{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T21:11:19Z","timestamp":1783717879655,"version":"3.55.0"},"reference-count":27,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,1,16]],"date-time":"2020-01-16T00:00:00Z","timestamp":1579132800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Marfan syndrome (MFS) is a dominant monogenic disorder caused by mutations in <jats:italic>fibrillin 1<\/jats:italic> (<jats:italic>FBN1<\/jats:italic>). Rarely, compound heterozygosity for <jats:italic>FBN1<\/jats:italic> mutations has been described.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A large kindred with MFS was assessed clinically over decades, and genetically using exome and\/or Sanger sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A previously identified <jats:italic>FBN1<\/jats:italic> missense variant (p.Tyr754Cys) was confirmed in all subjects with MFS. An additional variant (p.Met2273Thr), previously associated with incomplete MFS, was identified in three siblings. These three compound heterozygous individuals had aortic dilatation at early age (all &lt;30\u00a0years): one also had cerebral and ocular aneurysms; and one, who had undergone surgical repair aged 18\u00a0years, died from aortic dissection at 31\u00a0years. In contrast, their heterozygous father (p.Tyr754Cys) with MFS died at 57\u00a0years (myocardial infarction) without requiring surgical intervention and one heterozygous (p.Tyr754Cys) sibling has aortic dilatation presenting &gt;40\u00a0years but not requiring surgical intervention. Another heterozygous (p.Tyr754Cys) sibling did require aortic root repair (28\u00a0years). The heterozygous (p.Met2273Thr) mother had aortic dilatation diagnosed at age 68\u00a0years but has not required surgical repair.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Although compound heterozygosity or homozygosity is rare in MFS, it should be considered when there is an unusually severe phenotype in a subset of family members.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1116","type":"journal-article","created":{"date-parts":[[2020,1,17]],"date-time":"2020-01-17T04:28:31Z","timestamp":1579235311000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Compound heterozygous mutations in <i>FBN1<\/i> in a large family with Marfan syndrome"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0059-5732","authenticated-orcid":false,"given":"Aideen M.","family":"McInerney\u2010Leo","sequence":"first","affiliation":[{"name":"Dermatology Research Centre The University of Queensland Diamantina Institute University of Queensland Brisbane QLD Australia"},{"name":"Translational Genomics Group Institute of Health and Biomedical Innovation Queensland University of Technology at Translational Research Institute Woolloongabba QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"West","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine Prince Charles Hospital Clinical Unit The University of Queensland Brisbane QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrie","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Translational Genomics Group Institute of Health and Biomedical Innovation Queensland University of Technology at Translational Research Institute Woolloongabba QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Leo","sequence":"additional","affiliation":[{"name":"Translational Genomics Group Institute of Health and Biomedical Innovation Queensland University of Technology at Translational Research Institute Woolloongabba QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim M.","family":"Summers","sequence":"additional","affiliation":[{"name":"Mater Research Institute\u2010University of Queensland Translational Research Institute Woolloongabba QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Anderson","sequence":"additional","affiliation":[{"name":"Translational Genomics Group Institute of Health and Biomedical Innovation Queensland University of Technology at Translational Research Institute Woolloongabba QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Brown","sequence":"additional","affiliation":[{"name":"Translational Genomics Group Institute of Health and Biomedical Innovation Queensland University of Technology at Translational Research Institute Woolloongabba QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malcolm","family":"West","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine Prince Charles Hospital Clinical Unit The University of Queensland Brisbane QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma L.","family":"Duncan","sequence":"additional","affiliation":[{"name":"Translational Genomics Group Institute of Health and Biomedical Innovation Queensland University of Technology at Translational Research Institute Woolloongabba QLD Australia"},{"name":"Department of Endocrinology Royal Brisbane and Women's Hospital Herston QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,1,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2016-103996"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-018-0164-9"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv037"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21525"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.91"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10249"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9505"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/HJH.0000000000000286"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/4.suppl_1.1799"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115766"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1086\/520125"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)67789-6"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1101\/531210"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.86"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/352330a0"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20070"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2009.072785"},{"key":"e_1_2_8_20_1","first-page":"220","article-title":"Un cas de d\u00e9formation cong\u00e9nitale des quartre membres, plus prononc\u00e9e aux extr\u00e9miti\u00e9s, caract\u00e9ris\u00e9e par l'allongement des os avec un certain degr\u00e9 d'amincissement [A case of congenital deformation of the four limbs, more pronounced at the extremities, characterized by elongation of the bones with some degree of thinning]","volume":"13","author":"Marfan A.","year":"1896","journal-title":"Bulletins Et Memoires De La Soci\u00e9t\u00e9 Medicale Des H\u00f4spitaux De Paris"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22994"},{"key":"e_1_2_8_22_1","volume-title":"Heritable thoracic aortic disease overview","author":"Milewicz D. 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