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It is a multisystemic condition mainly characterized by a propensity for arterial aneurysms and dissections, skeletal manifestations, hypertelorism, bifid uvula, craniosynostosis, and cutaneous features. While LDS has significant clinical overlap with other heritable connective tissue disorders such as Marfan syndrome, the ocular manifestations of LDS have not yet been well characterized. We describe an individual with a variant in <jats:italic>SMAD3<\/jats:italic> with a predominantly ocular phenotype and only mild arterial manifestations. The proband presented with early\u2010onset high myopia (\u221225 diopters, bilaterally) and bilateral posterior subcapsular cataracts. Ocular phenotype also included esotropia, retinal hemorrhage, glaucoma, bilateral posterior staphylomas, and keratoconjunctivitis sicca. Extensive vascular imaging identified a right internal carotid artery dissection and mild tortuosity of numerous arteries. A molecular gene panel for heritable connective tissue disorders identified a heterozygous <jats:italic>SMAD3<\/jats:italic> c.221G\u2009&gt;\u2009T; p.(Arg74Leu) variant, initially reported as a variant of uncertain significance and subsequently re\u2010interpreted as likely pathogenic. Other missense variants at this residue have been reported as pathogenic for LDS. High\u2010grade myopia, premature cataracts, and premature glaucoma are part of the phenotypic spectrum in LDS caused by <jats:italic>SMAD3<\/jats:italic> variants. Inclusion of <jats:italic>SMAD3<\/jats:italic> in molecular gene panels for early\u2010onset high\u2010grade myopia should be considered.<\/jats:p>","DOI":"10.1002\/ajmg.a.64124","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T06:24:29Z","timestamp":1749018269000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ocular Findings as the Most Striking Manifestation of a <i>SMAD3<\/i> Variant"],"prefix":"10.1002","volume":"197","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9151-3550","authenticated-orcid":false,"given":"No\u00e9mie","family":"Villeneuve\u2010Cloutier","sequence":"first","affiliation":[{"name":"Department of Medical Genetics CHEO  Ottawa Ontario Canada"},{"name":"University of Ottawa  Ottawa Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christie 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