{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T14:37:01Z","timestamp":1777991821335,"version":"3.51.4"},"reference-count":91,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2024,2,6]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams\u2013Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams\u2013Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              We performed genome sequencing on 473 individuals with Williams\u2013Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway\u2010level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes\/pathways identified here and those ascertained through larger aortic disease\/trait genome\u2010wide association studies. We show that SVAS severity in Williams\u2013Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes (\n              <jats:italic>ACAN<\/jats:italic>\n              and\n              <jats:italic>LTBP4<\/jats:italic>\n              ) were uniquely expressed in the aorta. Many genes in the identified pathways were previously reported in genome\u2010wide association studies for aneurysm, bicuspid aortic valve, or aortic size.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta\u2010focused genome\u2010wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.123.031377","type":"journal-article","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T11:17:38Z","timestamp":1706699858000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Matrisome and Immune Pathways Contribute to Extreme Vascular Outcomes in Williams\u2013Beuren Syndrome"],"prefix":"10.1161","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4285-3637","authenticated-orcid":false,"given":"Delong","family":"Liu","sequence":"first","affiliation":[{"name":"National Heart, Lung, and Blood Institute National Institutes of Health Bethesda MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9826-1860","authenticated-orcid":false,"suffix":"Jr","given":"Charles J.","family":"Billington","sequence":"additional","affiliation":[{"name":"National Heart, Lung, and Blood Institute National Institutes of Health Bethesda MD"},{"name":"Department of Pediatrics University of Minnesota Minneapolis MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neelam","family":"Raja","sequence":"additional","affiliation":[{"name":"National Heart, Lung, and Blood Institute National Institutes of Health Bethesda MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6006-1233","authenticated-orcid":false,"given":"Zoe C.","family":"Wong","sequence":"additional","affiliation":[{"name":"National Heart, Lung, and Blood Institute National Institutes of Health Bethesda MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2241-9828","authenticated-orcid":false,"given":"Mark D.","family":"Levin","sequence":"additional","affiliation":[{"name":"National Heart, Lung, and Blood Institute National Institutes of Health Bethesda MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7594-5963","authenticated-orcid":false,"given":"Wulfgang","family":"Resch","sequence":"additional","affiliation":[{"name":"The High Performance Computing Facility Center for Information Technology, National Institutes of Health Bethesda MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0458-1629","authenticated-orcid":false,"given":"Camille","family":"Alba","sequence":"additional","affiliation":[{"name":"Henry M Jackson Foundation for the Advancement of Military Medicine Bethesda MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7816-2948","authenticated-orcid":false,"given":"Daniel N.","family":"Hupalo","sequence":"additional","affiliation":[{"name":"Henry M Jackson Foundation for the Advancement of Military Medicine Bethesda MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Biamino","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Turin Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6723-9177","authenticated-orcid":false,"given":"Maria Francesca","family":"Bedeschi","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico Medical Genetic Unit Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Cristina","family":"Digilio","sequence":"additional","affiliation":[{"name":"Medical Genetics Department Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3032-6955","authenticated-orcid":false,"given":"Gabriella Maria","family":"Squeo","sequence":"additional","affiliation":[{"name":"Laboratory of Regulatory and Functional Genomics Fondazione IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo (Foggia) Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberta","family":"Villa","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico Medical Genetic Unit Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3530-0105","authenticated-orcid":false,"given":"Pheobe C. 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