Margaret J. McMillin, Anita E. Beck, Jessica X. Chong, Kathryn M

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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, 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, Michael J. Bamshad The American Journal of Human Genetics Volume 94, Issue 5, Pages 734-744 (May 2014) DOI: 10.1016/j.ajhg.2014.03.015 Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 1 Phenotypic Characteristics of Each GS Individual Used for Exome Sequencing and the MWS Individual with a Mutation in PIEZO2 (A–F) Faces of individuals affected by GS. All individuals shown had PIEZO2 mutations. Note the deep-set eyes and micrognathia. Each individual had either cleft palate or a bifid uvula. (H and I) The hands (H) and feet (I) of an individual with GS demonstrate curved fingers with straight thumbs and clubfeet, respectively. (G) The face of an individual with MWS and a mutation in PIEZO2. Case identifiers for the individuals shown in this figure are A:I-2 (A), A:II-1 (B), B:II-1 (C), C:II-1 (D, H, and I), D:II-1 (E), E:II-1 (F), and II:II-1 (G) and correspond to those in Table 1, which includes a detailed description of the phenotype of each affected individual. Figure S1 provides a pedigree of each GS-affected family, and Figure S3 provides a pedigree of the MWS-affected family (II). The American Journal of Human Genetics 2014 94, 734-744DOI: (10.1016/j.ajhg.2014.03.015) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 2 Genomic Structure and Spectrum of PIEZO2 Mutations that Cause GS, DA5, or MWS PIEZO2 is composed of 52 exons that encode protein-coding sequence (blue). Arrows indicate the locations of 13 different mutations found in 35 families affected by GS, DA5 or MWS. The ¥ symbol indicates mutations that were inherited in families with an autosomal-dominant pattern of inheritance, and the † symbol indicates mutations that were confirmed to be de novo in simplex cases. PIEZO2 mutations identified in GS, DA5, and MWS individuals are indicated by red, yellow, and green circles, respectively. The American Journal of Human Genetics 2014 94, 734-744DOI: (10.1016/j.ajhg.2014.03.015) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 3 Phenotype Overlap among Families Affected by PIEZO2 Mutations and GS, DA5, or MWS Individuals with GS, DA5, or MWS share common clinical findings, including short stature, curved fingers with straight thumbs, and foot contractures and/or an increased space between the first and second toes (the so-called “sandal gap”). Specific additional clinical features (e.g., cleft palate in GS, ophthalmoplegia in DA5, and cerebellar malformations in MWS) are typically used for distinguishing these conditions from one another. Representative facial photos of individuals with GS (C:II-1), DA5 (Y:II-1), and MWS (II:II-1) are shown. In families affected by PIEZO2 mutations, some individuals had “intermediate phenotypes,” that is, they shared so-called “distinguishing features” among GS, DA5, and MWS. Individual E:II-1 had both cleft palate and ophthalmoplegia, individual I:II-1 had both cleft palate and a cerebellar malformation, and individual J:I-2 had cleft palate, ophthalmoplegia, and a cerebellar malformation. The American Journal of Human Genetics 2014 94, 734-744DOI: (10.1016/j.ajhg.2014.03.015) Copyright © 2014 The American Society of Human Genetics Terms and Conditions