2. Academic Validation
  3. Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5

Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5

  • Am J Hum Genet. 2014 May 1;94(5):734-44. doi: 10.1016/j.ajhg.2014.03.015.
Margaret J McMillin 1,  Anita E Beck 2,  Jessica X Chong 1,  Kathryn M Shively 1,  Kati J Buckingham 1,  Heidi I S Gildersleeve 1,  Mariana I Aracena 3,  Arthur S Aylsworth 4,  Pierre Bitoun 5,  John C Carey 6,  Carol L Clericuzio 7,  Yanick J Crow 8,  Cynthia J Curry 9,  Koenraad Devriendt 10,  David B Everman 11,  Alan Fryer 12,  Kate Gibson 13,  Maria Luisa Giovannucci Uzielli 14,  John M Graham Jr 15,  Judith G Hall 16,  Jacqueline T Hecht 17,  Randall A Heidenreich 7,  Jane A Hurst 18,  Sarosh Irani 19,  Ingrid P C Krapels 20,  Jules G Leroy 21,  David Mowat 22,  Gordon T Plant 23,  Stephen P Robertson 24,  Elizabeth K Schorry 25,  Richard H Scott 18,  Laurie H Seaver 26,  Elliott Sherr 27,  Miranda Splitt 28,  Helen Stewart 29,  Constance Stumpel 20,  Sehime G Temel 30,  David D Weaver 31,  Margo Whiteford 32,  Marc S Williams 33,  Holly K Tabor 34,  Joshua D Smith 35,  Jay Shendure 35,  Deborah A Nickerson 35,  University of Washington Center for Mendelian Genomics,  Michael J Bamshad 36
Affiliations

Affiliations

  • 1 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
  • 2 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.
  • 3 Genetic Unit, Hospital Dr. Luis Calvo Mackenna, Santiago 7500539, Chile; Division of Pediatrics, Pontificia Universidad Católica de Chile, Santiago 8330074, Chile.
  • 4 Departments of Pediatrics and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 5 Service de Pédiatrie, Hôpital Jean Verdier, Assistance Publique - Hôpitaux de Paris, Bondy 93143, France.
  • 6 Department of Pediatrics, University of Utah, Salt Lake City, UT 84108, USA.
  • 7 Department of Pediatrics, University of New Mexico, Albuquerque, NM 87131, USA.
  • 8 Manchester Academic Health Science Centre and University of Manchester, Manchester M13 9NT, UK.
  • 9 Genetic Medicine Central California, University of California, San Francisco, Fresno, CA 93701, USA.
  • 10 Centre for Human Genetics, University Hospitals KU Leuven, 3000 Leuven, Belgium.
  • 11 Greenwood Genetic Center, Greenwood, SC 29646, USA.
  • 12 Department of Clinical Genetics, Alder Hey Children's Hospital, Liverpool L12 2AP, UK.
  • 13 Genetic Health Service New Zealand, Christchurch Hospital, Christchurch 8140, New Zealand.
  • 14 Genetics and Molecular Medicine, Dipartimento di Scieze della Salute, University of Florence, Florence 50132, Italy.
  • 15 Division of Clinical Genetics and Dysmorphology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 16 Departments of Medical Genetics and Pediatrics, University of British Columbia and BC Children's Hospital, Vancouver, BC V6H 3N1, Canada.
  • 17 Department of Pediatrics, University of Texas Medical School, Houston, TX 77030, USA.
  • 18 North East Thames Regional Genetic Service, Great Ormond Street Hospital, London WC1N 3BH, UK.
  • 19 Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
  • 20 Department of Clinical Genetics, School for Oncology and Developmental Biology, Maastricht UMC+, Maastricht 6229 GR, the Netherlands.
  • 21 Princess Elisabeth Children's Hospital, Ghent University Hospital, 9000 Ghent, Belgium.
  • 22 Department of Medical Genetics, Sydney Children's Hospital, Sydney, NSW 2031, Australia; School of Women's and Children's Health, UNSW Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
  • 23 National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
  • 24 Department of Women's and Children's Health, University of Otago, Dunedin 9054, New Zealand.
  • 25 Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • 26 Department of Pediatrics, University of Hawai'i John A. Burns School of Medicine, Honolulu, HI 96826, USA.
  • 27 Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 28 Northern Genetics Service, Institute of Genetic Medicine, Newcastle upon Tyne NE1 3BZ, UK.
  • 29 Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford OX3 7LJ, UK.
  • 30 Department of Medical Genetics, Faculty of Medicine, Uludag University, Bursa 16059, Turkey; Department of Histology & Embryology, Faculty of Medicine, Uludag University, Bursa 16059, Turkey; Department of Histology & Embryology, Faculty of Medicine, Near East University, TRNC Mersin 10, Turkey.
  • 31 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 32 Department of Clinical Genetics, Southern General Hospital, Glasgow G51 4TF, UK.
  • 33 Genomic Medicine Institute, Geisinger Health System, Danville, PA 17822, USA.
  • 34 Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA; Treuman Katz Center for Pediatric Bioethics, Seattle Children's Research Institute, Seattle, WA 98101, USA.
  • 35 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
  • 36 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address: [email protected].
PMID: 24726473 DOI: 10.1016/j.ajhg.2014.03.015
Abstract

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.

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