ArticleThe Journal of clinical investigation2024
Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.
Open access · goldAbstract read
In one paragraph
Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31citing papers in PubMed
6.3field-weighted citation impact, top 3% of its field
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Who cites it
31 citing papers in PubMed, 41 citations in OpenAlex.
- [Spliceosome defects and neurodevelopmental disorders].Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics · 2026Review
- White matter disorders at the intersection of transcription, RNA processing and translation.Nature reviews. Neurology · 2026Review
- Vitamin BNature communications · 2026Article
- Neurodevelopmental Disorder with Dystonia and Chorea Linked to De Novo Variants in the Splicing Regulator SRRM4.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Cdk7 promotes neuritogenesis in cortical neurons and contributes to social behavior in mice.Cellular and molecular life sciences : CMLS · 2026Article
- Heterozygous loss of SRRM1 may be associated with neurodevelopmental phenotypes and anomalies in cell growth and neurite morphology.European journal of human genetics : EJHG · 2026Article
- De novo variants in the splicing factor gene SF3B1 are associated with neurodevelopmental disorders.Nature communications · 2026Article
- TET dioxygenases localize at splicing speckles and promote RNA splicing.Nucleus (Austin, Tex.) · 2025Article
- Alternative Splicing: Molecular Mechanisms, Biological Functions, Diseases, and Potential Therapeutic Targets.MedComm · 2025Review
- A scoping review of stem cell models of leukodystrophies: advances in understanding pathophysiological mechanisms.NPJ genomic medicine · 2025Article
- Genome-wide modulation of alternative splicing by a predicted alpha helix in U2AF2.Nucleic acids research · 2025Article
- Vitamin BResearch square · 2025Article
- The Role of mRNA Alternative Processing in Mammalian Neurodevelopment.International journal of molecular sciences · 2025Review
- Neurogenetic Disorders with Hearing Loss: Mechanisms, Classifications, and Emerging Insights.Current neurology and neuroscience reports · 2025Review
- Bioinformatics frameworks for single-cell long-read sequencing: unlocking isoform-level resolution.Briefings in bioinformatics · 2025Review
- A comparison of spermatogenesis between flies and men-conserved processes of male gamete production.Human reproduction update · 2025Review
- Article
- Mutations in the spliceosomal gene SNW1 cause neurodevelopment disorders with microcephaly.The Journal of clinical investigation · 2025Article
- Clusters of deep intronic RbFox motifs embedded in large assembly of splicing regulators sequences regulate alternative splicing.PLoS genetics · 2025Article
- Clinicopathologic features of allied disorders of Hirschsprung disease and status update.World journal of gastrointestinal surgery · 2025Review
Corrections and comments
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Authors and funding
153 authors at 20 institutions in 15 countries.
Dong LiCenter for Applied Genomics, and.
Qin WangRaymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Allan BayatDepartment of Regional Health Research, University of Southern Denmark, Odense, Denmark.
Mark R BattigCenter for Applied Genomics, and.
Yijing ZhouRaymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Daniëlle Gm BoschDepartment of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
Gijs van HaaftenDepartment of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Leslie GrangerDepartment of Genetics and Metabolism, Randall Children's Hospital at Legacy Emanuel Medical Center, Portland, Oregon, USA.
Andrea K PetersenDepartment of Genetics and Metabolism, Randall Children's Hospital at Legacy Emanuel Medical Center, Portland, Oregon, USA.
Luis A Pérez-JuradoCentro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.
Gemma Aznar-LaínUniversitat Pompeu Fabra, Barcelona, Spain.
Anushree AnejaRaymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Miroslava HancarovaDepartment of Biology and Medical Genetics, Charles University Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
Sarka BendovaDepartment of Biology and Medical Genetics, Charles University Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
Martin SchwarzDepartment of Biology and Medical Genetics, Charles University Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
Radka Kremlikova PourovaDepartment of Biology and Medical Genetics, Charles University Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
Zdenek SedlacekDepartment of Biology and Medical Genetics, Charles University Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
Beth A KeenaDivision of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Michael E MarchCenter for Applied Genomics, and.
