ArticleNature genetics2026
Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies.
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Article in Nature genetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11citing papers in PubMed
–field-weighted citation impact
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Who cites it
11 citing papers in PubMed.
- De novo variants in the poly(rC)-binding protein gene PCBP1 cause a neurodevelopmental disorder.Molecular psychiatry · 2026Article
- Genetic Diagnosis in Epilepsy: Implications for Clinical Management.Current neurology and neuroscience reports · 2026Review
- Whole-genome discovery of pathogenic snRNA variants and efficient extended-exome screening.iScience · 2026Article
- Guidance for clinical variant classification in genes for spliceosomal small nuclear RNAs.medRxiv : the preprint server for health sciences · 2026Article
- Beyond Coding Variants: RNA-Level Mechanisms in Human Disease and Precision Therapeutics.Genes · 2026Review
- Population-Based Study of Drug-Resistant Epilepsy Before Age Two: Predominance of Developmental and Epileptic Encephalopathies.Neurology international · 2026Article
- Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy.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
- Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder.Nature genetics · 2026Article
- The human branchpoint-interacting stem loop sequence and structure regulates U2 snRNA expression, branchpoint recognition, and transcriptome.bioRxiv : the preprint server for biology · 2025Article
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Authors and funding
228 authors.
Elsa Leitão *Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.ORCID http://orcid.org/0000-0001-5051-9714
Amandine Santini *Université Rouen Normandie, Normandie Université, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Abnormalities, Rouen, France.ORCID http://orcid.org/0009-0001-0738-0531
Benjamin Cogne *Nantes Université, CHU de Nantes, Service de Génétique Médicale, Nantes, France.ORCID http://orcid.org/0000-0002-5503-6292
Miriam EssidGenetics Department, Hospices Civils de Lyon, Lyon, France.ORCID http://orcid.org/0009-0009-8129-164X
Maria AthanasiadouCNRS, Inserm, Université de Strasbourg, IGBMC UMR 7104- UMR-S 1258, Illkirch, France.ORCID http://orcid.org/0000-0002-4286-0418
Christy W LaFlammeCenter for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID http://orcid.org/0000-0002-0808-3475
Pierre MarijonLaboratoire SeqOIA, Paris, France.ORCID http://orcid.org/0000-0002-6694-6873
Virginie BernardGCS AURAGEN, Lyon, France.
Kevin JousselinLaboratoire SeqOIA, Paris, France.
Nicolas ChatronGenetics Department, Hospices Civils de Lyon, Lyon, France.ORCID http://orcid.org/0000-0003-0538-0981
Giulia BarciaLaboratoire SeqOIA, Paris, France.
Boris KerenLaboratoire SeqOIA, Paris, France.
Cyril MignotDépartement de Génétique Médicale, Assistance Publique - Hôpitaux de Paris (APHP) Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Perrine CharlesDépartement de Génétique Médicale, Assistance Publique - Hôpitaux de Paris (APHP) Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Thomas BesnardNantes Université, CHU de Nantes, Service de Génétique Médicale, Nantes, France.ORCID http://orcid.org/0000-0003-4804-5147
Robin PaluchInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.ORCID http://orcid.org/0009-0005-8570-5126
Jean-Madeleine de Sainte AgatheLaboratoire SeqOIA, Paris, France.ORCID http://orcid.org/0000-0002-7753-8226
Edith P Almanza FuerteCenter for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID http://orcid.org/0009-0009-1344-080X
Soham SenguptaCenter for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID http://orcid.org/0000-0002-5013-1506
Mathieu MilhService de Neurologie Pediatrique, AP-HM, Marseille, France.
Francis RamondDépartement de Génétique, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France.ORCID http://orcid.org/0000-0003-4540-8096
Talia AllanDepartment of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.ORCID http://orcid.org/0000-0002-0970-6750
Isabelle AnDépartement de Neurologie, Assistance Publique - Hôpitaux de Paris (APHP) Sorbonne Université, Center of Reference for Rare Epilepsies, ERN EPICARE, Hôpital Pitié-Salpêtrière, Paris, France.
Camila AraujoDepartment of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirao Preto, Brazil.
Stéphanie ArpinService de Génétique, CHU de Tours, Tours, France.
Christina Austin-TseBroad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Stéphane AuvinDépartement de Neuropédiatrie, Assistance Publique - Hôpitaux de Paris (APHP), Hôpital Robert-Debré, Paris, France.
