Jessica X. Chong, Lindsay C. Burrage, Anita E. Beck, Colby T

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Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3 Jessica X. Chong, Lindsay C. Burrage, Anita E. Beck, Colby T. Marvin, Margaret.

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Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3 Jessica X. Chong, Lindsay C. Burrage, Anita E. Beck, Colby T. Marvin, Margaret J. McMillin, Kathryn M. Shively, Tanya M. Harrell, Kati J. Buckingham, Carlos A. Bacino, Mahim Jain, Yasemin Alanay, Susan A. Berry, John C. Carey, Richard A. Gibbs, Brendan H. Lee, Deborah Krakow, Jay Shendure, Deborah A. Nickerson Michael J. Bamshad, Jay Shendure, Deborah A. Nickerson, Gonçalo R. Abecasis, Peter Anderson, Elizabeth Marchani Blue, Marcus Annable, Brian L. Browning, Kati J. Buckingham, Christina Chen, Jennifer Chin, Jessica X. Chong, Gregory M. Cooper, Colleen P. Davis, Christopher Frazar, Tanya M. Harrell, Zongxiao He, Preti Jain, Gail P. Jarvik, Guillaume Jimenez, Eric Johanson, Goo Jun, Martin Kircher, Tom Kolar, Stephanie A. Krauter, Niklas Krumm, Suzanne M. Leal, Daniel Luksic, Colby T. Marvin, Margaret J. McMillin, Sean McGee, Patrick O’Reilly, Bryan Paeper, Karynne Patterson, Marcos Perez, Sam W. Phillips, Jessica Pijoan, Christa Poel, Frederic Reinier, Peggy D. Robertson, Regie Santos-Cortez, Tristan Shaffer, Cindy Shephard, Kathryn M. Shively, Deborah L. Siegel, Joshua D. Smith, Jeffrey C. Staples, Holly K. Tabor, Monica Tackett, Jason G. Underwood, Marc Wegener, Gao Wang, Marsha M. Wheeler, Qian Yi, Michael J. Bamshad Jessica X. Chong, Lindsay C. Burrage, Anita E. Beck, Colby T. Marvin, Margaret J. McMillin, Kathryn M. Shively, Tanya M. Harrell, Kati J. Buckingham, Carlos A. Bacino, Mahim Jain, Yasemin Alanay, Susan A. Berry, John C. Carey, Richard A. Gibbs, Brendan H. Lee, Deborah Krakow, Jay Shendure, Deborah A. Nickerson Michael J. Bamshad, Jay Shendure, Deborah A. Nickerson, Gonçalo R. Abecasis, Peter Anderson, Elizabeth Marchani Blue, Marcus Annable, Brian L. Browning, Kati J. Buckingham, Christina Chen, Jennifer Chin, Jessica X. Chong, Gregory M. Cooper, Colleen P. Davis, Christopher Frazar, Tanya M. Harrell, Zongxiao He, Preti Jain, Gail P. Jarvik, Guillaume Jimenez, Eric Johanson, Goo Jun, Martin Kircher, Tom Kolar, Stephanie A. Krauter, Niklas Krumm, Suzanne M. Leal, Daniel Luksic, Colby T. Marvin, Margaret J. McMillin, Sean McGee, Patrick O’Reilly, Bryan Paeper, Karynne Patterson, Marcos Perez, Sam W. Phillips, Jessica Pijoan, Christa Poel, Frederic Reinier, Peggy D. Robertson, Regie Santos-Cortez, Tristan Shaffer, Cindy Shephard, Kathryn M. Shively, Deborah L. Siegel, Joshua D. Smith, Jeffrey C. Staples, Holly K. Tabor, Monica Tackett, Jason G. Underwood, Marc Wegener, Gao Wang, Marsha M. Wheeler, Qian Yi, Michael J. Bamshad The American Journal of Human Genetics Volume 96, Issue 5, Pages 841-849 (May 2015) DOI: 10.1016/j.ajhg.2015.04.004 Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 1 Phenotypic Characteristics of Individuals with DA8 Five individuals affected by DA8; all individuals shown have MYH3 mutations. Note the downslanting palpebral fissures, ptosis, camptodactyly of the fingers, scoliosis, short stature, and neck webbing. ID numbers for the individuals shown in this figure correspond to those in Table 1, where there is a detailed description of the phenotype of each affected individual. Figure S1 provides a pedigree of each DA8-affected family. The American Journal of Human Genetics 2015 96, 841-849DOI: (10.1016/j.ajhg.2015.04.004) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 2 Radiograph of Severe Scoliosis and Vertebral Fusion Observed in a Person with DA8 Severe, convex rightward, rotatory scoliosis of the thoracic and lumbar spine in individual AIII-2 (Table 1 and Figure 1). Fusion of vertebral bodies from T10 to L3 is indicated by the arrow. The American Journal of Human Genetics 2015 96, 841-849DOI: (10.1016/j.ajhg.2015.04.004) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 3 Genomic Model of MYH3 and Stylized Structure of Embryonic Myosin Illustrate the Spectrum of Mutations that Cause DA Syndromes MYH3 is composed of 41 exons, 39 of which are protein coding (blue) and two of which are non-coding (orange). (A) Lines with attached dots indicate the approximate locations of MYH3 mutations that cause DA1 (green), DA2A (purple), DA2B (orange), and DA8 (red). The color of each dot reflects the diagnosis. (B) Schematic of an embryonic myosin dimer. The approximate locations of MYH3 mutations relative to each affected amino acid residue in the myosin domain are indicated by colored circles. All mutations causing DA1, DA2A, and DA2B affect amino acid residues located in the motor and neck of embryonic myosin, whereas the two mutations causing DA8 are the only mutations that alter amino acid residues located in the tail. (Both variants in the tail of MYH3 [c.4934A>C (p.Asp1622Ala) and c.2979C>T (p.Ala1637Val)] and reported by Toydemir et al.14 are now thought to be polymorphisms on the basis of additional family information and frequencies in large databases of control populations.) The American Journal of Human Genetics 2015 96, 841-849DOI: (10.1016/j.ajhg.2015.04.004) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 4 Expression of MYH3 in Bone and Cartilage (A) RNA was isolated from a 17-week-old fetus, and cDNA was generated according to standard protocols.27 MYH3 primers were predicted to yield 313-bp amplicons from genomic DNA (control) and 206-bp amplicons from cDNA. MYH3 cDNA expression was detected in the bone, thymus, placenta, heart, brain, and liver. Expression was not detected in cartilage, lungs, or kidneys. (B) qPCR was used for assessing the relative expression levels of MYH3 cDNA in bone, cartilage, brain, heart, liver, and lungs. MYH3 cDNA expression was detected in bone at a level similar to that observed in the brain and heart and was barely detectable in the lungs and cartilage. The American Journal of Human Genetics 2015 96, 841-849DOI: (10.1016/j.ajhg.2015.04.004) Copyright © 2015 The American Society of Human Genetics Terms and Conditions