Cuiping HouCenter for Applied Genomics, and.
Nora O'ConnorCenter for Applied Genomics, and.
Elizabeth J BhojCenter for Applied Genomics, and.
Margaret H HarrCenter for Applied Genomics, and.
Gabrielle LemireChildren's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Kym M BoycottChildren's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Meghan TowneAmbry Genetics, Aliso Viejo, California, USA.
Megan LiInvitae, San Francisco, California, USA.
Mark TarnopolskyDivision of Neuromuscular and Neurometabolic Disorders, Department of Paediatrics, McMaster University Children's Hospital, Hamilton, Ontario, Canada.
Lauren BradyDivision of Neuromuscular and Neurometabolic Disorders, Department of Paediatrics, McMaster University Children's Hospital, Hamilton, Ontario, Canada.
Michael J ParkerDepartment of Clinical Genetics, Sheffield Children's Hospital, Sheffield, United Kingdom.
Hanna FaghfouryUniversity Health Network, Toronto, Ontario, Canada.
Lea Kristin ParsleyUniversity of Illinois College of Medicine, Mercy Health Systems, Rockford, Illinois, USA.
Emanuele AgoliniLaboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Maria Lisa DenticiMedical Genetics Unit, Academic Department of Pediatrics, IRCCS, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
Antonio NovelliLaboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Meredith WrightRady Children's Institute for Genomic Medicine, San Diego, California, USA.
Rachel PalmquistDivision of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Khanh LaiDivision of Pediatric Pulmonary and Sleep Medicine, University of Utah, Salt Lake City, Utah, USA.
Marcello ScalaDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Genoa, Italy.
Pasquale StrianoDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Genoa, Italy.
Michele IacominoMedical Genetics Unit, IRCCS, Istituto Giannina Gaslini, Genoa, Italy.
Federico ZaraMedical Genetics Unit, IRCCS, Istituto Giannina Gaslini, Genoa, Italy.
Annina CooperDepartment of Genetics, Southern California Permanente Medical Group, Kaiser Permanente, San Diego, California, USA.
Timothy J MaarupDepartment of Genetics, Kaiser Permanente, Los Angeles, California, USA.
Melissa BylerCenter for Development, Behavior and Genetics, SUNY Upstate Medical University, Syracuse, New York, USA.
Robert Roger LebelCenter for Development, Behavior and Genetics, SUNY Upstate Medical University, Syracuse, New York, USA.
Tugce B BalciDivision of Genetics, Department of Paediatrics, London Health Sciences Centre, London, Ontario, Canada.
Raymond LouieGreenwood Genetic Center, Greenwood, South Carolina, USA.
Michael LyonsGreenwood Genetic Center, Greenwood, South Carolina, USA.
Jessica DouglasDivision of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.
Catherine NowakDivision of Genetics and Metabolism, Mass General Hospital for Children, Boston, Massachusetts, USA.
Alexandra AfenjarAPHP. SU, Reference Center for Intellectual Disabilities Caused by Rare Causes, Department of Genetics and Medical Embryology, Hôpital Trousseau, Paris, France.
Juliane HoyerInstitute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Boris KerenDepartment of Genetics, Hospital Pitié-Salpêtrière, Paris, France.
Saskia M MaasDepartment of Human Genetics, Academic Medical Center, and.
Mahdi M MotazackerLaboratory of Genome Diagnostics, Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Julian A Martinez-AgostoDivision of Medical Genetics, Department of Pediatrics, UCLA, Los Angeles, California, USA.
Ahna M RabaniDivision of Medical Genetics, Department of Pediatrics, UCLA, Los Angeles, California, USA.
Elizabeth M McCormickMitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics.
Marni J FalkDepartment of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
Sarah M RuggieroDivision of Neurology, and.
Ingo HelbigDivision of Neurology, and.