Sarah BaerService de Neuropédiatrie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Nadia Bahi-BuissonUniversité Paris Cité, INSERM, IHU Imagine - Institut des maladies génétiques, Paris, France.
Mads BakDepartment of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Denmark.ORCID http://orcid.org/0000-0003-2762-1002
Magalie BarthDepartment of Medical Genetics, Angers University Hospital, Angers, France.
Stéphanie BaulacInstitut du Cerveau - Paris Brain Institute - ICM, Sorbonne Université, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, France.ORCID http://orcid.org/0000-0001-6430-4693
Nathalie Bednarek-WeirauchService de Pédiatrie, CHU Reims, Reims, France.
Matthias BegemannCenter for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany.ORCID http://orcid.org/0000-0002-4659-8437
Mark F BennettDepartment of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
Uriel BensabathDépartement de Génétique Médicale, Assistance Publique - Hôpitaux de Paris (APHP) Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Stéphane BézieauNantes Université, CHU de Nantes, Service de Génétique Médicale, Nantes, France.ORCID http://orcid.org/0000-0003-0095-1319
Rakia BhouriService de Génétique Médicale, Centre Hospitalier Intercommunal de Créteil (CHIC), Créteil, France.
Margaux BiehlerLaboratoire de Diagnostic Génétique, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Trine Bjørg HammerDepartment of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Denmark.
Julie BogoinDépartement de Génétique Médicale, Assistance Publique - Hôpitaux de Paris (APHP) Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Emilie BonannoLaboratoire SeqOIA, Paris, France.ORCID http://orcid.org/0009-0003-3418-9024
Simon BoussionCHU Lille, Université Lille, ULR7364 - RADEME, Lille, France.
Céline BrisLaboratoire SeqOIA, Paris, France.
Adelaide Brosseau-BeauvirCenter for Intellectual Disability Reference, Brest University Hospital, Brest, France.
Ange-Line BruelLaboratoire de Génomique Médicale, Centre Neomics, FHU-TRANSLAD, Centre de Recherche Translationnelle en Médecine Moléculaire - Inserm UMR1231 équipe GAD, Université Bourgogne Europe, CHU Dijon Bourgogne, Dijon, France.ORCID http://orcid.org/0000-0002-0526-465X
Audrey Briand-SuleauLaboratoire SeqOIA, Paris, France.
Julien BurattiDépartement de Génétique Médicale, Assistance Publique - Hôpitaux de Paris (APHP) Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.ORCID http://orcid.org/0000-0002-0901-0905
Tristan CelseGCS AURAGEN, Lyon, France.
Pascal ChambonUniversité Rouen Normandie, Normandie Université, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Abnormalities, Rouen, France.
Nicole ChemalyUniversité Paris Cité, INSERM, IHU Imagine - Institut des maladies génétiques, Paris, France.
Bertrand ChesneauService de Génétique Médicale, CHU Purpan, Toulouse, France.ORCID http://orcid.org/0000-0001-9729-7346
Estelle ColinDepartment of Medical Genetics, Angers University Hospital, Angers, France.ORCID http://orcid.org/0000-0001-7913-3938
Maxime ColmardService de Neuropédiatrie, CHU Montpellier, Montpellier, France.
Cindy ColsonCHU Lille, Université Lille, ULR7364 - RADEME, Lille, France.
Solène ConradNantes Université, CHU de Nantes, Service de Génétique Médicale, Nantes, France.
Thomas CourtinAssistance Publique - Hôpitaux de Paris (APHP), Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants malades, Paris, France.
Isabelle CreveauxGCS AURAGEN, Lyon, France.
Anne-Charlotte CullierService de Pediatrie, CHR Metz-Thionville, Hôpital Mercy, Metz, France.
Louis T DangDepartment of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0003-4853-4952
Anne de Saint MartinService de Neuropédiatrie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Caroline de Vanssay de Blavous LegendreService de Pédiatrie, Consultation de Neurologie Pédiatrique GHH Jacques Monod, Le Havre, France.
Bénédicte DemeerService de Génétique Clinique et Oncogénétique, CLAD Nord-ouest, CHU Amiens-Picardie, Amiens, France.
