{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:28:53Z","timestamp":1790774933825,"version":"4.1.0"},"reference-count":27,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T00:00:00Z","timestamp":1629244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R00HD090198"],"award-info":[{"award-number":["R00HD090198"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UM1 HG006493"],"award-info":[{"award-number":["UM1 HG006493"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U24 HG008956"],"award-info":[{"award-number":["U24 HG008956"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10OD02155"],"award-info":[{"award-number":["S10OD02155"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["19CDA34660038"],"award-info":[{"award-number":["19CDA34660038"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"name":"John Ritter Foundation","award":["."],"award-info":[{"award-number":["."]}]},{"name":"Remembrin\u2019 Benjamin","award":["."],"award-info":[{"award-number":["."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cardiogenetics"],"abstract":"<jats:p>Thoracic aortic aneurysms (TAAs) that progress to acute thoracic aortic dissections (TADs) are life-threatening vascular events that have been associated with altered transforming growth factor (TGF) \u03b2 signaling. In addition to TAA, multiple genetic vascular disorders, including hereditary hemorrhagic telangiectasia (HHT), involve altered TGF\u03b2 signaling and vascular malformations. Due to the importance of TGF\u03b2, genomic variant databases have been curated for activin receptor-like kinase 1 (ALK1) and endoglin (ENG). This case report details seven variants in SMAD4 that are associated with either heritable or early-onset aortic dissections and compares them to pathogenic exon variants in gnomAD v2.1.1. The TAA and TAD variants were identified through whole exome sequencing of 346 families with unrelated heritable thoracic aortic disease (HTAD) and 355 individuals with early-onset (age \u2264 56 years old) thoracic aortic dissection (ESTAD). An allele frequency filter of less than 0.05% was applied in the Genome Aggregation Database (gnomAD exome v2.1.1) with a combined annotation-dependent depletion score (CADD) greater than 20. These seven variants also have a higher REVEL score (&gt;0.2), indicating pathogenic potential. Further in vivo and in vitro analysis is needed to evaluate how these variants affect SMAD4 mRNA stability and protein activity in association with thoracic aortic disease.<\/jats:p>","DOI":"10.3390\/cardiogenetics11030015","type":"journal-article","created":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T01:54:06Z","timestamp":1629251646000},"page":"132-138","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Human SMAD4 Genomic Variants Identified in Individuals with Heritable and Early-Onset Thoracic Aortic Disease"],"prefix":"10.3390","volume":"11","author":[{"given":"Shreyas A.","family":"Bhave","sequence":"first","affiliation":[{"name":"Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongchuan","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stoyan N.","family":"Angelov","sequence":"additional","affiliation":[{"name":"Division of Cardiology, University of Washington School of Medicine, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Bamshad","sequence":"additional","affiliation":[{"name":"Genome Sciences, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah A.","family":"Nickerson","sequence":"additional","affiliation":[{"name":"Genome Sciences, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7806-0068","authenticated-orcid":false,"given":"Dianna M.","family":"Milewicz","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary C.","family":"Wallingford","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA"},{"name":"Mother Infant Research Institute, Tufts Medical Center, Boston, MA 02111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1186\/s13023-020-01422-8","article-title":"For the RiHHTa investigators of the rare diseases working group from the spanish society of internal medicine. Current HHT genetic overview in Spain and its phenotypic correlation: Data from RiHHTa registry","volume":"15","author":"Iriarte","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1161\/CIRCULATIONAHA.116.009762","article-title":"Hereditary Influence in thoracic aortic aneurysm and dissection","volume":"133","author":"Isselbacher","year":"2016","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1161\/01.CIR.0000154569.08857.7A","article-title":"Thoracic and abdominal aortic aneurysms","volume":"111","author":"Isselbacher","year":"2005","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1002\/humu.22858","article-title":"The matchmaker exchange: A platform for rare disease gene discovery","volume":"36","author":"Philippakis","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1038\/s41431-019-0357-x","article-title":"SMAD4 rare variants in individuals and families with thoracic aortic aneurysms and dissections","volume":"27","author":"Duan","year":"2019","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.tcm.2013.06.004","article-title":"Successes and challenges of using whole exome sequencing to identify novel genes underlying