Rikke S MøllerDepartment of Regional Health Research, University of Southern Denmark, Odense, Denmark.
Lino TessarolloMouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI), Frederick, Maryland, USA.
Francesco Tomassoni ArdoriMouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI), Frederick, Maryland, USA.
Mary Ellen PalkoMouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI), Frederick, Maryland, USA.
Tzung-Chien HsiehInstitute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.
Peter M KrawitzInstitute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.
Mythily GanapathiNew York Genome Center, New York, New York, USA.
Bruce D GelbMindich Child Health and Development Institute and the Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine, New York, New York, USA.
Vaidehi JobanputraNew York Genome Center, New York, New York, USA.
Ashley WilsonNew York Genome Center, New York, New York, USA.
John GreallyDepartment of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA.
Sébastien JacquemontDivision of Genetics and Genomics, CHU Ste-Justine Hospital and CHU Sainte-Justine Research Centre, University of Montreal, Montreal, Quebec, Canada.
Khadijé JiziDivision of Genetics and Genomics, CHU Ste-Justine Hospital and CHU Sainte-Justine Research Centre, University of Montreal, Montreal, Quebec, Canada.
Ange-Line BruelINSERM UMR 1231, Genetics of Developmental Anomalies, Université de Bourgogne Franche-Comté, Dijon, France.
Chloé QuelinMedical Genetics Department, Centre de Référence Maladies Rares CLAD-Ouest, CHU Hôpital Sud, Rennes, France.
Vinod K MisraDivision of Genetic, Genomic, and Metabolic Disorders, Children's Hospital of Michigan, Detroit, Michigan, USA.
Erika ChickDivision of Genetic, Genomic, and Metabolic Disorders, Children's Hospital of Michigan, Detroit, Michigan, USA.
Corrado RomanoResearch Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, Troina, Italy.
Donatella GrecoOasi Research Institute-IRCCS, Troina, Italy.
Alessia ArenaOasi Research Institute-IRCCS, Troina, Italy.
Manuela MorleoTelethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
Vincenzo NigroTelethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
Rie SeyamaDepartment of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Yuri UchiyamaDepartment of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Naomichi MatsumotoDepartment of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Ryoji TairaDepartment of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Katsuya TashiroDepartment of Pediatrics, Karatsu Red Cross Hospital, Saga, Japan.
Yasunari SakaiDepartment of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Gökhan YigitInstitute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
Bernd WollnikInstitute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
Michael WagnerKinderzentrum Oldenburg, Sozialpädiatrisches Zentrum, Diakonisches Werk Oldenburg, Oldenburg, Germany.
Barbara KutscheKinderzentrum Oldenburg, Sozialpädiatrisches Zentrum, Diakonisches Werk Oldenburg, Oldenburg, Germany.
Anna Ce HurstDepartment of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Michelle L ThompsonHudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.
Ryan SchmidtDepartment of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California, USA.
Linda RandolphKeck School of Medicine of the University of Southern California, Los Angeles, California, USA.
Rebecca C SpillmannDepartment of Pediatrics-Medical Genetics, Duke University School of Medicine, Durham, North Carolina, USA.
Vandana ShashiDepartment of Pediatrics-Medical Genetics, Duke University School of Medicine, Durham, North Carolina, USA.
Edward J HigginbothamGenome Diagnostics, Department of Paediatric Laboratory Medicine, and.
Dawn CordeiroDivision of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Amanda CarnevaleDivision of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Gregory CostainDivision of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Tayyaba KhanDivision of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Benoît FunalotDepartment of Genetics, Hôpital Henri-Mondor APHP and CHI Creteil, University Paris Est Creteil, IMRB, Inserm U.955, Creteil, France.
Frederic Tran Mau-ThemINSERM UMR 1231, Genetics of Developmental Anomalies, Université de Bourgogne Franche-Comté, Dijon, France.
Luis Fernandez Garcia MoyaInstitute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Madrid, Spain.
Sixto García-MiñaúrInstitute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Madrid, Spain.
