2. Academic Validation
  3. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome

De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome

  • Am J Hum Genet. 2016 Sep 1;99(3):711-719. doi: 10.1016/j.ajhg.2016.06.029.
Jung-Hyun Kim 1,  Deepali N Shinde 2,  Margot R F Reijnders 3,  Natalie S Hauser 4,  Rebecca L Belmonte 5,  Gregory R Wilson 5,  Daniëlle G M Bosch 3,  Paula A Bubulya 6,  Vandana Shashi 7,  Slavé Petrovski 8,  Joshua K Stone 1,  Eun Young Park 1,  Joris A Veltman 9,  Margje Sinnema 10,  Connie T R M Stumpel 10,  Jos M Draaisma 11,  Joost Nicolai 12,  University of Washington Center for Mendelian Genomics,  Helger G Yntema 3,  Kristin Lindstrom 13,  Bert B A de Vries 3,  Tamison Jewett 14,  Stephanie L Santoro 15,  Julie Vogt 16,  Deciphering Developmental Disorders Study 17,  Kristine K Bachman 18,  Andrea H Seeley 18,  Alyson Krokosky 19,  Clesson Turner 19,  Luis Rohena 20,  Maja Hempel 21,  Fanny Kortüm 21,  Davor Lessel 21,  Axel Neu 22,  Tim M Strom 23,  Dagmar Wieczorek 24,  Nuria Bramswig 25,  Franco A Laccone 26,  Jana Behunova 26,  Helga Rehder 26,  Christopher T Gordon 27,  Marlène Rio 28,  Serge Romana 29,  Sha Tang 2,  Dima El-Khechen 2,  Megan T Cho 30,  Kirsty McWalter 30,  Ganka Douglas 30,  Berivan Baskin 30,  Amber Begtrup 30,  Tara Funari 30,  Kelly Schoch 7,  Alexander P A Stegmann 10,  Servi J C Stevens 10,  Dong-Er Zhang 31,  David Traver 32,  Xu Yao 33,  Daniel G MacArthur 34,  Han G Brunner 9,  Grazia M Mancini 35,  Richard M Myers 36,  Laurie B Owen 1,  Ssang-Taek Lim 37,  David L Stachura 5,  Lisenka E L M Vissers 38,  Eun-Young Erin Ahn 39
Affiliations

Affiliations

  • 1 Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
  • 2 Ambry Genetics, Aliso Viejo, CA 92656, USA.
  • 3 Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
  • 4 Medical Genetics and Metabolism, Valley Children's Hospital, Madera, CA 93636, USA.
  • 5 Department of Biological Sciences, California State University, Chico, Chico, CA 95929, USA.
  • 6 Department of Biological Sciences, Wright State University, Dayton, OH 45435, USA.
  • 7 Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
  • 8 Department of Medicine, University of Melbourne, Austin Hospital and Royal Melbourne Hospital, Parkville, VIC 3010, Australia; Institute for Genomic Medicine, Columbia University, New York, NY 10027, USA.
  • 9 Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands.
  • 10 Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands.
  • 11 Department of Pediatrics, Radboudumc Amalia Children's Hospital, 6500 HB Nijmegen, the Netherlands.
  • 12 Department of Neurology, Maastricht University Medical Center, 6299 HX Maastricht, the Netherlands.
  • 13 Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
  • 14 Section on Medical Genetics, Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
  • 15 Nationwide Children's Hospital, Columbus, OH 43205, USA; Ohio State University College of Medicine, Columbus, OH 43210, USA.
  • 16 West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham B15 2TG, UK.
  • 17 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  • 18 Geisinger Medical Center, Danville, PA 17822, USA.
  • 19 Division of Genetics, Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA.
  • 20 Division of Genetics, Department of Pediatrics, San Antonio Military Medical Center, Fort Sam Houston, TX 78234, USA; Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
  • 21 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 22 Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 23 Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technical University of Munich, 81675 Munich, Germany.
  • 24 Institute of Human Genetics, University Clinic Düsseldorf, Heinrich-Heine-University, 40225 Düsseldorf, Germany; Institute of Human Genetics, University Clinic Essen, University Duisburg-Essen, 45147 Essen, Germany.
  • 25 Institute of Human Genetics, University Clinic Essen, University Duisburg-Essen, 45147 Essen, Germany.
  • 26 Institute of Medical Genetics, Medical University of Vienna, Waehringer Strasse 10, 1090 Vienna, Austria.
  • 27 Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Institut Imagine, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
  • 28 Département de Génétique, Hôpital Necker-Enfants Malades, 75015 Paris, France.
  • 29 Service de Cytogénétique, Hôpital Necker-Enfants Malades, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France.
  • 30 GeneDx Inc., 205 Perry Parkway, Gaithersburg, MD 20877, USA.
  • 31 Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA; Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • 32 Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • 33 Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • 34 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 35 Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands.
  • 36 HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
  • 37 Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA.
  • 38 Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: lisenka.vissers@radboudumc.nl.
  • 39 Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA. Electronic address: eahn@health.southalabama.edu.
PMID: 27545680 DOI: 10.1016/j.ajhg.2016.06.029
Abstract

The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation Sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.

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