Anne-Sophie Denommé-PichonLaboratoire de Génomique Médicale, Centre Neomics, FHU-TRANSLAD, Centre de Recherche Translationnelle en Médecine Moléculaire - Inserm UMR1231 équipe GAD, Université Bourgogne Europe, CHU Dijon Bourgogne, Dijon, France.ORCID http://orcid.org/0000-0002-8986-8222
Philine DiekhoffInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Stephanie DiTroiaBroad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Martine Doco-FenzyNantes Université, CHU de Nantes, Service de Génétique Médicale, Nantes, France.
Christèle DubourgLaboratoire SeqOIA, Paris, France.ORCID http://orcid.org/0000-0003-1345-4522
Charlotte DubucsDépartement de Pathologie, Institut Universitaire du Cancer Toulouse - Oncopole, Toulouse, France.ORCID http://orcid.org/0000-0003-2371-4113
Stéphanie DucreuxLaboratoire SeqOIA, Paris, France.ORCID http://orcid.org/0000-0002-2306-6833
Louis DufourDépartement de Neuropédiatrie, Assistance Publique - Hôpitaux de Paris (APHP), Hôpital Robert-Debré, Paris, France.
Romain DuquetDépartement de Génétique Médicale, Assistance Publique - Hôpitaux de Paris (APHP) Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Benjamin DurandService de Génétique Médicale, Institut de Génétique Médicale d'Alsace (IGMA), CHU Strasbourg, Strasbourg, France.ORCID http://orcid.org/0000-0003-3434-1172
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
Miriam ElbrachtCenter for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany.ORCID http://orcid.org/0000-0001-5088-1369
Laurence FaivreCentre de Référence Anomalies du Développement et Syndromes Malformatifs, Université Bourgogne Europe, CHU Dijon Bourgogne, Inserm, CTM UMR1231, équipe GAD, FHU TRANSLAD, Centre de génétique, Centre de référence Déficiences Intellectuelles de Causes Rares et Centre de référence GénoPsy, Dijon, France.ORCID http://orcid.org/0000-0001-9770-444X
Marie FaoucherLaboratoire SeqOIA, Paris, France.
Anne FaudetDépartement de Génétique Médicale, Assistance Publique - Hôpitaux de Paris (APHP) Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Sylvie ForlaniInstitut du Cerveau - Paris Brain Institute - ICM, Sorbonne Université, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, France.
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
Pauline GaignardLaboratoire SeqOIA, Paris, France.
Benjamin GanneGCS AURAGEN, Lyon, France.ORCID http://orcid.org/0000-0001-5617-0023
Aurore GardeCentre de Génétique, Université Bourgogne Europe, CHU Dijon Bourgogne, Centre de Référence maladies rares 'Anomalies du Développement et syndromes malformatifs,' FHU-TRANSLAD, Dijon, France.ORCID http://orcid.org/0000-0003-3196-0453
Justine GéraudNeuropediatric Department, University Hospital Centre Toulouse, Toulouse, France.
Deepak GillKids Neuroscience Centre, Kids Research Institute, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0002-6219-9479
Alice GoldenbergUniversité Rouen Normandie, Normandie Université, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Abnormalities, Rouen, France.
David GrabliDépartement de Neurologie, Assistance Publique - Hôpitaux de Paris (APHP) Sorbonne Université, Center of Reference for Rare Epilepsies, ERN EPICARE, Hôpital Pitié-Salpêtrière, Paris, France.
Coraline GriselService de Pédiatrie, Centre Hospitalier Intercommunal de Créteil, Créteil, France.
Sophie GuedenDepartment of Pediatric Neurology, Angers University Hospital, Angers, France.
Paul GueguenLaboratoire SeqOIA, Paris, France.
Anne-Marie GuerrotUniversité Rouen Normandie, Normandie Université, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Abnormalities, Rouen, France.
Agnès GuichetLaboratoire SeqOIA, Paris, France.
Tobias B HaackInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0001-6033-4836
Nina HärtingInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Martin Georg HäuslerDepartment of Pediatrics, University Hospital, Division of Neuropediatrics and Social Pediatrics, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany.
Solveig HeideLaboratoire SeqOIA, Paris, France.
Theresia HergetInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Bénédicte HéronDépartement de Neurologie Pédiatrique, Assistance Publique - Hôpitaux de Paris (APHP) Sorbonne Université, Fédération Hospitalo-Universitaire I2-D2, Hôpital Armand Trousseau-La Roche Guyon, Paris, France.
