2. Academic Validation
  3. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

  • Am J Hum Genet. 2015 Aug 6;97(2):343-52. doi: 10.1016/j.ajhg.2015.07.004.
Lot Snijders Blok 1,  Erik Madsen 2,  Jane Juusola 3,  Christian Gilissen 1,  Diana Baralle 4,  Margot R F Reijnders 1,  Hanka Venselaar 5,  Céline Helsmoortel 6,  Megan T Cho 3,  Alexander Hoischen 1,  Lisenka E L M Vissers 1,  Tom S Koemans 1,  Willemijn Wissink-Lindhout 1,  Evan E Eichler 7,  Corrado Romano 8,  Hilde Van Esch 9,  Connie Stumpel 10,  Maaike Vreeburg 10,  Eric Smeets 10,  Karin Oberndorff 11,  Bregje W M van Bon 12,  Marie Shaw 13,  Jozef Gecz 13,  Eric Haan 14,  Melanie Bienek 15,  Corinna Jensen 15,  Bart L Loeys 6,  Anke Van Dijck 6,  A Micheil Innes 16,  Hilary Racher 16,  Sascha Vermeer 17,  Nataliya Di Donato 18,  Andreas Rump 18,  Katrina Tatton-Brown 19,  Michael J Parker 20,  Alex Henderson 21,  Sally A Lynch 22,  Alan Fryer 23,  Alison Ross 24,  Pradeep Vasudevan 25,  Usha Kini 26,  Ruth Newbury-Ecob 27,  Kate Chandler 28,  Alison Male 29,  DDD Study,  Sybe Dijkstra 30,  Jolanda Schieving 31,  Jacques Giltay 32,  Koen L I van Gassen 32,  Janneke Schuurs-Hoeijmakers 1,  Perciliz L Tan 2,  Igor Pediaditakis 2,  Stefan A Haas 33,  Kyle Retterer 3,  Patrick Reed 3,  Kristin G Monaghan 3,  Eden Haverfield 3,  Marvin Natowicz 34,  Angela Myers 35,  Michael C Kruer 36,  Quinn Stein 37,  Kevin A Strauss 38,  Karlla W Brigatti 38,  Katherine Keating 39,  Barbara K Burton 39,  Katherine H Kim 39,  Joel Charrow 39,  Jennifer Norman 40,  Audrey Foster-Barber 41,  Antonie D Kline 42,  Amy Kimball 42,  Elaine Zackai 43,  Margaret Harr 43,  Joyce Fox 44,  Julie McLaughlin 44,  Kristin Lindstrom 45,  Katrina M Haude 46,  Kees van Roozendaal 10,  Han Brunner 47,  Wendy K Chung 48,  R Frank Kooy 6,  Rolph Pfundt 1,  Vera Kalscheuer 15,  Sarju G Mehta 49,  Nicholas Katsanis 50,  Tjitske Kleefstra 51
Affiliations

Affiliations

  • 1 Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
  • 2 Center for Human Disease Modeling, Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
  • 3 GeneDx, Gaithersburg, MD 20877, USA.
  • 4 Human Development and Health, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
  • 5 Nijmegen Centre for Molecular and Biomolecular Informatics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
  • 6 Department of Medical Genetics, University of Antwerp and University Hospital Antwerp, 2650 Antwerp, Belgium.
  • 7 Department of Genome Sciences, University of Washington, Seattle, WA 98195-5065, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
  • 8 Pediatrics and Medical Genetics, IRCCS Associazione Oasi Maria Santissima, 94018 Troina, Italy.
  • 9 Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.
  • 10 Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht UMC+, 6202 AZ Maastricht, the Netherlands.
  • 11 Department of Pediatrics, Atrium-Orbis Medical Center, 6162 BG Sittard, the Netherlands.
  • 12 Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; School of Paediatrics and Reproductive Health and Robinson Research Institute, The University of Adelaide, Adelaide, SA 5006, Australia.
  • 13 School of Paediatrics and Reproductive Health and Robinson Research Institute, The University of Adelaide, Adelaide, SA 5006, Australia.
  • 14 School of Paediatrics and Reproductive Health and Robinson Research Institute, The University of Adelaide, Adelaide, SA 5006, Australia; South Australian Clinical Genetics Service, SA Pathology, Adelaide, SA 5006, Australia.
  • 15 Department of Human Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
  • 16 Department of Medical Genetics and Alberta Children's Hospital Research Institute for Child and Maternal Health, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • 17 Department of Genetics, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
  • 18 Faculty of Medicine, Carl Gustav Carus TU Dresden, 01307 Dresden, Germany.
  • 19 St George's University of London, London SW17 0RE, UK.
  • 20 Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH, UK.
  • 21 Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 3BZ, UK.
  • 22 National Centre for Medical Genetics, Temple Street Children's Hospital, Crumlin, Dublin 12, Ireland.
  • 23 Department of Clinical Genetics, Liverpool Women's Hospital and Alder Hey Children's Hospital, Liverpool L8 7SS, UK.
  • 24 North of Scotland Regional Genetics Service, Clinical Genetics Centre, Aberdeen AB25 2ZA, UK.
  • 25 Department of Clinical Genetics, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester LE1 5WW, UK.
  • 26 Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford OX3 7LE, UK.
  • 27 Department of Clinical Genetics, University Hospitals, Bristol BS1 3NU, UK.
  • 28 Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Manchester M13 9WL, UK.
  • 29 North East Thames Regional Genetics Service, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK.
  • 30 ORO, Organisation for People with Intellectual Disabilities, 5751 PH Deurne, the Netherlands.
  • 31 Department of Child Neurology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
  • 32 Department of Medical Genetics, University Medical Center Utrecht, 3508 AB Utrecht, the Netherlands.
  • 33 Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
  • 34 Pathology & Laboratory Medicine and Genomic Medicine Institutes, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 35 Sanford Children's Specialty Clinic, Sioux Falls, SD 57105, USA.
  • 36 Sanford Children's Specialty Clinic, Sioux Falls, SD 57105, USA; Barrow Neurological Institute and Ronald A. Matricaria Institute of Molecular Medicine, Phoenix Children's Hospital, Phoenix, AZ 57117, USA.
  • 37 Barrow Neurological Institute and Ronald A. Matricaria Institute of Molecular Medicine, Phoenix Children's Hospital, Phoenix, AZ 57117, USA.
  • 38 Clinic for Special Children, Franklin & Marshall College, Pennsylvania, PA 17579, USA.
  • 39 Division of Genetics, Birth Defects & Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
  • 40 Integris Pediatric Neurology, Oklahoma City, OK 73112, USA.
  • 41 Child Neurology and Palliative Care, Benioff Children's Hospital, San Francisco, CA 94925, USA.
  • 42 The Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, MD 21204, USA.
  • 43 Department of Pediatrics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 44 Division of Medical Genetics, Cohen Children's Medical Center, New Hyde Park, NY 11040, USA.
  • 45 Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85006, USA.
  • 46 University of Rochester Medical Center, Rochester, NY 14642, USA.
  • 47 Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht UMC+, 6202 AZ Maastricht, the Netherlands.
  • 48 Departments of Pediatrics & Medicine, Columbia University Medical Center, New York, NY 10032, USA.
  • 49 East Anglian Regional Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  • 50 Center for Human Disease Modeling, Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: nicholas.katsanis@duke.edu.
  • 51 Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: tjitske.kleefstra@radboudumc.nl.
PMID: 26235985 DOI: 10.1016/j.ajhg.2015.07.004
Abstract

Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome Sequencing in 38 females with ID and various Other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.

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