title: Heterozygous HNRNPU variants cause early onset epilepsy and severe intellectual disability.
abstract: Pathogenic variants in genes encoding subunits of the spliceosome are the cause of several human diseases, such as neurodegenerative diseases. The RNA splicing process is facilitated by the spliceosome, a large RNA-protein complex consisting of small nuclear ribonucleoproteins (snRNPs), and many other proteins, such as heterogeneous nuclear ribonucleoproteins (hnRNPs). The HNRNPU gene (OMIM *602869) encodes the heterogeneous nuclear ribonucleoprotein U, which plays a crucial role in mammalian development. HNRNPU is expressed in the fetal brain and adult heart, kidney, liver, brain, and cerebellum. Microdeletions in the 1q44 region encompassing HNRNPU have been described in patients with intellectual disability (ID) and other clinical features, such as seizures, corpus callosum abnormalities (CCA), and microcephaly. Recently, pathogenic HNRNPU variants were identified in large ID and epileptic encephalopathy cohorts. In this study, we provide detailed clinical information of five novels and review two of the previously published individuals with (likely) pathogenic de novo variants in the HNRNPU gene including three non-sense and two missense variants, one small intragenic deletion, and one duplication. The phenotype in individuals with variants in HNRNPU is characterized by early onset seizures (6/7), severe ID (6/6), severe speech impairment (6/6), hypotonia (6/7), and central nervous system (CNS) (5/6), cardiac (4/6), and renal abnormalities (3/4). In this study, we broaden the clinical and mutational HNRNPU-associated spectrum, and demonstrate that heterozygous HNRNPU variants cause epilepsy, severe ID with striking speech impairment and variable CNS, cardiac, and renal anomalies.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany. nuria.braemswig@uni-due.de.
authors.forename: Nuria C
authors.identifier: http://orcid.org/0000-0002-3367-586X
authors.initials: NC
authors.lastname: Bramswig
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany.|Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Lüdecke
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.|Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: Filippo
authors.initials: F
authors.lastname: Beleggia
authors.affiliation: Department of Pediatric Genetics, Marmara University Medical School, Istanbul, Turkey.|Eastern Mediterranean University, Cyprus, Mersin, 10, Turkey.
authors.forename: Nursel H
authors.initials: NH
authors.lastname: Elcioglu
authors.affiliation: Department of Neurology, University of California, San Francisco, USA.
authors.forename: Catharine
authors.initials: C
authors.lastname: Freyer
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Erica H
authors.initials: EH
authors.lastname: Gerkes
authors.affiliation: Department of Pediatric Genetics, Marmara University Medical School, Istanbul, Turkey.
authors.forename: Yasemin Kendir
authors.initials: YK
authors.lastname: Demirkol
authors.affiliation: Department of Pediatrics and Neurology, Children's Hospital Colorado, Anschutz Medical Campus, University of Colorado, Aurora, CO, USA.
authors.forename: Kelly G
authors.initials: KG
authors.lastname: Knupp
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany.
authors.forename: Alma
authors.initials: A
authors.lastname: Kuechler
authors.affiliation: Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurology, University of California, San Francisco, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Lowenstein
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.|Department of Pediatrics, Université de Montréal, Montreal, Canada.|Department of Neurosciences, Université de Montréal, Montreal, Canada.
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.affiliation: Department of Pediatrics and Neurology, Children's Hospital Colorado, Anschutz Medical Campus, University of Colorado, Aurora, CO, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Alexander P A
authors.initials: APA
authors.lastname: Stegmann
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hermine E
authors.initials: HE
authors.lastname: Veenstra-Knol
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany.|Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
mesh_terms: D017668:Age of Onset; D061085:Agenesis of Corpus Callosum / Q000235:genetics; D002490:Central Nervous System / Q000002:abnormalities / Q000473:pathology; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D034722:Heterogeneous-Nuclear Ribonucleoprotein U / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D007668:Kidney / Q000002:abnormalities; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics; D009123:Muscle Hypotonia / Q000175:diagnosis / Q000235:genetics; D010641:Phenotype; D012326:RNA Splicing; D017411:Ribonucleoproteins, Small Nuclear / Q000235:genetics; D012640:Seizures / Q000175:diagnosis / Q000235:genetics
chemical_list: C000621393:HNRNPU protein, human; D034722:Heterogeneous-Nuclear Ribonucleoprotein U; D017411:Ribonucleoproteins, Small Nuclear