Delphine HéronDépartement de Génétique Médicale, Assistance Publique - Hôpitaux de Paris (APHP) Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Johanna HerwigInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.ORCID http://orcid.org/0009-0005-9661-9717
Mathilde HeulinService de Neuropédiatrie, Hôpital Jean-Verdier, Bondy, France.
Tess HollingInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.ORCID http://orcid.org/0000-0001-9550-2270
Clara HoudayerDepartment of Medical Genetics, Angers University Hospital, Angers, France.ORCID http://orcid.org/0000-0001-9010-7722
Bertrand IsidorNantes Université, CHU de Nantes, Service de Génétique Médicale, Nantes, France.
Aurélia JacquetteConsultation de génétique, CCMR ANDDI rare, Centre Hospitalier d'Alençon, Alençon, France.ORCID http://orcid.org/0009-0007-3727-7934
Louis JanuelGenetics Department, Hospices Civils de Lyon, 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.
Frank J KaiserInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Sabine KayaInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Chontelle KingDepartment of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
Marina KonyukhLaboratoire SeqOIA, Paris, France.
Florian KraftCenter for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany.ORCID http://orcid.org/0000-0002-5324-9155
Jeremias KrauseCenter for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany.ORCID http://orcid.org/0000-0001-9915-7400
Rémi KirstetterAssistance Publique - Hôpitaux de Paris (APHP), Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants malades, Paris, France.ORCID http://orcid.org/0009-0000-2910-8531
Alma KuechlerInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Ingo KurthCenter for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany.ORCID http://orcid.org/0000-0002-5642-8378
Kerstin KutscheInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Audrey LabalmeGenetics Department, Hospices Civils de Lyon, Lyon, France.
Jean-Serene LaloyLaboratoire SeqOIA, Paris, France.
Vincent LaugelService de Neuropédiatrie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Floriane Le BricquirService de Pédiatrie, Nantes Université, CHU de Nantes, Service de Pédiatrie, Nantes, France.
Anne-Sophie LèbreUniversité Reims Champagne Ardenne (URCA), UFR médecine, Reims, France.ORCID http://orcid.org/0000-0002-7519-9822
Marine LebrunGCS AURAGEN, Lyon, France.
Eric LeguernDépartement de Génétique Médicale, Assistance Publique - Hôpitaux de Paris (APHP) Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Jonathan LevyLaboratoire SeqOIA, Paris, France.ORCID http://orcid.org/0000-0002-8822-816X
Nico LiefferingDepartment of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
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
Sian M W MacdonaldDepartment of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
Lamisse Mansour-HendiliLaboratoire SeqOIA, Paris, France.
Julien MaravalCentre de Référence Anomalies du Développement et Syndromes Malformatifs, Université Bourgogne Europe, CHU Dijon Bourgogne, Inserm, CTM UMR1231, équipe GAD, FHU TRANSLAD, Centre de génétique, Centre de référence Déficiences Intellectuelles de Causes Rares et Centre de référence GénoPsy, Dijon, France.ORCID http://orcid.org/0009-0003-6744-5821
Iris MarquardtMVZ Klinikum Oldenburg, Oldenburg, Germany.
Carolin MattauschInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.ORCID http://orcid.org/0009-0002-4981-0576
Sandra MercierNantes Université, CHU de Nantes, Service de Génétique Médicale, Nantes, France.
Olfa MessaoudBroad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-4547-0180
Godelieve MorelService de Génétique, CHU (Centre Hospitalier Universitaire) de La Réunion, Saint-Denis, France.ORCID http://orcid.org/0000-0002-4132-6264
Jérémie MortreuxGCS AURAGEN, Lyon, France.ORCID http://orcid.org/0000-0002-2914-1961
Arnold MunnichUniversité Paris Cité, INSERM, IHU Imagine - Institut des maladies génétiques, Paris, France.
Rima NabboutUniversité Paris Cité, INSERM, IHU Imagine - Institut des maladies génétiques, Paris, France.
