CHRU de Brest, Brest, France.
Annapurna PoduriEpilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0002-7350-5136
Céline PoirsierUF de Génétique clinique, CHU de Reims, Reims, France.
Antoine PouzetAssistance Publique-Hôpitaux de Paris (APHP), Département de Génétique, Hôpital Robert-Debré, Paris, France.
Bradley PrinceDepartment of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Clément ProuteauDepartment of Genetics, Angers University Hospital, Angers, France.
Aurora PujolNeurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.ORCID http://orcid.org/0000-0002-9606-0600
Caroline RacineCentre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Centre de Référence Déficiences Intellectuelles de Causes Rares, FHU TRANSLAD, Institut GIMI, Dijon, France.ORCID http://orcid.org/0000-0003-2378-5982
Mélanie RamaGCS AURAGEN, Lyon, France.
Francis RamondGCS AURAGEN, Lyon, France.ORCID http://orcid.org/0000-0003-4540-8096
Kara RanguinUnité de Génétique-Centre Hospitalier Universitaire de Guadeloupe, Guadeloupe, France.
Margaux RawayCentre de Génétique Humaine-CHU Besançon, Université de Bourgogne-Franche-Comté, Besançon, France.
André ReisInstitute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.ORCID http://orcid.org/0000-0002-6301-6363
Mathilde RenaudService de Génétique Clinique, CHRU Nancy, Vandoeuvre les Nancy, France.
Nicole RevencuCenter for Human Genetics, Cliniques universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
Anne-Claire RichardUniv. Rouen Normandie, Normandie Univ., Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Abnormalities, Rouen, France.
Lucile Riera-NavarroUniversité Côte d'Azur, Centre Hospitalier Universitaire de Nice, Inserm U1081, CNRS UMR7284, IRCAN, Nice, France.
Rocio RiusCentre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0002-9871-3126
Diana RodriguezAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Neurologie Pédiatrique, Hôpital Armand Trousseau-La Roche Guyon, Fédération Hospitalo-Universitaire I2-D2, Paris, France.ORCID http://orcid.org/0000-0001-6594-1985
Agustí Rodriguez-PalmeroPaediatric Neurology Unit, Department of Pediatrics, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain.
Sophie RondeauLaboratoire SeqOIA, Paris, France.
Annika Roser-UnruhLMU Klinikum-München, Munich, Germany.
Christelle Rougeot JungHospices Civils de Lyon, Hôpital Femme Mère Enfant, Service de Neuropédiatrie, Lyon, France.
Hana SafraouGCS AURAGEN, Lyon, France.
Véronique SatreGCS AURAGEN, Lyon, France.
Pascale Saugier-VeberLaboratoire SeqOIA, Paris, France.
Clément SauvestreService de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France.ORCID http://orcid.org/0009-0001-5645-5560
Elise SchaeferService de Génétique Médicale, Institut de Génétique Médicale d'Alsace (IGMA), CHU Strasbourg, Strasbourg, France.
Wanqing ShaoChildren's Rare Disease Collaborative, Boston Children's Hospital, Boston, MA, USA.
Ina SchanzeInstitute of Human Genetics, Magdeburg, Germany.
Jan-Ulrich SchlumpDepartment of Pediatrics, Centre for Neuromedicine, Gemeinschaftskrankenhaus Herdecke Gerhard-Kienle-Weg, Herdecke, Germany.
Agatha Schlüter MartinNeurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.ORCID http://orcid.org/0000-0001-6732-1528
Caroline Schluth-BolardGCS AURAGEN, Lyon, France.
Sarah SchuhmannInstitute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Christopher SchröderInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.ORCID http://orcid.org/0000-0002-4483-8951
Monisha SebastinDepartment of Pediatrics, Division of Pediatric Genetic, Medicine, Children's Hospital at Montefiore/Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.
Sabine SigaudyMedical Genetics Department, Timone Children's Hospital, APHM, Marseille, France.
Malte SpielmannInstitute of Human Genetics, University Hospitals Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Kiel, Germany.ORCID http://orcid.org/0000-0002-0583-4683
Marta SpodenkiewiczDepartment of Genetics, La Réunion University Hospital, Saint-Pierre, France.
Laura St ClairDepartment of Clinical Genetics, Sydney Children's Hospitals Network Westmead, Sydney, New South Wales, Australia.