Matthew OsmondChildren's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Lauren ChadDepartment of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Nada QuerciaDepartment of Genetic Counselling, Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Ottawa, Ontario, Canada.
Diana CarrascoDepartment of Clinical Genetics, Cook Children's Hospital, Fort Worth, Texas, USA.
Chumei LiDivision of Genetics, Department of Paediatrics, McMaster University, Hamilton, Ontario, Canada.
Amarilis Sanchez-ValleDivision of Genetics and Metabolism, Department of Pediatrics, University of South Florida, Tampa, Florida, USA.
Meghan KelleyDivision of Genetics and Metabolism, Department of Pediatrics, University of South Florida, Tampa, Florida, USA.
Mathilde NizonNantes Université, CHU Nantes, Medical Genetics Department, Nantes, France.
Brynjar O JenssondeCODE genetics/Amgen Inc., Reykjavik, Iceland.
Patrick SulemdeCODE genetics/Amgen Inc., Reykjavik, Iceland.
Kari StefanssondeCODE genetics/Amgen Inc., Reykjavik, Iceland.
Svetlana GorokhovaAix Marseille University, Inserm, U1251-MMG, Marseille Medical Genetics, Marseille, France.
Tiffany BusaDepartment of Medical Genetics, Timone Hospital, APHM, Marseille, France.
Marlène RioDepartment of Genomic Medicine of Rare Disorders, Necker Hospital, APHP Center, University Paris Cité, Paris, France.
Hamza Hadj HabdallahDepartment of Genomic Medicine of Rare Disorders, Necker Hospital, APHP Center, University Paris Cité, Paris, France.
Marion Lesieur-SebellinDepartment of Genomic Medicine of Rare Disorders, Necker Hospital, APHP Center, University Paris Cité, Paris, France.
Jeanne AmielRare Disease Genetics Department, APHP, Hôpital Necker, Paris, France.
Véronique PingaultRare Disease Genetics Department, APHP, Hôpital Necker, Paris, France.
Sandra MercierNantes Université, CHU Nantes, Medical Genetics Department, Nantes, France.
Marie VincentNantes Université, CHU Nantes, Medical Genetics Department, Nantes, France.
Christophe PhilippeINSERM UMR 1231, Genetics of Developmental Anomalies, Université de Bourgogne Franche-Comté, Dijon, France.
Clemence Fatus-FauconnierReference Center for Hereditary Metabolic Diseases, CHU Dijon Bourgogne, Dijon, France.
Kathryn FriendGenetics and Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia.
Rebecca K HalliganMetabolic Clinic, and.
Sunita BiswasMetabolic Clinic, and.
Jane RosserDepartment of General Medicine, Women's and Children's Hospital, Adelaide, South Australia, Australia.
Cheryl ShoubridgeAdelaide Medical School and Robinson Research Institute, The University of Adelaide, South Australia, Australia.
Mark CorbettAdelaide Medical School and Robinson Research Institute, The University of Adelaide, South Australia, Australia.
Christopher BarnettAdelaide Medical School and Robinson Research Institute, The University of Adelaide, South Australia, Australia.
Jozef GeczAdelaide Medical School and Robinson Research Institute, The University of Adelaide, South Australia, Australia.
Kathleen LeppigGenetic Services, Kaiser Permenante of Washington, Seattle, Washington, USA.
Anne SlavotinekDepartment of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Carlo MarcelisDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Rolph PfundtDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Bert Ba de VriesDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Marjon A van SlegtenhorstDepartment of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
Alice S BrooksDepartment of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
Benjamin CogneNantes Université, CHU Nantes, Medical Genetics Department, Nantes, France.
Thomas RambaudLaboratoire de Biologie Médicale Multi-Sites SeqOIA (laboratoire-seqoia.fr), Paris, France.
Zeynep TümerKennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
Elaine H ZackaiDivision of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Naiara AkizuRaymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Yuanquan SongRaymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Hakon HakonarsonCenter for Applied Genomics, and.
