De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders.

Autor:	Chen Y; Big Data Institute, University of Oxford, Oxford, UK.; Centre for Human Genetics, University of Oxford, Oxford, UK., Dawes R; Big Data Institute, University of Oxford, Oxford, UK.; Centre for Human Genetics, University of Oxford, Oxford, UK., Kim HC; Big Data Institute, University of Oxford, Oxford, UK.; Centre for Human Genetics, University of Oxford, Oxford, UK., Stenton SL; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Walker S; Genomics England, London, UK., Ljungdahl A; Institute of Developmental and Regenerative Medicine, Department of Paediatrics, University of Oxford, Oxford, UK.; Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, USA., Lord J; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK., Ganesh VS; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Ma J; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Martin-Geary AC; Big Data Institute, University of Oxford, Oxford, UK.; Centre for Human Genetics, University of Oxford, Oxford, UK., Lemire G; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., D'Souza EN; Big Data Institute, University of Oxford, Oxford, UK.; Centre for Human Genetics, University of Oxford, Oxford, UK., Dong S; Institute of Developmental and Regenerative Medicine, Department of Paediatrics, University of Oxford, Oxford, UK.; Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, USA., Ellingford JM; Genomics England, London, UK.; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK.; Division of Evolution, Infection and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, UK., Adams DR; Undiagnosed Disesases Program, National Human Genome Research Institute, Bethesda, MD, USA., Allan K; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia., Bakshi M; Department of Clinical Genetics, Liverpool Hospital, Sydney, NSW, Australia., Baldwin EE; Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA., Berger SI; Center for Genetic Medicine Research, Children's National Research Institute, Washington, DC, USA.; Division of Genetics and Metabolism, Children's National Hospital, Washington, DC, USA., Bernstein JA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.; GREGoR Stanford Site, Stanford University School of Medicine, Stanford, CA, USA.; Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USA., Brown NJ; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia., Burrage LC; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Chapman K; Division of Genetics and Metabolism, Children's National Hospital, Washington, DC, USA., Compton AG; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.; Murdoch Children's Research Institute, Melbourne, VIC, Australia., Cunningham CA; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia., D'Souza P; Undiagnosed Disesases Program, National Human Genome Research Institute, Bethesda, MD, USA., Délot EC; Center for Genetic Medicine Research, Children's National Research Institute, Washington, DC, USA., Dias KR; Neuroscience Research Australia, Sydney, NSW, Australia.; Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia., Elias ER; Department of Pediatrics, Children's Hospital Colorado, Aurora, CO, USA.; University of Colorado School of Medicine, University of Colorado, Aurora, CO, USA., Evans CA; Neuroscience Research Australia, Sydney, NSW, Australia.; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia., Ewans L; Discipline of Paediatrics and Child Health, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia.; Centre for Clinical Genetics, Sydney Children's Hospitals Network, Randwick, NSW, Australia.; Genomics and Inherited Disease Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia., Ezell K; Division of Medical Genetics & Genomic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Fraser JL; Center for Genetic Medicine Research, Children's National Research Institute, Washington, DC, USA.; Division of Genetics and Metabolism, Children's National Hospital, Washington, DC, USA., Gallacher L; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia., Genetti CA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Grant CL; Division of Genetics and Metabolism, Children's National Hospital, Washington, DC, USA., Haack T; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.; Center for Rare Diseases Tübingen, University of Tübingen, Tübingen, Germany., Kuechler A; Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany., Lalani SR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Leitão E; Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany., Fevre AL; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia., Leventer RJ; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.; Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Royal Children's Hospital, Melbourne, VIC, Australia., Liebelt JE; Paediatric and Reproductive Genetics Unit, South Australian Clinical Genetics Service, Women's and Children's Hospital, North Adelaide, SA, Australia.; Repromed, Dulwich, SA, Australia., Lockhart PJ; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.; Bruce Lefroy Centre, Murdoch Children's Research Institute, Melbourne, VIC, Australia., Ma AS; Department of Clinical Genetics, Sydney Children's Hospitals Network Westmead, Sydney, NSW, Australia.; Specialty of Genomic Medicine, University of Sydney, Sydney, NSW, Australia., Macnamara EF; Undiagnosed Disesases Program, National Human Genome Research Institute, Bethesda, MD, USA., Maurer TM; GREGoR Stanford Site, Stanford University School of Medicine, Stanford, CA, USA.; Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USA.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Mendez HR; GREGoR Stanford Site, Stanford University School of Medicine, Stanford, CA, USA.; Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USA.; Department of Medicine - Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA., Montgomery SB; GREGoR Stanford Site, Stanford University School of Medicine, Stanford, CA, USA.; Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pathology, Department of Genetics, Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA., Nassogne MC; Service de Neurologie Pédiatrique, Cliniques Universitaires Saint-Luc, UCLouvain, B-1200, Brussels, Belgium.; Institut des Maladies Rares, Cliniques Universitaires Saint-Luc, UCLouvain, B-1200, Brussels, Belgium., Neumann S; Division of Medical Genetics & Genomic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., O'Leary M; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Palmer EE; Discipline of Paediatrics and Child Health, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia.; Centre for Clinical Genetics, Sydney Children's Hospitals Network, Randwick, NSW, Australia., Phillips J; Division of Medical Genetics & Genomic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Pitsava G; Institute for Clinical and Translational Research, University of California, Irvine, CA, USA., Pysar R; Discipline of Paediatrics and Child Health, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia.; Centre for Clinical