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.

Adelaide Medical School and Robinson Research Institute The University of Adelaide South Australia Australia

Aix Marseille University Inserm U1251 MMG Marseille Medical Genetics Marseille France

Ambry Genetics Aliso Viejo California USA

APHP SU Reference Center for Intellectual Disabilities Caused by Rare Causes Department of Genetics and Medical Embryology Hôpital Trousseau Paris France

Center for Applied Genomics and

Center for Development Behavior and Genetics SUNY Upstate Medical University Syracuse New York USA

Central Michigan University College of Medicine Discipline of Pediatrics Mount Pleasant Michigan USA

Centro de Investigación Biomédica en Red de Enfermedades Raras ISCIII Madrid Spain

Children's Hospital of Eastern Ontario Research Institute University of Ottawa Ottawa Ontario Canada

Cluster of Excellence Multiscale Bioimaging from Molecular Machines to Networks of Excitable Cells University of Göttingen Göttingen Germany

Department for Epilepsy Genetics and Personalized Medicine Danish Epilepsy Centre Dianalund Denmark

Department of Biology and Medical Genetics Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Biomedical and Health Informatics Children's Hospital of Philadelphia Philadelphia Pennsylvania USA

Department of Clinical Genetics Cook Children's Hospital Fort Worth Texas USA

Department of Clinical Genetics Erasmus Medical Center Rotterdam The Netherlands

Department of Clinical Genetics Sheffield Children's Hospital Sheffield United Kingdom

Department of Clinical Medicine University of Copenhagen Copenhagen Denmark

Department of Drug Design and Pharmacology University of Copenhagen Copenhagen Denmark

Department of Epilepsy Genetics and Personalized Medicine Danish Epilepsy Centre Dianalund Denmark

Department of General Medicine Women's and Children's Hospital Adelaide South Australia Australia

Department of Genetic Counselling Division of Clinical and Metabolic Genetics Hospital for Sick Children Ottawa Ontario Canada

Department of Genetics Albert Einstein College of Medicine Bronx New York USA

Department of Genetics and Metabolism Randall Children's Hospital at Legacy Emanuel Medical Center Portland Oregon USA

Department of Genetics Center for Molecular Medicine University Medical Center Utrecht Utrecht University Utrecht The Netherlands

Department of Genetics Hôpital Henri Mondor APHP and CHI Creteil University Paris Est Creteil IMRB Inserm U 955 Creteil France

Department of Genetics Hospital Pitié Salpêtrière Paris France

Department of Genetics Kaiser Permanente Los Angeles California USA

Department of Genetics Southern California Permanente Medical Group Kaiser Permanente San Diego California USA

Department of Genetics University of Alabama at Birmingham Birmingham Alabama USA

Department of Genomic Medicine of Rare Disorders Necker Hospital APHP Center University Paris Cité Paris France

Department of Human Genetics Academic Medical Center and

Department of Human Genetics Donders Institute for Brain Cognition and Behaviour Radboud University Medical Center Nijmegen The Netherlands

Department of Human Genetics Yokohama City University Graduate School of Medicine Yokohama Japan

Department of Medical Genetics Timone Hospital APHM Marseille France

Department of Molecular Genetics University of Toronto Toronto Ontario Canada

Department of Neurology University of Pennsylvania Philadelphia Pennsylvania USA

Department of Neurosciences Rehabilitation Ophthalmology Genetics Maternal and Child Health Università Degli Studi di Genova Genoa Italy

Department of Obstetrics and Gynecology Juntendo University Tokyo Japan

Department of Pathology and Laboratory Medicine Children's Hospital Los Angeles Los Angeles California USA

Department of Pathology and Laboratory Medicine University of Pennsylvania Philadelphia Pennsylvania USA

Department of Pathology Columbia University Irving Medical Center New York New York USA

Department of Pediatrics Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA

Department of Pediatrics Division of Clinical and Metabolic Genetics The Hospital for Sick Children University of Toronto Toronto Ontario Canada

Department of Pediatrics Graduate School of Medical Sciences Kyushu University Fukuoka Japan

Department of Pediatrics Karatsu Red Cross Hospital Saga Japan

Department of Pediatrics Medical Genetics Duke University School of Medicine Durham North Carolina USA