an inherited predisposition for thoracic aortic aneurysms and acute aortic dissections","volume":"24","author":"Milewicz","year":"2014","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/s41586-020-2287-8","article-title":"A structural variation reference for medical and population genetics","volume":"581","author":"Collins","year":"2020","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8213","DOI":"10.1093\/nar\/gkr500","article-title":"Structural basis for the cooperative DNA recognition by Smad4 MH1 dimers","volume":"39","author":"Baburajendran","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3477","DOI":"10.1093\/nar\/gkq046","article-title":"Structure of Smad1 MH1\/DNA complex reveals distinctive rearrangements of BMP and TGF-beta effectors","volume":"38","author":"BabuRajendran","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"9051","DOI":"10.1093\/nar\/gkv848","article-title":"Structural basis for the Smad5 MH1 domain to recognize different DNA sequences","volume":"43","author":"Chai","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1161\/CIRCRESAHA.118.312436","article-title":"Genetics of thoracic and abdominal aortic diseases","volume":"124","author":"Pinard","year":"2019","journal-title":"Circ. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.jacc.2018.04.089","article-title":"Clinical validity of genes for heritable thoracic aortic aneurysm and dissection","volume":"72","author":"Renard","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/ng.2348","article-title":"TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome","volume":"44","author":"Boileau","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1038\/ng.2007.6","article-title":"Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections","volume":"39","author":"Guo","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1038\/ng.934","article-title":"Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1","volume":"43","author":"LeMaire","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1161\/ATVBAHA.116.303229","article-title":"Altered smooth muscle cell force generation as a driver of thoracic aortic aneurysms and dissections","volume":"37","author":"Milewicz","year":"2017","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1146\/annurev-med-100415-022956","article-title":"Therapeutics targeting drivers of thoracic aortic aneurysms and acute aortic dissections: Insights from predisposing genes and mouse models","volume":"68","author":"Milewicz","year":"2017","journal-title":"Annu. Rev. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"111","DOI":"10.7150\/ijbs.23230","article-title":"The role of TGF-\u03b2\/SMAD4 signaling in cancer","volume":"14","author":"Zhao","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3501","DOI":"10.1242\/dev.01248","article-title":"Differential requirements for Smad4 in TGFbeta-dependent patterning of the early mouse embryo","volume":"131","author":"Chu","year":"2004","journal-title":"Development"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7683","DOI":"10.1128\/MCB.00577-07","article-title":"Essential role of endothelial smad4 in vascular remodeling and integrity","volume":"27","author":"Lan","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_22","first-page":"6113","article-title":"Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice","volume":"59","author":"Takaku","year":"1999","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s10456-018-9602-0","article-title":"Vascular deficiency of Smad4 causes arteriovenous malformations: A mouse model of hereditary hemorrhagic telangiectasia","volume":"21","author":"Crist","year":"2018","journal-title":"Angiogenesis"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1161\/CIRCULATIONAHA.118.036952","article-title":"Angiopoietin-2 Inhibition rescues arteriovenous malformation in a Smad4 hereditary hemorrhagic telangiectasia mouse model","volume":"139","author":"Crist","year":"2019","journal-title":"Circulation"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1002\/ajmg.a.33206","article-title":"Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP\u2013HHT syndrome","volume":"152","author":"Gallione","year":"2010","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/ng.1016","article-title":"Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome","volume":"44","author":"Mahaut","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.gene.2017.07.042","article-title":"Functional characteristics of a novel SMAD4 mutation from thoracic aortic aneurysms (TAA)","volume":"628","author":"Wu","year":"2017","journal-title":"Gene"}],"container-title":["Cardiogenetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2035-8148\/11\/3\/15\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:46:10Z","timestamp":1760165170000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2035-8148\/11\/3\/15"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,18]]},"references-count":27,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["cardiogenetics11030015"],"URL":"https:\/\/doi.org\/10.3390\/cardiogenetics11030015","relation":{},"ISSN":["2035-8148"],"issn-type":[{"value":"2035-8148","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,18]]}}}