{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T20:47:34Z","timestamp":1781210854339,"version":"3.54.1"},"reference-count":49,"publisher":"BMJ","issue":"3","funder":[{"DOI":"10.13039\/501100007660","name":"University of Antwerp","doi-asserted-by":"crossref","award":["GOA 33933"],"award-info":[{"award-number":["GOA 33933"]}],"id":[{"id":"10.13039\/501100007660","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100007660","name":"University of Antwerp","doi-asserted-by":"crossref","award":["Methusalem-OEC grant \u201cGenomed\u201d 40709"],"award-info":[{"award-number":["Methusalem-OEC grant \u201cGenomed\u201d 40709"]}],"id":[{"id":"10.13039\/501100007660","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"crossref","award":["2013T093"],"award-info":[{"award-number":["2013T093"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["FWO, Belgium, G044720N"],"award-info":[{"award-number":["FWO, Belgium, G044720N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","award":["Genomia \u2013 ERC-COG-2017-771945"],"award-info":[{"award-number":["Genomia \u2013 ERC-COG-2017-771945"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Belgian Cardiac Surgery Foundation and the Marfan Foundation","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}]},{"name":"VASCERN","award":["project ID: 769036"],"award-info":[{"award-number":["project ID: 769036"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2024,12,2]]},"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Individuals harbouring <jats:italic>SMAD3<\/jats:italic> pathogenic variants are at risk for aneurysms\/dissections throughout the arterial tree. Based on prior reports of sex differences in thoracic aortic aneurysm\/dissection, we investigated the sexual dimorphism for vascular events in <jats:italic>SMAD3-<\/jats:italic>variant-harbouring patients.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We analysed two large pedigrees comprising 84 individuals segregating pathogenic missense variants affecting the same p.Arg287 residue in <jats:italic>SMAD3<\/jats:italic>. We excluded individuals&lt;40 years without vascular involvement, as they were too young to be classified. Individuals were subcategorised according to sex, the presence or absence and localisation (aneurysm\/dissection with or without involvement of the aortic root\/ascending aorta) of vascular lesions. We complemented our familial patient cohort with 178 <jats:italic>SMAD3<\/jats:italic> patients reported in the literature between 2011 and 2023.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In our two pedigrees, 11\/30 (37%) variant-harbouring females had no vascular involvement, whereas none of the variant-harboring males (n=23) had no vascular involvement (p=0.001). While the two groups did not differ by age, males were at higher risk of vascular complications (p=0.037), there was no age difference between sexes. Of the 19 females with vascular involvement, six (32%) had vascular involvment sparing the aortic root\/ascending aorta, whereas of the 23 males with vascular invovlement, only one (4%) had vascular involvement sparing the aortic root\/ascending aorta (p=0.034). In the literature, we identified 116 male and 62 female additional patients. In the combined cohort of 220 patients, we demonstrated an over-representation of males (p&lt;0.001) and non-penetrance in females for vascular pathology involving the aortic root\/ascending aorta (p=0.028).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Non-penetrance is more common in women, and normal echocardiography in at-risk females is not as reassuring for risk of vasculopathy in other locations. The higher non-penetrance in women creates an ascertainment bias and results in an over-representation of male patients in the literature.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2024-110219","type":"journal-article","created":{"date-parts":[[2025,1,2]],"date-time":"2025-01-02T13:20:30Z","timestamp":1735824030000},"page":"199-205","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Sexual dimorphism in <i>SMAD3<\/i> pathogenic variant-harbouring individuals"],"prefix":"10.1136","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3510-0697","authenticated-orcid":false,"given":"Julie","family":"Richer","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Children's Hospital of Eastern Ontario Regional Genetics Program, Ottawa, Ontario, Canada"},{"name":"Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, 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Erasmus MC, Rotterdam, Zuid-Holland, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith M A","family":"Verhagen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, Rotterdam, Zuid-Holland, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marja W","family":"Wessels","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, Rotterdam, Zuid-Holland, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolien W","family":"Roos-Hesselink","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Erasmus MC, Rotterdam, Zuid-Holland, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9668-0535","authenticated-orcid":false,"given":"Ilse","family":"Luyckx","sequence":"additional","affiliation":[{"name":"Center of Medical Genetics, University of 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