Multiple pterygium syndrome (MPS) is a phenotypically and genetically heterogeneous group of rare Mendelian conditions characterized by multiple pterygia, scoliosis, and congenital contractures of the limbs. MPS typically segregates as an autosomal-recessive disorder, but rare instances of autosomal-dominant transmission have been reported. Whereas several mutations causing recessive MPS have been identified, the genetic basis of dominant MPS remains unknown. We identified four families affected by dominantly transmitted MPS characterized by pterygia, camptodactyly of the hands, vertebral fusions, and scoliosis. Exome sequencing identified predicted protein-altering mutations in embryonic myosin heavy chain (MYH3) in three families. MYH3 mutations underlie distal arthrogryposis types 1, 2A, and 2B, but all mutations reported to date occur in the head and neck domains. In contrast, two of the mutations found to cause MPS in this study occurred in the tail domain. The phenotypic overlap among persons with MPS, coupled with physical findings distinct from other conditions caused by mutations in MYH3, suggests that the developmental mechanism underlying MPS differs from that of other conditions and/or that certain functions of embryonic myosin might be perturbed by disruption of specific residues and/or domains. Moreover, the vertebral fusions in persons with MPS, coupled with evidence of MYH3 expression in bone, suggest that embryonic myosin plays a role in skeletal development.
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We thank the families for their participation and support; Christa Poel, Karynne Patterson, Jennifer Chin, Yuqing Chen, Alyssa Tran, Philippe Campeau, and James Lu for technical assistance; and Alice Ward Racca for helpful comments. Our work was supported in part by grants from the NIH National Human Genome Research Institute and NHLBI (1U54HG006493 to M.B., D.N., and J.S.; 1RC2HG005608 to M.B., D.N., and J.S.; 5R000HG004316 to H.K.T.), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; 1R01HD048895 to M.J.B.), the Life Sciences Discovery Fund (2065508 and 0905001), and the Washington Research Foundation. This work was also supported by the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (HD024064), funded by the Eunice Kennedy Shriver NICHD (U54HG003273 and U54 U54HG006542 to R.A.G.; T32GM07526 to M.J. and L.C.B.; P01HD070394 to B.L.). L.C.B. was also supported by the Medical Genetics Training Award in Clinical Biochemical Genetics from Genzyme and the Annual Clinical Genetics Meeting Foundation for Genetic and Genomic Medicine, the National Urea Cycle Disorders Foundation Fellowship, and a fellowship from the Urea Cycle Disorders Consortium (U54HD061221), which is a part of the NIH Rare Disease Clinical Research Network, supported through collaboration among the Office of Rare Diseases Research, the National Center for Advancing Translational Science, and the Eunice Kennedy Shriver NICHD. D.K. was supported by the NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR066124).
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