Department of Pediatrics University of Pennsylvania Perelman School of Medicine Philadelphia Pennsylvania USA

Department of Precision Medicine University of Campania Luigi Vanvitelli Naples Italy

Department of Rare Disease Genomics Yokohama City University Hospital Yokohama Japan

Department of Regional Health Research University of Southern Denmark Odense Denmark

Division of Clinical and Metabolic Genetics The Hospital for Sick Children Toronto Ontario Canada

Division of Genetic Genomic and Metabolic Disorders Children's Hospital of Michigan Detroit Michigan USA

Division of Genetics and Genomics Boston Children's Hospital Boston Massachusetts USA

Division of Genetics and Genomics CHU Ste Justine Hospital and CHU Sainte Justine Research Centre University of Montreal Montreal Quebec Canada

Division of Genetics and Metabolism Department of Pediatrics University of South Florida Tampa Florida USA

Division of Genetics and Metabolism Mass General Hospital for Children Boston Massachusetts USA

Division of Genetics Department of Paediatrics London Health Sciences Centre London Ontario Canada

Division of Genetics Department of Paediatrics McMaster University Hamilton Ontario Canada

Division of Human Genetics The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA

Division of Medical Genetics Children's Hospital Los Angeles California USA

Division of Medical Genetics Department of Pediatrics UCLA Los Angeles California USA

Division of Neurology and

Division of Neuromuscular and Neurometabolic Disorders Department of Paediatrics McMaster University Children's Hospital Hamilton Ontario Canada

Division of Pediatric Neurology Department of Pediatrics University of Utah School of Medicine Salt Lake City Utah USA

Division of Pediatric Pulmonary and Sleep Medicine University of Utah Salt Lake City Utah USA

DZHK partner site Göttingen Göttingen Germany

eCODE genetics Amgen Inc Reykjavik Iceland

Faculty of Medicine School of Health Sciences University of Iceland Reykjavik Iceland

FHU TRANSLAD Fédération Hospitalo Universitaire Translational Medicine in Developmental Anomalies CHU Dijon Bourgogne Dijon France

Genetic Service Hospital del Mar Research Institute Barcelona Spain

Genetic Services Kaiser Permenante of Washington Seattle Washington USA

Genetics and Molecular Pathology SA Pathology Adelaide South Australia Australia

Genetics and Rare Diseases Research Division Ospedale Pediatrico Bambino Gesù IRCCS Rome Italy

Genome Diagnostics Department of Paediatric Laboratory Medicine and

Greenwood Genetic Center Greenwood South Carolina USA

HudsonAlpha Institute for Biotechnology Huntsville Alabama USA

INSERM UMR 1231 Genetics of Developmental Anomalies Université de Bourgogne Franche Comté Dijon France

Institute for Genomic Statistics and Bioinformatics University Hospital Bonn Rheinische Friedrich Wilhelms Universität Bonn Bonn Germany

Institute of Human Genetics Friedrich Alexander Universität Erlangen Nürnberg Erlangen Germany

Institute of Human Genetics University Medical Center Göttingen Göttingen Germany

Institute of Medical and Molecular Genetics Hospital Universitario La Paz Madrid Spain

Invitae San Francisco California USA

Keck School of Medicine of the University of Southern California Los Angeles California USA

Kennedy Center Department of Clinical Genetics Copenhagen University Hospital Rigshospitalet Glostrup Denmark

Kinderzentrum Oldenburg Sozialpädiatrisches Zentrum Diakonisches Werk Oldenburg Oldenburg Germany

Laboratoire de Biologie Médicale Multi Sites SeqOIA Paris France

Laboratory of Genome Diagnostics Department of Human Genetics Amsterdam UMC University of Amsterdam Amsterdam The Netherlands

Laboratory of Medical Genetics Translational Cytogenomics Research Unit Bambino Gesù Children's Hospital IRCCS Rome Italy

Medical Genetics Department Centre de Référence Maladies Rares CLAD Ouest CHU Hôpital Sud Rennes France

Medical Genetics Department of Biomedical and Biotechnological Sciences University of Catania Catania Italy

Medical Genetics Unit Academic Department of Pediatrics IRCCS Ospedale Pediatrico Bambino Gesù Rome Italy

