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Am J Hum Genet. 2014 May 1;94(5):734-44. doi: 10.1016/j.ajhg.2014.03.015. Epub 2014 Apr 10.

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

Author information

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

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.

Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PMID:
24726473
[PubMed - indexed for MEDLINE]
PMCID:
PMC4067551
Free PMC Article
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