{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T05:10:48Z","timestamp":1788757848494,"version":"build-2803163510"},"reference-count":18,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T00:00:00Z","timestamp":1788652800000},"content-version":"vor","delay-in-days":248,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"\n Background<\/jats:title>\n \n Loeys\u2013Dietz syndrome (LDS) is a heritable connective tissue disorder caused by pathogenic variants in genes of the transforming growth factor\u2010\n \u03b2<\/jats:italic>\n (TGF\u2010\n \u03b2<\/jats:italic>\n ) signaling pathway. Although genotype\u2013phenotype correlations have been suggested, comprehensive comparative data across LDS subtypes remain limited. Improved understanding of these correlations is essential to guide individualized surveillance and management strategies.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We conducted a retrospective cohort study of adults with genetically confirmed LDS evaluated between 2018 and 2024 across Mayo Clinic sites. Patients with pathogenic, likely pathogenic, or suspicious variants in\n TGFBR1<\/jats:italic>\n ,\n TGFBR2<\/jats:italic>\n , or\n SMAD3<\/jats:italic>\n were included. Clinical characteristics, physical examination findings, cardiovascular and noncardiovascular manifestations, surgical interventions, and mortality were compared across genotypes. Categorical variables were analyzed using chi\u2010square tests and continuous variables using parametric or nonparametric methods as appropriate.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A total of 93 patients were included (29\n TGFBR1<\/jats:italic>\n , 33\n TGFBR2<\/jats:italic>\n , 31\n SMAD3<\/jats:italic>\n ). Demographics and mortality did not differ significantly between groups. Patients with\n TGFBR1<\/jats:italic>\n and\n TGFBR2<\/jats:italic>\n demonstrated trends toward higher rates of ascending aortic aneurysm and aortic dissection compared with\n SMAD3<\/jats:italic>\n patients, though these differences were not statistically significant. Renal artery aneurysms were significantly more common in\n TGFBR1<\/jats:italic>\n patients (13.8%,\n p<\/jats:italic>\n = 0.010). SMAD3 patients had significantly higher rates of mitral regurgitation (54.8%,\n p<\/jats:italic>\n = 0.04), peripheral neuropathy (29.0%,\n p<\/jats:italic>\n = 0.018), and trends toward increased atrial fibrillation and osteoarthritis. A novel association was identified between\n TGFBR1<\/jats:italic>\n variants and migraine, which was significantly more prevalent in this group (62.1%,\n p<\/jats:italic>\n = 0.017). The rates of major cardiovascular surgical interventions were high and comparable across all genotypes.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Distinct genotype\u2013phenotype associations exist among LDS subtypes.\n TGFBR1<\/jats:italic>\n and\n TGFBR2<\/jats:italic>\n variants are associated with a greater burden of aggressive vascular disease, whereas\n SMAD3<\/jats:italic>\n variants are linked to mitral valve disease, peripheral neuropathy, and osteoarthritis. We also identified a novel association between\n TGFBR1<\/jats:italic>\n genotype and migraine. These findings reinforce the importance of comprehensive genetic testing to inform personalized surveillance and management strategies in LDS.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1155\/humu\/2861205","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T04:20:45Z","timestamp":1788754845000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Role of Genetic Variation in Phenotypic Variability in Loeys\u2013Dietz Syndrome"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0940-0168","authenticated-orcid":false,"given":"Hussein Abdul","family":"Nabi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5144-9292","authenticated-orcid":false,"given":"Luke","family":"Dreher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Hartnett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4273-1429","authenticated-orcid":false,"given":"Ashley","family":"Crossley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hussein","family":"El Ghandour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6658-3964","authenticated-orcid":false,"given":"Mayowa","family":"Osundiji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2470-2862","authenticated-orcid":false,"given":"Hicham","family":"El Masry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5877-7478","authenticated-orcid":false,"given":"Chadi","family":"Ayoub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadi E.","family":"Shamoun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4230-5032","authenticated-orcid":false,"given":"Linnea M.","family":"Baudhuin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,6]]},"reference":[{"key":"e_1_2_11_1_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23407"},{"key":"e_1_2_11_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.11"},{"key":"e_1_2_11_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/genes10100764"},{"key":"e_1_2_11_4_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2021-107695"},{"key":"e_1_2_11_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa055695"},{"key":"e_1_2_11_6_2","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2015-308535"},{"key":"e_1_2_11_7_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2018-105583"},{"key":"e_1_2_11_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.118.002329"},{"key":"e_1_2_11_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.744"},{"key":"e_1_2_11_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001106"},{"key":"e_1_2_11_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddae044"},{"key":"e_1_2_11_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2024.131984"},{"key":"e_1_2_11_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacadv.2025.102269"},{"key":"e_1_2_11_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0096387"},{"key":"e_1_2_11_15_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11604-010-0420-6"},{"key":"e_1_2_11_16_2","doi-asserted-by":"publisher","DOI":"10.3174\/ajnr.A1651"},{"key":"e_1_2_11_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2025.04.020"},{"key":"e_1_2_11_18_2","doi-asserted-by":"publisher","DOI":"10.2106\/JBJS.I.01140"}],"container-title":["Human 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