Mutations in PIEZO2 Cause Gordon Syndrome, Marden-Walker Syndrome, and Distal Arthrogryposis Type 5

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• 作者：Margaret J. McMillin¹ ; ⁴⁰ ; Anita E. Beck¹ ; ² ; ⁴⁰ ; Jessica X. Chong¹ ; Kathryn M. Shively¹ ; Kati J. Buckingham¹ ; Heidi I.S. Gildersleeve¹ ; Mariana I. Aracena³ ; ⁴ ; Arthur S. Aylsworth⁵ ; Pierre Bitoun⁶ ; John C. Carey⁷ ; Carol L. Clericuzio⁸ ; Yanick J. Crow⁹ ; Cynthia J. Curry¹⁰ ; Koenraad Devriendt¹¹ ; David B. Everman¹² ; Alan Fryer¹³ ; Kate Gibson¹⁴ ; Maria Luisa Giovannucci Uzielli¹⁵ ; John M. Graham Jr.¹⁶ ; Judith G. Hall¹⁷ ; Jacqueline T. Hecht¹⁸ ; Randall A. Heidenreich⁸ ; Jane A. Hurst¹⁹ ; Sarosh Irani²⁰ ; Ingrid P.C. Krapels²¹ ; Jules G. Leroy²² ; David Mowat²³ ; ²⁴ ; Gordon T. Plant²⁵ ; Stephen P. Robertson²⁶ ; Elizabeth K. Schorry²⁷ ; Richard H. Scott¹⁹ ; Laurie H. Seaver²⁸ ; Elliott Sherr²⁹ ; Miranda Splitt³⁰ ; Helen Stewart³¹ ; Constance Stumpel²¹ ; Sehime G. Temel³² ; ³³ ; ³⁴ ; David D. Weaver³⁵ ; Margo Whiteford³⁶ ; Marc S. Williams³⁷ ; Holly K. Tabor² ; ³⁸ ; Joshua D. Smith³⁹ ; Jay Shendure³⁹ ; Deborah A. Nickerson³⁹ ; University of Washington Center for Mendelian Genomics
• 刊名：The American Journal of Human Genetics
• 出版年：1 May 2014
• 年：2014
• 卷：94
• 期：5
• 页码：734-744
• 全文大小：957 K

文摘

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.