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Vascular complications of SMDS include patent ductus arteriosus (PDA) or aortopulmonary window, early\u2010onset thoracic aortic disease (TAD), moyamoya\u2010like cerebrovascular disease, and primary pulmonary hypertension. Patients also have dysfunction of other smooth muscle\u2010dependent systems, including congenital mydriasis, hypotonic bladder, and gut hypoperistalsis. Here,\u00a0we\u00a0describe five patients with novel heterozygous <jats:italic>ACTA2<\/jats:italic> missense variants,\u00a0p.Arg179Gly, p.Met46Arg, p.Thr204Ile, p.Arg39Cys, and p.Ile66Asn, who have clinical complications that align or overlap with SMDS. Patients with the <jats:italic>ACTA2<\/jats:italic> p.Arg179Gly and p.Thr204Ile variants display classic features of SMDS. The patient with the <jats:italic>ACTA2<\/jats:italic> p.Met46Arg variant exhibits exclusively vascular complications of SMDS, including early\u2010onset TAD, PDA, and moyamoya\u2010like cerebrovascular disease. The\u00a0patient with the <jats:italic>ACTA2<\/jats:italic> p.Ile66Asn variant has an unusual vascular complication, a\u00a0large fusiform internal carotid artery aneurysm. The patient with the <jats:italic>ACTA2<\/jats:italic> p.Arg39Cys variant has pulmonary, gastrointestinal, and genitourinary complications of SMDS\u00a0but no vascular manifestations. Identifying pathogenic <jats:italic>ACTA2<\/jats:italic> variants associated with features of SMDS is critical for aggressive surveillance and management of vascular and nonvascular complications and delineating the molecular pathogenesis of SMDS.<\/jats:p>","DOI":"10.1002\/ajmg.a.62775","type":"journal-article","created":{"date-parts":[[2022,5,14]],"date-time":"2022-05-14T14:53:37Z","timestamp":1652540017000},"page":"2389-2396","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Expanding <scp><i>ACTA2<\/i><\/scp> genotypes with corresponding phenotypes overlapping with smooth muscle dysfunction syndrome"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3690-711X","authenticated-orcid":false,"given":"Anita","family":"Kaw","sequence":"first","affiliation":[{"name":"Division of Medical Genetic, Department of Internal Medicine, McGovern Medical School University of Texas Health 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