Children's Hospital of Philadelphia · USCharles University · CZHôpital Necker-Enfants Malades · FRHospital for Sick Children · CAInserm · FRCentre National de la Recherche Scientifique · FRWomen's and Children's Hospital · AUBambino Gesù Children's Hospital · ITColumbia University Irving Medical Center · USdeCODE Genetics (Iceland) · ISErasmus MC · NLFrederick National Laboratory for Cancer Research · USRadboud University Nijmegen · NLUniversity of Ottawa · CACarl von Ossietzky Universität Oldenburg · DECentre Hospitalier Universitaire Sainte-Justine · CADuke University · USGreenwood Genetic Center · USHospital Universitario La Paz · ESIstituto Giannina Gaslini · IT
Funding
Incorporating genomics into the clinical care of diverse NYC childrenU01HG009610 · NHGRI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI GELB, BRUCE D, HOROWITZ, CAROL R · 2017 to 2021
$17.0MRole of Neurotrophins in the Development of the Mammalian Nervous SystemZIABC010390 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI TESSAROLLO, LINO · 2009 to 2025
$14.2MAn integrated and diverse genomic medicine program for undiagnosed diseasesU01HG007672 · NHGRI · DUKE UNIVERSITY · PI SHASHI, VANDANA · 2014 to 2022
$13.4MSouth-seq: DNA sequencing for newborn nurseries in the SouthU01HG007301 · NHGRI · HUDSON-ALPHA INSTITUTE FOR BIOTECHNOLOGY · PI BARSH, GREGORY STEFAN, COOPER, GREGORY MICHAEL · 2017 to 2021
$11.9MThe Intellectual and Developmental Disabilities Research Center (IDDRC) at CHOP/PennP50HD105354 · NICHD · CHILDREN'S HOSP OF PHILADELPHIA · PI Michael Byrne Robinson · 2021 to 2026
$9.2MSUPPORT FOR THE ROSE F KENNEDY IDDRC P50P50HD105352 · NICHD · ALBERT EINSTEIN COLLEGE OF MEDICINE · PI SOPHIE MOLHOLM, Steven Upshaw Walkley · 2021 to 2026
$7.0MAn integrated and diverse genomic medicine program for undiagnosed diseasesU01NS134350 · NINDS · DUKE UNIVERSITY · PI VANDANA SHASHI · 2023 to 2026
$3.6MA computational phenotyping approach to characterize neurogenetic disordersR01NS131512 · NINDS · CHILDREN'S HOSP OF PHILADELPHIA · PI Ingo Helbig · 2023 to 2026
$2.8MTargeting Atr to promote regeneration and functional recovery after neural injuryR01NS107392 · NINDS · CHILDREN'S HOSP OF PHILADELPHIA · PI SONG, YUANQUAN · 2018 to 2022
$1.9MJoint analysis of genomic and electronic medical record data to assess outcomes and drug response in pediatric epilepsiesK02NS112600 · NINDS · CHILDREN'S HOSP OF PHILADELPHIA · PI HELBIG, INGO · 2020 to 2024
$963kNHGRI NIH HHS U01 HG007301NHGRI NIH HHS U01 HG007672NHGRI NIH HHS U01 HG009610NICHD NIH HHS P50 HD105352NICHD NIH HHS P50 HD105354NINDS NIH HHS K02 NS112600NINDS NIH HHS R01 NS107392NINDS NIH HHS R01 NS131512NINDS NIH HHS U01 NS134350Wellcome Trust
Abstract
Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.
Indexed as
Neurodevelopmental DisordersSpliceosomesDNA Repair EnzymesGene Regulatory NetworksHumansMutation, MissenseNuclear ProteinsRNA SplicingRNA Splicing FactorsDNA Repair EnzymesNuclear ProteinsPRPF19 protein, humanRNA Splicing FactorsDevelopmentGenetic diseasesGeneticsiPS cellsNeurodevelopment
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