{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:19:16Z","timestamp":1790360356909,"version":"4.1.0"},"reference-count":30,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,5,20]],"date-time":"2020-05-20T00:00:00Z","timestamp":1589932800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ecole Polytechnique Paris","award":["2016"],"award-info":[{"award-number":["2016"]}]},{"name":"Fondation Coeur et Recherche","award":["2018"],"award-info":[{"award-number":["2018"]}]},{"DOI":"10.13039\/501100003100","name":"Federation Francaise de Cardiologie","doi-asserted-by":"publisher","award":["2017"],"award-info":[{"award-number":["2017"]}],"id":[{"id":"10.13039\/501100003100","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-14-CE15-0012"],"award-info":[{"award-number":["ANR-14-CE15-0012"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with considerable inter- and intra-familial clinical variability. The contribution of inherited modifiers to variability has not been quantified. We analyzed the distribution of 23 clinical features in 1306 well-phenotyped MFS patients carrying FBN1 mutations. We found strong correlations between features within the same system (i.e., ophthalmology vs. skeletal vs. cardiovascular) suggesting common underlying determinants, while features belonging to different systems were largely uncorrelated. We adapted a classical quantitative genetics model to estimate the heritability of each clinical feature from phenotypic correlations between relatives. Most clinical features showed strong familial aggregation and high heritability. We found a significant contribution by the major locus on the phenotypic variance only for ectopia lentis using a new strategy. Finally, we found evidence for the \u201cCarter effect\u201d in the MFS cardiovascular phenotype, which supports a polygenic model for MFS cardiovascular variability and indicates additional risk for children of MFS mothers with an aortic event. Our results demonstrate that an important part of the phenotypic variability in MFS is under the control of inherited modifiers, widely shared between features within the same system, but not among different systems. Further research must be performed to identify genetic modifiers of MFS severity.<\/jats:p>","DOI":"10.3390\/genes11050574","type":"journal-article","created":{"date-parts":[[2020,5,20]],"date-time":"2020-05-20T10:37:38Z","timestamp":1589971058000},"page":"574","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability"],"prefix":"10.3390","volume":"11","author":[{"given":"Thomas","family":"Grange","sequence":"first","affiliation":[{"name":"INSERM U1148, 75018 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4383-7930","authenticated-orcid":false,"given":"M\u00e9lodie","family":"Aubart","sequence":"additional","affiliation":[{"name":"INSERM U1148, 75018 Paris, France"},{"name":"Service de Neurologie P\u00e9diatrique, H\u00f4pital Necker-Enfants malades, AP-HP, Universit\u00e9 de Paris, Facult\u00e9 de m\u00e9decine Paris Centre, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maud","family":"Langeois","sequence":"additional","affiliation":[{"name":"Centre national de r\u00e9f\u00e9rence pour le syndrome de Marfan et apparent\u00e9s, AP-HP, H\u00f4pital Bichat, 75018 Paris, France"},{"name":"CHU Toulouse, 31300 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2805-9170","authenticated-orcid":false,"given":"Louise","family":"Benarroch","sequence":"additional","affiliation":[{"name":"INSERM U1148, 75018 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9727-1592","authenticated-orcid":false,"given":"Pauline","family":"Arnaud","sequence":"additional","affiliation":[{"name":"INSERM U1148, 75018 Paris, France"},{"name":"Centre national de r\u00e9f\u00e9rence pour le syndrome de Marfan et apparent\u00e9s, D\u00e9partement de g\u00e9n\u00e9tique, AP-HP, H\u00f4pital Bichat, 75018 Paris, France"},{"name":"Universit\u00e9 de Paris, UFR M\u00e9decine Paris Nord, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Milleron","sequence":"additional","affiliation":[{"name":"Centre national de r\u00e9f\u00e9rence pour le syndrome de Marfan et apparent\u00e9s, Service de cardiologie, AP-HP, H\u00f4pital Bichat, 75018 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludivine","family":"Eliahou","sequence":"additional","affiliation":[{"name":"Centre national de r\u00e9f\u00e9rence pour le syndrome de Marfan et apparent\u00e9s, Service de cardiologie, AP-HP, H\u00f4pital Bichat, 75018 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Sylvie","family":"Gross","sequence":"additional","affiliation":[{"name":"INSERM U1148, 75018 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Hanna","sequence":"additional","affiliation":[{"name":"Centre national de r\u00e9f\u00e9rence pour le syndrome de Marfan et apparent\u00e9s, D\u00e9partement de g\u00e9n\u00e9tique, AP-HP, H\u00f4pital Bichat, 75018 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0371-7539","authenticated-orcid":false,"given":"Catherine","family":"Boileau","sequence":"additional","affiliation":[{"name":"INSERM U1148, 75018 Paris, France"},{"name":"Centre national de r\u00e9f\u00e9rence pour le syndrome de Marfan et apparent\u00e9s, D\u00e9partement de g\u00e9n\u00e9tique, AP-HP, H\u00f4pital Bichat, 75018 Paris, France"},{"name":"Universit\u00e9 de Paris, UFR M\u00e9decine Paris Nord, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Gouya","sequence":"additional","affiliation":[{"name":"Centre national de r\u00e9f\u00e9rence pour le syndrome de Marfan et apparent\u00e9s, AP-HP, H\u00f4pital Bichat, 75018 Paris, France"},{"name":"INSERM U1159, 75018 Paris"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0101-2076","authenticated-orcid":false,"given":"Guillaume","family":"Jondeau","sequence":"additional","affiliation":[{"name":"INSERM U1148, 75018 Paris, France"},{"name":"Universit\u00e9 de Paris, UFR M\u00e9decine Paris Nord, 75010 Paris, France"},{"name":"Centre national de r\u00e9f\u00e9rence pour le syndrome de Marfan et apparent\u00e9s, Service de cardiologie, AP-HP, H\u00f4pital Bichat, 75018 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1136\/jmg.2009.072785","article-title":"The revised Ghent nosology for the Marfan syndrome","volume":"47","author":"Loeys","year":"2010","journal-title":"J. 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