Medical Genetics Unit IRCCS Istituto Giannina Gaslini Genoa Italy

Metabolic Clinic and

Mindich Child Health and Development Institute and the Departments of Pediatrics and Genetics and Genomic Sciences Icahn School of Medicine New York New York USA

Mitochondrial Medicine Frontier Program Division of Human Genetics Department of Pediatrics

Mouse Cancer Genetics Program Center for Cancer Research National Cancer Institute Frederick Maryland USA

Nantes Université CHU Nantes Medical Genetics Department Nantes France

Nantes Université CNRS INSERM l'Institut du Thorax Nantes France

New York Genome Center New York New York USA

Oasi Research Institute IRCCS Troina Italy

Pediatric and Reproductive Genetics Unit Women's and Children's Hospital North Adelaide South Australia Australia

Pediatric Neurology and Muscular Diseases Unit and

Pediatric Neurology Hospital del Mar Research Institute Barcelona Spain

Rady Children's Institute for Genomic Medicine San Diego California USA

Rare Disease Genetics Department APHP Hôpital Necker Paris France

Raymond G Perelman Center for Cellular and Molecular Therapeutics Children's Hospital of Philadelphia Philadelphia Pennsylvania USA

Reference Center for Hereditary Metabolic Diseases CHU Dijon Bourgogne Dijon France

Research Unit of Rare Diseases and Neurodevelopmental Disorders Oasi Research Institute IRCCS Troina Italy

South Australian Health and Medical Research Institute Adelaide South Australia Australia

Telethon Institute of Genetics and Medicine Pozzuoli Naples Italy

The Epilepsy NeuroGenetics Initiative Children's Hospital of Philadelphia Philadelphia Pennsylvania USA

UF Innovation en Diagnostic Génomique des Maladies Rares CHU Dijon Bourgogne Dijon France

Universitat Pompeu Fabra Barcelona Spain

Université Paris Cité Inserm Institut Imagine Embryology and Genetics of Malformations Laboratory Paris France

University Health Network Toronto Ontario Canada

University of Illinois College of Medicine Mercy Health Systems Rockford Illinois USA

Zobrazit více v PubMed

Vissers LE, et al. Genetic studies in intellectual disability and related disorders. Nat Rev Genet. 2016;17(1):9–18. doi: 10.1038/nrg3999. PubMed DOI

Vissers LE, et al. A de novo paradigm for mental retardation. Nat Genet. 2010;42(12):1109–1112. doi: 10.1038/ng.712. PubMed DOI

Ropers HH. Genetics of early onset cognitive impairment. Annu Rev Genomics Hum Genet. 2010;11:161–187. doi: 10.1146/annurev-genom-082509-141640. PubMed DOI

Leblond CS, et al. Operative list of genes associated with autism and neurodevelopmental disorders based on database review. Mol Cell Neurosci. 2021;113:103623. doi: 10.1016/j.mcn.2021.103623. PubMed DOI

Bryant L, et al. Histone H3.3 beyond cancer: germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients. Sci Adv. 2020;6(49):eabc9207. doi: 10.1126/sciadv.abc9207. PubMed DOI PMC

Sheppard SE, et al. Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome. Am J Med Genet A. 2021;185(6):1649–1665. doi: 10.1002/ajmg.a.62124. PubMed DOI PMC

Sobering AK, et al. Variants in PHF8 cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology. HGG Adv. 2022;3(3):100102. doi: 10.1016/j.xhgg.2022.100102. PubMed DOI PMC

Li D, et al. Further supporting SMARCC2-related neurodevelopmental disorder through exome analysis and reanalysis in two patients. Am J Med Genet A. 2022;188(3):878–882. doi: 10.1002/ajmg.a.62597. PubMed DOI

Li D, et al. Pathogenic variants in SMARCA5, a chromatin remodeler, cause a range of syndromic neurodevelopmental features. Sci Adv. 2021;7(20):eabf2066. doi: 10.1126/sciadv.abf2066. PubMed DOI PMC

Drivas TG, et al. A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome. Eur J Hum Genet. 2020;28(10):1422–1431. doi: 10.1038/s41431-020-0654-4. PubMed DOI PMC