Sophie NambotCentre de Génétique, Université Bourgogne Europe, CHU Dijon Bourgogne, Centre de Référence maladies rares 'Anomalies du Développement et syndromes malformatifs,' FHU-TRANSLAD, Dijon, France.ORCID http://orcid.org/0000-0002-9630-5049
Vincent NavarroDépartement de Neurologie, Assistance Publique - Hôpitaux de Paris (APHP) Sorbonne Université, Center of Reference for Rare Epilepsies, ERN EPICARE, Hôpital Pitié-Salpêtrière, Paris, France.
Ashana NealeBroad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Laetitia NguyenDépartement de Génétique Médicale, Assistance Publique - Hôpitaux de Paris (APHP) Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Mathilde NizonNantes Université, CHU de Nantes, Service de Génétique Médicale, Nantes, France.
Frédérique NowakHealth Technologies Institute, Inserm, Paris, France.
Melanie C O'LearyBroad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-8718-4759
Sylvie OdentIGDR (Institut de Génétique et Développement de Rennes)-UMR 6290, Université Rennes, CNRS, INSERM, Rennes, France.ORCID http://orcid.org/0000-0002-0635-5940
Naomi Meave OjedaDepartment of Neurosciences, University of California San Diego, La Jolla, CA, USA.
Valérie OlinDépartement de Génétique Médicale, Assistance Publique - Hôpitaux de Paris (APHP) Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Simone OlivieriInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Katrin ÕunapDepartment of Genetics and Personalized Medicine, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.ORCID http://orcid.org/0000-0002-4594-6364
Lynn S PaisBroad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Eleni PanagiotakakiDepartment of Clinical Epileptology, Sleep Disorders and Functional Neurology in Children, University Hospital of Lyon (HCL), Lyon, France.ORCID http://orcid.org/0000-0003-2611-0227
Olivier PatatService de Génétique Médicale, CHU Purpan, Toulouse, France.ORCID http://orcid.org/0000-0001-5759-1540
Laurence Perrin-SabourinDépartement de génétique, Assistance Publique - Hôpitaux de Paris (APHP), Hôpital Robert-Debré, Paris, France.
Florence PetitCHU Lille, Université Lille, ULR7364 - RADEME, Lille, France.
Christophe PhilippeGCS AURAGEN, Lyon, France.ORCID http://orcid.org/0000-0001-7098-6520
Amélie PitonGCS AURAGEN, Lyon, France.ORCID http://orcid.org/0000-0003-0408-7468
Marc PlanesMedical Genetics Department, Brest University Hospital, Brest, France.
Céline PoirsierUF de Génétique Clinique, CHU de Reims, Reims, France.
Antoine PouzetDépartement de génétique, Assistance Publique - Hôpitaux de Paris (APHP), Hôpital Robert-Debré, Paris, France.
Clément ProuteauDepartment of Medical Genetics, Angers University Hospital, Angers, France.
Sylvia Quéméner-RedonLaboratoire SeqOIA, Paris, France.
Mathilde RenaudService de Génétique Clinique, CHRU Nancy, Vandoeuvre les Nancy, France.
Anne-Claire RichardUniversité Rouen Normandie, Normandie Université, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Abnormalities, Rouen, 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
Clotilde RivierDepartment of Pediatrics, Hôpital Nord-Ouest, Villefranche sur Saône, France.
Florence Robin-RenaldoDépartement de Neurologie Pédiatrique, Assistance Publique - Hôpitaux de Paris (APHP) Sorbonne Université, Fédération Hospitalo-Universitaire I2-D2, Hôpital Armand Trousseau-La Roche Guyon, Paris, France.
Paul RollierIGDR (Institut de Génétique et Développement de Rennes)-UMR 6290, Université Rennes, CNRS, INSERM, Rennes, France.ORCID http://orcid.org/0000-0001-7303-8825
Massimiliano RossiGenetics Department, Hospices Civils de Lyon, Lyon, France.ORCID http://orcid.org/0000-0002-5797-8152
Agathe RoubertieService de Neuropédiatrie, CHU Montpellier, Montpellier, France.
Valentin RuaultClinical Genetic Unit, Reference Center for Congenital Anomalies, CHU Montpellier, University of Montpellier, Montpellier, France.
Maïlys Rupin-MasDepartment of Pediatric Neurology, Angers University Hospital, Angers, France.
Pascale Saugier-VeberUniversité Rouen Normandie, Normandie Université, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Abnormalities, Rouen, France.
Aline SaunierLaboratoire de Génétique Médicale, CHR Metz-Thionville, Hôpital Mercy, Metz, France.
