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

Margaret J McMillin; Anita E Beck; Jessica X Chong; Kathryn M Shively; Kati J Buckingham; Heidi I S Gildersleeve; Mariana I Aracena; Arthur S Aylsworth; Pierre Bitoun; John C Carey; Carol L Clericuzio; Yanick J Crow; Cynthia J Curry; Koenraad Devriendt; David B Everman; Alan Fryer; Kate Gibson; Maria Luisa Giovannucci Uzielli; John M Graham Jr; Judith G Hall; Jacqueline T Hecht; Randall A Heidenreich; Jane A Hurst; Sarosh Irani; Ingrid P C Krapels; Jules G Leroy; David Mowat; Gordon T Plant; Stephen P Robertson; Elizabeth K Schorry; Richard H Scott; Laurie H Seaver; Elliott Sherr; Miranda Splitt; Helen Stewart; Constance Stumpel; Sehime G Temel; David D Weaver; Margo Whiteford; Marc S Williams; Holly K Tabor; Joshua D Smith; Jay Shendure; Deborah A Nickerson; University of Washington Center for Mendelian Genomics; Michael J Bamshad

doi:10.1016/j.ajhg.2014.03.015

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. Epub 2014 Apr 10.

Authors

Margaret J McMillin¹, Anita E Beck², Jessica X Chong¹, Kathryn M Shively¹, Kati J Buckingham¹, Heidi I S Gildersleeve¹, Mariana I Aracena³, Arthur S Aylsworth⁴, Pierre Bitoun⁵, John C Carey⁶, Carol L Clericuzio⁷, Yanick J Crow⁸, Cynthia J Curry⁹, Koenraad Devriendt¹⁰, David B Everman¹¹, Alan Fryer¹², Kate Gibson¹³, Maria Luisa Giovannucci Uzielli¹⁴, John M Graham Jr¹⁵, Judith G Hall¹⁶, Jacqueline T Hecht¹⁷, Randall A Heidenreich⁷, Jane A Hurst¹⁸, Sarosh Irani¹⁹, Ingrid P C Krapels²⁰, Jules G Leroy²¹, David Mowat²², Gordon T Plant²³, Stephen P Robertson²⁴, Elizabeth K Schorry²⁵, Richard H Scott¹⁸, Laurie H Seaver²⁶, Elliott Sherr²⁷, Miranda Splitt²⁸, Helen Stewart²⁹, Constance Stumpel²⁰, Sehime G Temel³⁰, David D Weaver³¹, Margo Whiteford³², Marc S Williams³³, Holly K Tabor³⁴, Joshua D Smith³⁵, Jay Shendure³⁵, Deborah A Nickerson³⁵; University of Washington Center for Mendelian Genomics; Michael J Bamshad³⁶

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].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Abnormalities, Multiple / genetics*
Abnormalities, Multiple / pathology
Arachnodactyly / genetics*
Arachnodactyly / pathology
Arthrogryposis / genetics*
Arthrogryposis / pathology
Blepharophimosis / genetics*
Blepharophimosis / pathology
Child
Child, Preschool
Cleft Palate / genetics*
Cleft Palate / pathology
Clubfoot / genetics*
Clubfoot / pathology
Connective Tissue Diseases / genetics*
Connective Tissue Diseases / pathology
Contracture / genetics*
Contracture / pathology
Exome / genetics
Female
Hand Deformities, Congenital / genetics*
Hand Deformities, Congenital / pathology
Humans
Ion Channels / genetics*
Male
Mutation
Ophthalmoplegia / genetics*
Ophthalmoplegia / pathology
Pedigree
Retinal Diseases / genetics*
Retinal Diseases / pathology

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

Authors

Affiliations

Abstract

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MeSH terms

Substances

Supplementary concepts

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