Li D, et al. The variability of SMARCA4-related Coffin-Siris syndrome: Do nonsense candidate variants add to milder phenotypes? Am J Med Genet A. 2020;182(9):2058–2067. doi: 10.1002/ajmg.a.61732. PubMed DOI

Thiffault I, et al. On the verge of diagnosis: detection, reporting, and investigation of de novo variants in novel genes identified by clinical sequencing. Hum Mutat. 2018;39(11):1505–1516. doi: 10.1002/humu.23646. PubMed DOI

Gebauer F, et al. RNA-binding proteins in human genetic disease. Nat Rev Genet. 2021;22(3):185–198. doi: 10.1038/s41576-020-00302-y. PubMed DOI

Matera AG, Wang Z. A day in the life of the spliceosome. Nat Rev Mol Cell Biol. 2014;15(2):108–121. doi: 10.1038/nrm3742. PubMed DOI PMC

Shi Y. Mechanistic insights into precursor messenger RNA splicing by the spliceosome. Nat Rev Mol Cell Biol. 2017;18(11):655–670. doi: 10.1038/nrm.2017.86. PubMed DOI

Lalli MA, et al. High-throughput single-cell functional elucidation of neurodevelopmental disease-associated genes reveals convergent mechanisms altering neuronal differentiation. Genome Res. 2020;30(9):1317–1331. doi: 10.1101/gr.262295.120. PubMed DOI PMC

Marchetto MC, et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell. 2010;143(4):527–539. doi: 10.1016/j.cell.2010.10.016. PubMed DOI PMC

Van Bokhoven H. Genetic and epigenetic networks in intellectual disabilities. Annu Rev Genet. 2011;45:81–104. doi: 10.1146/annurev-genet-110410-132512. PubMed DOI

Scotti MM, Swanson MS. RNA mis-splicing in disease. Nat Rev Genet. 2016;17(1):19–32. doi: 10.1038/nrg.2015.3. PubMed DOI PMC

Wang T, et al. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders. Nat Commun. 2020;11(1):4932. doi: 10.1038/s41467-020-18723-y. PubMed DOI PMC

Kalscheuer VM, et al. Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation. Nat Genet. 2003;35(4):313–315. doi: 10.1038/ng1264. PubMed DOI

Lee YR, et al. Mutations in FAM50A suggest that Armfield XLID syndrome is a spliceosomopathy. Nat Commun. 2020;11(1):3698. doi: 10.1038/s41467-020-17452-6. PubMed DOI PMC

Von Elsner L, et al. Biallelic FRA10AC1 variants cause a neurodevelopmental disorder with growth retardation. Brain. 2022;145(4):1551–1563. doi: 10.1093/brain/awab403. PubMed DOI PMC

Modafferi EF, Black DL. A complex intronic splicing enhancer from the c-src pre-mRNA activates inclusion of a heterologous exon. Mol Cell Biol. 1997;17(11):6537–6545. doi: 10.1128/MCB.17.11.6537. PubMed DOI PMC

Jin Y, et al. A vertebrate RNA-binding protein Fox-1 regulates tissue-specific splicing via the pentanucleotide GCAUG. EMBO J. 2003;22(4):905–912. doi: 10.1093/emboj/cdg089. PubMed DOI PMC

Sobreira N, et al. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36(10):928–930. doi: 10.1002/humu.22844. PubMed DOI PMC

Philippakis AA, et al. The Matchmaker Exchange: a platform for rare disease gene discovery. Hum Mutat. 2015;36(10):915–921. doi: 10.1002/humu.22858. PubMed DOI PMC

Bowling KM, et al. Genome sequencing as a first-line diagnostic test for hospitalized infants. Genet Med. 2022;24(4):851–861. doi: 10.1016/j.gim.2021.11.020. PubMed DOI PMC

Hsieh TC, et al. GestaltMatcher facilitates rare disease matching using facial phenotype descriptors. Nat Genet. 2022;54(3):349–357. doi: 10.1038/s41588-021-01010-x. PubMed DOI PMC

Zamore PD, Green MR. Identification, purification, and biochemical characterization of U2 small nuclear ribonucleoprotein auxiliary factor. Proc Natl Acad Sci U S A. 1989;86(23):9243–9247. doi: 10.1073/pnas.86.23.9243. PubMed DOI PMC