Julie SteffannLaboratoire SeqOIA, Paris, France.
Radka StoevaService de Génétique Médicale, Centre Hospitalier du Mans, Le Mans, France.
Harald SurowyInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.ORCID http://orcid.org/0000-0002-3595-9188
Mark A TarnopolskyDepartment of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada.ORCID http://orcid.org/0000-0003-0312-3746
Calina TodosiCentre de Référence des Epilepsies Rares (CRéER), CHRU Nancy, Vandoeuvre les Nancy, France.
Annick ToutainGénétique Médicale, Centre Hospitalier Universitaire; Université de Tours, INSERM, Imaging Brain & Neuropsychiatry iBraiN U1253, Tours, France.ORCID http://orcid.org/0000-0002-5999-5300
Frédéric Tran Mau-ThemGCS AURAGEN, Lyon, France.ORCID http://orcid.org/0000-0002-3795-9456
Astrid UnterlauftDepartment of Neurology, University of Leipzig Medical Center, Leipzig, Germany.
Julien Van-GilsService de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France.ORCID http://orcid.org/0000-0003-1497-9363
Clémence VanlerbergheUniv. Lille, CHU Lille, ULR7364 - RADEME, Lille, France.
Georgia VasileiouInstitute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Gabriella VeraUniv. Rouen Normandie, Normandie Univ., Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Abnormalities, Rouen, France.ORCID http://orcid.org/0000-0001-8352-5563
André VerdelUniversité Grenoble Alpes, INSERM U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, Grenoble, France.ORCID http://orcid.org/0000-0001-6048-3794
Alain VerloesAssistance Publique-Hôpitaux de Paris (APHP), Département de Génétique, Hôpital Robert-Debré, Paris, France.ORCID http://orcid.org/0000-0003-4819-0264
Yoann VialLaboratoire SeqOIA, Paris, France.ORCID http://orcid.org/0000-0003-1437-0427
Cédric VignalAssistance Publique-Hôpitaux de Paris (APHP), Département de Génétique, Hôpital Robert-Debré, Paris, France.
Marie VincentNantes Université, CHU de Nantes Service de Génétique Médicale, Nantes, France.ORCID http://orcid.org/0000-0003-1010-5618
Catherine Vincent-DelormeUniv. Lille, CHU Lille, ULR7364 - RADEME, Lille, France.
Aline Vincent-DevulderService de Génétique, CHU Caen, Caen, France.
Antonio VitobelloGCS AURAGEN, Lyon, France.
Sacha WeberService de Génétique, CHU Caen, Caen, France.
Marjolaine WillemsService de Génétique Médicale, CHU de Montpellier, Institute for Neurosciences of Montpellier, University of Montpellier, INSERM, Montpellier, France.
Khaoula Zaafrane-KhachnaouiUniversité Côte d'Azur, Centre Hospitalier Universitaire de Nice, Inserm U1081, CNRS UMR7284, IRCAN, Nice, France.
Pia ZacherEpilepsy Center Kleinwachau, Radeberg, Germany.
Lena ZeltnerDepartment of Neurology, University Hospital Tübingen, Tübingen, Germany.
Alban ZieglerGCS AURAGEN, Lyon, France.
Wojciech P GalejEuropean Molecular Biology Laboratory, EMBL Grenoble, Grenoble, France.ORCID http://orcid.org/0000-0001-8859-5229
Hélène DollfusService de Génétique Médicale, Institut de Génétique Médicale d'Alsace (IGMA), CHU Strasbourg, Strasbourg, France.
Christel ThauvinCentre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Centre de Référence Déficiences Intellectuelles de Causes Rares, FHU TRANSLAD, Institut GIMI, Dijon, France.
Kym M BoycottChildren's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Pierre MarijonLaboratoire SeqOIA, Paris, France.ORCID http://orcid.org/0000-0002-6694-6873
Alban LermineLaboratoire SeqOIA, Paris, France.
Valérie MalanLaboratoire SeqOIA, Paris, France.
Marlène RioAssistance Publique-Hôpitaux de Paris (APHP), Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants malades, Paris, France.ORCID http://orcid.org/0000-0003-2049-5058
Alma KuechlerInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Bertrand IsidorNantes Université, CHU de Nantes Service de Génétique Médicale, Nantes, France.