Genetics, Sydney Children's Hospitals Network, Randwick, NSW, Australia.; Department of Clinical Genetics, The Children's Hospital at Westmead, Westmead, NSW, Australia., Rehm HL; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Reuter CM; GREGoR Stanford Site, Stanford University School of Medicine, Stanford, CA, USA.; Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USA.; Department of Medicine - Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA., Revencu N; Center for Human Genetics, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium., Riess A; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Rius R; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.; Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, New South Wales, Australia.; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia., Rodan L; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Roscioli T; Neuroscience Research Australia, Sydney, NSW, Australia.; Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia., Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Sachdev R; Discipline of Paediatrics and Child Health, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia.; Centre for Clinical Genetics, Sydney Children's Hospitals Network, Randwick, NSW, Australia., Simons C; Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, New South Wales, Australia.; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia., Sisodiya SM; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.; UK and Chalfont Centre for Epilepsy, Bucks, UK., Snell P; Bruce Lefroy Centre, Murdoch Children's Research Institute, Melbourne, VIC, Australia., Clair L; Department of Clinical Genetics, Sydney Children's Hospitals Network Westmead, Sydney, NSW, Australia., Stark Z; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia., Tan TY; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia., Tan NB; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia., Temple SE; Department of Clinical Genetics, Liverpool Hospital, Sydney, NSW, Australia.; School of Women's and Childrens's Health, University of New South Wales, Sydney, NSW, Australia., Thorburn DR; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.; Murdoch Children's Research Institute, Melbourne, VIC, Australia., Tifft CJ; Undiagnosed Disesases Program, National Human Genome Research Institute, Bethesda, MD, USA., Uebergang E; Murdoch Children's Research Institute, Melbourne, VIC, Australia., VanNoy GE; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Vilain E; Institute for Clinical and Translational Science, University of California, Irvine, CA, USA., Viskochil DH; Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA., Wedd L; Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, New South Wales, Australia.; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia., Wheeler MT; GREGoR Stanford Site, Stanford University School of Medicine, Stanford, CA, USA.; Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USA.; Department of Medicine - Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA., White SM; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia., Wojcik M; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Wolfe LA; Undiagnosed Disesases Program, National Human Genome Research Institute, Bethesda, MD, USA., Wolfenson Z; Undiagnosed Disesases Program, National Human Genome Research Institute, Bethesda, MD, USA., Xiao C; Department of Neurology, University of California, Irvine, CA, USA., Zocche D; North West Thames Regional Genetics Service, Northwick Park & St Mark's Hospitals, London, UK., Rubenstein JL; Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, USA., Markenscoff-Papadimitriou E; Department of Psychiatry, Langley Porter Psychiatric Institute, UCSF Weill Institute for Neurosciences, University of California, San Francisco, USA., Fica SM; Department of Biochemistry, University of Oxford, Oxford, UK., Baralle D; School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.; National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, University Hospital Southampton National Health Service (NHS) Foundation Trust, Southampton, UK., Depienne C; Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany., MacArthur DG; Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, New South Wales, Australia.; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia., Howson JM; Human Genetics Centre of Excellence, Novo Nordisk Research Centre, Oxford, UK., Sanders SJ; Institute of Developmental and Regenerative Medicine, Department of Paediatrics, University of Oxford, Oxford, UK.; Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, USA., O'Donnell-Luria A; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Whiffin N; Big Data Institute, University of Oxford, Oxford, UK.; Centre for Human Genetics, University of Oxford, Oxford, UK.; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2024 Apr 09. Date of Electronic Publication: 2024 Apr 09.
DOI:	10.1101/2024.04.07.24305438
Abstrakt:	Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes 1 . Increasingly, large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a novel syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome 2 . We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 119 individuals with NDD. The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). We estimate that variants in this region explain 0.41% of individuals with NDD. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to its contiguous counterpart RNU4-1 and other U4 homologs, supporting RNU4-2 's role as the primary U4 transcript in the brain. Overall, this work underscores the importance of non-coding genes in rare disorders. It will provide a diagnosis to thousands of individuals with NDD worldwide and pave the way for the development of effective treatments for these individuals. Competing Interests: Competing interests NW receives research funding from Novo Nordisk and has consulted for ArgoBio studio. SJS receives research funding from BioMarin Pharmaceutical. AODL is on the scientific advisory board for Congenica, was a paid consultant for Tome Biosciences and Ono Pharma USA Inc., and received reagents from PacBio to support rare disease research. HLR has received support from Illumina and Microsoft to support rare disease gene discovery and diagnosis. MHW has consulted for Illumina and Sanofi and received speaking honoraria from Illumina and GeneDx. SBM is an advisor for BioMarin, Myome and Tenaya Therapeutics. SMS has received honoraria for educational events or advisory boards from Angelini Pharma, Biocodex, Eisai, Zogenix/UCB and institutional contributions for advisory boards, educational events or consultancy work from Eisai, Jazz/GW Pharma, Stoke Therapeutics, Takeda, UCB and Zogenix. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories. JMMH is a full-time employee of Novo Nordisk and holds shares in Novo Nordisk A/S. DGM is a paid consultant for GlaxoSmithKline, Insitro, and Overtone Therapeutics and receives research support from Microsoft.
Databáze:	MEDLINE
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