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    Relation: Kaw, Anita; Kaw, Kaveeta; Hostetler, Ellen M.; Beleza-Meireles, Ana; Smith-Collins, Adam; Armstrong, Catherine; Scurr, Ingrid; Cotts, Timothy; Aatre, Rajani; Bamshad, Michael J.; Earl, Dawn; Groner, Abraham; Agre, Katherine; Raveh, Yehuda; Kwartler, Callie S.; Milewicz, Dianna M. (2022). "Expanding ACTA2 genotypes with corresponding phenotypes overlapping with smooth muscle dysfunction syndrome." American Journal of Medical Genetics Part A 188(8): 2389-2396.; https://hdl.handle.net/2027.42/173096; American Journal of Medical Genetics Part A; Diness, B. R., Palmquist, R. N., Norling, R., Hove, H., Bundgaard, H., Hertz, J. M., Kondziella, D., Krieger, D., Dunø, M., & Grønborg, S. ( 2020 ). Expanding the cerebrovascular phenotype of the p.R258H variant in ACTA2 related hereditary thoracic aortic disease (HTAD). Journal of the Neurological Sciences, 415, 116897. https://doi.org/10.1016/j.jns.2020.116897; Biesecker, L. G., Adam, M. P., Alkuraya, F. S., Amemiya, A. R., Bamshad, M. J., Beck, A. E., Bennett, J. T., Bird, L. M., Carey, J. C., Chung, B., Clark, R. D., Cox, T. C., Curry, C., Dinulos, M. B. P., Dobyns, W. B., Giampietro, P. F., Girisha, K. M., Glass, I. A., Graham, J. M., Jr., … Zarate, Y. A. ( 2021 ). A dyadic approach to the delineation of diagnostic entities in clinical genomics. American Journal of Human Genetics, 108 ( 1 ), 8 – 15. https://doi.org/10.1016/j.ajhg.2020.11.013; Ware, S. M., Shikany, A., Landis, B. J., James, J. F., & Hinton, R. B. ( 2014 ). Twins with progressive thoracic aortic aneurysm, recurrent dissection and ACTA2 mutation. Pediatrics, 134 ( 4 ), e1218 – e1223. https://doi.org/10.1542/peds.2013-2503; Lu, H., Fagnant, P. M., Bookwalter, C. S., Joel, P., & Trybus, K. M. ( 2015 ). Vascular disease-causing mutation R258C in ACTA2 disrupts actin dynamics and interaction with myosin. Proceedings of the National Academy of Sciences, 112 ( 31 ), E4168 – E4177. https://doi.org/10.1073/pnas.1507587112; Lauer, A., Speroni, S. L., Patel, J. B., Regalado, E., Choi, M., Smith, E., Kalpathy-Kramer, J., Caruso, P., Milewicz, D. M., & Musolino, P. L. ( 2021 ). Cerebrovascular disease progression in patients with ACTA2 Arg179 pathogenic variants. Neurology, 96 ( 4 ), e538 – e552. https://doi.org/10.1212/wnl.0000000000011210; Guo, D. C., Papke, C. L., Tran-Fadulu, V., Regalado, E. S., Avidan, N., Johnson, R. J., Kim, D. H., Pannu, H., Willing, M. C., Sparks, E., Pyeritz, R. E., Singh, M. N., Dalman, R. L., Grotta, J. C., Marian, A. J., Boerwinkle, E. A., Frazier, L. Q., LeMaire, S. A., Coselli, J. S., … Milewicz, D. M. ( 2009 ). Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and moyamoya disease, along with thoracic aortic disease. American Journal of Human Genetics, 84 ( 5 ), 617 – 627. https://doi.org/10.1016/j.ajhg.2009.04.007; Guo, D. C., Pannu, H., Tran-Fadulu, V., Papke, C. L., Yu, R. K., Avidan, N., Bourgeois, S., Estrera, A. L., Safi, H. J., Sparks, E., Amor, D., Ades, L., McConnell, V., Willoughby, C. E., Abuelo, D., Willing, M., Lewis, R. A., Kim, D. H., Scherer, S., … Milewicz, D. M. ( 2007 ). Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nature Genetics, 39 ( 12 ), 1488 – 1493. https://doi.org/10.1038/ng.2007.6; Georgescu, M. M., Pinho Mda, C., Richardson, T. E., Torrealba, J., Buja, L. M., Milewicz, D. M., Raisanen, J. M., & Burns, D. K. ( 2015 ). The defining pathology of the new clinical and histopathologic entity ACTA2-related cerebrovascular disease. Acta Neuropathologica Communications, 3, 81. https://doi.org/10.1186/s40478-015-0262-7; Gauthier, J., Ouled Amar Bencheikh, B., Hamdan, F. F., Harrison, S. M., Baker, L. A., Couture, F., Thiffault, I., Ouazzani, R., Samuels, M. E., Mitchell, G. A., Rouleau, G. A., Michaud, J. L., & Soucy, J.-F. ( 2015 ). A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome. European Journal of Human Genetics, 23 ( 9 ), 1266 – 1268. https://doi.org/10.1038/ejhg.2014.256; Amans, M. R., Stout, C., Fox, C., Narvid, J., Hetts, S. W., Cooke, D. L., Higashida, R. T., Dowd, C. F., McSwain, H., & Halbach, V. V. ( 2013 ). Cerebral arteriopathy associated with Arg179His ACTA2 mutation. BML Case Reports, 2013. https://doi.org/10.1136/bcr-2013-010997; Wang, Q., Zhang, J., Wang, H., Feng, Q., Luo, F., & Xie, J. ( 2019 ). Compound heterozygous variants in MYH11 underlie autosomal recessive megacystis-microcolon-intestinal hypoperistalsis syndrome in a Chinese family. Journal of Human Genetics, 64 ( 11 ), 1067 – 1073. https://doi.org/10.1038/s10038-019-0651-z; Shalhub, S., Roman, M. J., Eagle, K. A., LeMaire, S. A., Zhang, Q., Evangelista, A., & Milewicz, D. M. ( 2020 ). Type B aortic dissection in young individuals with confirmed and presumed heritable thoracic aortic disease. The Annals of Thoracic Surgery, 109 ( 2 ), 534 – 540. https://doi.org/10.1016/j.athoracsur.2019.07.004; Richer, J., Milewicz, D. M., Gow, R., de Nanassy, J., Maharajh, G., Miller, E., Oppenheimer, L., Weiler, G., & O’Connor, M. ( 2012 ). R179H mutation in ACTA2 expanding the phenotype to include prune-belly sequence and skin manifestations. American Journal of Medical Genetics Part A, 158A ( 3 ), 664 – 668. https://doi.org/10.1002/ajmg.a.35206; Regalado, E. S., Mellor-Crummey, L., De Backer, J., Braverman, A. C., Ades, L., Benedict, S., Bradley, T. J., Brickner, M. E., Chatfield, K. C., Child, A., Feist, C., Holmes, K. W., Iannucci, G., Lorenz, B., Mark, P., Morisaki, T., Morisaki, H., Morris, S. A., Mitchell, A. L., … Milewicz, D. M. ( 2018, Oct). Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to ACTA2 arginine 179 alterations. Genetics in Medicine, 20 ( 10 ), 1206 – 1215. https://doi.org/10.1038/gim.2017.245; Regalado, E. S., Guo, D.-C., Prakash, S., Bensend, T. A., Flynn, K., Estrera, A., Safi, H., Liang, D., Hyland, J., Child, A., Arno, G., Boileau, C., Jondeau, G., Braverman, A., Moran, R., Morisaki, T., Morisaki, H., Pyeritz, R., Coselli, J., … Milewicz, D. M. ( 2015 ). Aortic disease presentation and outcome associated with ACTA2 mutations. Circulation: Cardiovascular Genetics, 8 ( 3 ), 457 – 464. https://doi.org/10.1161/CIRCGENETICS.114.000943; Pinto, M. ( 2020 ). A novel ACTA2 gene disease-causing variant presenting with a complex brain phenotype. Sinapse, 20 ( 4 ), 181 – 183. https://doi.org/10.46531/sinapse/CC/200032/2020; Munot, P., Saunders, D. E., Milewicz, D. M., Regalado, E. S., Ostergaard, J. R., Braun, K. P., Kerr, T., Lichtenbelt, K. D., Philip, S., Rittey, C., Jacques, T. S., Cox, T. C., & Ganesan, V. ( 2012 ). A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations. Brain, 135 ( Pt 8 ), 2506 – 2514. https://doi.org/10.1093/brain/aws172; Halim, D., Brosens, E., Muller, F., Wangler, M. F., Beaudet, A. L., Lupski, J. R., Akdemir, Z. H. C., Doukas, M., Stoop, H. J., de Graaf, B. M., Brouwer, R. W. W., van Ijcken, W. F. J., Oury, J.