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
  • 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.