Russell SanetoDivision of Pediatric Neurology, Neuroscience Institute, Norcliff Center for Integrative Brain Research, Seattle Children's Hospital/University of Washington, Seattle, WA, USA.
Elisabeth SarrazinCaribbean Reference Center for Neuromuscular Diseases, University Hospital Fort de France, Martinique, France.
Catherine SarretNeurologie Pédiatrique et Génétique Médicale, CHU de Clermont-Ferrand, Clermont-Ferrand, France.
Elise SchaeferService de Génétique Médicale, Institut de Génétique Médicale d'Alsace (IGMA), CHU Strasbourg, Strasbourg, France.
Caroline Schluth-BolardGCS AURAGEN, Lyon, France.
Amy SchneiderDepartment of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.ORCID http://orcid.org/0000-0001-5260-7187
Isabell SchumannDepartment of Medical Genetics, Centre of Medical Genetics, University and University Hospital Münster, Münster, Germany.
Vladimir B SeplyarskiyDepartment of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0003-3161-8770
Stephanie SprangerMVZ Humangenetik Bremen, Limbach Genetics, Bremen, Germany.
Thomas SmolLaboratoire SeqOIA, Paris, France.
Marc SturmInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0002-6552-8362
Shamil R SunyaevDepartment of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0001-5715-5677
Brian Sperelakis-BeedhamLaboratoire SeqOIA, Paris, France.
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
Friedrich StockInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Mylène TharreauLaboratory of Molecular Genetics of Rare Diseases, Montpellier University Hospital, Montpellier, France.
Deniz TorunDepartment of Medical Genetics, Gulhane Faculty of Medicine, University of Health Sciences, Ankara, Turkey.
Joseph ToulouseDepartment of Clinical Epileptology, Sleep Disorders and Functional Neurology in Children, University Hospital of Lyon (HCL), Lyon, France.
Harshini ThiyagarajahDepartment of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
Stéphanie ValenceDépartement de Neurologie Pédiatrique, Assistance Publique - Hôpitaux de Paris (APHP) Sorbonne Université, Fédération Hospitalo-Universitaire I2-D2, Hôpital Armand Trousseau-La Roche Guyon, Paris, France.ORCID http://orcid.org/0000-0003-4530-4537
Sophie ValleixLaboratoire SeqOIA, Paris, France.
Julien Van-GilsService de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France.ORCID http://orcid.org/0000-0003-1497-9363
Laurent VillardService de Génétique Médicale, AP-HM, Marseille, France.
Dorothée VilleDepartment of Pediatric Neurology and Reference Center for Rare Children Epilepsy and Tuberous Sclerosis, Hôpital Femme Mere Enfant, Centre Hospitalier Universitaire de Lyon, Lyon, France.
Nathalie VilleneuveService de Neurologie Pediatrique, AP-HM, Marseille, France.
Antonio VitobelloGCS AURAGEN, Lyon, France.
Aurélie WaernessyckleDépartement de Génétique Médicale, Assistance Publique - Hôpitaux de Paris (APHP) Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Jan WagnerDepartment of Neurology, Epilepsy Center Ulm, University Hospital Ulm, Ulm, Germany.ORCID http://orcid.org/0000-0002-0459-8885
Yvonne WeberDepartment Neurology, Section of Epileptology, Medical Faculty, University RWTH Aachen, Aachen, Germany.ORCID http://orcid.org/0000-0002-0806-5592
Dagmar WieczorekInstitute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.ORCID http://orcid.org/0000-0003-2812-6492
Tom WitkowskiDepartment of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
Manya YadavilliDepartment of Neurosciences, University of California San Diego, La Jolla, CA, USA.
Tony YammineLaboratoire de Génétique, CHU de Reims, Reims, France.
Khaoula Zaafrane-KhachnaouiCentre Hospitalier Universitaire de Nice, Inserm U1081, CNRS UMR7284, IRCAN, Université Côte d'Azur, Nice, France.
Maha S ZakiClinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.ORCID http://orcid.org/0000-0001-7840-0002
Alban ZieglerGCS AURAGEN, Lyon, France.
Nuria C BramswigDepartment of Medical Genetics, Centre of Medical Genetics, University and University Hospital Münster, Münster, Germany.ORCID http://orcid.org/0000-0002-3367-586X
Alban LermineLaboratoire SeqOIA, Paris, France.