-F., Rosenblatt, J., Burns, A. J., Tibboel, D., Hofstra, R. M. W., & Alves, M. M. ( 2017 ). Loss-of-function variants in MYLK cause recessive megacystis microcolon intestinal hypoperistalsis syndrome. The American Journal of Human Genetics, 101 ( 1 ), 123 – 129. https://doi.org/10.1016/j.ajhg.2017.05.011; Hoffjan, S., Waldmüller, S., Blankenfeldt, W., Kötting, J., Gehle, P., Binner, P., Epplen, J. T., & Scheffold, T. ( 2011 ). Three novel mutations in the ACTA2 gene in German patients with thoracic aortic aneurysms and dissections. European Journal of Human Genetics, 19 ( 5 ), 520 – 524. https://doi.org/10.1038/ejhg.2010.239; Ke, T., Han, M., Zhao, M., Wang, Q. K., Zhang, H., Zhao, Y., Ruan, X., Li, H., Xu, C., & Sun, T. ( 2016 ). Alpha-actin-2 mutations in Chinese patients with a non-syndromatic thoracic aortic aneurysm. BMC Medical Genetics, 17 ( 1 ), 45. https://doi.org/10.1186/s12881-016-0310-6; Morisaki, H., Akutsu, K., Ogino, H., Kondo, N., Yamanaka, I., Tsutsumi, Y., Yoshimuta, T., Okajima, T., Matsuda, H., Minatoya, K., Sasaki, H., Tanaka, H., Ishibashi-Ueda, H., & Morisaki, T. ( 2009 ). Mutation of ACTA2 gene as an important cause of familial and nonfamilial nonsyndromatic thoracic aortic aneurysm and/or dissection (TAAD). Human Mutation, 30 ( 10 ), 1406 – 1411. https://doi.org/10.1002/humu.21081; Zhang, A., Jo, A., Grajewski, K., & Kim, J. ( 2019 ). Characteristic cerebrovascular findings associated with ACTA2 gene mutations. Canadian Journal of Neurological Sciences, 46 ( 3 ), 342 – 343. https://doi.org/10.1017/cjn.2019.20; Milewicz, D. M., Trybus, K. M., Guo, D. C., Sweeney, H. L., Regalado, E., Kamm, K., & Stull, J. T. ( 2017 ). Altered smooth muscle cell force generation as a driver of thoracic aortic aneurysms and dissections. Arteriosclerosis, Thrombosis, and Vascular Biology, 37 ( 1 ), 26 – 34. https://doi.org/10.1161/atvbaha.116.303229; Milewicz, D. M., Ostergaard, J. R., Ala-Kokko, L. M., Khan, N., Grange, D. K., Mendoza-Londono, R., Bradley, T. J., Olney, A. H., Ades, L., Maher, J. F., Guo, D., Buja, L. M., Kim, D., Hyland, J. C., & Regalado, E. S. ( 2010 ). De novo ACTA2 mutation causes a novel syndrome of multisystemic smooth muscle dysfunction. American Journal of Medical Genetics. Part A, 152A ( 10 ), 2437 – 2443. https://doi.org/10.1002/ajmg.a.33657; Milewicz, D. M., Guo, D. C., Tran-Fadulu, V., Lafont, A. L., Papke, C. L., Inamoto, S., Kwartler, C. S., & Pannu, H. ( 2008 ). Genetic basis of thoracic aortic aneurysms and dissections: Focus on smooth muscle cell contractile dysfunction. Annual Review of Genomics and Human Genetics, 9, 283 – 302. https://doi.org/10.1146/annurev.genom.8.080706.092303; Mc Glacken-Byrne, A. B., Prentice, D., Roshandel, D., Brown, M. R., Tuch, P., Yau, K. S. Y., Sivadorai, P., Davis, M. R., Laing, N. G., & Chen, F. K. ( 2020 ). High-resolution iris and retinal imaging in multisystemic smooth muscle dysfunction syndrome due to a novel Asn117Lys substitution in ACTA2: A case report. BMC Ophthalmology, 20 ( 1 ), 68. https://doi.org/10.1186/s12886-020-01344-w; Lu, H., Fagnant, P. M., Krementsova, E. B., & Trybus, K. M. ( 2016 ). Severe molecular defects exhibited by the R179H mutation in human vascular smooth muscle α-actin. The Journal of Biological Chemistry, 291 ( 41 ), 21729 – 21739. https://doi.org/10.1074/jbc.M116.744011

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