Singh R, et al. Distinct binding specificities and functions of higher eukaryotic polypyrimidine tract-binding proteins. Science. 1995;268(5214):1173–1176. doi: 10.1126/science.7761834. PubMed DOI

Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017;542(7642):433–438. doi: 10.1038/nature21062. PubMed DOI PMC

Miller JA, et al. Transcriptional landscape of the prenatal human brain. Nature. 2014;508(7495):199–206. doi: 10.1038/nature13185. PubMed DOI PMC

Schlegelmilch K, et al. Yap1 acts downstream of α-catenin to control epidermal proliferation. Cell. 2011;144(5):782–795. doi: 10.1016/j.cell.2011.02.031. PubMed DOI PMC

King I, et al. Drosophila tao controls mushroom body development and ethanol-stimulated behavior through par-1. J Neurosci. 2011;31(3):1139–1148. doi: 10.1523/JNEUROSCI.4416-10.2011. PubMed DOI PMC

Simon AF, et al. A simple assay to study social behavior in Drosophila: measurement of social space within a group. Genes Brain Behav. 2012;11(2):243–252. doi: 10.1111/j.1601-183X.2011.00740.x. PubMed DOI PMC

Parkes TL, et al. Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. Nat Genet. 1998;19(2):171–174. doi: 10.1038/534. PubMed DOI

Han C, et al. Enhancer-driven membrane markers for analysis of nonautonomous mechanisms reveal neuron-glia interactions in Drosophila. Proc Natl Acad Sci U S A. 2011;108(23):9673–9678. doi: 10.1073/pnas.1106386108. PubMed DOI PMC

Zhang Y, et al. Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron. 2013;78(5):785–798. doi: 10.1016/j.neuron.2013.05.029. PubMed DOI PMC

Cvitkovic I, Jurica MS. Spliceosome database: a tool for tracking components of the spliceosome. Nucleic Acids Res. 2013;41(database issue):D132–D141. doi: 10.1093/nar/gks999. PubMed DOI PMC

Tarn WY, et al. Yeast precursor mRNA processing protein PRP19 associates with the spliceosome concomitant with or just after dissociation of U4 small nuclear RNA. Proc Natl Acad Sci U S A. 1993;90(22):10821–10825. doi: 10.1073/pnas.90.22.10821. PubMed DOI PMC

Tarn WY, et al. Functional association of essential splicing factor(s) with PRP19 in a protein complex. EMBO J. 1994;13(10):2421–2431. doi: 10.1002/j.1460-2075.1994.tb06527.x. PubMed DOI PMC

Chan SP, et al. The Prp19p-associated complex in spliceosome activation. Science. 2003;302(5643):279–282. doi: 10.1126/science.1086602. PubMed DOI

Ohi MD, Gould KL. Characterization of interactions among the Cef1p-Prp19p-associated splicing complex. RNA. 2002;8(6):798–815. doi: 10.1017/S1355838202025050. PubMed DOI PMC

Chanarat S, Strasser K. Splicing and beyond: the many faces of the Prp19 complex. Biochim Biophys Acta. 2013;1833(10):2126–2134. doi: 10.1016/j.bbamcr.2013.05.023. PubMed DOI

Rasche N, et al. Cwc2 and its human homologue RBM22 promote an active conformation of the spliceosome catalytic centre. EMBO J. 2012;31(6):1591–1604. doi: 10.1038/emboj.2011.502. PubMed DOI PMC

De Moura TR, et al. Prp19/Pso4 is an autoinhibited ubiquitin ligase activated by stepwise assembly of three splicing factors. Mol Cell. 2018;69(6):979–992. doi: 10.1016/j.molcel.2018.02.022. PubMed DOI

David CJ, et al. The RNA polymerase II C-terminal domain promotes splicing activation through recruitment of a U2AF65-Prp19 complex. Genes Dev. 2011;25(9):972–983. doi: 10.1101/gad.2038011. PubMed DOI PMC

Venselaar H, et al. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics. 2010;11:548. doi: 10.1186/1471-2105-11-548. PubMed DOI PMC