Séverine DrunatLaboratoire SeqOIA, Paris, France.ORCID http://orcid.org/0000-0002-6777-4639
Thomas SmolLaboratoire SeqOIA, Paris, France.
Nicolas ChatronGCS AURAGEN, Lyon, France.ORCID http://orcid.org/0000-0003-0538-0981
Amélie PitonInstitute of Genetics and Cellular and Molecular Biology (IGBMC), INSERM-U964, CNRS-UMR7104, University of Strasbourg, Illkirch, France.ORCID http://orcid.org/0000-0003-0408-7468
Gael NicolasLaboratoire SeqOIA, Paris, France.ORCID http://orcid.org/0000-0001-9391-7800
Matias WagnerDivision of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Munich University Hospital, Munich, Germany.ORCID http://orcid.org/0000-0002-4454-8823
Rami Abou JamraInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.ORCID http://orcid.org/0000-0002-1542-1399
Delphine HéronAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Génétique Médicale, Hôpital Pitié-Salpêtrière, Paris, France.
Cyril MignotAssistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Génétique Médicale, Hôpital Pitié-Salpêtrière, Paris, France.
Pierre BlancLaboratoire SeqOIA, Paris, France.
Anne O'Donnell-LuriaBroad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-6418-9592
Nicola WhiffinBig Data Institute, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0003-1554-6594
Camille CharbonnierUniv. Rouen Normandie, Normandie Univ., Inserm U1245 and CHU Rouen, Department of Biostatistics and Reference Center for Developmental Abnormalities, Rouen, France.
Clément CharentonCNRS, Inserm, Université de Strasbourg, IGBMC UMR 7104-UMR-S 1258, Illkirch, France.
Julien ThevenonGCS AURAGEN, Lyon, France.
Christel DepienneLaboratoire SeqOIA, Paris, France. christel.depienne@uk-essen.de.ORCID http://orcid.org/0000-0002-7212-9554
Funding
Joint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MBroad Institute Mendelian Genomic Research CenterU01HG011755 · NHGRI · BROAD INSTITUTE, INC. · PI Anne O'Donnell-Luria, MICHAEL E TALKOWSKI · 2021 to 2026
$14.6MSUPPORT FOR THE ROSE F KENNEDY IDDRC P50P50HD105352 · NICHD · ALBERT EINSTEIN COLLEGE OF MEDICINE · PI SOPHIE MOLHOLM, Steven Upshaw Walkley · 2021 to 2026
$7.0MNHGRI NIH HHS U01 HG011755NHGRI NIH HHS UM1 HG008900NICHD NIH HHS P50 HD105352Wellcome Trust
Abstract
The major spliceosome contains five small nuclear RNAs (snRNAs; U1, U2, U4, U5 and U6) essential for splicing. Variants in RNU4-2, encoding U4, cause a neurodevelopmental disorder called ReNU syndrome. We investigated de novo variants in 50 snRNA-encoding genes in a French cohort of 23,649 individuals with rare disorders and gathered additional cases through international collaborations. Altogether, we identified 145 previously unreported probands with (likely) pathogenic variants in RNU4-2 and 21 individuals with de novo and/or recurrent variants in RNU5B-1 and RNU5A-1, encoding U5. Pathogenic variants typically arose de novo on the maternal allele and cluster in regions critical for splicing. RNU4-2 variants mainly localize to two structures, the stem III and T-loop/quasi-pseudoknot, which position the U6 ACAGAGA box for 5' splice site recognition and associate with different phenotypic severity. RNU4-2 variants result in specific defects in alternative 5' splice site usage and methylation patterns (episignatures) that correlate with variant location and clinical severity. This study establishes RNU5B-1 as a neurodevelopmental disorder gene, suggests RNU5A-1 as a strong candidate and highlights the role of de novo variants in snRNAs.
Indexed as
Fetal Growth RetardationNeurodevelopmental DisordersRNA, Small NuclearRNA SplicingSpliceosomesChildChild, PreschoolCohort StudiesDwarfismFemaleHumansMaleMicrocephalyMuscle HypotoniaMutationOsteochondrodysplasiasRNA, Small NuclearRNA Splice SitesU4 small nuclear RNAU5 small nuclear RNA
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