title: Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5.
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.
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: McMillin
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: Anita E
authors.initials: AE
authors.lastname: Beck
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jessica X
authors.initials: JX
authors.lastname: Chong
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Shively
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Kati J
authors.initials: KJ
authors.lastname: Buckingham
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Heidi I S
authors.initials: HI
authors.lastname: Gildersleeve
authors.affiliation: Genetic Unit, Hospital Dr. Luis Calvo Mackenna, Santiago 7500539, Chile; Division of Pediatrics, Pontificia Universidad Católica de Chile, Santiago 8330074, Chile.
authors.forename: Mariana I
authors.initials: MI
authors.lastname: Aracena
authors.affiliation: Departments of Pediatrics and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Aylsworth
authors.affiliation: Service de Pédiatrie, Hôpital Jean Verdier, Assistance Publique - Hôpitaux de Paris, Bondy 93143, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bitoun
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, UT 84108, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Carey
authors.affiliation: Department of Pediatrics, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Carol L
authors.initials: CL
authors.lastname: Clericuzio
authors.affiliation: Manchester Academic Health Science Centre and University of Manchester, Manchester M13 9NT, UK.
authors.forename: Yanick J
authors.initials: YJ
authors.lastname: Crow
authors.affiliation: Genetic Medicine Central California, University of California, San Francisco, Fresno, CA 93701, USA.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Curry
authors.affiliation: Centre for Human Genetics, University Hospitals KU Leuven, 3000 Leuven, Belgium.
authors.forename: Koenraad
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authors.lastname: Devriendt
authors.affiliation: Greenwood Genetic Center, Greenwood, SC 29646, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Everman
authors.affiliation: Department of Clinical Genetics, Alder Hey Children's Hospital, Liverpool L12 2AP, UK.
authors.forename: Alan
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authors.lastname: Fryer
authors.affiliation: Genetic Health Service New Zealand, Christchurch Hospital, Christchurch 8140, New Zealand.
authors.forename: Kate
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authors.lastname: Gibson
authors.affiliation: Genetics and Molecular Medicine, Dipartimento di Scieze della Salute, University of Florence, Florence 50132, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Giovannucci Uzielli
authors.affiliation: Division of Clinical Genetics and Dysmorphology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: John M
authors.initials: JM
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authors.affiliation: Departments of Medical Genetics and Pediatrics, University of British Columbia and BC Children's Hospital, Vancouver, BC V6H 3N1, Canada.
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authors.initials: JG
authors.lastname: Hall
authors.affiliation: Department of Pediatrics, University of Texas Medical School, Houston, TX 77030, USA.
authors.forename: Jacqueline T
authors.initials: JT
authors.lastname: Hecht
authors.affiliation: Department of Pediatrics, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Randall A
authors.initials: RA
authors.lastname: Heidenreich
authors.affiliation: North East Thames Regional Genetic Service, Great Ormond Street Hospital, London WC1N 3BH, UK.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Hurst
authors.affiliation: Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Sarosh
authors.initials: S
authors.lastname: Irani
authors.affiliation: Department of Clinical Genetics, School for Oncology and Developmental Biology, Maastricht UMC+, Maastricht 6229 GR, the Netherlands.
authors.forename: Ingrid P C
authors.initials: IP
authors.lastname: Krapels
authors.affiliation: Princess Elisabeth Children's Hospital, Ghent University Hospital, 9000 Ghent, Belgium.
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authors.initials: JG
authors.lastname: Leroy
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Mowat
authors.affiliation: National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Gordon T
authors.initials: GT
authors.lastname: Plant
authors.affiliation: Department of Women's and Children's Health, University of Otago, Dunedin 9054, New Zealand.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Schorry
authors.affiliation: North East Thames Regional Genetic Service, Great Ormond Street Hospital, London WC1N 3BH, UK.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Scott
authors.affiliation: Department of Pediatrics, University of Hawai'i John A. Burns School of Medicine, Honolulu, HI 96826, USA.
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Seaver
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Elliott
authors.initials: E
authors.lastname: Sherr
authors.affiliation: Northern Genetics Service, Institute of Genetic Medicine, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Miranda
authors.initials: M
authors.lastname: Splitt
authors.affiliation: Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford OX3 7LJ, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Stewart
authors.affiliation: Department of Clinical Genetics, School for Oncology and Developmental Biology, Maastricht UMC+, Maastricht 6229 GR, the Netherlands.
authors.forename: Constance
authors.initials: C
authors.lastname: Stumpel
authors.affiliation: 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.
authors.forename: Sehime G
authors.initials: SG
authors.lastname: Temel
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Weaver
authors.affiliation: Department of Clinical Genetics, Southern General Hospital, Glasgow G51 4TF, UK.
authors.forename: Margo
authors.initials: M
authors.lastname: Whiteford
authors.affiliation: Genomic Medicine Institute, Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Williams
authors.affiliation: 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.
authors.forename: Holly K
authors.initials: HK
authors.lastname: Tabor
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: 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: mbamshad@uw.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D054119:Arachnodactyly / Q000235:genetics* / Q000473:pathology; D001176:Arthrogryposis / Q000235:genetics* / Q000473:pathology; D016569:Blepharophimosis / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002972:Cleft Palate / Q000235:genetics* / Q000473:pathology; D003025:Clubfoot / Q000235:genetics* / Q000473:pathology; D003240:Connective Tissue Diseases / Q000235:genetics* / Q000473:pathology; D003286:Contracture / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D006228:Hand Deformities, Congenital / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D008297:Male; D009154:Mutation; D009886:Ophthalmoplegia / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D012164:Retinal Diseases / Q000235:genetics* / Q000473:pathology
chemical_list: D007473:Ion Channels; C000589132:PIEZO2 protein, human
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