Gael NicolasUniversité Rouen Normandie, Normandie Université, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Abnormalities, Rouen, France.ORCID http://orcid.org/0000-0001-9391-7800
Joseph G GleesonDepartment of Neurosciences, University of California San Diego, La Jolla, CA, USA.ORCID http://orcid.org/0000-0002-0889-9220
Lynette G SadleirDepartment of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
Michael S HildebrandDepartment of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.ORCID http://orcid.org/0000-0003-2739-0515
Ingrid E SchefferDepartment of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
Nicola WhiffinBroad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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
Heather C MeffordCenter for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID http://orcid.org/0000-0001-7188-522X
Pierre BlancLaboratoire SeqOIA, Paris, France.
Julien ThevenonGCS AURAGEN, Lyon, France.
Camille CharbonnierDepartment of Biostatistics and Reference Center for Developmental Abnormalities, Université Rouen Normandie, Normandie Université, Inserm U1245 and CHU Rouen, Rouen, France.ORCID http://orcid.org/0000-0003-1172-0196
Clément CharentonCNRS, Inserm, Université de Strasbourg, IGBMC UMR 7104- UMR-S 1258, Illkirch, France.
Christel DepienneInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany. christel.depienne@uk-essen.de.ORCID http://orcid.org/0000-0002-7212-9554
Gaetan LescaGenetics Department, Hospices Civils de Lyon, Lyon, France. gaetan.lesca@chu-lyon.fr.ORCID http://orcid.org/0000-0001-7691-9492
Caroline NavaLaboratoire SeqOIA, Paris, France. caroline.nava@aphp.fr.ORCID http://orcid.org/0000-0003-1272-0518
Funding
GMKF competing renewalU24HD090743 · NICHD · BROAD INSTITUTE, INC. · PI Stacey Gabriel · 2016 to 2026
$68.3MJoint 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
$14.6MA powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9MUnderstanding Disparities in Genomic MedicineR21HG012397 · NHGRI · BOSTON CHILDREN'S HOSPITAL · PI O'DONNELL-LURIA, ANNE, WOJCIK, MONICA HSIUNG · 2022 to 2023
$487kAXA Research Fund (Le Fonds AXA pour la Recherche) RNU-SPLICEDepartment of Health | National Health and Medical Research Council (NHMRC) GNT2006841Department of Health | National Health and Medical Research Council (NHMRC) GNT2033247Deutsche Forschungsgemeinschaft (German Research Foundation) 458099954 (DE 2979/6-1)Deutsche Forschungsgemeinschaft (German Research Foundation) KU 1240/17-1EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council) SPLIFEMEesti Teadusagentuur (Estonian Research Council) PRG2040NHGRI NIH HHS R01 HG009141NHGRI NIH HHS R21 HG012397NHGRI NIH HHS U01 HG011755NHGRI NIH HHS UM1 HG008900NICHD NIH HHS U24 HD090743U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) R01HG009141U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) R21HG012397U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) U01HG011755U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) U24HD090743Wellcome Trust
Abstract
Small nuclear RNAs (snRNAs) are essential components of the spliceosome. De novo variants in snRNA genes RNU4-2 (ReNU syndrome), RNU5B-1 and RNU2-2 have been linked to dominant neurodevelopmental disorders (NDDs), revealing a large unexpected contribution of noncoding RNA genes to genetic diseases. Here, through international collaborations, we analyze systematically 200 potentially functional snRNA genes in a French cohort of 34,329 people with rare disorders. We report RNU2-2 variants in 141 individuals, including 35 with recurrent dominant pathogenic variants and 91 affected members from 73 families with biallelic variants. Recessive RNU2-2 NDD is at least twice as frequent as the dominant form and often involves a de novo variant in trans with an inherited allele, consistent with the high mutability of snRNA genes. Dominant and recessive RNU2-2 NDDs share overlapping clinical features, with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our results support a gradient-of-impact model bridging dominant and recessive inheritance, and establish RNU2-2 variants as a principal contributor to NDDs, nearly as prevalent as ReNU syndrome.
Indexed as
EpilepsyNeurodevelopmental DisordersRNA, Small NuclearFemaleFranceGenes, DominantGenes, RecessiveHumansMaleMutationRNA SplicingRNA, Small Nuclear
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