2. Academic Validation
  3. Rare De Novo Missense Variants in RNA Helicase DDX6 Cause Intellectual Disability and Dysmorphic Features and Lead to P-Body Defects and RNA Dysregulation

Rare De Novo Missense Variants in RNA Helicase DDX6 Cause Intellectual Disability and Dysmorphic Features and Lead to P-Body Defects and RNA Dysregulation

  • Am J Hum Genet. 2019 Sep 5;105(3):509-525. doi: 10.1016/j.ajhg.2019.07.010.
Chris Balak 1,  Marianne Benard 2,  Elise Schaefer 3,  Sumaiya Iqbal 4,  Keri Ramsey 5,  Michèle Ernoult-Lange 2,  Francesca Mattioli 6,  Lorida Llaci 5,  Véronique Geoffroy 7,  Maité Courel 2,  Marcus Naymik 5,  Kristine K Bachman 8,  Rolph Pfundt 9,  Patrick Rump 10,  Johanna Ter Beest 9,  Ingrid M Wentzensen 11,  Kristin G Monaghan 11,  Kirsty McWalter 11,  Ryan Richholt 12,  Antony Le Béchec 13,  Wayne Jepsen 5,  Matt De Both 5,  Newell Belnap 14,  Anne Boland 15,  Ignazio S Piras 5,  Jean-François Deleuze 15,  Szabolcs Szelinger 5,  Hélène Dollfus 3,  Jamel Chelly 16,  Jean Muller 17,  Arthur Campbell 4,  Dennis Lal 18,  Sampathkumar Rangasamy 5,  Jean-Louis Mandel 19,  Vinodh Narayanan 5,  Matt Huentelman 5,  Dominique Weil 2,  Amélie Piton 20
Affiliations

Affiliations

  • 1 Translational Genomics Research Institute, Neurogenomics Division, Phoenix, AZ 85004, USA; Translational Genomics Research Institute's Center for Rare Childhood Disorders, Phoenix, AZ 85012, USA. Electronic address: [email protected].
  • 2 Sorbonne Université, CNRS, Institut de Biologie Paris-Seine, Laboratoire de Biologie du Développement, F-75005 Paris, France.
  • 3 Medical Genetics Department, University Hospitals of Strasbourg, the Institute of Medical Genetics of Alsace, 67000 Strasbourg, France; Laboratoire de Génétique Médicale, Institut de Génétique Médicale d'Alsace, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, 67081 Strasbourg, France.
  • 4 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 5 Translational Genomics Research Institute, Neurogenomics Division, Phoenix, AZ 85004, USA; Translational Genomics Research Institute's Center for Rare Childhood Disorders, Phoenix, AZ 85012, USA.
  • 6 Institute of Genetics and Molecular and Cellular Biology, Illkirch, France; French National Center for Scientific Research, UMR7104, 67400 Illkirch, France; National Institute of Health and Medical Research U964, 67400 Illkirch, France; University of Strasbourg, 67081 Illkirch, France.
  • 7 Laboratoire de Génétique Médicale, Institut de Génétique Médicale d'Alsace, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, 67081 Strasbourg, France.
  • 8 Geisinger Medical Center, Dansville, PA 17822, USA.
  • 9 Department of Genetics, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, the Netherlands.
  • 10 Radboud University Nijmegen Medical Center, Department of Human Genetics, Division of Genome Diagnostics, 6525 GA Nijmegen, the Netherlands.
  • 11 GeneDx, Gaithersburg, MD 20877, USA.
  • 12 Translational Genomics Research Institute, Neurogenomics Division, Phoenix, AZ 85004, USA.
  • 13 Medical Bioinformatics Unit, UF7363, Strasbourg University Hospital, 67000 Strasbourg, France.
  • 14 Translational Genomics Research Institute's Center for Rare Childhood Disorders, Phoenix, AZ 85012, USA.
  • 15 Centre National de Recherche en Génomique Humaine, Institut de Biologie François Jacob, CEA, Université Paris-Saclay, F-91057, Evry, France.
  • 16 Institute of Genetics and Molecular and Cellular Biology, Illkirch, France; French National Center for Scientific Research, UMR7104, 67400 Illkirch, France; National Institute of Health and Medical Research U964, 67400 Illkirch, France; University of Strasbourg, 67081 Illkirch, France; Molecular Genetics Unit, Strasbourg University Hospital, 67000 Strasbourg, France.
  • 17 Laboratoire de Génétique Médicale, Institut de Génétique Médicale d'Alsace, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, 67081 Strasbourg, France; Molecular Genetics Unit, Strasbourg University Hospital, 67000 Strasbourg, France.
  • 18 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Genomic Medicine Institute, Lerner Research Institute Cleveland Clinic, Cleveland, OH 44195, USA; Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
  • 19 Institute of Genetics and Molecular and Cellular Biology, Illkirch, France; French National Center for Scientific Research, UMR7104, 67400 Illkirch, France; National Institute of Health and Medical Research U964, 67400 Illkirch, France; University of Strasbourg, 67081 Illkirch, France; University of Strasbourg Institute of Advanced Studies, 67081 Strasbourg, France.
  • 20 Institute of Genetics and Molecular and Cellular Biology, Illkirch, France; French National Center for Scientific Research, UMR7104, 67400 Illkirch, France; National Institute of Health and Medical Research U964, 67400 Illkirch, France; University of Strasbourg, 67081 Illkirch, France; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: [email protected].
PMID: 31422817 DOI: 10.1016/j.ajhg.2019.07.010
Abstract

The human RNA helicase DDX6 is an essential component of membrane-less organelles called processing bodies (PBs). PBs are involved in mRNA metabolic processes including translational repression via coordinated storage of mRNAs. Previous studies in human cell lines have implicated altered DDX6 in molecular and cellular dysfunction, but clinical consequences and pathogenesis in humans have yet to be described. Here, we report the identification of five rare de novo missense variants in DDX6 in probands presenting with intellectual disability, developmental delay, and similar dysmorphic features including telecanthus, epicanthus, arched eyebrows, and low-set ears. All five missense variants (p.His372Arg, p.Arg373Gln, p.Cys390Arg, p.Thr391Ile, and p.Thr391Pro) are located in two conserved motifs of the RecA-2 domain of DDX6 involved in RNA binding, helicase activity, and protein-partner binding. We use functional studies to demonstrate that the first variants identified (p.Arg373Gln and p.Cys390Arg) cause significant defects in PB assembly in primary fibroblast and model human cell lines. These variants' interactions with several protein partners were also disrupted in immunoprecipitation assays. Further investigation via complementation assays included the additional variants p.Thr391Ile and p.Thr391Pro, both of which, similarly to p.Arg373Gln and p.Cys390Arg, demonstrated significant defects in P-body assembly. Complementing these molecular findings, modeling of the variants on solved protein structures showed distinct spatial clustering near known protein binding regions. Collectively, our clinical and molecular data describe a neurodevelopmental syndrome associated with pathogenic missense variants in DDX6. Additionally, we suggest DDX6 join the DExD/H-box genes DDX3X and DHX30 in an emerging class of neurodevelopmental disorders involving RNA helicases.

Keywords

DDX6; DEAD-box; DExD/H-box; RNA helicase; RecA domain; helicase; intellectual disability; mRNA metabolism; missense variants; neurodevelopmental disorder; p-bodies; processing bodies.

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