Anders S, et al. Detecting differential usage of exons from RNA-seq data. Genome Res. 2012;22(10):2008–2017. doi: 10.1101/gr.133744.111. PubMed DOI PMC

Ritchie ME, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47. doi: 10.1093/nar/gkv007. PubMed DOI PMC

Hartley SW, Mullikin JC. Detection and visualization of differential splicing in RNA-Seq data with JunctionSeq. Nucleic Acids Res. 2016;44(15):e127. doi: 10.1093/nar/gkw501. PubMed DOI PMC

Hogg R, et al. The function of the NineTeen Complex (NTC) in regulating spliceosome conformations and fidelity during pre-mRNA splicing. Biochem Soc Trans. 2010;38(4):1110–1115. doi: 10.1042/BST0381110. PubMed DOI PMC

Underwood JG, et al. Homologues of the Caenorhabditis elegans Fox-1 protein are neuronal splicing regulators in mammals. Mol Cell Biol. 2005;25(22):10005–10016. doi: 10.1128/MCB.25.22.10005-10016.2005. PubMed DOI PMC

Tomassoni-Ardori F, et al. Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels. Elife. 2019;8:e49673. doi: 10.7554/eLife.49673. PubMed DOI PMC

El Chehadeh S, et al. Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature. Eur J Hum Genet. 2016;25(1):43–51. doi: 10.1038/ejhg.2016.133. PubMed DOI PMC

Yoshida K, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478(7367):64–69. doi: 10.1038/nature10496. PubMed DOI

Kaplanis J, et al. Evidence for 28 genetic disorders discovered by combining healthcare and research data. Nature. 2020;586(7831):757–762. doi: 10.1038/s41586-020-2832-5. PubMed DOI PMC

Hiraide T, et al. Global developmental delay, systemic dysmorphism and epilepsy in a patient with a de novo U2AF2 variant. J Hum Genet. 2021;66(12):1185–1187. doi: 10.1038/s10038-021-00948-4. PubMed DOI

Kittock CM, et al. U2AF2 variant in a patient with developmental delay, dysmorphic features, and epilepsy. Am J Med Genet A. 2023;191(7):1968–1972. doi: 10.1002/ajmg.a.63221. PubMed DOI

Wang X, et al. A presumed missense variant in the U2AF2 gene causes exon skipping in neurodevelopmental diseases. J Hum Genet. 2023;68(6):375–382. doi: 10.1038/s10038-023-01128-2. PubMed DOI

Neumuller RA, et al. Genome-wide analysis of self-renewal in Drosophila neural stem cells by transgenic RNAi. Cell Stem Cell. 2011;8(5):580–593. doi: 10.1016/j.stem.2011.02.022. PubMed DOI PMC

Fortschegger K, et al. Early embryonic lethality of mice lacking the essential protein SNEV. Mol Cell Biol. 2007;27(8):3123–3130. doi: 10.1128/MCB.01188-06. PubMed DOI PMC

Gong NN, et al. The chromatin remodeler ISWI acts during Drosophila development to regulate adult sleep. Sci Adv. 2021;7(8):eabe2597. doi: 10.1126/sciadv.abe2597. PubMed DOI PMC

Corthals K, et al. Neuroligins Nlg2 and Nlg4 affect social behavior in Drosophila melanogaster. Front Psychiatry. 2017;8:113. doi: 10.3389/fpsyt.2017.00113. PubMed DOI PMC

Merkin J, et al. Evolutionary dynamics of gene and isoform regulation in Mammalian tissues. Science. 2012;338(6114):1593–1599. doi: 10.1126/science.1228186. PubMed DOI PMC

Li Q, et al. Neuronal regulation of alternative pre-mRNA splicing. Nat Rev Neurosci. 2007;8(11):819–831. doi: 10.1038/nrn2237. PubMed DOI

Raj B, Blencowe BJ. Alternative splicing in the mammalian nervous system: recent insights into mechanisms and functional roles. Neuron. 2015;87(1):14–27. doi: 10.1016/j.neuron.2015.05.004. PubMed DOI

Staley JP, Guthrie C. Mechanical devices of the spliceosome: motors, clocks, springs, and things. Cell. 1998;92(3):315–326. doi: 10.1016/S0092-8674(00)80925-3. PubMed DOI