{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:38:51Z","timestamp":1760240331384,"version":"build-2065373602"},"reference-count":38,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,5,15]],"date-time":"2019-05-15T00:00:00Z","timestamp":1557878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and objectives: Loeys\u2013Dietz syndrome 3, also known as aneurysms-\u2013osteoarthritis syndrome, is an autosomal dominant genetic connective tissue disease caused by pathogenic variants in SMAD3, a transcription factor involved in TGF-\u03b2 signaling. This disorder is characterized by early-onset osteoarthritis and arterial aneurysms. Common features include scoliosis, uvula abnormalities, striae, and velvety skin. Materials and Methods: The pathogenicity of a variant of uncertain significance in the SMAD3 gene was evaluated (variant c.220C &gt; T) through personalized protein informatics and molecular studies. Results: The case of a 44-year-old male, who was originally presumed to have Marfan syndrome, is presented. An expanded gene panel determined the probable cause to be a variant in SMAD3, c.220C &gt; T (p.R74W). His case was complicated by a history of stroke, but his phenotype was otherwise characteristic for Loeys\u2013Dietz syndrome 3. Conclusion: This case emphasizes the importance of comprehensive genetic testing to evaluate patients for connective tissue disorders, as well as the potential benefit of utilizing a protein informatics platform for the assessment of variant pathogenicity.<\/jats:p>","DOI":"10.3390\/medicina55050137","type":"journal-article","created":{"date-parts":[[2019,5,15]],"date-time":"2019-05-15T11:37:40Z","timestamp":1557920260000},"page":"137","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Genomic Observations of a Rare\/Pathogenic SMAD3 Variant in Loeys\u2013Dietz Syndrome 3 Confirmed by Protein Informatics and Structural Investigations"],"prefix":"10.3390","volume":"55","author":[{"suffix":"Jr.","given":"John E.","family":"Richter","sequence":"first","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8144-1892","authenticated-orcid":false,"given":"Ayesha","family":"Samreen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charitha","family":"Vadlamudi","sequence":"additional","affiliation":[{"name":"Department of Pulmonology and Critical Care, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haytham","family":"Helmi","sequence":"additional","affiliation":[{"name":"Department of Pulmonology and Critical Care, Mayo Clinic, Jacksonville, FL 32224, USA"},{"name":"Department of Internal Medicine, Mayo Clinic, Jacksonville, FL 32224, USA"},{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"},{"name":"Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA"},{"name":"Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA"},{"name":"Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed N.","family":"Mohammad","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaas","family":"Wierenga","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Hines","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paldeep S.","family":"Atwal","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1055-3069","authenticated-orcid":false,"given":"Thomas R.","family":"Caulfield","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"},{"name":"Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA"},{"name":"Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA"},{"name":"Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1002\/jcb.21255","article-title":"A tale of two proteins: Differential roles and regulation of Smad2 and Smad3 in TGF-beta signaling","volume":"101","author":"Brown","year":"2007","journal-title":"J. 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