2. Academic Validation
  3. Paralog Studies Augment Gene Discovery: DDX and DHX Genes

Paralog Studies Augment Gene Discovery: DDX and DHX Genes

  • Am J Hum Genet. 2019 Aug 1;105(2):302-316. doi: 10.1016/j.ajhg.2019.06.001.
Ingrid Paine 1,  Jennifer E Posey 1,  Christopher M Grochowski 1,  Shalini N Jhangiani 2,  Sarah Rosenheck 3,  Robert Kleyner 3,  Taylor Marmorale 3,  Margaret Yoon 3,  Kai Wang 4,  Reid Robison 5,  Gerarda Cappuccio 6,  Michele Pinelli 6,  Adriano Magli 7,  Zeynep Coban Akdemir 1,  Joannie Hui 8,  Wai Lan Yeung 9,  Bibiana K Y Wong 10,  Lucia Ortega 11,  Mir Reza Bekheirnia 12,  Tatjana Bierhals 13,  Maja Hempel 13,  Jessika Johannsen 14,  René Santer 14,  Dilek Aktas 15,  Mehmet Alikasifoglu 15,  Sevcan Bozdogan 16,  Hatip Aydin 17,  Ender Karaca 18,  Yavuz Bayram 19,  Hadas Ityel 20,  Michael Dorschner 21,  Janson J White 22,  Ekkehard Wilichowski 23,  Saskia B Wortmann 24,  Erasmo B Casella 25,  Joao Paulo Kitajima 26,  Fernando Kok 27,  Fabiola Monteiro 26,  Donna M Muzny 28,  Michael Bamshad 29,  Richard A Gibbs 28,  V Reid Sutton 1,  University of Washington Center for Mendelian Genomics, Baylor-Hopkins Center for Mendelian Genomics, Telethon Undiagnosed Diseases Program,  Hilde Van Esch 30,  Nicola Brunetti-Pierri 6,  Friedhelm Hildebrandt 20,  Ariel Brautbar 11,  Ignatia B Van den Veyver 31,  Ian Glass 32,  Davor Lessel 13,  Gholson J Lyon 33,  James R Lupski 34
Affiliations

Affiliations

  • 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 2 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • 3 Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, NY 11724, USA.
  • 4 Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 5 Utah Foundation for Biomedical Research, Salt Lake City, UT 84107, USA.
  • 6 Department of Translational Medicine, University of Naples "Federico II," 80131 Napoli, Italy; Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy.
  • 7 Department of Pediatric Ophthalmology, University of Salerno, 84081 Baronissi SA, Italy.
  • 8 Department of Pediatrics, Prince of Wales Hospital, the Chinese University of Hong Kong, Hong Kong SAR, China.
  • 9 Department of Pediatrics and Adolescent Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong SAR, China.
  • 10 Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, USA; The Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
  • 11 Medical Genetics Department, Cook Children's Hospital, Fort Worth, TX 76104, USA.
  • 12 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Section of Pediatric Renal, Baylor College of Medicine, Houston, TX 77030, USA; Department of Genetics, Texas Children's Hospital, Houston, TX 76104, USA.
  • 13 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 14 Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 15 DAMAGEN Genetic Diagnostic Center, 06690 Ankara, Turkey.
  • 16 Department of Medical Genetics, Cukurova University Faculty of Medicine, 01330 Adana, Turkey.
  • 17 Department of Medical Genetics, Medical Faculty of Namik Kemal University, Tekirdag 59100, Turkey.
  • 18 Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 19 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA.
  • 20 Division of Nephrology, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
  • 21 Center for Precision Diagnostics, University of Washington, Seattle, WA 98195, USA.
  • 22 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
  • 23 Department of Pediatrics and Pediatric Neurology, Georg-August-Universität Göttingen, 37075 Göttingen, Germany.
  • 24 Institute of Human Genetics, Technical University München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum Munchen, 85764 Neuherberg, Germany; University Children's Hospital, Paracelsus Medical University, 5020 Salsburg, Austria.
  • 25 Children's Institute, Hospital das Clinicas, University of Sao Paulo, 05405-000 Sao Paulo, Brazil.
  • 26 Mendelics Genomic Analysis, 04013-000 Sao Paulo, Brazil.
  • 27 Mendelics Genomic Analysis, 04013-000 Sao Paulo, Brazil; Department of Neurology, University of Sao Paulo School of Medicine, 01246-903 Sao Paulo, Brazil.
  • 28 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • 29 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
  • 30 Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.
  • 31 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, USA; The Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
  • 32 Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
  • 33 Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, NY 11724, USA; Utah Foundation for Biomedical Research, Salt Lake City, UT 84107, USA; Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
  • 34 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: jlupski@bcm.edu.
PMID: 31256877 DOI: 10.1016/j.ajhg.2019.06.001
Abstract

Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome Sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.

Keywords

DExD/H-box RNA helicase family; developmental delay; human paralogs; intellectual disability.

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